Selective phenyl-oxime algicides with low non-target acute toxicity: efficacy against green microalgae vs glutaraldehyde

Selective phenyl-oxime algicides with low non-target acute toxicity: efficacy against green microalgae vs glutaraldehyde | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Selective phenyl-oxime algicides with low non-target acute toxicity: efficacy against green microalgae vs glutaraldehyde Jun Young Lee, Yeo Jin Kim, Bong Gyu Choi, Jin-Seog Kim, Hasoo Seong, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7558839/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Harmful algal blooms (HABs) impair water quality and threaten aquatic life, while common chemical controls (e.g., cooper salts, glutaraldehyde) raise non-target toxicity concerns. We synthesized 31 phenyl-oxime derivatives and quantified algicidal activity as in vivo chlorophyll-reduction in standardized microalgal assays, alongside non-target acute toxicity tests. A lead compound, ( E )-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1 H -1,2,4-triazol-1-yl)ethan-1-one O -benzyl oxime ( KH08 ), strongly inhibited green microalgae (notably Scenedesmus rotundus ) while showing minimal activity toward Lemna paucicostata . Under matched conditions, KH08 achieved comparable or greater inhibition of green microalgae versus glutaraldehyde, whereas activity against cyanobacteria was modest. Acute-toxicity studies indicated low toxicity to Daphnia magna , Oryzias latipes , Danio rerio , and mice. These data position KH08 as a selective algicide candidate with practical relevance for microalgal control. algal growth inhibition applied phycology chlorophyll-based assay Lemna paucicostata non-target toxicity phenyl-oxime selective algicide Scenedesmus rotundus Figures Figure 1 Figure 2 INTRODUCTION Algal blooms are a natural phenomenon in aquatic environments. But, they are classified as harmful algal blooms when they negatively impact ecosystems (Lan et al. 2020 ). Occurrences of HABs worldwide have increased due to eutrophication caused by anthropogenic activities, including discharges of agricultural sewage and industrial waste, port development, and aquaculture expansion (Heisler et al. 2008 ). The mass proliferation of some harmful algae may cause the death of marine life through resource competition, and toxic HAB species can be absorbed by aquatic organisms, including shellfish, producing toxins that pose significant threats to human health (Harrison et al. 2017 , Furuya et al. 2018 ). For instance, Microcystis and Aphanizomenon , produce the toxins microcystin and saxitoxin, respectively, while Anabaena and Oscillatoria produce anatoxin and microcystin (Jeon et al. 2015 ). Microcystin exposure in humans can result in allergic reactions, vomiting, inflammation, liver cirrhosis, visual impairment, and kidney and liver damage (Ding et al. 1998 ). A long-term strategy for controlling HABs involves reducing nutrient inputs into aquatic ecosystems. Rapid and effective inhibition of the growth of HABs has often been achieved through physical, biological, and chemical methods (Sun et al. 2018 , Jančula et al. 2011, Gallardo-Rodríguez et al. 2019 , Yue et al. 2021 ). Physical methods such as coagulation, sonication, isolation, and salvage, are more commonly applied in freshwater systems than saltwater systems (Gallardo-Rodríguez et al. 2019 ). Recent research on HABs has focused on environmentally friendly control methods that target harmful species without adversely affecting other aquatic organisms or the environment. One promising approach is the use of biological controls, such as bacteria, which can inhibit algal growth via physical association or production of algicidal compounds (Coyne et al. 2022 ). Various chemical methods are employed to control HABs, including the application of commercial chemicals like copper sulfate and herbicides over large areas (Jančula et al. 2011). The use of copper ions to kill algae is affected by ionic conductivity, alkalinity, and pH, but the process is slow and can lead to environmental hazards, such as copper accumulation (Matthijs et al. 2016 ). Although herbicides are effective in controlling HABs, their use in drinking or aquaculture waters is greatly restricted due to the risk of unwanted secondary contamination (Giacomazzi et al. 2004). Many studies have attempted to utilize low molecular weight substances derived from natural products to remove harmful algae, but their use is limited due to low economic feasibility (Balaji Prasath et al. 2022 , Gil et al. 2021 , Kim et al. 2006 , Rastogi et al. 2015 , Zhu et al. 2021 ). In addition, novel organic substances, derived from pyridazinoquinoline, thiazolidinedione, triazole, N 1 -benzyl-N 3 , and N 3 -diethylpropane-1,3-diamine have been synthesized and their algicidal activities investigated (Kurasawa et al. 2009, Lee et al. 2018 , Cho et al. 2021 , Kim et al. 2022 , Park et al. 2023 ). The development of plant factories or smart farms aims to produce food more safely, but the concentration of nutrients in urban environments can promote the growth of microalgae and mosses, reducing crop productivity under sunny conditions (Schwarz et al. 2004). As public awareness of safety requirements and environmental protection increases, there is a demand for algicides that meet the new standards. In addition to being able to control problematic microorganisms efficiently, these novel algicides must be safer than existing compounds, especially when used near human residences and living spaces. Current algicides used recently include products containing copper or silver, ozone, hypochlorous acid, and glutaraldehyde, all of which contain risks to crops or users. Therefore, novel replacements are required (Jeon et al. 2015 , Balaji Prasath et al. 2022 , Strohmeyer 2008 ). Algicides used in domestic environments must have excellent efficacy and a relatively low impact on non-target organisms. Algicidal chemicals used in environments that people are likely to frequent, must have lower toxicity to humans and wildlife than those used to control algal growth in agricultural settings, rivers, and lake (Kim et al. 2021 ). In this study, we synthesized various compounds through structural modification of phenyl oxime derivatives and explored the corresponding changes in their biological activities. Furthermore, we examined the potential of these newly synthesized compounds to replace currently used algicides. Oxime ethers are a class of compounds that can be described by the general formula: R(R 1 ) > C = N-O-R 2 . The oxime ether moiety affects the biological activity of the compounds. Various biological activities, including bactericidal, fungicidal, antidepressant, anticancer, and herbicidal activities, have been reported for such compounds (Kosmalski et al. 2023 , Cui et al. 2022 ). Despite the diverse biological activities of oxime compounds, their efficacy against microalgae has not been previously studied. Therefore, we synthesized a series of novel phenyl oxime derivatives and investigated the relationship between their structure and algicidal activity. The structures of the phenyl oxime derivatives designed and synthesized in this study were inspired by the structure of loreclezole, a compound whose algicidal efficacy has been previously studied (Kim et al. 2021 , Fig. 1 ). We introduced an oxime group to the olefin site of loreclezole and modified the phenyl group to diphenyl. Additionally, the triazole was modified by changing the number or position of the nitrogen atoms while retaining a five-membered heterocyclic ring structure. MATERIALS AND METHODS Materials and Instruments. All reagents and solvents used in experiments were supplied from the commercial suppliers like Sigma-Aldrich (Burlington, USA), Alfa Aesar (Ward Hill, USA), TCI (Tokyo, Japan), Combi-Blocks (San Diego, USA) and Angene (Nanjing, China) and they were used without further purification. The organic solvents remaining in synthetic reaction mixture were evaporated by using the Büchi rotary evaporator (R300, Flawil, Switzerland) under low pressure and appropriate temperature. Synthesis of the reaction product in the reaction process was confirmed through Thin Layer Chromatography (TLC, silica gel 60 F254 plate, Merck, Darmstadt, Germany), and the synthesized compound was purified through column chromatography by using 230–400 mesh silica gel (Merck, Darmstadt, Germany). 1 H NMR and 13 C NMR spectra of the purified compounds were obtained by Bruker Avance (Billerica, USA) 300 MHz Spectrometer or 400 MHz Spectrometer or 500 MHz Spectrometer. The CDCl 3 and (CD 3 ) 2 SO having characteristic 1 H NMR peak of 7.26 and 2.50 ppm, respectively, were used as NMR solvent which were obtained from Cambridge Isotope Laboratories, Inc (Tewksbury, USA) or Zeotope (Rüti, Switzerland). Chemical shifts are provided in ppm (δ) from downfield from tetramethylsilane (internal standard) with coupling constants in hertz (Hz). Multiplicity is indicated by the following abbreviations: singlet (s), doublet (d), doublet of doublet (dd), doublet of triplet (dt), doublet of multiplet (dm), triplet (t), triplet of doublet (td), triplet of triplet (tt), quartet (q), quartet of doublet (qd), quartet of triplet (qt), multiplet (m) and broad (br). Mass spectrometry of the purified compound was determined by using high-resolution mass spectrometer (Agilent, Santa Clara, USA). Melting points were measured by Mettler Toledo MP50 instrument. Synthesis. Synthesis of 2-bromo-1-(4'-bromo-[1,1'-biphenyl]-4-yl)ethan-1-one 2 . To a solution of 4-bromobiphenyl, 1 (1000 mg, 4.29 mmol) in dichloromethane the bromoacetyl bromide (0.39 mL, 4.54 mmol) was slowly added. Then, the reaction mixture was cooled with ice bath to 0 o C and aluminum chloride (686 mg, 5.14 mmol) was poured into reaction mixture. The mixture was stirred at rt for 20 h. After reaction was completed, the mixture was poured into a saturated aqueous NaHCO 3 solution and extracted with ethyl acetate. The combined organic layer was dried with anhydrous MgSO 4 , filtered and concentrated in vacuo . The solid crude product was purified by column chromatography on silica gel using ethyl acetate/hexane (1/50 ~ 1/2) as eluent to give 2-bromo-1-(4'-bromo-[1,1'-biphenyl]-4-yl)ethan-1-one, 2 as white solid (1.22 g, 80%). m.p.: 140–145 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J = 8.1 Hz, 2H), 7.64 (dd, J = 26.7, 8.1 Hz, 4H), 7.49 (d, J = 8.1 Hz, 2H), 4.47 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 190.94, 145.47, 138.57, 133.05, 132.31, 129.80, 128.96, 127.40, 123.10, 30.86.; HRMS (FAB) for C 14 H 10 Br 2 O m/z : calculated, 352.9171; found, 352.9169 [M + H] + . Synthesis of 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one 3 . The 2-bromo-1-(4'-bromo-[1,1'-biphenyl]-4-yl)ethan-1-one, 2 (87 mg, 0.24 mmol) and 1 H -1,2,4-triazole (25 mg, 0.36 mmol) were dissolved in toluene. The sodium bicarbonate (30 mg, 0.36 mmol) was poured into the reaction mixture. The mixture was heated at 120 o C and stirred 17 h. After reaction was completed, the mixture was poured into water and brine, extracted with dichloromethane. Combined organic layer was dried over MgSO 4 and filtered, concentrated in vacuo . The solid crude product was purified by column chromatography on silica gel using methanol/dichloromethane (1/19 ~ 1/9) as eluent to give 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one, 3 as white solid (56 mg, 68%). m.p.: 210–220 o C, 1 H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.14 (d, J = 8.3 Hz, 2H), 8.04 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.74 (q, J = 8.7 Hz, 4H), 6.03 (s, 2H).; 13 C NMR (100 MHz, DMSO) δ 192.12, 151.33, 145.67, 144.04, 137.79, 133.28, 132.02, 129.16, 128.92, 127.02, 122.23, 55.23.; HRMS (FAB) for C 16 H 12 BrN 3 O m/z : calculated, 342.0237; found, 342.0250 [M + H] + . Synthesis of 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-pyrazol-1-yl)ethan-1-one 4 . The 2-bromo-1-(4'-bromo-[1,1'-biphenyl]-4-yl)ethan-1-one, 2 (100 mg, 0.28 mmol) and 1,2-diazole (23 mg, 0.33 mmol) were dissolved in DMF. The potassium carbonate (117 mg, 0.84 mmol) was slowly poured into the reaction mixture. The reaction mixture was heated at 80 o C and stirred for 19 h. After the reaction was completed, the reaction mixture was poured into water and brine, extracted with dichloromethane. Extracted organic layer was dried over MgSO 4 and filtered, concentrated in vacuo . The solid crude product was purified by column chromatography on silica gel using methanol/dichloromethane (1/19 ~ 1/9) as eluent to give 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1 H -pyrazol-1-yl)ethan-1-one, 4 as white solid (56 mg, 58%). m.p.: 180–190 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.64–7.58 (m, 3H), 7.54 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 6.39 (d, J = 2.2 Hz, 1H), 5.64 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 192.06, 145.62, 140.15, 138.57, 133.63, 132.34, 131.10, 129.02, 128.98, 127.52, 123.13, 106.82, 57.84.; HRMS (FAB) for C 17 H 13 BrN 2 O m/z : calculated, 341.0284; found, 341.0287 [M + H] + . 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-imidazol-1-yl)ethan-1-one 5 . White solid, yield 79%, m.p.: 220–230 o C, 1 H NMR (300 MHz, CDCl 3 ) δ 8.07–8.02 (m, 2H), 7.75–7.69 (m, 2H), 7.65–7.60 (m, 2H), 7.55–7.47 (m, 3H), 7.16 (t, J = 1.1 Hz, 1H), 6.97 (t, J = 1.3 Hz, 1H), 5.43 (s, 2H).; 13 C NMR (100 MHz, DMSO) δ 193.17, 143.81, 138.33, 137.85, 133.58, 132.03, 129.13, 128.77, 127.88, 126.96, 122.19, 120.91, 52.62.; HRMS (FAB) for C 17 H 13 BrN 2 O m/z : calculated, 341.0284; found, 341.0287 [M + H] + . 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one 6 . White solid, yield 34%, m.p.: 235–240 o C, 1 H NMR (400 MHz, DMSO) δ 8.16 (d, J = 8.1 Hz, 2H), 8.12 (s, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.81 (s, 1H), 7.78–7.68 (m, 4H), 6.25 (s, 2H).; 13 C NMR (100 MHz, DMSO) δ 191.79, 144.08, 137.80, 133.26, 133.24, 132.04, 129.17, 128.97, 127.02, 126.53, 122.25, 55.64.; HRMS (FAB) for C 16 H 12 BrN 3 O m/z : calculated, 342.0237; found, 342.0242 [M + H] + . 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one 7 . White solid, yield 28%, m.p.: 205–210 o C, 1 H NMR (300 MHz, DMSO) δ 8.15–8.09 (m, 2H), 7.90 (d, J = 9.2 Hz, 4H), 7.78–7.69 (m, 4H), 6.29 (s, 2H).; 13 C NMR (100 MHz, DMSO) δ 192.22, 144.07, 137.83, 135.02, 133.31, 132.03, 129.19, 129.01, 127.01, 122.24, 60.42.; HRMS (FAB) for C 16 H 12 BrN 3 O m/z : calculated, 342.0237; found, 342.0285 [M + H] + . 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-tetrazol-1-yl)ethan-1-one 8 . White solid, yield 36.6%, m.p.: 210–220 o C, 1 H NMR (400 MHz, DMSO) δ 9.39 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.1 Hz, 2H), 7.79–7.70 (m, 4H), 6.40 (s, 2H).; 13 C NMR (100 MHz, DMSO) δ 190.84, 145.29, 144.32, 137.72, 132.87, 132.05, 129.19, 129.06, 127.07, 122.32, 53.99.; HRMS (FAB) for C 15 H 11 BrN 4 O m/z : calculated, 343.0189; found, 343.0181 [M + H] + . 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(2H-tetrazol-2-yl)ethan-1-one 9 . White solid, yield 29%, m.p.: 205–210 o C, 1 H NMR (300 MHz, DMSO) δ 9.09 (s, 1H), 8.17–8.13 (m, 2H), 7.96–7.92 (m, 2H), 7.80–7.71 (m, 4H), 6.72 (s, 2H). 13 C NMR (100 MHz, DMSO) δ 190.78, 153.52, 144.42, 137.75, 132.85, 132.05, 129.22, 129.19, 127.07, 122.34, 58.71. HRMS (FAB) for C 15 H 11 BrN 4 O m/z : calculated, 343.0189; found, 343.0191 [M + H] + . Synthesis of 1-(4-bromophenyl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one 11 . The 4-bromophenacyl bromide, 10 (1000 mg, 3.6 mmol) and 1,2,4-triazole (273 mg, 3.96 mmol) were dissolved with acetone (7.2 mL). The reaction mixture was cooled with ice bath to 0 o C and the triethylamine (0.552 mL, 3.96 mmol) was slowly added. The reaction mixture was stirred at rt for 17 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was combined and dried over MgSO 4 and filtered, concentrated in vacuo. The solid crude product was purified by column chromatography on silica gel using methanol/dichloromethane (1/24 ~ 1/9) as eluent to give 1-(4-bromophenyl)-2-(1 H -1,2,4-triazol-1-yl)ethan-1-one, 11 as white solid (541 mg, 56.5%). m.p.: 180–186 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.24 (s, 1H), 8.02 (s, 1H), 7.88–7.83 (m, 2H), 7.73–7.67 (m, 2H), 5.64 (s, 2H).; 13 C NMR (100 MHz, DMSO) δ 191.97, 151.32, 145.59, 133.21, 132.07, 130.10, 128.33, 55.18.; HRMS (FAB) for C 10 H 8 BrN 3 O m/z : calculated, 265.9924; found, 265.9925 [M + H] + . Synthesis of 1-(2'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one 12 . The 1-(4-bromophenyl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one, 11 (100 mg, 0.376 mmol) and 2-bromophenylboronic acid (91 mg, 0.451 mmol) were dissolved in dimethyl acetamide (1 mL) and water (1 mL). Then, the tetrakis(triphenylphosphine)palladium (43.5 mg, 0.0376 mmol) and sodium carbonate (120 mg, 1.128 mmol) were added. The reaction mixture was heated at 100 o C and stirred for 20 h. After the reaction was completed, the mixture was filtered through celite and dissolved in water. The mixture was extracted ethyl acetate several times. The combined organic layer was dried over MgSO 4 and filtered, concentrated in vacuo . The solid crude product purified by column chromatography on silica gel using methanol/dichloromethane (1/24 ~ 1/9) as eluent to give 1-(2'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one, 12 as white solid (104.8 mg, 81%). m.p.: 200–210 o C, 1 H NMR (400 MHz, DMSO) δ 8.53 (s, 1H), 8.14 (d, J = 8.4 Hz, 2H), 8.04 (s, 1H), 7.79 (dd, J = 8.0, 1.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.54–7.50 (m, 1H), 7.45 (dd, J = 7.7, 1.9 Hz, 1H), 7.39 (td, J = 7.7, 1.9 Hz, 1H), 6.05 (s, 2H).; 13 C NMR (100 MHz, DMSO) δ 192.24, 151.34, 145.87, 140.72, 133.35, 133.13, 131.26, 130.09, 129.85, 128.15, 128.04, 121.35, 55.26.; HRMS (FAB) for C 16 H 12 BrN 3 O m/z : calculated, 342.0237; found, 342.0236 [M + H] + . Synthesis of 1-(3'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one 13 . White solid, yield 72%, m.p.: 170–175 o C, 1 H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.14 (d, J = 8.5 Hz, 2H), 8.04 (s, 1H), 7.99 (t, J = 1.9 Hz, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.80 (dt, J = 8.0, 1.3 Hz, 1H), 7.65 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 6.04 (s, 2H).; 13 C NMR (100 MHz, DMSO) δ 192.16, 151.32, 145.63, 143.67, 141.04, 133.50, 131.25 (d, J = 11.3 Hz), 129.64, 128.86, 127.34, 126.20, 122.55, 55.25.; HRMS (FAB) for C 16 H 12 BrN 3 O m/z : calculated, 342.0237; found, 342.1041 [M + H] + . 2-(1H-1,2,4-triazol-1-yl)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethan-1-one 14 . White solid, yield 71%, m.p.: 150–155 o C, 1 H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.21–8.14 (m, 2H), 8.08 (s, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.99–7.96 (m, 2H), 7.87 (d, J = 8.2 Hz, 2H), 6.06 (s, 2H).; 13 C NMR (100 MHz, DMSO) δ 192.18, 151.12, 145.59, 143.73, 142.68, 133.80, 128.97, 127.98, 127.60, 125.95 (q, J = 3.7 Hz), 125.60, 122.90, 55.38.; HRMS (FAB) for C 17 H 12 F 3 N 3 O m/z : calculated, 332.1005; found, 332.1021 [M + H] + . 1-(2'-methyl-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one 15 . White solid, yield 90%, m.p.: 90–95 o C. 1 H NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 8.17–8.10 (m, 2H), 8.08 (s, 1H), 7.60–7.55 (m, 2H), 7.34 (dq, J = 4.1, 1.9 Hz, 2H), 7.30 (td, J = 5.0, 2.5 Hz, 1H), 7.27–7.23 (m, 1H), 6.05 (s, 2H), 2.26 (s, 3H).; 13 C NMR (100 MHz, DMSO) δ 192.65, 151.56, 147.51, 140.53, 135.16, 133.19, 131.04, 130.08, 129.83, 128.65, 128.55, 126.61, 55.76, 20.55.; HRMS (FAB) for C 17 H 15 N 3 O m/z : calculated, 278.1288; found, 278.1293 [M + H] + . 1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one 16 . Yellow solid, yield 80%, m.p.: 170–175 o C. 1 H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.16–8.11 (m, 2H), 8.04 (s, 1H), 7.91–7.87 (m, 2H), 7.87–7.82 (m, 2H), 7.38–7.32 (m, 2H), 6.03 (s, 2H).; 13 C NMR (100 MHz, DMSO) δ 192.10, 163.76, 161.31, 151.31, 145.63, 144.31, 135.10 (d, J = 3.2 Hz), 129.23 (d, J = 8.4 Hz), 128.88, 127.02, 115.99 (d, J = 21.3 Hz), 55.23.; HRMS (FAB) for C 16 H 12 FN 3 O m/z : calculated, 282.1037; found, 282.1037 [M + H] + . 1-(2'-chloro-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one 17 . Yellow solid, yield 95%, m.p.: 100–110 o C. 1 H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.17–8.13 (m, 2H), 8.12 (s, 1H), 7.70–7.65 (m, 2H), 7.61 (ddt, J = 5.9, 3.7, 1.9 Hz, 1H), 7.48 (q, J = 2.8 Hz, 3H), 6.07 (s, 2H).; 13 C NMR (100 MHz, DMSO) δ 192.17, 158.38 (q, J = 38.2 Hz), 150.85, 145.52, 144.24, 138.68, 133.37, 131.40, 131.16, 130.19–129.78 (m), 128.15, 127.73, 55.44.; HRMS (FAB) for C 16 H 12 ClN 3 O m/z : calculated, 298.0742; found, 298.0742 [M + H] + . Synthesis of (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one oxime KH01 . 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one, 3 (50 mg, 0.14 mmol) was added to the reaction mixture which consist of hydroxylamine (0.1 mL, 1.46 mmol), PPTS (3.67 mg, 10 mol%) and EtOH (1.4 mL, 0.1 M). The mixture was stirred at 90 o C for 15 h. Then the mixture was poured into water and extracted with DCM, washed with water and dried with anhydrous MgSO 4 . The solvent was then evaporated under reduced pressure, and the solid crude product was purified by column chromatography on silica gel using methanol/dichloromethane (1/24 ~ 1/9) as eluent to give ( E )-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1 H -1,2,4-triazol-1-yl)ethan-1-one oxime as white solid (40 mg, 79%). m.p.: 220–230 o C. 1 H NMR (400 MHz, DMSO) δ 12.24 (s, 1H), 8.55 (s, 2H), 7.80 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.65 (s, 4H), 5.44 (s, 2H).; 13 C NMR (100 MHz, DMSO) δ 150.83, 139.57, 138.37, 132.97, 131.88, 128.74, 126.76 (d, J = 3.9 Hz), 121.34, 37.69. HRMS (FAB) for C 16 H 13 BrN 4 O m/z : calculated, 357.0346; found, 357.0341 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-methyl oxime KH02 . White solid, yield 63%, m.p.: 85–95 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (s, 1H), 7.94 (s, 1H), 7.86–7.82 (m, 2H), 7.57 (dq, J = 9.1, 2.3 Hz, 4H), 7.47–7.43 (m, 2H), 5.43 (s, 2H), 4.10 (s, 3H).; 13 C NMR (100 MHz, CDCl 3 ) δ 150.81, 141.61, 139.18, 132.71, 132.16, 128.77, 127.38, 127.13, 122.29, 63.07, 43.70. HRMS (FAB) for C 17 H 15 BrN 4 O m/z : calculated, 371.0502; found, 371.0503 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-butyl oxime KH03 . White solid, yield 69%, m.p.: 100–110 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (s, 1H), 7.93 (s, 1H), 7.87–7.82 (m, 2H), 7.57 (dt, J = 8.8, 2.0 Hz, 4H), 7.45 (dd, J = 8.6, 2.0 Hz, 2H), 5.43 (d, J = 1.8 Hz, 2H), 4.30 (td, J = 6.8, 1.7 Hz, 2H), 1.77–1.70 (m, 2H), 1.46–1.37 (m, 2H), 0.97 (td, J = 7.5, 1.7 Hz, 3H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.67, 150.34, 144.22, 141.43, 139.23, 133.05, 132.14, 128.75, 127.34, 127.07, 122.23, 75.43, 43.76, 31.35, 19.28, 14.01.; HRMS (FAB) for C 20 H 21 BrN 4 O m/z : calculated, 413.0972; found, 413.0964 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(tert-butyl) oxime KH04 . White solid, yield 25%, m.p.: 110–120 o C, 1 H NMR (300 MHz, CDCl 3 ) δ 8.21 (s, 1H), 7.91 (d, J = 4.3 Hz, 2H), 7.88 (d, J = 1.9 Hz, 1H), 7.59 (d, J = 1.6 Hz, 2H), 7.56 (d, J = 1.7 Hz, 2H), 7.47–7.43 (m, 2H), 5.40 (s, 2H), 1.40 (s, 9H).; 13 C NMR (100 MHz, CDCl 3 ) δ 149.10, 141.28, 139.34, 133.68, 132.17, 128.76, 127.35, 126.94, 122.21, 81.39, 27.83.; HRMS (FAB) for C 20 H 21 BrN 4 O m/z : calculated, 413.0972; found, 413.0970 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-allyl oxime KH05 . White solid, yield 50%, m.p.: 110–114 o C, 1 H NMR (500 MHz, CDCl 3 ) δ 8.20 (s, 1H), 7.92 (s, 1H), 7.86–7.84 (m, 2H), 7.59–7.56 (m, 4H), 7.46–7.44 (m, 2H), 6.04 (ddt, J = 17.3, 10.4, 6.0 Hz, 1H), 5.45 (s, 2H), 5.35 (dq, J = 17.3, 1.5 Hz, 1H), 5.30 (dq, J = 10.4, 1.2 Hz, 1H), 4.79 (dt, J = 5.9, 1.3 Hz, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.49, 150.94, 141.49, 139.07, 133.23, 132.68, 132.03, 128.63, 127.24, 127.06, 122.15, 118.96, 76.22, 43.69.; HRMS (FAB) for C 19 H 17 BrN 4 O m/z : calculated, 397.0659; found, 397.0674 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-cyclopropyl methyl oxime KH06 . White solid, yield 55%, m.p.: 130–138 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.30 (s, 1H), 7.93 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.57 (dd, J = 8.5, 3.4 Hz, 4H), 7.45 (d, J = 8.5 Hz, 2H), 5.45 (s, 2H), 4.11 (d, J = 7.3 Hz, 2H), 1.22 (dt, J = 9.5, 3.9 Hz, 1H), 0.65–0.59 (m, 2H), 0.34 (dt, J = 6.1, 4.6 Hz, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 150.32, 141.32, 139.11, 132.93, 132.02, 128.63, 127.22, 126.94, 122.11, 80.24, 43.71, 10.29, 3.23.; HRMS (FAB) for C 20 H 19 BrN 4 O m/z : calculated, 411.0815; found, 411.0818 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-phenyl oxime KH07 . White solid, yield 11%, m.p.: 105–115 o C, 1 H NMR (500 MHz, CDCl 3 ) δ 8.29 (s, 1H), 7.98 (s, 1H), 7.95 (d, J = 4.7 Hz, 2H), 7.65–7.61 (m, 2H), 7.61–7.57 (m, 2H), 7.49–7.46 (m, 2H), 7.40–7.36 (m, 2H), 7.32–7.28 (m, 2H), 7.12 (dd, J = 8.0, 6.6 Hz, 1H), 5.66 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 158.79, 153.81, 151.92, 142.33, 139.03, 132.23, 132.10, 129.70, 128.81, 127.71, 127.51, 123.65, 122.50, 115.15, 44.29.; HRMS (FAB) for C 22 H 17 BrN 4 O m/z : calculated, 433.0659; found, 433.0642 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-benzyl oxime KH08 . White solid, yield 73%, m.p.: 125–130 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (s, 1H), 7.91 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.57 (dd, J = 8.4, 1.8 Hz, 4H), 7.47–7.43 (m, 2H), 7.39 (d, J = 4.0 Hz, 5H), 5.43 (s, 2H), 5.31 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.70, 151.22, 141.61, 139.18, 136.66, 132.78, 132.15, 128.81, 128.78, 128.75, 128.63, 127.34, 127.20, 122.28, 77.68, 43.78.; HRMS (FAB) for C 23 H 19 BrN 4 O m/z : calculated, 447.0815; found, 447.0864 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(2-fluorobenzyl) oxime KH09 . White solid, yield 44%, m.p.: 135–140 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (s, 1H), 7.89 (s, 1H), 7.88–7.83 (m, 2H), 7.57 (d, J = 8.2 Hz, 4H), 7.47–7.42 (m, 2H), 7.37 (dt, J = 15.5, 7.5 Hz, 2H), 7.19–7.08 (m, 2H), 5.43 (s, 2H), 5.38 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 162.59, 160.12, 151.61, 151.46, 144.24, 141.67, 139.18, 132.67, 132.15, 131.25 (d, J = 4.0 Hz), 130.66 (d, J = 8.2 Hz), 128.75, 127.29 (d, J = 12.0 Hz), 124.38 (d, J = 3.7 Hz), 123.95, 123.80, 122.29, 71.29 (d, J = 3.4 Hz), 43.67.; HRMS (FAB) for C 23 H 18 BrFN 4 O m/z : calculated, 465.0721; found, 465.0733 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(3-fluorobenzyl) oxime KH10 . White solid, yield 48.7%, m.p.: 109–115 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (s, 1H), 7.96 (s, 1H), 7.86–7.80 (m, 2H), 7.58 (dd, J = 8.5, 3.3 Hz, 4H), 7.49–7.41 (m, 2H), 7.36 (td, J = 7.9, 5.8 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.10–7.01 (m, 2H), 5.46 (s, 2H), 5.29 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 164.25, 161.79, 151.45, 141.83, 139.27 (d, J = 7.0 Hz), 139.13, 132.53, 132.19, 130.41 (d, J = 8.2 Hz), 128.77, 127.33 (d, J = 17.9 Hz), 124.08 (d, J = 2.9 Hz), 122.37, 115.47 (dd, J = 21.4, 6.7 Hz), 76.79 (d, J = 1.9 Hz), 43.98.; HRMS (FAB) for C 23 H 18 BrFN 4 O m/z : calculated, 465.0721; found, 465.0733 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(4-fluorobenzyl) oxime KH11 . White solid, yield 42%, m.p.: 135–140 o C, 1 H NMR (300 MHz, CDCl 3 ) δ 8.07 (s, 1H), 7.90 (s, 1H), 7.87–7.80 (m, 2H), 7.60–7.54 (m, 4H), 7.47–7.42 (m, 2H), 7.39–7.33 (m, 2H), 7.11–7.04 (m, 2H), 5.42 (s, 2H), 5.26 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.71, 151.35, 144.21, 141.69, 139.14, 132.68, 132.53 (d, J = 3.3 Hz), 132.16, 130.71 (d, J = 8.3 Hz), 128.75, 127.29 (d, J = 17.4 Hz), 122.31, 115.85, 115.63, 43.81.; HRMS (FAB) for C 23 H 18 BrFN 4 O m/z : calculated, 465.0721; found, 465.0720 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(2-chlorobenzyl) oxime KH12 . White solid, yield 40%, m.p.: 120–125 o C, 1 H NMR (300 MHz, CDCl 3 ) δ 8.14 (s, 1H), 7.90 (s, 1H), 7.88–7.83 (m, 2H), 7.59–7.55 (m, 4H), 7.47–7.41 (m, 3H), 7.41–7.37 (m, 1H), 7.33–7.27 (m, 2H), 5.46 (s, 2H), 5.44 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.67, 151.56, 144.32, 141.66, 139.13, 134.46, 134.14, 132.61, 132.14, 130.74, 129.90 (d, J = 8.0 Hz), 128.73, 127.28 (d, J = 10.8 Hz), 127.09, 122.28, 74.76, 43.68.; HRMS (FAB) for C 23 H 18 BrClN 4 O m/z : calculated, 481.0425; found, 481.0426 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(3-chlorobenzyl) oxime KH13 . White solid, yield 46%, m.p.: 110–117 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.25 (s, 1H), 7.99 (s, 1H), 7.86–7.81 (m, 2H), 7.58 (ddd, J = 9.1, 4.6, 2.2 Hz, 4H), 7.47–7.43 (m, 2H), 7.36 (q, J = 1.4 Hz, 1H), 7.34–7.30 (m, 2H), 7.24 (ddd, J = 4.8, 3.4, 1.6 Hz, 1H), 5.46 (s, 2H), 5.27 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.48, 141.80, 139.10, 138.78, 134.64, 132.50, 132.17, 130.11, 128.76, 128.69 (d, J = 5.9 Hz), 127.32 (d, J = 16.5 Hz), 126.63, 122.34, 76.71, 43.95.; HRMS (FAB) for C 23 H 18 BrClN 4 O m/z : calculated, 481.0425; found, 481.0445 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(4-chlorobenzyl) oxime KH14 . White solid, yield 35%, m.p.: 158–161 o C, 1 H NMR (300 MHz, CDCl 3 ) δ 8.08 (s, 1H), 7.91 (s, 1H), 7.86–7.80 (m, 2H), 7.60–7.54 (m, 4H), 7.47–7.42 (m, 2H), 7.39–7.29 (m, 4H), 5.42 (s, 2H), 5.26 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.73, 151.48, 144.21, 141.73, 139.12, 135.22, 134.52, 132.61, 132.16, 130.09, 128.87 (d, J = 24.5 Hz), 127.30 (d, J = 16.1 Hz), 122.32, 76.71, 43.82.; HRMS (FAB) for C 23 H 18 BrClN 4 O m/z : calculated, 481.0425; found, 481.0442 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(3-(trifluoromethyl)benzyl) oxime KH15 . White solid, yield 38%, m.p.: 90–95 o C, 1 H NMR (300 MHz, CDCl 3 ) δ 8.09 (s, 1H), 7.92 (s, 1H), 7.84–7.80 (m, 2H), 7.66–7.60 (m, 2H), 7.59–7.55 (m, 4H), 7.55–7.48 (m, 2H), 7.47–7.42 (m, 2H), 5.45 (s, 2H), 5.35 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.80 (d, J = 4.1 Hz), 144.13, 141.80, 139.09, 137.85, 132.50, 132.16, 131.80, 131.30, 130.98, 129.31, 128.75, 127.33 (d, J = 13.1 Hz), 125.33 (qd, J = 3.8, 2.0 Hz), 122.34, 76.61, 43.85. HRMS (FAB) for C 24 H 18 BrF 3 N 4 O m/z : calculated, 515.0689; found, 515.0689 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(4-(trifluoromethyl)benzyl) oxime KH16 . White solid, yield 38%, m.p.: 120–125 o C, 1 H NMR (500 MHz, CDCl 3 ) δ 8.11 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.83 (dt, J = 8.4, 1.8 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.57 (dq, J = 8.5, 1.9 Hz, 4H), 7.45 (dd, J = 10.7, 7.9 Hz, 4H), 5.45 (s, 2H), 5.35 (s, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.69 (d, J = 3.2 Hz), 144.06, 141.72, 140.73 (d, J = 1.6 Hz), 138.97, 132.37, 132.05, 130.71, 130.38, 128.56 (d, J = 14.3 Hz), 127.21 (d, J = 14.2 Hz), 125.63 (q, J = 3.7 Hz), 125.38, 122.67, 122.24, 76.42, 43.73.; HRMS (FAB) for C 24 H 18 BrF 3 N 4 O m/z : calculated, 515.0689; found, 515.0687 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(3-methoxybenzyl) oxime KH17 . White solid, yield 49%, m.p.: 90–95 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.28 (s, 1H), 8.00 (s, 1H), 7.88–7.84 (m, 2H), 7.60–7.56 (m, 4H), 7.47–7.44 (m, 2H), 7.31 (td, J = 7.5, 1.2 Hz, 1H), 6.98–6.95 (m, 1H), 6.90 (dd, J = 7.6, 1.1 Hz, 2H), 5.45 (s, 2H), 5.29 (s, 2H), 3.82 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 159.94, 150.87, 141.74, 139.10, 138.06, 132.55, 132.16, 129.91, 128.75, 127.40, 127.16, 122.33, 120.96, 114.34, 114.02, 77.67, 55.39, 44.09.; HRMS (FAB) for C 24 H 21 BrN 4 O 2 m/z : calculated, 477.0921; found, 477.0930 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(4-methoxybenzyl) oxime KH18 . White solid, yield 35%, m.p.: 160–170 o C, 1 H NMR (500 MHz, CDCl 3 ) δ 8.06 (d, J = 2.6 Hz, 1H), 7.89 (d, J = 2.6 Hz, 1H), 7.88–7.84 (m, 2H), 7.57 (dt, J = 7.9, 2.9 Hz, 4H), 7.47–7.43 (m, 2H), 7.34 (dd, J = 8.7, 2.7 Hz, 2H), 6.92 (dd, J = 7.8, 2.1 Hz, 2H), 5.40 (d, J = 2.6 Hz, 2H), 5.23 (d, J = 2.6 Hz, 2H), 3.83 (d, J = 2.7 Hz, 3H).; 13 C NMR (100 MHz, CDCl 3 ) δ 159.96, 150.99, 141.52, 139.18, 132.86, 132.13, 130.57, 128.74, 127.33, 127.16, 122.25, 114.17, 77.38, 55.42, 43.77.; HRMS (FAB) for C 24 H 21 BrN 4 O 2 m/z : calculated, 477.0921; found, 477.0913 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-pyridin-3-ylmethyl oxime KH19 . White solid, yield 37%, m.p.: 140–145 o C, 1 H NMR (300 MHz, CDCl 3 ) δ 8.71–8.65 (m, 1H), 8.61 (dd, J = 4.9, 1.7 Hz, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.84–7.80 (m, 2H), 7.69 (dt, J = 7.8, 2.0 Hz, 1H), 7.60–7.55 (m, 4H), 7.47–7.42 (m, 2H), 7.33 (ddd, J = 7.8, 4.8, 0.9 Hz, 1H), 5.43 (s, 2H), 5.32 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.85, 151.83, 150.06, 149.93, 144.11, 141.80, 139.05, 136.42, 132.42, 132.33, 132.14, 128.73, 127.36, 127.23, 123.71, 122.32, 74.82, 43.77.; HRMS (FAB) for C 22 H 18 BrN 5 O m/z : calculated, 448.0767; found, 448.0768 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-pyrazol-1-yl)ethan-1-one O-benzyl oxime KH20 . White solid, yield 67%, m.p.: 95–105 o C, 1 H NMR (300 MHz, CDCl 3 ) δ 7.83–7.78 (m, 2H), 7.58–7.51 (m, 4H), 7.48 (dd, J = 1.9, 0.7 Hz, 1H), 7.44 (s, 1H), 7.44–7.34 (m, 7H), 6.19 (t, J = 2.1 Hz, 1H), 5.46 (s, 2H), 5.33 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 152.46, 141.16, 139.36 (d, J = 1.8 Hz), 137.22, 133.29, 132.08, 130.06, 128.88–128.51 (m), 128.34, 127.19 (d, J = 13.4 Hz), 122.10, 106.18, 77.29, 46.17.; HRMS (FAB) for C 24 H 20 BrN 3 O m/z : calculated, 446.0863; found, 446.0862 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-imidazol-1-yl)ethan-1-one O-benzyl oxime KH21 . White solid, yield 64%, m.p.: 120–130 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.93 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.56 (dd, J = 8.3, 2.0 Hz, 4H), 7.43–7.40 (m, 2H), 7.40–7.35 (m, 5H), 7.22 (s, 1H), 7.00 (s, 1H), 5.47 (s, 2H), 5.33 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 149.99, 142.26, 138.78, 136.28, 132.20, 131.38, 129.02–128.82 (m), 128.73, 127.74, 126.78, 122.53, 121.46, 120.88, 78.07, 42.14.; HRMS (FAB) for C 24 H 20 BrN 3 O m/z : calculated, 446.0863; found, 446.0876 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one O-benzyl oxime KH22 . White solid, yield 55%, m.p.: 150–155 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (d, J = 8.2 Hz, 2H), 7.62 (s, 1H), 7.54 (q, J = 7.8 Hz, 5H), 7.45–7.35 (m, 7H), 5.69 (s, 2H), 5.35 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 150.94, 141.65, 139.12, 136.77, 134.19, 132.43, 132.15, 128.81, 128.74, 128.64, 127.34, 127.09, 124.32, 122.29, 77.68, 43.90.; HRMS (FAB) for C 23 H 19 BrN 4 O m/z : calculated, 447.0815; found, 447.0815 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one O-benzyl oxime KH23 . White solid, yield 76%, m.p.: 130–135 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J = 8.0 Hz, 2H), 7.56 (s, 3H), 7.54–7.46 (m, 3H), 7.37 (td, J = 15.4, 6.8 Hz, 7H), 5.81 (s, 2H), 5.33 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.24, 141.06, 139.33, 137.40, 134.68, 132.99, 132.07, 128.72, 128.54, 128.34, 128.13, 127.24, 127.02, 122.09, 77.23, 48.98.; HRMS (FAB) for C 23 H 19 BrN 4 O m/z : calculated, 447.0815; found, 447.0819 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-tetrazol-1-yl)ethan-1-one O-benzyl oxime KH24 . White solid, yield 56%, m.p.: 160–162 o C, 1 H NMR (300 MHz, CDCl 3 ) δ 8.53 (s, 1H), 7.87–7.83 (m, 2H), 7.62–7.56 (m, 4H), 7.47–7.43 (m, 2H), 7.43–7.38 (m, 5H), 5.65 (s, 2H), 5.34 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 149.91, 142.09, 138.94, 136.13, 132.21, 131.88, 129.01, 128.99, 128.76, 127.55, 127.03, 122.47, 78.11, 42.07.; HRMS (FAB) for C 22 H 18 BrN 5 O m/z : calculated, 448.0767; found, 448.0782 [M + H] + . (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(2H-tetrazol-2-yl)ethan-1-one O-benzyl oxime KH25 . White solid, yield 71%, m.p.: 90–100 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.44 (s, 1H), 7.74–7.69 (m, 2H), 7.57–7.51 (m, 4H), 7.42 (d, J = 8.4 Hz, 2H), 7.39–7.31 (m, 5H), 5.97 (s, 2H), 5.32 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 153.11, 149.31, 141.55, 139.11, 136.95, 132.27, 132.14, 128.68 (d, J = 12.0 Hz), 128.39 (d, J = 10.1 Hz), 127.20 (d, J = 15.9 Hz), 122.28, 77.53, 46.94.; HRMS (FAB) for C 22 H 18 BrN 5 O m/z : calculated, 448.0767; found, 448.0741 [M + H] + . (E)-1-(2'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-benzyl oxime KH26 . White solid, yield 20%, m.p.: 95–100 o C 1 H NMR (400 MHz, CDCl 3 ) δ 8.25 (s, 1H), 7.99 (s, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.67 (dd, J = 8.0, 1.2 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 9.6 Hz, 5H), 7.35 (d, J = 1.2 Hz, 1H), 7.30 (dd, J = 7.7, 1.9 Hz, 1H), 7.24–7.20 (m, 1H), 5.45 (s, 2H), 5.31 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.17, 142.88, 141.78, 136.65, 133.37, 132.76, 131.23, 130.02, 129.23, 128.82 (d, J = 3.5 Hz), 128.65, 127.63, 126.28, 122.51, 77.70, 44.16.; HRMS (FAB) for C 23 H 19 BrN 4 O m/z : calculated, 447.0815; found, 447.0805 [M + H] + . (E)-1-(3'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-benzyl oxime KH27 . White solid, yield 48.9%, m.p.: 90–95 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (s, 1H), 7.96 (s, 1H), 7.88–7.85 (m, 2H), 7.73 (t, J = 1.9 Hz, 1H), 7.60–7.57 (m, 2H), 7.50 (dt, J = 8.1, 2.0 Hz, 2H), 7.42–7.37 (m, 5H), 7.33 (d, J = 7.9 Hz, 1H), 5.44 (s, 2H), 5.32 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.08, 142.39, 141.33, 136.59, 132.97, 130.86, 130.54, 130.24, 128.83, 128.68, 127.57, 127.19, 125.82, 123.15, 77.74, 43.88. HRMS (FAB) for C 23 H 19 BrN 4 O m/z : calculated, 447.0815; found, 447.0819 [M + H] + . (E)-2-(1H-1,2,4-triazol-1-yl)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethan-1-one O-benzyl oxime KH28 . White solid, yield 46%, m.p.: 90–100 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (s, 1H), 7.94 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 2.0 Hz, 4H), 7.63 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 3.9 Hz, 5H), 5.45 (s, 2H), 5.32 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.02, 143.77 (d, J = 1.6 Hz), 141.36, 136.56, 133.29, 128.84 (d, J = 1.5 Hz), 128.71, 127.75, 127.50, 127.27, 125.98 (q, J = 3.8 Hz), 77.80, 43.89.; HRMS (FAB) for C 24 H 19 F 3 N 4 O m/z : calculated, 437.1584; found, 437.1584 [M + H] + . (E)-1-(2'-methyl-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-benzyl oxime KH29 . White solid, yield 72%, m.p.: 90–100 o C, 1 H NMR (500 MHz, CDCl 3 ) δ 8.09 (s, 1H), 7.92 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 5.7 Hz, 4H), 7.38–7.34 (m, 3H), 7.29–7.27 (m, 2H), 7.24 (q, J = 3.9 Hz, 1H), 7.22–7.19 (m, 1H), 5.44 (s, 2H), 5.31 (s, 2H), 2.26 (s, 3H).; 13 C NMR (100 MHz, CDCl 3 ) δ 151.64, 151.45, 144.29, 143.89, 141.07, 136.71, 135.38, 132.02, 130.56, 129.73 (d, J = 6.6 Hz), 128.76 (d, J = 4.4 Hz), 128.58, 127.75, 126.38, 125.99, 77.59, 43.92, 20.55.; HRMS (FAB) for C 24 H 22 N 4 O m/z : calculated, 383.1866; found, 383.1881 [M + H] + . (E)-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-benzyl oxime KH30 . White solid, yield 19%, m.p.: 90–100 o C, 1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (s, 1H), 7.95 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.59–7.52 (m, 4H), 7.43–7.34 (m, 5H), 7.14 (t, J = 8.7 Hz, 2H), 5.44 (s, 2H), 5.31 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 164.13, 161.67, 151.03, 141.95, 136.59, 136.37 (d, J = 3.3 Hz), 132.28, 128.83, 128.73 (d, J = 7.3 Hz), 127.45, 127.11, 115.95 (d, J = 21.5 Hz), 77.74, 44.00.; HRMS (FAB) for C 23 H 19 FN 4 O m/z : calculated, 387.1616; found, 387.1618 [M + H] + . (E)-1-(2'-chloro-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-benzyl oxime KH31 . White solid, yield 53%, m.p.: 110–120 o C 1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (s, 1H), 7.98 (s, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.52–7.46 (m, 3H), 7.42–7.35 (m, 5H), 7.34–7.29 (m, 3H), 5.44 (s, 2H), 5.32 (s, 2H).; 13 C NMR (100 MHz, CDCl 3 ) δ 150.95, 150.49, 141.32, 139.69, 136.54, 132.57 (d, J = 10.4 Hz), 131.29, 130.20, 130.09, 129.08, 128.84, 128.71, 127.08, 126.31, 77.80, 44.16.; HRMS (FAB) for C 23 H 19 ClN 4 O m/z : calculated, 403.1320; found, 403.1326 [M + H] + . Assay of algicidal activity against Scenedesmus rotundus Algicidal activity of the synthesized compound was tested in two to three replicates. Activity was tested in a static manner without replacing the test solution during the test period. A 20 mL volume of culture medium containing Scenedesmus rotundus (A1283, FBCC, Sangju, Republic of Korea), subcultured in BG11 sterile medium (pH 7.1) at a concentration of approximately 2.0–10.0 × 10 4 cells/mL media (absorbance less than 0.001 at λ max of 680 nm), was dispensed into a 60 mL volumetric cell culture flask. Solutions of the test compound were prepared at concentrations of 0.2, 2.0, and 20 µM using dimethyl sulfoxide (DMSO) containing 2.0% Tween 20. Next, 40 µL of the solution was dispensed into the cell culture flask containing Scero in culture medium. All operations were performed in a sterile room. The final concentrations of DMSO and Tween 20 in this experiment were 0.1% and 20.0 ppm, respectively. Scero treated with the test compound was cultured for 6 days at 25 o C with a light intensity of 45–55 µmol m -2 s -1 for 14 h per day. The culture flask was shaken at least three times per day during that period. When the period of culture was completed, the degree of growth inhibition was graded from 0 (no inhibition) to 100 (complete inhibition). The in vivo chlorophyll (Chl.) absorbances (A680 - A780 nm) of Scero cultures treated with the test compounds, and of untreated controls, were measured using a UV/VIS spectrophotometer (DU800, Bechman Coulter, Brea, CA, USA). The absorbances were converted to a percentage to express the degree of Scero growth inhibition associated with each compound. Assay of herbicidal activity against Lemna paucicostata Evaluations of the herbicidal activity of the synthesized compounds against an aquatic lower plant, duckweed ( Lemna paucicostata ; hereafter, LEMPA) (PC3034, KCTC, Jeongeup, Republic of Korea), were performed by adding 30 mL of culture medium to a circular transparent plastic cup with an upper diameter of 52 mm, a lower diameter of 36 mm, a height of 60 mm, and a volume of 90 mL. The experiments were conducted in a static manner without replacing the test solution during the test period. Solution of the test compound were prepared at concentrations of 0.2, 2.0, and 20.0 µM using DMSO containing 2.0% Tween 20. Next, 60 µL of each test solution was dispensed into a plastic cup containing 30 mL of basic culture medium (1x mDM, pH 7.6). Afterwards, five LEMPA plants at the 3.9–4.1 frond growth stage, which had been subcultured in the plant growth room, were inoculated into the test solution. Each container containing test solution and LEMPA was placed in a rectangular translucent plastic box, supplied with a specific amount of moisture, and covered with a transparent film to prevent moisture evaporation. Plants treated with the test solution were cultured in a growth room for 6 days at 25 o C with a light intensity of 45–55 µmol m -2 s -1 for 14 h per day. To evaluate the herbicidal activity of the compound, the growth status and overall condition of the plants were initially examined following cultivation. Next, the number of fronds was determined and the plants collected. Moisture was completely removed from plants by blotting with soft, absorbent paper and their fresh weight was measured. The plants were then immersed in 10 mL methanol for 1 day at room temperature in the dark to extract the pigments. The absorbance of the sample was measured at 470, 652.4, and 665.2 nm using the UV/VIS spectrophotometer. Photosynthetic pigments in the samples were quantified by the Lichtenthaler ( 1987 ) method. The inhibitory activity of the test compound against LEMPA growth was expressed as the relative ratio of the amount of photosynthetic pigment in LEMPA treated with the test compound to the amount of photosynthetic pigment in untreated controls. Algicidal activities of KH08 against different algae The algicidal effect of KH08 on various strains of microalgae was measured to obtain an algicidal activity spectrum. This investigation compared KH08 , a compound with excellent algicidal activity against the green alga Scenedesmus rotundus (Scero), with a control compound, glutaraldehyde, which is commonly used as an algicide. The strains of green and cyanobacteria used in this experiment are listed in Table 1 . Other than using microalgae as test organisms, the methodology was as described above (“Assay of algicidal activity against Scenedesmus rotundus ”). Table 1 Strains of green algae and cyanobacteria used in this study. Group Abbreviation Scientific name Microbial bank Green algae Cv-K Desar Desas Rs Scero Chlorella vulgaris (AG10002) Desmodesmus armatus (A1320) Desmodesmus asymmetricus (A1320) Raphidocelis subcapitata Scenedesmus rotundus (A1283) a KCTC b FBCC FBCC c KTR FBCC Cyanobacteria Ana Ma-F Ma-K Osc Anabaena affinis (AG10008) Microcystis aeruginosa (A68) Microcystis aeruginosa (AG60752) Oscillatoria spp. (AG10195) KCTC FBCC KCTC KCTC a KCTC: Korean Collection for Type Cultures, Korea Research Institute of Bioscience and Biotechnology, Jeongup, Republic of Korea; b FBCC: Freshwater Bioresources Culture Collection, Sangju, Republic of Korea. c KTR: Korea Testing & Research Institute, Gwacheon, Republic of Korea. Abbreviation rule. Species abbreviations may include a hyphen followed by a strain-source code: “-K” = KCTC; “-F” = FBCC. E.g. , Ma-F denotes the FBCC strain of the listed Microcystis aeruginosa ; Cv-K denotes the KCTC strain of the corresponding species. All microalgal strains used in this study were obtained from KCTC, FBCC and KTR under their terms of use; no wild collections were performed. Acute toxicity tests Acute toxicity tests of KH08 were conducted on an aquatic invertebrate (water flea, Daphnia magna ), two species of freshwater fish (minnow, Oryzias latipes ; zebra fish, Danio rerio ), and a mammal (ICR mouse, Mus musculus ). Acute toxicity tests on D. magna were conducted using a static method in accordance with the OECD guideline for testing of chemicals 202, Daphnia sp., Acute Immobilization Test (13 April 2004). The concentrations of KH08 in the test solution were 1, 1.6, 2.6, 4.1, 6.6 and 10.5 mg/L based on 100% KH08 . M4 medium, prepared according to the methodology described in “Daphnia sp., Acute Immobilization Test, Annex 3 Elendt M7 and M4 medium” (OECD TG 202, 2004-04-13), was used as test water. Potassium dichromate (lot no. MKCQ8035; Sigma-Aldrich) was used as a positive control. The results were expressed as the half maximal effect concentration (EC 50 ) and no observed effect concentration (NOEC). The effects of compound KH08 on O. latipes , and D. rerio were evaluated using a static acute toxicity test. Fish were exposed to three treatments: a negative control (freshwater), a solvent control (0.1 mL acetone/L freshwater), and a test solution (2.0 mg KH08 /L solvent) based on 100% test compound. The results were expressed as the median lethal concentration (LC 50 ) of the test compound KH08 after observing mortality and abnormal symptoms of O. latipes and D. rerio in each treatment during the test period. An acute oral toxicity test of KH08 was performed using ICR mice. KH08 was orally administered to mice at a dose of 2,000 mg/kg body weight (BW) using corn oil as a vehicle. The acute oral toxicity of the compound was represented as the median lethal dose (LD 50 ) of the compound after observing the number of fatalities, general toxicity symptoms, and BW changes in the test group receiving the compound. RESULTS Chemistry The synthetic routes of the phenyl oxime derivatives are described in Scheme 1 . There were three synthetic routes for each moiety. In route A , 4-bromobiphenyl ( 1 ) was used as a starting material. Compound 2 was obtained in a good yield through Friedel-Craft acylation reacting with AlCl 3 and bromoacetyl bromide. In the next step, compound 2 was reacted with 1 H -1,2,4-triazole in S N 2 reaction to obtain compound 3 in moderate yield. In the final step in route A , condensation of the ketone in compound 3 with various forms of O -substituted hydroxyl amine gave KH01 - 19 in moderate yield. Synthetic route B was devised to modify the triazole moiety of the target compound. Compound 2 was used as the starting material. By reacting compound 2 with 1,2-diazole, 1,3-diazole, 1,2,3-triazole, and 1,2,3,4-tetrazole, compounds 4 to 9 , respectively, were obtained in suitable yields. These intermediates were reacted with O -benzylhydroxylamine to obtain, KH20 - 25 . Synthetic route C was a method for deriving the biphenyl moiety of the target compound. 2-bromo-1-(4-bromophenyl)ethan-1-one ( 10 ) was used as the starting material. Compound 10 was reacted with 1 H -1,2,4-triazole in a S N 2 reaction to obtain compound 11 in good yield. Subsequently, compound 11 was used in Pd-catalyzed cross-coupling reactions with various forms of phenyl boronic acid to synthesize compounds 12 to 17 . Finally, compounds KH26 to 31 were synthesized by reacting the intermediates 12 to 17 with O -benzylhydroxylamine. Biological activity and structure-activity relationships Evaluations of algicidal and herbicidal activity focused on discovering compounds that strongly inhibited Scero, a green alga, and showed high selectivity against different strains of microalgae, but had no or low inhibitory effect on LEMPA, a lower plant. We determined the algicidal activity against Scero, and also of the herbicidal activity against LEMPA, of each of the synthesized phenyl oxime derivatives by using a UV/VIS spectrophotometer to measure the in vivo chlorophyll absorption. The absorbance values were converted into percentage growth inhibition. First, the effect of the functional group, R, of KH01-19 on algicidal activity was examined (Table 2). KH01 , which had no functional group substitution, exhibited moderate efficacy, inhibiting Scero by 95% at 2.0 μM. It showed no herbicidal effect on LEMPA, even at 20.0 μM, thus demonstrating exceptional selectivity. Next, compounds in which R was substituted with aliphatic groups were synthesized and their algicidal activities investigated. KH02 (methyl substitution) exhibited higher algicidal activity against Scero (16.5% inhibition at 0.2 μM) than KH01 (4.4% inhibition at 0.2 μM). However, KH02 showed herbicidal activity against LEMPA (72.7% inhibition at 20.0 μM), in contrast to the lack of herbicidal activity of KH01 at 20.0 μM. KH03 ( n -butyl substitution) exhibited high algicidal activity (75.7% inhibition at 0.2 μM), but herbicidal activity against LEMPA was not observed (0% inhibition at 20 μM). KH04 ( t -butyl substitution) demonstrated the highest algicidal activity of the synthesized derivatives (95.4% inhibition at 0.2 μM). However, it also showed a low level of herbicidal activity against LEMPA (8.8% inhibition at 20 μM). KH05 ( propylene substitution) exhibited a relatively high algicidal activity (76.4% inhibition at 0.2 μM) but had herbicidal activity at high concentration (26.0% inhibition at 2.0 μM). KH06 ( cyclopropyl substitution) demonstrated high algicidal activity (73.7% inhibition at 0.2 μM) but no herbicidal activity (0% inhibition at 20 μM), indicating good selectivity. As the next step in the optimization, the R group was replaced with an aromatic ring. KH07 (substitution with phenyl moiety) exhibited lower algicidal activity (30.2% inhibition at 0.2 μM) than derivatives KH03 to KH06 that had aliphatic substitutions at R, although KH07 had no observable herbicidal effects on LEMPA (0% inhibition at 20.0 μM). KH08 ( substitution with benzyl moiety) was the compound with third highest algicidal activity (85.5% inhibition at 0.2 μM). Additionally, KH08 exhibited remarkable selectivity, as it showed no herbicidal activity (0% inhibition at 20 μM). The R group was further optimized by modifying the substituents on the aromatic ring. KH09 , KH10 and KH11 were synthesized by substituting, respectively, the ortho -, meta - and para - positions of the benzyl group in KH08 with fluorine. All three compounds had relatively high algicidal activities (34-78% inhibition at 0.2 μM) and also exhibited some level of herbicidal activity (>10% inhibition at 20.0 μM). KH12 , KH13 and KH14 were similarly synthesized from KH08 by substituting chlorine at the ortho -, meta - and para - positions, respectively, of the aromatic ring. Algicidal activity decreased slightly when the benzyl group of KH08 was substituted with chlorine (27%-62% inhibition at 0.2 μM) rather than fluorine (34-78% inhibition at 0.2 μM). By contrast, herbicidal activities of the chlorinated compounds (0-12% inhibition at 20.0 μM) were comparable with those of the fluorinated compounds (0-7% inhibition at 20.0 μM). As the next stage in optimizing the aromatic ring, an electron-withdrawing group, CF 3 , was substituted at the meta - and para - positions of the benzyl group in KH08 to synthesize, respectively, KH15 and KH16 . KH15 and KH16 showed reduced algicidal activities (15-38% inhibition at 0.2 μM) compared with the KH08 derivatives that contained halogen substitutions. The herbicidal activities of KH15 and KH16 (12-14% inhibition at 20 μM) were higher, however, than those of the derivatives containing halogen substitutions. Next, an electron-donating group, methoxy, was introduced at the meta - and para - positions of the benzyl group in KH08 to synthesize, respectively, KH17 and KH18 . These compounds showed relatively inferior algicidal activities (33%-46% inhibition at 0.2 μM) when compared with the other derivatives. On the other hand, these compounds had no herbicidal activity (0% inhibition at 20.0 μM). Finally, the effects on biological activity of substituting pyridyl at the R group were investigated. KH19 was synthesized by substituting a 3-pyridyl group. It exhibited moderate algicidal activities (57% inhibition at 0.2 μM) and herbicidal activities (34% inhibition at 20.0 μM). In summary, we synthesized 19 derivatives with substitutions at the R group. Most exhibited a higher level of algicidal activity than the reference compound glutaraldehyde, as well as low herbicidal activity. Additionally, these compounds showed superior efficacy, in terms of activity and selectivity, than loreclezole, which had been identified previously as a promising active compound (Kim et al. 2021). KH04 and KH08 could be considered the “best” of the synthesized derivatives. Both exhibited high activities with over 85% inhibiton of Scero at 0.2 μM. KH04 was not suitable as an algicide for environmental use, however, because of its herbicidal effect on LEMPA. Therefore, KH08 was tentatively designated our lead compound and taken forward for further optimization. Subsequent modifications of KH08 focused on optimizing the triazole moiety (Table 3). Although the five-membered ring comprising 1,2,4-triazole was retained, further iterations of KH08 were derived through slight modifications of the position and number of the heteroatom, N. KH20 was obtained by substituting 1,2,4-triazole with 1,2-diazole. This compound exhibited inferior algicidal activity (26.6% inhibition) and did not show any herbicidal activity (0% inhibition at 20 μM). By contrast, KH21 , a KH08 derivative in which 1,3-diazole, which has a different N position from 1,2-diazole, was substituted, showed greatly improved algicidal activity (96.5% inhibition at 0.2 μM) and relatively low herbicidal activity (25.6% inhibition at 20.0 μM). The next step of heterocyclic ring optimization involved substituting 1,2,3-triazole and 1,2,5-triazole to synthesize KH22 and KH23 , respectively. Both compounds had inferior algicidal activity (15-26% inhibition at 20 μM) and lacked any herbicidal activity (0% inhibition). Finally, we synthesized KH24 and KH25 by substituting with 1,2,3,4-tetrazole and 1,2,3,5-tetrazole, respectively. These compounds also showed inferior algicidal activity (20-40% inhibition at 20 μM) with no herbicidal activity (0% inhibition). To summarize, all compounds with modifications within the five-membered heterocyclic ring, other than KH21 , showed weaker activity than the reference compounds. Although KH21 exhibited the highest algicidal activity, it was unsuitable for use in the environment due to its herbicidal activity. KH08 therefore retained its status as the most promising lead compound. In our final optimization stage, an aromatic ring in the biphenyl group of the phenyl oxime derivative was substituted with an electron-withdrawing group, an electron-donating, and a halogen group (Table 4). The biological properties of KH08 , in which Br was substituted at the para -position of the aromatic ring, were compared with those of the newly synthesized compounds KH26 and KH27 , in which Br was substituted at ortho- and meta- positions, respectively. Both KH26 and KH27 demonstrated inferior algicidal activity (0-20.2% inhibition at 0.2 μM). KH28 was synthesized by substituting an electron-withdrawing group, CF 3 , at the para -position of the aromatic ring in the biphenyl group. This compound showed reduced algicidal activity (19.4% inhibition at 0.2 μM). Moreover, as shown in Table 4, KH29 , in which an electron-donating group, methyl, was substituted at the ortho -position of the aromatic ring in the biphenyl group, showed a considerable decrease in algicidal activity (8.7% inhibition at 0.2 μM). To determine the effect on the biological activities of substituting a halogen in the aromatic ring, KH30 and KH31 were synthesized by substituting F or Cl, respectively. Both compounds exhibited negligible or low algicidal activity (0-36.2% inhibition at 0.2 μM). Furthermore, these compounds showed relatively low herbicidal activities (10-30% inhibition at 20 μM). Taken together, the studies of the effect of modifying functional groups in the biphenyl ring revealed that KH08 , which had a Br substitution at the para -position, had the highest level of algicidal activity, as well as high microalgal selectivity. To discover a novel compound that had high algicidal activity, but was not toxic to aquatic ecosystems, we synthesized 31 phenyl oxime derivatives and investigated the relationship between their structure and their algicidal activity. KH04 , KH08 , and KH21 all showed excellent algicidal activity, as they inhibited growth of a green alga, Scero, by more than 85% when tested at a concentration of 0.2 μM. At a higher concentration (20 μM), KH04 and KH21 inhibited growth of an aquatic plant, LEMPA, by 8.8% and 25.6%, respectively, but KH08 did not inhibit plant growth at all. KH08 was therefore selected as a candidate for further investigations due to its excellent activity against green algae and minimal toxicity to lower plants. Algicidal spectra of KH08 The algicidal activity spectra of the lead compound KH08 were determined by measuring its effects on different species of green and cyanobacteria. The algicidal activity spectra of KH08 were compared with those of glutaraldehyde, a conventional algicide. KH08 had high algicidal activity against green algae but showed relatively low algicidal activity against cyanobacteria. A concentration of 0.16 μM KH08 inhibited growth of green algae Scenedesmus rotundus (Scero), Desmodesmus asymmetricus (Desas) and Chlorella vulgaris (Cv-K) by 60% - 70%; in addition, 1.25 μM KH08 inhibited growth of the green alga, Raphidocelis subcapitata (Rs), by 48.7% (Fig. 2A). However, although 0.63 μM KH08 inhibited growth of the cyanobacteria, Microcystis aeruginosa (Ma-F), by 60%, concentrations of up to 5.0 μM KH08 did not inhibit growth of the cyanobacteria, Microcystis aeruginosa (Ma-K), Anabaena affinis (Ana) and Oscillatoria spp. (Osc), by more than 20% (Fig. 2B). The algicidal activity spectra of glutaraldehyde contrasted with those of KH08 . Glutaraldehyde inhibited growth of glutaraldehyde-sensitive microalgae species by more than 30% at 10.0 μM, but inhibited the growth of glutaraldehyde-insensitive microalgae species by less than 60%, even at 40.0 μM. Specifically, 10.0 μM glutaraldehyde inhibited growth of the green algae, Scero and Desar, by 40%-60%, and 40.0 μM glutaraldehyde inhibited growth of the green algae, Cv-K and Rs, by about 60% (Fig. 2C). A concentration of 10 μM glutaraldehyde inhibited growth of the cyanobacteria, Ma-F, Ana and Osc by 35.9%, 26.9%, and 50.0%, respectively. However, growth of a cyanobacteria, Ma-K, was only inhibited by 45.6% by 40.0 μM glutaraldehyde (Fig. 2D). Under matched assay conditions, KH08 inhibited green microalgae at lower μM concentrations than glutaraldehyde, while activity toward cyanobacteria was comparatively weak. Acute toxicity of KH08 To investigate the toxicity of KH08 , to different animal species, acute toxicity tests of the compound were conducted on a water flea ( Daphnia magna ), two freshwater fish species ( Oryzias latipes and Danio rerio ), and ICR mice. Water flea (Daphnia magna) Observations of immobilization and abnormal behavior of D. magna exposed to KH08 indicated that the EC 50 of KH08 was 4.800 mg/L after 24 h and 3.107 mg/L after 48 h. These values were, respectively, 2.88× and 2.94× higher than the EC 50 of potassium dichromate, a positive control compound (Table 5). The NOEC of KH08 , that is, the maximum concentration at which KH08 had no observable effect on D. magna , was 1.000 mg/mL over observation periods of 24 h and 48 h. Freshwater fish ( Oryzias latipes and Danio rerio) To evaluate the acute toxicity of KH08 to O. latipes and D. rerio , test groups of fish were treated with 2.0 mg/L of KH08 . A negative control group was treated with fresh water, and a solvent control group with 0.01% acetone aqueous solution. None of these treatments caused death or abnormal symptoms during the acute toxicity test periods of 48 h and 96 h (Table 6). Therefore, the LC 50 of KH08 for O. latipes and D. rerio was concluded to exceed 2.0 mg/L. ICR mice KH08 , orally administered at a dose of 2,000 mg/kg BW, did not cause death of ICR mice, nor were symptoms of general poisoning observed (Table7). The BW of the mice increased over the test period following KH08 administration. Necropsy after the test was completed did not reveal any abnormal findings in animals that had received oral KH08 . The LD 50 of KH08 for ICR mice thus appeared to be greater than 2,000 mg/kg BW. Conclusion Thirty-one phenyl-oxime derivatives were synthesized and evaluated for algicidal activity against the green microalga Scenedesmus rotundus (Scero) and herbicidal activity against Lemna paucicostata (LEMPA), enabling identification of selective compounds. The lead, ( E )-1-(4′-bromo-[1,1′-biphenyl]-4-yl)-2-(1 H -1,2,4-triazol-1-yl)ethan-1-one O -benzyl oxime ( KH08 ), strongly inhibited S. rotundus while showing no measurable activity toward L. paucicostata . Under matched assay conditions, KH08 achieved comparable or greater inhibition of green microalgae at lower μM concentrations than glutaraldehyde, whereas activity toward cyanobacteria was modest. Acute-toxicity tests indicated low toxicity under our test conditions ( Daphnia magna EC₅₀ = 3.11–4.80 mg L⁻¹; fish LC₅₀ > 2.0 mg L⁻¹; mouse LD₅₀ > 2000 mg kg⁻¹). Collectively, these findings position KH08 as a selective algicide candidate with practical relevance for microalgal control. Declarations Author’s Contribution Jun Young Lee: Conceptualization, Data Curation, Investigation, Visualization, Writing – Original Draft, Writing – Review and Editing. Yeo Jin Kim: Data Curation, Investigation, Methodology. Bong Gyu Choi: Investigation, Validation. Jin-Seog Kim: Investigation, Validation, Visualization. Hasoo Seong: Data Curation, Writing – Review and Editing. Chul Min Park: Methodology, Resources. Hyun Suk Yeom: Data curation, Formal Analysis. Seok Ki Min: Data Curation, Formal Analysis. Hyeung-geun Park: Resources, Supervision, Writing – Review and Editing. Joon Ho Lee: Funding Acquisition, Project Administration, Supervision, Writing – Review and Editing. Funding This research was supported by grants from the Korea Environmental Industry & Technology Institute, funded by the Ministry of Environment (RS-2022-KE002109). Partial funding was provided by Korea Research Institute Chemical Technology intramural funding (Grant Number KK2532-10). Data availability The datasets and analysis sheets that support the findings of this study are provided in the Supplementary Information; additional raw data are available from the corresponding authors upon reasonable request. Competing interests The authors declare no competing financial interest. References Balaji Prasath, B.; Wang, Y.; Su, Y.P.; Hamilton, D.P.; Lin, H.; Zheng, L.; Zhang, Y. (2022). Methods to control harmful algal blooms: a review. Environmental Chemistry Letters , 20 , 3133-3152. Cho, I.K.; Seol, J.U.; Rahman, M.M.; Lee, D.-G.; Son, H.; Cho, H. (2021). Laboratory studies of the algaecide GreenTD: Stability, algaecidal activity and reduction of microcystin production. Applied Biological Chemistry , 64 , 22. Coyne, K.J.; Wang, Y.; Johnson, G. (2022). Algicidal Bacteria: A Review of Current Knowledge and Applications to Control Harmful Algal Blooms. Frontiers in Microbiology , 13 , 871177. Cui, Y.; Wang, X.; Lin, G.; Duan, W.; Wu, X.; Lan, H.; Li, B. (2022). Synthesis of ( E )/( Z )-Verbenone Oxime Ethers and Photoresponsive Behavior to Herbicidal Activity. Journal of Agricultural and Food Chemistry , 70 , 13862–13872. Ding, W.X.; Shen, H.M.; Shen, Y.; Zhu, H. G.; Ong, C.N. (1998). Microcystic cyanobacteria causes mitochondrial membrane potential alteration and reactive oxygen species formation in primary cultured rat hepatocytes. Environmental Health Perspectives , 106 , 409-413. Furuya, K.; Iwataki, M.; Lim, P.T.; Lu, S.; Leaw, C.-P.; Azanza, R.V.; Kim, H.-G.; Fukuyo, Y. (2018). Overview of harmful algal blooms in Asia. In Global Ecology and Oceanography of Harmful Algal Blooms; Springer: Berlin/Heidelberg, Germany, 289-308. Gallardo-Rodríguez, J.J.; Astuya-Villalón, A.; Llanos-Rivera, A.; Avello-Fontalba, V.; Ulloa-Jofré, V. (2019). A critical review on control methods for harmful algal blooms. Reviews in Aquaculture , 11 , 661–684. Giacomazzi, S.; Cochet, N. (2004). Environmental impact of diuron transformation: a review, Chemosphere , 56 , 1021-1032. Gil, C.S.; Duan, S.; Kim, J.H.; Eom, S.H. (2021) Allelopathic efficiency of plant extracts to control cyanobacteria in Hydroponic culture. Agronomy , 11 , 2350. Heisler, J.; Glibert, P.M.; Burkholder, J.M.; Anderson, D.M.; Cochlan, W.C.; Dennison, W.C.; Gobler, C.A.; Dortch, Q.; Gobler, C.J.; Heil, C.A.; Humphries, E.; Lewitus, A.; Magnien, R.; Marshall, H.G.; Sellner, K.; Stockwell, D.A.; Stoecker, D.K.; Suddleson, M. (2008). Eutrophication and Harmful Algal Blooms: A Scientific Consensus. Harmful Algae , 8 , 3-13. Harrison, P.J.; Piontkovski, S.; Al-Hashmi, K. (2017). Understanding how physical-biological coupling influences harmful algal blooms, low oxygen and fish kills in the Sea of Oman and the Western Arabian Sea. Marine Pollution Bulletin , 114 , 25-34. Jančula, D.; Maršálek, B. (2011). Critical review of actually available chemical compounds for prevention and management of cyanobacterial blooms. Chemosphere , 85 , 1415-1422. Jeon, B-s.; Han, J.; Kim, S.-K.; Ahn, J.-H.; Oh, H.-C.; Park, H.-D. (2015). An Overview of Problems Cyanotoxins Produced by Cyanobacteria and the Solutions Thereby. Journal of Korean Society of Environmental Engineers , 37 , 657-667. Kim, J.S.; Kim, B.G.; Hwang, Y.G.; Choi, J.H.; Lee, B.S.; Lee, I.Y. (2021). Growth Inhibition Effects of Loreclezole on the Various Microalgae and Plant Species. Weed & Turfgrass Science , 10 , 277-289. Kim, J.S.; Kim, B.G.; Hwang, Y.G.; Choi, J.H.; Park, H.J.; Lee, B.S.; Lee, I.Y. (2022). Development of Loreclezole Derivatives K31565 and K31567 Having Highly Selective Algicidal Effects. Weed & Turfgrass Science , 11 , 261-275. Kim, J.-S.; Kim, J.-C.; Lee, S., Lee, B.-H.; Cho, K.Y. (2006). Biological activity of L-2-azetidinecarboxylic acid, isolated from Polygonatum odoratum var. pluriflorum, against several algae. Aquatic Botany , 85 ,1-6. Kosmalski, T.; Kupczyk, D.; Baumgart, S.; Paprocka, R.; Studzińska, R. (2023). A Review of Biologically Active Oxime Ethers. Molecules , 28 , 5041. Kurasawa, Y. and Kim, H.S. (2009). Synthesis of biologically active pyridazinoquinoxalines. Journal of Heterocyclic Chemistry , 423 , 387-393. Lan, Y.; Chen, Q.; Gou, T.; Sun, K.; Zhang, J.; Sun, D.; Duan, S. (2020). Algicidal Activity of Cyperus rotundus Aqueous Extracts Reflected by Photosynthetic Efficiency and Cell Integrity of Harmful Algae Phaeocystis globosa . Water , 12 , 3256. Lee, M.; Shin, J.; Kim, J.H.; Lim, Y.K.; Cho, H.; Baek, S.H. (2018). Selective Algicidal Effects of a Newly Developed GreenTD against Red Tide Harmful Alga. Korean Journal of Environmental Biology , 36 , 359-369. Lichtenthaler H.K. (1987). Chlorophylls and carotenoids: Pigments of photosynthetic biomembranes. Methods in Enzymology , 148 , 350-382 Matthijs, H.C.P.; Jančula, D.; Visser, P.M.; Maršálek, B. (2016). Existing and emerging cyanocidal compounds: new perspectives for cyanobacterial bloom mitigation. Aquatic Ecology , 50 , 443-460. Park, K.S.; Choi, D.; Son, H.K.; Chang, Y.-C.; Cho, H. (2023). An Algicidal Agent against Harmful Algae Using Novel N 1 -benzyl-N 3 , N 3 -diethylpropane-1,3-diamine Derivatives. Biotechnology and Bioprocess Engineering , 28 , 215-225. Rastogi, R.P.; Madamwar, D.; Incharoensakdi, A. (2015). Bloom Dynamics of Cyanobacteria and Their Toxins: Environmental Health Impacts and Mitigation Strategies. Frontiers in Microbiology , 6 ,1254. Schwarz, D. and Gross, W. Algae affecting lettuce growth in hydroponic systems. (2004). Journal of Horticultural Science and Biotechnology , 79 , 554-559. Strohmeyer, C. (2008). Aquarium algae control; brown diatom, hair, marine, BBA, green spot & water. https://www.aquarium-pond-answers.com/2008/04/aquarium-algae.html (Accessed Sept. 5, 2023). Sun, R.; Sun, P.; Zhang, J.; Esquivel-Elizondo, S.; Wu, Y. (2018). Microorganisms-based methods for harmful algal blooms control: A review. Bioresource Technology , 248 , 12-20. Yue, Q.; He, X.; Yan, N.; Tian, S.; Liu, C.; Wang, W.-X.; Luo, L.; Tang, B.Z. (2021). Photodynamic control of harmful algal blooms by an ultra-efficient and degradable AIEgen-based photosensitizer. Chemical Engineering Journal , 417 , 127890. Zhu, X.; Dao, G.; Tao, Y.; Zhan, X; Hu, H. (2021). A review on control of harmful algal blooms by plant-derived allelochemicals. Journal of Hazardous Materials , 401 , 123403. Scheme Scheme 1 is available in the Supplementary Files section. Tables Tables 2 to 7 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files PhenylOximeDerivativesSupplementaryInformation10JournalofAppliedPhycology250902.docx Scheme1.docx Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7558839","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":512817030,"identity":"948d6f2a-089f-4fa3-b20a-da7eb5b02388","order_by":0,"name":"Jun Young Lee","email":"","orcid":"","institution":"Korea Research Institute of Chemical Technology","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"Young","lastName":"Lee","suffix":""},{"id":512817031,"identity":"5cef42e7-17db-467c-aeed-1a713eade34e","order_by":1,"name":"Yeo Jin Kim","email":"","orcid":"","institution":"Korea Research Institute of Chemical Technology","correspondingAuthor":false,"prefix":"","firstName":"Yeo","middleName":"Jin","lastName":"Kim","suffix":""},{"id":512817032,"identity":"7712a068-9286-4919-887e-02594b43678a","order_by":2,"name":"Bong Gyu Choi","email":"","orcid":"","institution":"Korea Research Institute of Chemical Technology","correspondingAuthor":false,"prefix":"","firstName":"Bong","middleName":"Gyu","lastName":"Choi","suffix":""},{"id":512817033,"identity":"af0801ca-0fcd-4118-b33b-d440f310067e","order_by":3,"name":"Jin-Seog Kim","email":"","orcid":"","institution":"Korea Research Institute of Chemical Technology","correspondingAuthor":false,"prefix":"","firstName":"Jin-Seog","middleName":"","lastName":"Kim","suffix":""},{"id":512817034,"identity":"cee67630-8218-4282-896a-e24c7a11fe74","order_by":4,"name":"Hasoo Seong","email":"","orcid":"","institution":"Korea Research Institute of Chemical Technology","correspondingAuthor":false,"prefix":"","firstName":"Hasoo","middleName":"","lastName":"Seong","suffix":""},{"id":512817035,"identity":"a12e3658-b82a-410d-ba66-8f4b6ab042d2","order_by":5,"name":"Chul Min Park","email":"","orcid":"","institution":"Korea Research Institute of Chemical Technology","correspondingAuthor":false,"prefix":"","firstName":"Chul","middleName":"Min","lastName":"Park","suffix":""},{"id":512817036,"identity":"3a00ae02-a892-47f4-a6c0-5470b2c190c1","order_by":6,"name":"Hyun Suk Yeom","email":"","orcid":"","institution":"Korea Research Institute of Chemical Technology","correspondingAuthor":false,"prefix":"","firstName":"Hyun","middleName":"Suk","lastName":"Yeom","suffix":""},{"id":512817037,"identity":"a05516bd-e7eb-4302-ad39-64e000e1f261","order_by":7,"name":"Seok Ki Min","email":"","orcid":"","institution":"Korea Testing \u0026 Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Seok","middleName":"Ki","lastName":"Min","suffix":""},{"id":512817038,"identity":"8db7e671-bdf1-461e-9e70-83d1ca01385e","order_by":8,"name":"Hyeung-geun Park","email":"","orcid":"","institution":"Seoul National University","correspondingAuthor":false,"prefix":"","firstName":"Hyeung-geun","middleName":"","lastName":"Park","suffix":""},{"id":512817039,"identity":"18fac59c-b022-43d3-84d0-09b65ba6ad48","order_by":9,"name":"Joon-Ho Lee","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuUlEQVRIie3PMQqDMBTG8U8eOAVcHQq9gtKlhUKvkiI4BTp0cQy4eoCUFryKEHDyAE49Q0aHDlXQOW8sNP8pgfx4L0Ao9INFBgTXQax3ySORWUjMJUhBJLr5wCb01HQ4D+9d0urYOZQ3/2Kvjgo13kXagx4G6qS9xEiyykmRxcuGqDL/lIUcN/LhkgLjSgDFI3kzyPkv1zpqstJP8pmkUy8vSW0tpqpgEJ24baAG/ADYM96EQqHQv/cFuakx0xNmM6oAAAAASUVORK5CYII=","orcid":"","institution":"Korea Research Institute of Chemical Technology","correspondingAuthor":true,"prefix":"","firstName":"Joon-Ho","middleName":"","lastName":"Lee","suffix":""}],"badges":[],"createdAt":"2025-09-08 00:38:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7558839/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7558839/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91544396,"identity":"7edbe495-88cd-463c-b1f7-e275944d7171","added_by":"auto","created_at":"2025-09-17 14:34:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23665,"visible":true,"origin":"","legend":"\u003cp\u003eDesign of oxime derivatives containing novel moieties.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7558839/v1/3ed0e1bce21787ac0f1059dd.png"},{"id":91544398,"identity":"1b53b3d5-49c4-4a3d-bbca-f7f432931b54","added_by":"auto","created_at":"2025-09-17 14:34:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":142853,"visible":true,"origin":"","legend":"\u003cp\u003eAlgicidal spectra of \u003cstrong\u003eKH08\u003c/strong\u003e. Effect of \u003cstrong\u003eKH08\u003c/strong\u003e on (A) green microalgae and (B) cyanobacteria. For comparison, the algicidal spectra of glutaraldehyde against (C) green microalgae and (D) cyanobacteria. Full names of all the microalgae species shown in these graphs are listed in Table 1.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7558839/v1/52b9a94761310f06122ecc3f.png"},{"id":92630746,"identity":"7b395d8d-e1b2-4443-9ae5-2f8e417ec14f","added_by":"auto","created_at":"2025-10-02 03:08:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1605199,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7558839/v1/32e066d4-8273-4a9d-a29b-14084be98bcc.pdf"},{"id":91545407,"identity":"0798d1c0-010e-4ed7-92d5-dc6040b3d4bc","added_by":"auto","created_at":"2025-09-17 14:42:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":8124897,"visible":true,"origin":"","legend":"","description":"","filename":"PhenylOximeDerivativesSupplementaryInformation10JournalofAppliedPhycology250902.docx","url":"https://assets-eu.researchsquare.com/files/rs-7558839/v1/e23050b37fb46ea92d6b0a7b.docx"},{"id":91545760,"identity":"9db2ea46-d812-40d6-9761-b22201ed834f","added_by":"auto","created_at":"2025-09-17 14:50:31","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":50780,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7558839/v1/28d0399c5aaedd6d9ede1cf2.docx"},{"id":91544397,"identity":"80345e07-c928-453a-a023-b34ae5dd82e8","added_by":"auto","created_at":"2025-09-17 14:34:31","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":47247,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7558839/v1/219d4afaef35e32aa33e72f6.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Selective phenyl-oxime algicides with low non-target acute toxicity: efficacy against green microalgae vs glutaraldehyde","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAlgal blooms are a natural phenomenon in aquatic environments. But, they are classified as harmful algal blooms when they negatively impact ecosystems (Lan et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Occurrences of HABs worldwide have increased due to eutrophication caused by anthropogenic activities, including discharges of agricultural sewage and industrial waste, port development, and aquaculture expansion (Heisler et al. \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). The mass proliferation of some harmful algae may cause the death of marine life through resource competition, and toxic HAB species can be absorbed by aquatic organisms, including shellfish, producing toxins that pose significant threats to human health (Harrison et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2017\u003c/span\u003e, Furuya et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). For instance, \u003cem\u003eMicrocystis\u003c/em\u003e and \u003cem\u003eAphanizomenon\u003c/em\u003e, produce the toxins microcystin and saxitoxin, respectively, while \u003cem\u003eAnabaena\u003c/em\u003e and \u003cem\u003eOscillatoria\u003c/em\u003e produce anatoxin and microcystin (Jeon et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Microcystin exposure in humans can result in allergic reactions, vomiting, inflammation, liver cirrhosis, visual impairment, and kidney and liver damage (Ding et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e1998\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eA long-term strategy for controlling HABs involves reducing nutrient inputs into aquatic ecosystems. Rapid and effective inhibition of the growth of HABs has often been achieved through physical, biological, and chemical methods (Sun et al. \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2018\u003c/span\u003e, Jančula et al. 2011, Gallardo-Rodr\u0026iacute;guez et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2019\u003c/span\u003e, Yue et al. \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Physical methods such as coagulation, sonication, isolation, and salvage, are more commonly applied in freshwater systems than saltwater systems (Gallardo-Rodr\u0026iacute;guez et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Recent research on HABs has focused on environmentally friendly control methods that target harmful species without adversely affecting other aquatic organisms or the environment. One promising approach is the use of biological controls, such as bacteria, which can inhibit algal growth via physical association or production of algicidal compounds (Coyne et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eVarious chemical methods are employed to control HABs, including the application of commercial chemicals like copper sulfate and herbicides over large areas (Jančula et al. 2011). The use of copper ions to kill algae is affected by ionic conductivity, alkalinity, and pH, but the process is slow and can lead to environmental hazards, such as copper accumulation (Matthijs et al. \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Although herbicides are effective in controlling HABs, their use in drinking or aquaculture waters is greatly restricted due to the risk of unwanted secondary contamination (Giacomazzi et al. 2004). Many studies have attempted to utilize low molecular weight substances derived from natural products to remove harmful algae, but their use is limited due to low economic feasibility (Balaji Prasath et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2022\u003c/span\u003e, Gil et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2021\u003c/span\u003e, Kim et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2006\u003c/span\u003e, Rastogi et al. \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2015\u003c/span\u003e, Zhu et al. \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In addition, novel organic substances, derived from pyridazinoquinoline, thiazolidinedione, triazole, N\u003csup\u003e1\u003c/sup\u003e-benzyl-N\u003csup\u003e3\u003c/sup\u003e, and N\u003csup\u003e3\u003c/sup\u003e-diethylpropane-1,3-diamine have been synthesized and their algicidal activities investigated (Kurasawa et al. 2009, Lee et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2018\u003c/span\u003e, Cho et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2021\u003c/span\u003e, Kim et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2022\u003c/span\u003e, Park et al. \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2023\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe development of plant factories or smart farms aims to produce food more safely, but the concentration of nutrients in urban environments can promote the growth of microalgae and mosses, reducing crop productivity under sunny conditions (Schwarz et al. 2004). As public awareness of safety requirements and environmental protection increases, there is a demand for algicides that meet the new standards. In addition to being able to control problematic microorganisms efficiently, these novel algicides must be safer than existing compounds, especially when used near human residences and living spaces.\u003c/p\u003e\u003cp\u003eCurrent algicides used recently include products containing copper or silver, ozone, hypochlorous acid, and glutaraldehyde, all of which contain risks to crops or users. Therefore, novel replacements are required (Jeon et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2015\u003c/span\u003e, Balaji Prasath et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2022\u003c/span\u003e, Strohmeyer \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). Algicides used in domestic environments must have excellent efficacy and a relatively low impact on non-target organisms. Algicidal chemicals used in environments that people are likely to frequent, must have lower toxicity to humans and wildlife than those used to control algal growth in agricultural settings, rivers, and lake (Kim et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn this study, we synthesized various compounds through structural modification of phenyl oxime derivatives and explored the corresponding changes in their biological activities. Furthermore, we examined the potential of these newly synthesized compounds to replace currently used algicides.\u003c/p\u003e\u003cp\u003eOxime ethers are a class of compounds that can be described by the general formula: R(R\u003csup\u003e1\u003c/sup\u003e)\u0026thinsp;\u0026gt;\u0026thinsp;C\u0026thinsp;=\u0026thinsp;N-O-R\u003csup\u003e2\u003c/sup\u003e. The oxime ether moiety affects the biological activity of the compounds. Various biological activities, including bactericidal, fungicidal, antidepressant, anticancer, and herbicidal activities, have been reported for such compounds (Kosmalski et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2023\u003c/span\u003e, Cui et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Despite the diverse biological activities of oxime compounds, their efficacy against microalgae has not been previously studied. Therefore, we synthesized a series of novel phenyl oxime derivatives and investigated the relationship between their structure and algicidal activity.\u003c/p\u003e\u003cp\u003eThe structures of the phenyl oxime derivatives designed and synthesized in this study were inspired by the structure of loreclezole, a compound whose algicidal efficacy has been previously studied (Kim et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2021\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). We introduced an oxime group to the olefin site of loreclezole and modified the phenyl group to diphenyl. Additionally, the triazole was modified by changing the number or position of the nitrogen atoms while retaining a five-membered heterocyclic ring structure.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003e\u003cb\u003eMaterials and Instruments.\u003c/b\u003e All reagents and solvents used in experiments were supplied from the commercial suppliers like Sigma-Aldrich (Burlington, USA), Alfa Aesar (Ward Hill, USA), TCI (Tokyo, Japan), Combi-Blocks (San Diego, USA) and Angene (Nanjing, China) and they were used without further purification. The organic solvents remaining in synthetic reaction mixture were evaporated by using the B\u0026uuml;chi rotary evaporator (R300, Flawil, Switzerland) under low pressure and appropriate temperature.\u003c/p\u003e\u003cp\u003eSynthesis of the reaction product in the reaction process was confirmed through Thin Layer Chromatography (TLC, silica gel 60 F254 plate, Merck, Darmstadt, Germany), and the synthesized compound was purified through column chromatography by using 230\u0026ndash;400 mesh silica gel (Merck, Darmstadt, Germany).\u003c/p\u003e\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eH NMR and \u003csup\u003e13\u003c/sup\u003eC NMR spectra of the purified compounds were obtained by Bruker Avance (Billerica, USA) 300 MHz Spectrometer or 400 MHz Spectrometer or 500 MHz Spectrometer. The CDCl\u003csub\u003e3\u003c/sub\u003e and (CD\u003csub\u003e3\u003c/sub\u003e)\u003csub\u003e2\u003c/sub\u003eSO having characteristic \u003csup\u003e1\u003c/sup\u003eH NMR peak of 7.26 and 2.50 ppm, respectively, were used as NMR solvent which were obtained from Cambridge Isotope Laboratories, Inc (Tewksbury, USA) or Zeotope (R\u0026uuml;ti, Switzerland). Chemical shifts are provided in ppm (δ) from downfield from tetramethylsilane (internal standard) with coupling constants in hertz (Hz). Multiplicity is indicated by the following abbreviations: singlet (s), doublet (d), doublet of doublet (dd), doublet of triplet (dt), doublet of multiplet (dm), triplet (t), triplet of doublet (td), triplet of triplet (tt), quartet (q), quartet of doublet (qd), quartet of triplet (qt), multiplet (m) and broad (br).\u003c/p\u003e\u003cp\u003eMass spectrometry of the purified compound was determined by using high-resolution mass spectrometer (Agilent, Santa Clara, USA). Melting points were measured by Mettler Toledo MP50 instrument.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSynthesis.\u003c/b\u003e \u003cem\u003eSynthesis of 2-bromo-1-(4'-bromo-[1,1'-biphenyl]-4-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e2\u003c/b\u003e. To a solution of 4-bromobiphenyl, \u003cb\u003e1\u003c/b\u003e (1000 mg, 4.29 mmol) in dichloromethane the bromoacetyl bromide (0.39 mL, 4.54 mmol) was slowly added. Then, the reaction mixture was cooled with ice bath to 0 \u003csup\u003eo\u003c/sup\u003eC and aluminum chloride (686 mg, 5.14 mmol) was poured into reaction mixture. The mixture was stirred at rt for 20 h. After reaction was completed, the mixture was poured into a saturated aqueous NaHCO\u003csub\u003e3\u003c/sub\u003e solution and extracted with ethyl acetate. The combined organic layer was dried with anhydrous MgSO\u003csub\u003e4\u003c/sub\u003e, filtered and concentrated \u003cem\u003ein vacuo\u003c/em\u003e. The solid crude product was purified by column chromatography on silica gel using ethyl acetate/hexane (1/50\u0026thinsp;~\u0026thinsp;1/2) as eluent to give 2-bromo-1-(4'-bromo-[1,1'-biphenyl]-4-yl)ethan-1-one, \u003cb\u003e2\u003c/b\u003e as white solid (1.22 g, 80%). m.p.: 140\u0026ndash;145 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.06 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 7.64 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;26.7, 8.1 Hz, 4H), 7.49 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 4.47 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 190.94, 145.47, 138.57, 133.05, 132.31, 129.80, 128.96, 127.40, 123.10, 30.86.; HRMS (FAB) for C\u003csub\u003e14\u003c/sub\u003eH\u003csub\u003e10\u003c/sub\u003eBr\u003csub\u003e2\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 352.9171; found, 352.9169 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003eSynthesis of 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e3\u003c/b\u003e. The 2-bromo-1-(4'-bromo-[1,1'-biphenyl]-4-yl)ethan-1-one, \u003cb\u003e2\u003c/b\u003e (87 mg, 0.24 mmol) and 1\u003cem\u003eH\u003c/em\u003e-1,2,4-triazole (25 mg, 0.36 mmol) were dissolved in toluene. The sodium bicarbonate (30 mg, 0.36 mmol) was poured into the reaction mixture. The mixture was heated at 120 \u003csup\u003eo\u003c/sup\u003eC and stirred 17 h. After reaction was completed, the mixture was poured into water and brine, extracted with dichloromethane. Combined organic layer was dried over MgSO\u003csub\u003e4\u003c/sub\u003e and filtered, concentrated \u003cem\u003ein vacuo\u003c/em\u003e. The solid crude product was purified by column chromatography on silica gel using methanol/dichloromethane (1/19\u0026thinsp;~\u0026thinsp;1/9) as eluent to give 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one, \u003cb\u003e3\u003c/b\u003e as white solid (56 mg, 68%). m.p.: 210\u0026ndash;220 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.14 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.3 Hz, 2H), 8.04 (s, 1H), 7.91 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.3 Hz, 2H), 7.74 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.7 Hz, 4H), 6.03 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 192.12, 151.33, 145.67, 144.04, 137.79, 133.28, 132.02, 129.16, 128.92, 127.02, 122.23, 55.23.; HRMS (FAB) for C\u003csub\u003e16\u003c/sub\u003eH\u003csub\u003e12\u003c/sub\u003eBrN\u003csub\u003e3\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 342.0237; found, 342.0250 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003eSynthesis of 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-pyrazol-1-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e4\u003c/b\u003e. The 2-bromo-1-(4'-bromo-[1,1'-biphenyl]-4-yl)ethan-1-one, \u003cb\u003e2\u003c/b\u003e (100 mg, 0.28 mmol) and 1,2-diazole (23 mg, 0.33 mmol) were dissolved in DMF. The potassium carbonate (117 mg, 0.84 mmol) was slowly poured into the reaction mixture. The reaction mixture was heated at 80 \u003csup\u003eo\u003c/sup\u003eC and stirred for 19 h. After the reaction was completed, the reaction mixture was poured into water and brine, extracted with dichloromethane. Extracted organic layer was dried over MgSO\u003csub\u003e4\u003c/sub\u003e and filtered, concentrated \u003cem\u003ein vacuo\u003c/em\u003e. The solid crude product was purified by column chromatography on silica gel using methanol/dichloromethane (1/19\u0026thinsp;~\u0026thinsp;1/9) as eluent to give 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1\u003cem\u003eH\u003c/em\u003e-pyrazol-1-yl)ethan-1-one, \u003cb\u003e4\u003c/b\u003e as white solid (56 mg, 58%). m.p.: 180\u0026ndash;190 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.05 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 7.68 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 7.64\u0026ndash;7.58 (m, 3H), 7.54 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.4 Hz, 1H), 7.49 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 2H), 6.39 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.2 Hz, 1H), 5.64 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 192.06, 145.62, 140.15, 138.57, 133.63, 132.34, 131.10, 129.02, 128.98, 127.52, 123.13, 106.82, 57.84.; HRMS (FAB) for C\u003csub\u003e17\u003c/sub\u003eH\u003csub\u003e13\u003c/sub\u003eBrN\u003csub\u003e2\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 341.0284; found, 341.0287 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-imidazol-1-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e5\u003c/b\u003e. White solid, yield 79%, m.p.: 220\u0026ndash;230 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (300 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.07\u0026ndash;8.02 (m, 2H), 7.75\u0026ndash;7.69 (m, 2H), 7.65\u0026ndash;7.60 (m, 2H), 7.55\u0026ndash;7.47 (m, 3H), 7.16 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.1 Hz, 1H), 6.97 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.3 Hz, 1H), 5.43 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 193.17, 143.81, 138.33, 137.85, 133.58, 132.03, 129.13, 128.77, 127.88, 126.96, 122.19, 120.91, 52.62.; HRMS (FAB) for C\u003csub\u003e17\u003c/sub\u003eH\u003csub\u003e13\u003c/sub\u003eBrN\u003csub\u003e2\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 341.0284; found, 341.0287 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e6\u003c/b\u003e. White solid, yield 34%, m.p.: 235\u0026ndash;240 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 8.16 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 8.12 (s, 1H), 7.92 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 7.81 (s, 1H), 7.78\u0026ndash;7.68 (m, 4H), 6.25 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 191.79, 144.08, 137.80, 133.26, 133.24, 132.04, 129.17, 128.97, 127.02, 126.53, 122.25, 55.64.; HRMS (FAB) for C\u003csub\u003e16\u003c/sub\u003eH\u003csub\u003e12\u003c/sub\u003eBrN\u003csub\u003e3\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 342.0237; found, 342.0242 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e7\u003c/b\u003e. White solid, yield 28%, m.p.: 205\u0026ndash;210 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (300 MHz, DMSO) δ 8.15\u0026ndash;8.09 (m, 2H), 7.90 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.2 Hz, 4H), 7.78\u0026ndash;7.69 (m, 4H), 6.29 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 192.22, 144.07, 137.83, 135.02, 133.31, 132.03, 129.19, 129.01, 127.01, 122.24, 60.42.; HRMS (FAB) for C\u003csub\u003e16\u003c/sub\u003eH\u003csub\u003e12\u003c/sub\u003eBrN\u003csub\u003e3\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 342.0237; found, 342.0285 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-tetrazol-1-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e8\u003c/b\u003e. White solid, yield 36.6%, m.p.: 210\u0026ndash;220 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 9.39 (s, 1H), 8.16 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 7.94 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 7.79\u0026ndash;7.70 (m, 4H), 6.40 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 190.84, 145.29, 144.32, 137.72, 132.87, 132.05, 129.19, 129.06, 127.07, 122.32, 53.99.; HRMS (FAB) for C\u003csub\u003e15\u003c/sub\u003eH\u003csub\u003e11\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 343.0189; found, 343.0181 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(2H-tetrazol-2-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e9\u003c/b\u003e. White solid, yield 29%, m.p.: 205\u0026ndash;210 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (300 MHz, DMSO) δ 9.09 (s, 1H), 8.17\u0026ndash;8.13 (m, 2H), 7.96\u0026ndash;7.92 (m, 2H), 7.80\u0026ndash;7.71 (m, 4H), 6.72 (s, 2H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 190.78, 153.52, 144.42, 137.75, 132.85, 132.05, 129.22, 129.19, 127.07, 122.34, 58.71. HRMS (FAB) for C\u003csub\u003e15\u003c/sub\u003eH\u003csub\u003e11\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 343.0189; found, 343.0191 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003eSynthesis of 1-(4-bromophenyl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e11\u003c/b\u003e. The 4-bromophenacyl bromide, \u003cb\u003e10\u003c/b\u003e (1000 mg, 3.6 mmol) and 1,2,4-triazole (273 mg, 3.96 mmol) were dissolved with acetone (7.2 mL). The reaction mixture was cooled with ice bath to 0 \u003csup\u003eo\u003c/sup\u003eC and the triethylamine (0.552 mL, 3.96 mmol) was slowly added. The reaction mixture was stirred at rt for 17 h. After the reaction was completed, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was combined and dried over MgSO\u003csub\u003e4\u003c/sub\u003e and filtered, concentrated in vacuo. The solid crude product was purified by column chromatography on silica gel using methanol/dichloromethane (1/24\u0026thinsp;~\u0026thinsp;1/9) as eluent to give 1-(4-bromophenyl)-2-(1\u003cem\u003eH\u003c/em\u003e-1,2,4-triazol-1-yl)ethan-1-one, \u003cb\u003e11\u003c/b\u003e as white solid (541 mg, 56.5%). m.p.: 180\u0026ndash;186 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.24 (s, 1H), 8.02 (s, 1H), 7.88\u0026ndash;7.83 (m, 2H), 7.73\u0026ndash;7.67 (m, 2H), 5.64 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 191.97, 151.32, 145.59, 133.21, 132.07, 130.10, 128.33, 55.18.; HRMS (FAB) for C\u003csub\u003e10\u003c/sub\u003eH\u003csub\u003e8\u003c/sub\u003eBrN\u003csub\u003e3\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 265.9924; found, 265.9925 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003eSynthesis of 1-(2'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e12\u003c/b\u003e. The 1-(4-bromophenyl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one, \u003cb\u003e11\u003c/b\u003e (100 mg, 0.376 mmol) and 2-bromophenylboronic acid (91 mg, 0.451 mmol) were dissolved in dimethyl acetamide (1 mL) and water (1 mL). Then, the tetrakis(triphenylphosphine)palladium (43.5 mg, 0.0376 mmol) and sodium carbonate (120 mg, 1.128 mmol) were added. The reaction mixture was heated at 100 \u003csup\u003eo\u003c/sup\u003eC and stirred for 20 h. After the reaction was completed, the mixture was filtered through celite and dissolved in water. The mixture was extracted ethyl acetate several times. The combined organic layer was dried over MgSO\u003csub\u003e4\u003c/sub\u003e and filtered, concentrated \u003cem\u003ein vacuo\u003c/em\u003e. The solid crude product purified by column chromatography on silica gel using methanol/dichloromethane (1/24\u0026thinsp;~\u0026thinsp;1/9) as eluent to give 1-(2'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one, \u003cb\u003e12\u003c/b\u003e as white solid (104.8 mg, 81%). m.p.: 200\u0026ndash;210 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 8.53 (s, 1H), 8.14 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 8.04 (s, 1H), 7.79 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.0, 1.2 Hz, 1H), 7.63 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 7.54\u0026ndash;7.50 (m, 1H), 7.45 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.7, 1.9 Hz, 1H), 7.39 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.7, 1.9 Hz, 1H), 6.05 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 192.24, 151.34, 145.87, 140.72, 133.35, 133.13, 131.26, 130.09, 129.85, 128.15, 128.04, 121.35, 55.26.; HRMS (FAB) for C\u003csub\u003e16\u003c/sub\u003eH\u003csub\u003e12\u003c/sub\u003eBrN\u003csub\u003e3\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 342.0237; found, 342.0236 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003eSynthesis of 1-(3'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e13\u003c/b\u003e. White solid, yield 72%, m.p.: 170\u0026ndash;175 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.14 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 2H), 8.04 (s, 1H), 7.99 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.9 Hz, 1H), 7.94 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 2H), 7.80 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.0, 1.3 Hz, 1H), 7.65 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.0, 2.0, 0.9 Hz, 1H), 7.48 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.9 Hz, 1H), 6.04 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 192.16, 151.32, 145.63, 143.67, 141.04, 133.50, 131.25 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11.3 Hz), 129.64, 128.86, 127.34, 126.20, 122.55, 55.25.; HRMS (FAB) for C\u003csub\u003e16\u003c/sub\u003eH\u003csub\u003e12\u003c/sub\u003eBrN\u003csub\u003e3\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 342.0237; found, 342.1041 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e2-(1H-1,2,4-triazol-1-yl)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e14\u003c/b\u003e. White solid, yield 71%, m.p.: 150\u0026ndash;155 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 8.21\u0026ndash;8.14 (m, 2H), 8.08 (s, 1H), 8.01 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 7.99\u0026ndash;7.96 (m, 2H), 7.87 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 2H), 6.06 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 192.18, 151.12, 145.59, 143.73, 142.68, 133.80, 128.97, 127.98, 127.60, 125.95 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.7 Hz), 125.60, 122.90, 55.38.; HRMS (FAB) for C\u003csub\u003e17\u003c/sub\u003eH\u003csub\u003e12\u003c/sub\u003eF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 332.1005; found, 332.1021 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e1-(2'-methyl-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e15\u003c/b\u003e. White solid, yield 90%, m.p.: 90\u0026ndash;95 \u003csup\u003eo\u003c/sup\u003eC. \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 8.17\u0026ndash;8.10 (m, 2H), 8.08 (s, 1H), 7.60\u0026ndash;7.55 (m, 2H), 7.34 (dq, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.1, 1.9 Hz, 2H), 7.30 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.0, 2.5 Hz, 1H), 7.27\u0026ndash;7.23 (m, 1H), 6.05 (s, 2H), 2.26 (s, 3H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 192.65, 151.56, 147.51, 140.53, 135.16, 133.19, 131.04, 130.08, 129.83, 128.65, 128.55, 126.61, 55.76, 20.55.; HRMS (FAB) for C\u003csub\u003e17\u003c/sub\u003eH\u003csub\u003e15\u003c/sub\u003eN\u003csub\u003e3\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 278.1288; found, 278.1293 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e16\u003c/b\u003e. Yellow solid, yield 80%, m.p.: 170\u0026ndash;175 \u003csup\u003eo\u003c/sup\u003eC. \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.16\u0026ndash;8.11 (m, 2H), 8.04 (s, 1H), 7.91\u0026ndash;7.87 (m, 2H), 7.87\u0026ndash;7.82 (m, 2H), 7.38\u0026ndash;7.32 (m, 2H), 6.03 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 192.10, 163.76, 161.31, 151.31, 145.63, 144.31, 135.10 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.2 Hz), 129.23 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz), 128.88, 127.02, 115.99 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;21.3 Hz), 55.23.; HRMS (FAB) for C\u003csub\u003e16\u003c/sub\u003eH\u003csub\u003e12\u003c/sub\u003eFN\u003csub\u003e3\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 282.1037; found, 282.1037 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e1-(2'-chloro-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one\u003c/em\u003e \u003cb\u003e17\u003c/b\u003e. Yellow solid, yield 95%, m.p.: 100\u0026ndash;110 \u003csup\u003eo\u003c/sup\u003eC. \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.17\u0026ndash;8.13 (m, 2H), 8.12 (s, 1H), 7.70\u0026ndash;7.65 (m, 2H), 7.61 (ddt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.9, 3.7, 1.9 Hz, 1H), 7.48 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.8 Hz, 3H), 6.07 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 192.17, 158.38 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;38.2 Hz), 150.85, 145.52, 144.24, 138.68, 133.37, 131.40, 131.16, 130.19\u0026ndash;129.78 (m), 128.15, 127.73, 55.44.; HRMS (FAB) for C\u003csub\u003e16\u003c/sub\u003eH\u003csub\u003e12\u003c/sub\u003eClN\u003csub\u003e3\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 298.0742; found, 298.0742 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003eSynthesis of (E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one oxime\u003c/em\u003e \u003cb\u003eKH01\u003c/b\u003e. 1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one, \u003cb\u003e3\u003c/b\u003e (50 mg, 0.14 mmol) was added to the reaction mixture which consist of hydroxylamine (0.1 mL, 1.46 mmol), PPTS (3.67 mg, 10 mol%) and EtOH (1.4 mL, 0.1 M). The mixture was stirred at 90 \u003csup\u003eo\u003c/sup\u003eC for 15 h. Then the mixture was poured into water and extracted with DCM, washed with water and dried with anhydrous MgSO\u003csub\u003e4\u003c/sub\u003e. The solvent was then evaporated under reduced pressure, and the solid crude product was purified by column chromatography on silica gel using methanol/dichloromethane (1/24\u0026thinsp;~\u0026thinsp;1/9) as eluent to give (\u003cem\u003eE\u003c/em\u003e)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1\u003cem\u003eH\u003c/em\u003e-1,2,4-triazol-1-yl)ethan-1-one oxime as white solid (40 mg, 79%). m.p.: 220\u0026ndash;230 \u003csup\u003eo\u003c/sup\u003eC. \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO) δ 12.24 (s, 1H), 8.55 (s, 2H), 7.80 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 7.70 (d, J\u0026thinsp;=\u0026thinsp;8.3 Hz, 2H), 7.65 (s, 4H), 5.44 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO) δ 150.83, 139.57, 138.37, 132.97, 131.88, 128.74, 126.76 (d, J\u0026thinsp;=\u0026thinsp;3.9 Hz), 121.34, 37.69. HRMS (FAB) for C\u003csub\u003e16\u003c/sub\u003eH\u003csub\u003e13\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 357.0346; found, 357.0341 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-methyl oxime\u003c/em\u003e \u003cb\u003eKH02\u003c/b\u003e. White solid, yield 63%, m.p.: 85\u0026ndash;95 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.22 (s, 1H), 7.94 (s, 1H), 7.86\u0026ndash;7.82 (m, 2H), 7.57 (dq, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.1, 2.3 Hz, 4H), 7.47\u0026ndash;7.43 (m, 2H), 5.43 (s, 2H), 4.10 (s, 3H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 150.81, 141.61, 139.18, 132.71, 132.16, 128.77, 127.38, 127.13, 122.29, 63.07, 43.70. HRMS (FAB) for C\u003csub\u003e17\u003c/sub\u003eH\u003csub\u003e15\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 371.0502; found, 371.0503 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-butyl oxime\u003c/em\u003e \u003cb\u003eKH03\u003c/b\u003e. White solid, yield 69%, m.p.: 100\u0026ndash;110 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.20 (s, 1H), 7.93 (s, 1H), 7.87\u0026ndash;7.82 (m, 2H), 7.57 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.8, 2.0 Hz, 4H), 7.45 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.6, 2.0 Hz, 2H), 5.43 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.8 Hz, 2H), 4.30 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.8, 1.7 Hz, 2H), 1.77\u0026ndash;1.70 (m, 2H), 1.46\u0026ndash;1.37 (m, 2H), 0.97 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.5, 1.7 Hz, 3H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.67, 150.34, 144.22, 141.43, 139.23, 133.05, 132.14, 128.75, 127.34, 127.07, 122.23, 75.43, 43.76, 31.35, 19.28, 14.01.; HRMS (FAB) for C\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 413.0972; found, 413.0964 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(tert-butyl) oxime\u003c/em\u003e \u003cb\u003eKH04\u003c/b\u003e. White solid, yield 25%, m.p.: 110\u0026ndash;120 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (300 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.21 (s, 1H), 7.91 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.3 Hz, 2H), 7.88 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.9 Hz, 1H), 7.59 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.6 Hz, 2H), 7.56 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.7 Hz, 2H), 7.47\u0026ndash;7.43 (m, 2H), 5.40 (s, 2H), 1.40 (s, 9H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 149.10, 141.28, 139.34, 133.68, 132.17, 128.76, 127.35, 126.94, 122.21, 81.39, 27.83.; HRMS (FAB) for C\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 413.0972; found, 413.0970 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-allyl oxime\u003c/em\u003e \u003cb\u003eKH05\u003c/b\u003e. White solid, yield 50%, m.p.: 110\u0026ndash;114 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.20 (s, 1H), 7.92 (s, 1H), 7.86\u0026ndash;7.84 (m, 2H), 7.59\u0026ndash;7.56 (m, 4H), 7.46\u0026ndash;7.44 (m, 2H), 6.04 (ddt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17.3, 10.4, 6.0 Hz, 1H), 5.45 (s, 2H), 5.35 (dq, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17.3, 1.5 Hz, 1H), 5.30 (dq, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.4, 1.2 Hz, 1H), 4.79 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.9, 1.3 Hz, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.49, 150.94, 141.49, 139.07, 133.23, 132.68, 132.03, 128.63, 127.24, 127.06, 122.15, 118.96, 76.22, 43.69.; HRMS (FAB) for C\u003csub\u003e19\u003c/sub\u003eH\u003csub\u003e17\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 397.0659; found, 397.0674 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-cyclopropyl methyl oxime\u003c/em\u003e \u003cb\u003eKH06\u003c/b\u003e. White solid, yield 55%, m.p.: 130\u0026ndash;138 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.30 (s, 1H), 7.93 (s, 1H), 7.87 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 7.57 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5, 3.4 Hz, 4H), 7.45 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 2H), 5.45 (s, 2H), 4.11 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.3 Hz, 2H), 1.22 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.5, 3.9 Hz, 1H), 0.65\u0026ndash;0.59 (m, 2H), 0.34 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.1, 4.6 Hz, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 150.32, 141.32, 139.11, 132.93, 132.02, 128.63, 127.22, 126.94, 122.11, 80.24, 43.71, 10.29, 3.23.; HRMS (FAB) for C\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 411.0815; found, 411.0818 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-phenyl oxime\u003c/em\u003e \u003cb\u003eKH07\u003c/b\u003e. White solid, yield 11%, m.p.: 105\u0026ndash;115 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.29 (s, 1H), 7.98 (s, 1H), 7.95 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.7 Hz, 2H), 7.65\u0026ndash;7.61 (m, 2H), 7.61\u0026ndash;7.57 (m, 2H), 7.49\u0026ndash;7.46 (m, 2H), 7.40\u0026ndash;7.36 (m, 2H), 7.32\u0026ndash;7.28 (m, 2H), 7.12 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.0, 6.6 Hz, 1H), 5.66 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 158.79, 153.81, 151.92, 142.33, 139.03, 132.23, 132.10, 129.70, 128.81, 127.71, 127.51, 123.65, 122.50, 115.15, 44.29.; HRMS (FAB) for C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e17\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 433.0659; found, 433.0642 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-benzyl oxime\u003c/em\u003e \u003cb\u003eKH08\u003c/b\u003e. White solid, yield 73%, m.p.: 125\u0026ndash;130 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.09 (s, 1H), 7.91 (s, 1H), 7.85 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 7.57 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4, 1.8 Hz, 4H), 7.47\u0026ndash;7.43 (m, 2H), 7.39 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.0 Hz, 5H), 5.43 (s, 2H), 5.31 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.70, 151.22, 141.61, 139.18, 136.66, 132.78, 132.15, 128.81, 128.78, 128.75, 128.63, 127.34, 127.20, 122.28, 77.68, 43.78.; HRMS (FAB) for C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 447.0815; found, 447.0864 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(2-fluorobenzyl) oxime\u003c/em\u003e \u003cb\u003eKH09\u003c/b\u003e. White solid, yield 44%, m.p.: 135\u0026ndash;140 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.11 (s, 1H), 7.89 (s, 1H), 7.88\u0026ndash;7.83 (m, 2H), 7.57 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 4H), 7.47\u0026ndash;7.42 (m, 2H), 7.37 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;15.5, 7.5 Hz, 2H), 7.19\u0026ndash;7.08 (m, 2H), 5.43 (s, 2H), 5.38 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 162.59, 160.12, 151.61, 151.46, 144.24, 141.67, 139.18, 132.67, 132.15, 131.25 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.0 Hz), 130.66 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz), 128.75, 127.29 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.0 Hz), 124.38 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.7 Hz), 123.95, 123.80, 122.29, 71.29 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.4 Hz), 43.67.; HRMS (FAB) for C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrFN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 465.0721; found, 465.0733 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(3-fluorobenzyl) oxime\u003c/em\u003e \u003cb\u003eKH10\u003c/b\u003e. White solid, yield 48.7%, m.p.: 109\u0026ndash;115 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.21 (s, 1H), 7.96 (s, 1H), 7.86\u0026ndash;7.80 (m, 2H), 7.58 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5, 3.3 Hz, 4H), 7.49\u0026ndash;7.41 (m, 2H), 7.36 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.9, 5.8 Hz, 1H), 7.14 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6 Hz, 1H), 7.10\u0026ndash;7.01 (m, 2H), 5.46 (s, 2H), 5.29 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 164.25, 161.79, 151.45, 141.83, 139.27 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.0 Hz), 139.13, 132.53, 132.19, 130.41 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz), 128.77, 127.33 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17.9 Hz), 124.08 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.9 Hz), 122.37, 115.47 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;21.4, 6.7 Hz), 76.79 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.9 Hz), 43.98.; HRMS (FAB) for C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrFN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 465.0721; found, 465.0733 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(4-fluorobenzyl) oxime\u003c/em\u003e \u003cb\u003eKH11\u003c/b\u003e. White solid, yield 42%, m.p.: 135\u0026ndash;140 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (300 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.07 (s, 1H), 7.90 (s, 1H), 7.87\u0026ndash;7.80 (m, 2H), 7.60\u0026ndash;7.54 (m, 4H), 7.47\u0026ndash;7.42 (m, 2H), 7.39\u0026ndash;7.33 (m, 2H), 7.11\u0026ndash;7.04 (m, 2H), 5.42 (s, 2H), 5.26 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.71, 151.35, 144.21, 141.69, 139.14, 132.68, 132.53 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.3 Hz), 132.16, 130.71 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.3 Hz), 128.75, 127.29 (d, J\u0026thinsp;=\u0026thinsp;17.4 Hz), 122.31, 115.85, 115.63, 43.81.; HRMS (FAB) for C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrFN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 465.0721; found, 465.0720 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(2-chlorobenzyl) oxime\u003c/em\u003e \u003cb\u003eKH12\u003c/b\u003e. White solid, yield 40%, m.p.: 120\u0026ndash;125 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (300 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.14 (s, 1H), 7.90 (s, 1H), 7.88\u0026ndash;7.83 (m, 2H), 7.59\u0026ndash;7.55 (m, 4H), 7.47\u0026ndash;7.41 (m, 3H), 7.41\u0026ndash;7.37 (m, 1H), 7.33\u0026ndash;7.27 (m, 2H), 5.46 (s, 2H), 5.44 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.67, 151.56, 144.32, 141.66, 139.13, 134.46, 134.14, 132.61, 132.14, 130.74, 129.90 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.0 Hz), 128.73, 127.28 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.8 Hz), 127.09, 122.28, 74.76, 43.68.; HRMS (FAB) for C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrClN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 481.0425; found, 481.0426 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(3-chlorobenzyl) oxime\u003c/em\u003e \u003cb\u003eKH13\u003c/b\u003e. White solid, yield 46%, m.p.: 110\u0026ndash;117 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.25 (s, 1H), 7.99 (s, 1H), 7.86\u0026ndash;7.81 (m, 2H), 7.58 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.1, 4.6, 2.2 Hz, 4H), 7.47\u0026ndash;7.43 (m, 2H), 7.36 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.4 Hz, 1H), 7.34\u0026ndash;7.30 (m, 2H), 7.24 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.8, 3.4, 1.6 Hz, 1H), 5.46 (s, 2H), 5.27 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.48, 141.80, 139.10, 138.78, 134.64, 132.50, 132.17, 130.11, 128.76, 128.69 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.9 Hz), 127.32 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.5 Hz), 126.63, 122.34, 76.71, 43.95.; HRMS (FAB) for C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrClN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 481.0425; found, 481.0445 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(4-chlorobenzyl) oxime\u003c/em\u003e \u003cb\u003eKH14\u003c/b\u003e. White solid, yield 35%, m.p.: 158\u0026ndash;161 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (300 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.08 (s, 1H), 7.91 (s, 1H), 7.86\u0026ndash;7.80 (m, 2H), 7.60\u0026ndash;7.54 (m, 4H), 7.47\u0026ndash;7.42 (m, 2H), 7.39\u0026ndash;7.29 (m, 4H), 5.42 (s, 2H), 5.26 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.73, 151.48, 144.21, 141.73, 139.12, 135.22, 134.52, 132.61, 132.16, 130.09, 128.87 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;24.5 Hz), 127.30 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16.1 Hz), 122.32, 76.71, 43.82.; HRMS (FAB) for C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrClN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 481.0425; found, 481.0442 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(3-(trifluoromethyl)benzyl) oxime\u003c/em\u003e \u003cb\u003eKH15\u003c/b\u003e. White solid, yield 38%, m.p.: 90\u0026ndash;95 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (300 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.09 (s, 1H), 7.92 (s, 1H), 7.84\u0026ndash;7.80 (m, 2H), 7.66\u0026ndash;7.60 (m, 2H), 7.59\u0026ndash;7.55 (m, 4H), 7.55\u0026ndash;7.48 (m, 2H), 7.47\u0026ndash;7.42 (m, 2H), 5.45 (s, 2H), 5.35 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.80 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.1 Hz), 144.13, 141.80, 139.09, 137.85, 132.50, 132.16, 131.80, 131.30, 130.98, 129.31, 128.75, 127.33 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.1 Hz), 125.33 (qd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.8, 2.0 Hz), 122.34, 76.61, 43.85. HRMS (FAB) for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 515.0689; found, 515.0689 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(4-(trifluoromethyl)benzyl) oxime\u003c/em\u003e \u003cb\u003eKH16\u003c/b\u003e. White solid, yield 38%, m.p.: 120\u0026ndash;125 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.11 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.4 Hz, 1H), 7.92 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.1 Hz, 1H), 7.83 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4, 1.8 Hz, 2H), 7.64 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.0 Hz, 2H), 7.57 (dq, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5, 1.9 Hz, 4H), 7.45 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.7, 7.9 Hz, 4H), 5.45 (s, 2H), 5.35 (s, 2H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.69 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.2 Hz), 144.06, 141.72, 140.73 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.6 Hz), 138.97, 132.37, 132.05, 130.71, 130.38, 128.56 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.3 Hz), 127.21 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.2 Hz), 125.63 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.7 Hz), 125.38, 122.67, 122.24, 76.42, 43.73.; HRMS (FAB) for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 515.0689; found, 515.0687 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(3-methoxybenzyl) oxime\u003c/em\u003e \u003cb\u003eKH17\u003c/b\u003e. White solid, yield 49%, m.p.: 90\u0026ndash;95 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.28 (s, 1H), 8.00 (s, 1H), 7.88\u0026ndash;7.84 (m, 2H), 7.60\u0026ndash;7.56 (m, 4H), 7.47\u0026ndash;7.44 (m, 2H), 7.31 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.5, 1.2 Hz, 1H), 6.98\u0026ndash;6.95 (m, 1H), 6.90 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6, 1.1 Hz, 2H), 5.45 (s, 2H), 5.29 (s, 2H), 3.82 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 159.94, 150.87, 141.74, 139.10, 138.06, 132.55, 132.16, 129.91, 128.75, 127.40, 127.16, 122.33, 120.96, 114.34, 114.02, 77.67, 55.39, 44.09.; HRMS (FAB) for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e \u003cem\u003em/z\u003c/em\u003e: calculated, 477.0921; found, 477.0930 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-(4-methoxybenzyl) oxime\u003c/em\u003e \u003cb\u003eKH18\u003c/b\u003e. White solid, yield 35%, m.p.: 160\u0026ndash;170 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.06 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.6 Hz, 1H), 7.89 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.6 Hz, 1H), 7.88\u0026ndash;7.84 (m, 2H), 7.57 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.9, 2.9 Hz, 4H), 7.47\u0026ndash;7.43 (m, 2H), 7.34 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.7, 2.7 Hz, 2H), 6.92 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.8, 2.1 Hz, 2H), 5.40 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.6 Hz, 2H), 5.23 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.6 Hz, 2H), 3.83 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.7 Hz, 3H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 159.96, 150.99, 141.52, 139.18, 132.86, 132.13, 130.57, 128.74, 127.33, 127.16, 122.25, 114.17, 77.38, 55.42, 43.77.; HRMS (FAB) for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e \u003cem\u003em/z\u003c/em\u003e: calculated, 477.0921; found, 477.0913 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-pyridin-3-ylmethyl oxime\u003c/em\u003e \u003cb\u003eKH19\u003c/b\u003e. White solid, yield 37%, m.p.: 140\u0026ndash;145 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (300 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.71\u0026ndash;8.65 (m, 1H), 8.61 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.9, 1.7 Hz, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.84\u0026ndash;7.80 (m, 2H), 7.69 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.8, 2.0 Hz, 1H), 7.60\u0026ndash;7.55 (m, 4H), 7.47\u0026ndash;7.42 (m, 2H), 7.33 (ddd, J\u0026thinsp;=\u0026thinsp;7.8, 4.8, 0.9 Hz, 1H), 5.43 (s, 2H), 5.32 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.85, 151.83, 150.06, 149.93, 144.11, 141.80, 139.05, 136.42, 132.42, 132.33, 132.14, 128.73, 127.36, 127.23, 123.71, 122.32, 74.82, 43.77.; HRMS (FAB) for C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrN\u003csub\u003e5\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 448.0767; found, 448.0768 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-pyrazol-1-yl)ethan-1-one O-benzyl oxime\u003c/em\u003e \u003cb\u003eKH20\u003c/b\u003e. White solid, yield 67%, m.p.: 95\u0026ndash;105 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (300 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.83\u0026ndash;7.78 (m, 2H), 7.58\u0026ndash;7.51 (m, 4H), 7.48 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.9, 0.7 Hz, 1H), 7.44 (s, 1H), 7.44\u0026ndash;7.34 (m, 7H), 6.19 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.1 Hz, 1H), 5.46 (s, 2H), 5.33 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 152.46, 141.16, 139.36 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.8 Hz), 137.22, 133.29, 132.08, 130.06, 128.88\u0026ndash;128.51 (m), 128.34, 127.19 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.4 Hz), 122.10, 106.18, 77.29, 46.17.; HRMS (FAB) for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e20\u003c/sub\u003eBrN\u003csub\u003e3\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 446.0863; found, 446.0862 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-imidazol-1-yl)ethan-1-one O-benzyl oxime\u003c/em\u003e \u003cb\u003eKH21\u003c/b\u003e. White solid, yield 64%, m.p.: 120\u0026ndash;130 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.93 (s, 1H), 7.73 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.0 Hz, 2H), 7.56 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.3, 2.0 Hz, 4H), 7.43\u0026ndash;7.40 (m, 2H), 7.40\u0026ndash;7.35 (m, 5H), 7.22 (s, 1H), 7.00 (s, 1H), 5.47 (s, 2H), 5.33 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 149.99, 142.26, 138.78, 136.28, 132.20, 131.38, 129.02\u0026ndash;128.82 (m), 128.73, 127.74, 126.78, 122.53, 121.46, 120.88, 78.07, 42.14.; HRMS (FAB) for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e20\u003c/sub\u003eBrN\u003csub\u003e3\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 446.0863; found, 446.0876 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one O-benzyl oxime\u003c/em\u003e \u003cb\u003eKH22\u003c/b\u003e. White solid, yield 55%, m.p.: 150\u0026ndash;155 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.83 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 2H), 7.62 (s, 1H), 7.54 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.8 Hz, 5H), 7.45\u0026ndash;7.35 (m, 7H), 5.69 (s, 2H), 5.35 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 150.94, 141.65, 139.12, 136.77, 134.19, 132.43, 132.15, 128.81, 128.74, 128.64, 127.34, 127.09, 124.32, 122.29, 77.68, 43.90.; HRMS (FAB) for C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 447.0815; found, 447.0815 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one O-benzyl oxime\u003c/em\u003e \u003cb\u003eKH23\u003c/b\u003e. White solid, yield 76%, m.p.: 130\u0026ndash;135 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 7.68 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.0 Hz, 2H), 7.56 (s, 3H), 7.54\u0026ndash;7.46 (m, 3H), 7.37 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;15.4, 6.8 Hz, 7H), 5.81 (s, 2H), 5.33 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.24, 141.06, 139.33, 137.40, 134.68, 132.99, 132.07, 128.72, 128.54, 128.34, 128.13, 127.24, 127.02, 122.09, 77.23, 48.98.; HRMS (FAB) for C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 447.0815; found, 447.0819 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-tetrazol-1-yl)ethan-1-one O-benzyl oxime\u003c/em\u003e \u003cb\u003eKH24\u003c/b\u003e. White solid, yield 56%, m.p.: 160\u0026ndash;162 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (300 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.53 (s, 1H), 7.87\u0026ndash;7.83 (m, 2H), 7.62\u0026ndash;7.56 (m, 4H), 7.47\u0026ndash;7.43 (m, 2H), 7.43\u0026ndash;7.38 (m, 5H), 5.65 (s, 2H), 5.34 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 149.91, 142.09, 138.94, 136.13, 132.21, 131.88, 129.01, 128.99, 128.76, 127.55, 127.03, 122.47, 78.11, 42.07.; HRMS (FAB) for C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrN\u003csub\u003e5\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 448.0767; found, 448.0782 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(2H-tetrazol-2-yl)ethan-1-one O-benzyl oxime\u003c/em\u003e \u003cb\u003eKH25\u003c/b\u003e. White solid, yield 71%, m.p.: 90\u0026ndash;100 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.44 (s, 1H), 7.74\u0026ndash;7.69 (m, 2H), 7.57\u0026ndash;7.51 (m, 4H), 7.42 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 7.39\u0026ndash;7.31 (m, 5H), 5.97 (s, 2H), 5.32 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 153.11, 149.31, 141.55, 139.11, 136.95, 132.27, 132.14, 128.68 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.0 Hz), 128.39 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.1 Hz), 127.20 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;15.9 Hz), 122.28, 77.53, 46.94.; HRMS (FAB) for C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrN\u003csub\u003e5\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 448.0767; found, 448.0741 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(2'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-benzyl oxime\u003c/em\u003e \u003cb\u003eKH26\u003c/b\u003e. White solid, yield 20%, m.p.: 95\u0026ndash;100 \u003csup\u003eo\u003c/sup\u003eC \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.25 (s, 1H), 7.99 (s, 1H), 7.86 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 7.67 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.0, 1.2 Hz, 1H), 7.45 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 7.38 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.6 Hz, 5H), 7.35 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.2 Hz, 1H), 7.30 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.7, 1.9 Hz, 1H), 7.24\u0026ndash;7.20 (m, 1H), 5.45 (s, 2H), 5.31 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.17, 142.88, 141.78, 136.65, 133.37, 132.76, 131.23, 130.02, 129.23, 128.82 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.5 Hz), 128.65, 127.63, 126.28, 122.51, 77.70, 44.16.; HRMS (FAB) for C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 447.0815; found, 447.0805 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(3'-bromo-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-benzyl oxime\u003c/em\u003e \u003cb\u003eKH27\u003c/b\u003e. White solid, yield 48.9%, m.p.: 90\u0026ndash;95 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.19 (s, 1H), 7.96 (s, 1H), 7.88\u0026ndash;7.85 (m, 2H), 7.73 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.9 Hz, 1H), 7.60\u0026ndash;7.57 (m, 2H), 7.50 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1, 2.0 Hz, 2H), 7.42\u0026ndash;7.37 (m, 5H), 7.33 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.9 Hz, 1H), 5.44 (s, 2H), 5.32 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.08, 142.39, 141.33, 136.59, 132.97, 130.86, 130.54, 130.24, 128.83, 128.68, 127.57, 127.19, 125.82, 123.15, 77.74, 43.88. HRMS (FAB) for C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eBrN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 447.0815; found, 447.0819 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-2-(1H-1,2,4-triazol-1-yl)-1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethan-1-one O-benzyl oxime\u003c/em\u003e \u003cb\u003eKH28\u003c/b\u003e. White solid, yield 46%, m.p.: 90\u0026ndash;100 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.13 (s, 1H), 7.94 (s, 1H), 7.90 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 7.70 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.0 Hz, 4H), 7.63 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.3 Hz, 2H), 7.39 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.9 Hz, 5H), 5.45 (s, 2H), 5.32 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.02, 143.77 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.6 Hz), 141.36, 136.56, 133.29, 128.84 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.5 Hz), 128.71, 127.75, 127.50, 127.27, 125.98 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.8 Hz), 77.80, 43.89.; HRMS (FAB) for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eF\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 437.1584; found, 437.1584 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(2'-methyl-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-benzyl oxime\u003c/em\u003e \u003cb\u003eKH29\u003c/b\u003e. White solid, yield 72%, m.p.: 90\u0026ndash;100 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.09 (s, 1H), 7.92 (s, 1H), 7.84 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 7.40 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.7 Hz, 4H), 7.38\u0026ndash;7.34 (m, 3H), 7.29\u0026ndash;7.27 (m, 2H), 7.24 (q, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.9 Hz, 1H), 7.22\u0026ndash;7.19 (m, 1H), 5.44 (s, 2H), 5.31 (s, 2H), 2.26 (s, 3H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 151.64, 151.45, 144.29, 143.89, 141.07, 136.71, 135.38, 132.02, 130.56, 129.73 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.6 Hz), 128.76 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.4 Hz), 128.58, 127.75, 126.38, 125.99, 77.59, 43.92, 20.55.; HRMS (FAB) for C\u003csub\u003e24\u003c/sub\u003eH\u003csub\u003e22\u003c/sub\u003eN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 383.1866; found, 383.1881 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-benzyl oxime\u003c/em\u003e \u003cb\u003eKH30\u003c/b\u003e. White solid, yield 19%, m.p.: 90\u0026ndash;100 \u003csup\u003eo\u003c/sup\u003eC, \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.17 (s, 1H), 7.95 (s, 1H), 7.85 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 7.59\u0026ndash;7.52 (m, 4H), 7.43\u0026ndash;7.34 (m, 5H), 7.14 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.7 Hz, 2H), 5.44 (s, 2H), 5.31 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 164.13, 161.67, 151.03, 141.95, 136.59, 136.37 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.3 Hz), 132.28, 128.83, 128.73 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.3 Hz), 127.45, 127.11, 115.95 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;21.5 Hz), 77.74, 44.00.; HRMS (FAB) for C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eFN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 387.1616; found, 387.1618 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cem\u003e(E)-1-(2'-chloro-[1,1'-biphenyl]-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one O-benzyl oxime\u003c/em\u003e \u003cb\u003eKH31\u003c/b\u003e. White solid, yield 53%, m.p.: 110\u0026ndash;120 \u003csup\u003eo\u003c/sup\u003eC \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 8.22 (s, 1H), 7.98 (s, 1H), 7.87 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 2H), 7.52\u0026ndash;7.46 (m, 3H), 7.42\u0026ndash;7.35 (m, 5H), 7.34\u0026ndash;7.29 (m, 3H), 5.44 (s, 2H), 5.32 (s, 2H).; \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e) δ 150.95, 150.49, 141.32, 139.69, 136.54, 132.57 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.4 Hz), 131.29, 130.20, 130.09, 129.08, 128.84, 128.71, 127.08, 126.31, 77.80, 44.16.; HRMS (FAB) for C\u003csub\u003e23\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eClN\u003csub\u003e4\u003c/sub\u003eO \u003cem\u003em/z\u003c/em\u003e: calculated, 403.1320; found, 403.1326 [M\u0026thinsp;+\u0026thinsp;H]\u003csup\u003e+\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAssay of algicidal activity against\u003c/b\u003e \u003cb\u003eScenedesmus rotundus\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAlgicidal activity of the synthesized compound was tested in two to three replicates. Activity was tested in a static manner without replacing the test solution during the test period. A 20 mL volume of culture medium containing \u003cem\u003eScenedesmus rotundus\u003c/em\u003e (A1283, FBCC, Sangju, Republic of Korea), subcultured in BG11 sterile medium (pH 7.1) at a concentration of approximately 2.0\u0026ndash;10.0 \u0026times; 10\u003csup\u003e4\u003c/sup\u003e cells/mL media (absorbance less than 0.001 at λ \u003csub\u003emax\u003c/sub\u003e of 680 nm), was dispensed into a 60 mL volumetric cell culture flask. Solutions of the test compound were prepared at concentrations of 0.2, 2.0, and 20 \u0026micro;M using dimethyl sulfoxide (DMSO) containing 2.0% Tween 20. Next, 40 \u0026micro;L of the solution was dispensed into the cell culture flask containing Scero in culture medium. All operations were performed in a sterile room. The final concentrations of DMSO and Tween 20 in this experiment were 0.1% and 20.0 ppm, respectively.\u003c/p\u003e\u003cp\u003eScero treated with the test compound was cultured for 6 days at 25 \u003csup\u003eo\u003c/sup\u003eC with a light intensity of 45\u0026ndash;55 \u0026micro;mol m\u003csup\u003e-2\u003c/sup\u003e s\u003csup\u003e-1\u003c/sup\u003e for 14 h per day. The culture flask was shaken at least three times per day during that period. When the period of culture was completed, the degree of growth inhibition was graded from 0 (no inhibition) to 100 (complete inhibition). The \u003cem\u003ein vivo\u003c/em\u003e chlorophyll (Chl.) absorbances (A680 - A780 nm) of Scero cultures treated with the test compounds, and of untreated controls, were measured using a UV/VIS spectrophotometer (DU800, Bechman Coulter, Brea, CA, USA). The absorbances were converted to a percentage to express the degree of Scero growth inhibition associated with each compound.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAssay of herbicidal activity against\u003c/b\u003e \u003cb\u003eLemna paucicostata\u003c/b\u003e\u003c/p\u003e\u003cp\u003eEvaluations of the herbicidal activity of the synthesized compounds against an aquatic lower plant, duckweed (\u003cem\u003eLemna paucicostata\u003c/em\u003e; hereafter, LEMPA) (PC3034, KCTC, Jeongeup, Republic of Korea), were performed by adding 30 mL of culture medium to a circular transparent plastic cup with an upper diameter of 52 mm, a lower diameter of 36 mm, a height of 60 mm, and a volume of 90 mL. The experiments were conducted in a static manner without replacing the test solution during the test period. Solution of the test compound were prepared at concentrations of 0.2, 2.0, and 20.0 \u0026micro;M using DMSO containing 2.0% Tween 20. Next, 60 \u0026micro;L of each test solution was dispensed into a plastic cup containing 30 mL of basic culture medium (1x mDM, pH 7.6). Afterwards, five LEMPA plants at the 3.9\u0026ndash;4.1 frond growth stage, which had been subcultured in the plant growth room, were inoculated into the test solution. Each container containing test solution and LEMPA was placed in a rectangular translucent plastic box, supplied with a specific amount of moisture, and covered with a transparent film to prevent moisture evaporation. Plants treated with the test solution were cultured in a growth room for 6 days at 25 \u003csup\u003eo\u003c/sup\u003eC with a light intensity of 45\u0026ndash;55 \u0026micro;mol m\u003csup\u003e-2\u003c/sup\u003e s\u003csup\u003e-1\u003c/sup\u003e for 14 h per day.\u003c/p\u003e\u003cp\u003eTo evaluate the herbicidal activity of the compound, the growth status and overall condition of the plants were initially examined following cultivation. Next, the number of fronds was determined and the plants collected. Moisture was completely removed from plants by blotting with soft, absorbent paper and their fresh weight was measured. The plants were then immersed in 10 mL methanol for 1 day at room temperature in the dark to extract the pigments. The absorbance of the sample was measured at 470, 652.4, and 665.2 nm using the UV/VIS spectrophotometer. Photosynthetic pigments in the samples were quantified by the Lichtenthaler (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e1987\u003c/span\u003e) method. The inhibitory activity of the test compound against LEMPA growth was expressed as the relative ratio of the amount of photosynthetic pigment in LEMPA treated with the test compound to the amount of photosynthetic pigment in untreated controls.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eAlgicidal activities of KH08 against different algae\u003c/h2\u003e\u003cp\u003eThe algicidal effect of \u003cb\u003eKH08\u003c/b\u003e on various strains of microalgae was measured to obtain an algicidal activity spectrum. This investigation compared \u003cb\u003eKH08\u003c/b\u003e, a compound with excellent algicidal activity against the green alga \u003cem\u003eScenedesmus rotundus\u003c/em\u003e (Scero), with a control compound, glutaraldehyde, which is commonly used as an algicide. The strains of green and cyanobacteria used in this experiment are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Other than using microalgae as test organisms, the methodology was as described above (\u0026ldquo;Assay of algicidal activity against \u003cem\u003eScenedesmus rotundus\u003c/em\u003e\u0026rdquo;).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eStrains of green algae and cyanobacteria used in this study.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGroup\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAbbreviation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eScientific name\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMicrobial bank\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGreen algae\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCv-K\u003c/p\u003e\u003cp\u003eDesar\u003c/p\u003e\u003cp\u003eDesas\u003c/p\u003e\u003cp\u003eRs\u003c/p\u003e\u003cp\u003eScero\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eChlorella vulgaris\u003c/em\u003e (AG10002)\u003c/p\u003e\u003cp\u003e\u003cem\u003eDesmodesmus armatus\u003c/em\u003e (A1320)\u003c/p\u003e\u003cp\u003e\u003cem\u003eDesmodesmus asymmetricus\u003c/em\u003e (A1320)\u003c/p\u003e\u003cp\u003e\u003cem\u003eRaphidocelis subcapitata\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eScenedesmus rotundus\u003c/em\u003e (A1283)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eKCTC\u003c/p\u003e\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eFBCC\u003c/p\u003e\u003cp\u003eFBCC\u003c/p\u003e\u003cp\u003e\u003csup\u003ec\u003c/sup\u003eKTR\u003c/p\u003e\u003cp\u003eFBCC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCyanobacteria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAna\u003c/p\u003e\u003cp\u003eMa-F\u003c/p\u003e\u003cp\u003eMa-K\u003c/p\u003e\u003cp\u003eOsc\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eAnabaena affinis\u003c/em\u003e (AG10008)\u003c/p\u003e\u003cp\u003e\u003cem\u003eMicrocystis aeruginosa\u003c/em\u003e (A68)\u003c/p\u003e\u003cp\u003e\u003cem\u003eMicrocystis aeruginosa\u003c/em\u003e (AG60752)\u003c/p\u003e\u003cp\u003e\u003cem\u003eOscillatoria spp.\u003c/em\u003e (AG10195)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eKCTC\u003c/p\u003e\u003cp\u003eFBCC\u003c/p\u003e\u003cp\u003eKCTC\u003c/p\u003e\u003cp\u003eKCTC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eKCTC: Korean Collection for Type Cultures, Korea Research Institute of Bioscience and Biotechnology, Jeongup, Republic of Korea; \u003csup\u003eb\u003c/sup\u003eFBCC: Freshwater Bioresources Culture Collection, Sangju, Republic of Korea. \u003csup\u003ec\u003c/sup\u003eKTR: Korea Testing \u0026amp; Research Institute, Gwacheon, Republic of Korea. Abbreviation rule. Species abbreviations may include a hyphen followed by a strain-source code: \u0026ldquo;-K\u0026rdquo; = KCTC; \u0026ldquo;-F\u0026rdquo; = FBCC. \u003cem\u003eE.g.\u003c/em\u003e, Ma-F denotes the FBCC strain of the listed \u003cem\u003eMicrocystis aeruginosa\u003c/em\u003e; Cv-K denotes the KCTC strain of the corresponding species.\u003c/p\u003e\u003cp\u003eAll microalgal strains used in this study were obtained from KCTC, FBCC and KTR under their terms of use; no wild collections were performed.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eAcute toxicity tests\u003c/h3\u003e\n\u003cp\u003eAcute toxicity tests of \u003cb\u003eKH08\u003c/b\u003e were conducted on an aquatic invertebrate (water flea, \u003cem\u003eDaphnia magna\u003c/em\u003e), two species of freshwater fish (minnow, \u003cem\u003eOryzias latipes\u003c/em\u003e; zebra fish, \u003cem\u003eDanio rerio\u003c/em\u003e), and a mammal (ICR mouse, \u003cem\u003eMus musculus\u003c/em\u003e).\u003c/p\u003e\u003cp\u003eAcute toxicity tests on \u003cem\u003eD. magna\u003c/em\u003e were conducted using a static method in accordance with the OECD guideline for testing of chemicals 202, \u003cem\u003eDaphnia\u003c/em\u003e sp., Acute Immobilization Test (13 April 2004). The concentrations of \u003cb\u003eKH08\u003c/b\u003e in the test solution were 1, 1.6, 2.6, 4.1, 6.6 and 10.5 mg/L based on 100% \u003cb\u003eKH08\u003c/b\u003e. M4 medium, prepared according to the methodology described in \u0026ldquo;Daphnia sp., Acute Immobilization Test, Annex 3 Elendt M7 and M4 medium\u0026rdquo; (OECD TG 202, 2004-04-13), was used as test water. Potassium dichromate (lot no. MKCQ8035; Sigma-Aldrich) was used as a positive control. The results were expressed as the half maximal effect concentration (EC\u003csub\u003e50\u003c/sub\u003e) and no observed effect concentration (NOEC).\u003c/p\u003e\u003cp\u003eThe effects of compound \u003cb\u003eKH08\u003c/b\u003e on \u003cem\u003eO. latipes\u003c/em\u003e, and \u003cem\u003eD. rerio\u003c/em\u003e were evaluated using a static acute toxicity test. Fish were exposed to three treatments: a negative control (freshwater), a solvent control (0.1 mL acetone/L freshwater), and a test solution (2.0 mg \u003cb\u003eKH08\u003c/b\u003e/L solvent) based on 100% test compound. The results were expressed as the median lethal concentration (LC\u003csub\u003e50\u003c/sub\u003e) of the test compound \u003cb\u003eKH08\u003c/b\u003e after observing mortality and abnormal symptoms of \u003cem\u003eO. latipes\u003c/em\u003e and \u003cem\u003eD. rerio\u003c/em\u003e in each treatment during the test period.\u003c/p\u003e\u003cp\u003eAn acute oral toxicity test of \u003cb\u003eKH08\u003c/b\u003e was performed using ICR mice. \u003cb\u003eKH08\u003c/b\u003e was orally administered to mice at a dose of 2,000 mg/kg body weight (BW) using corn oil as a vehicle. The acute oral toxicity of the compound was represented as the median lethal dose (LD\u003csub\u003e50\u003c/sub\u003e) of the compound after observing the number of fatalities, general toxicity symptoms, and BW changes in the test group receiving the compound.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eChemistry\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe synthetic routes of the phenyl oxime derivatives are described in \u003cstrong\u003eScheme 1\u003c/strong\u003e. There were three synthetic routes for each moiety. In route \u003cstrong\u003eA\u003c/strong\u003e, 4-bromobiphenyl (\u003cstrong\u003e1\u003c/strong\u003e) was used as a starting material. Compound \u003cstrong\u003e2\u003c/strong\u003e was obtained in a good yield through Friedel-Craft acylation reacting with AlCl\u003csub\u003e3\u003c/sub\u003e and bromoacetyl bromide. In the next step, compound \u003cstrong\u003e2\u003c/strong\u003e was reacted with 1\u003cem\u003eH\u003c/em\u003e-1,2,4-triazole in S\u003csub\u003eN\u003c/sub\u003e2 reaction to obtain compound \u003cstrong\u003e3\u003c/strong\u003e in moderate yield. In the final step in route \u003cstrong\u003eA\u003c/strong\u003e, condensation of the ketone in compound \u003cstrong\u003e3\u003c/strong\u003e with various forms of \u003cem\u003eO\u003c/em\u003e-substituted hydroxyl amine gave \u003cstrong\u003eKH01\u003c/strong\u003e-\u003cstrong\u003e19\u003c/strong\u003e in moderate yield.\u003c/p\u003e\n\u003cp\u003eSynthetic route \u003cstrong\u003eB\u003c/strong\u003e was devised to modify the triazole moiety of the target compound. Compound \u003cstrong\u003e2\u003c/strong\u003e was used as the starting material. By reacting compound \u003cstrong\u003e2\u003c/strong\u003e with 1,2-diazole, 1,3-diazole, 1,2,3-triazole, and 1,2,3,4-tetrazole, compounds \u003cstrong\u003e4\u0026nbsp;\u003c/strong\u003eto\u003cstrong\u003e\u0026nbsp;9\u003c/strong\u003e, respectively, were obtained in suitable yields. These intermediates were reacted with \u003cem\u003eO\u003c/em\u003e-benzylhydroxylamine to obtain, \u003cstrong\u003eKH20\u003c/strong\u003e-\u003cstrong\u003e25\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eSynthetic route \u003cstrong\u003eC\u003c/strong\u003e was a method for deriving the biphenyl moiety of the target compound. 2-bromo-1-(4-bromophenyl)ethan-1-one (\u003cstrong\u003e10\u003c/strong\u003e) was used as the starting material. Compound \u003cstrong\u003e10\u003c/strong\u003e was reacted with 1\u003cem\u003eH\u003c/em\u003e-1,2,4-triazole in a S\u003csub\u003eN\u003c/sub\u003e2 reaction to obtain compound \u003cstrong\u003e11\u003c/strong\u003e in good yield. Subsequently, compound \u003cstrong\u003e11\u003c/strong\u003e was used in Pd-catalyzed cross-coupling reactions with various forms of phenyl boronic acid to synthesize compounds \u003cstrong\u003e12\u0026nbsp;\u003c/strong\u003eto\u003cstrong\u003e\u0026nbsp;17\u003c/strong\u003e. Finally, compounds \u003cstrong\u003eKH26\u0026nbsp;\u003c/strong\u003eto\u003cstrong\u003e\u0026nbsp;31\u0026nbsp;\u003c/strong\u003ewere synthesized by reacting the intermediates \u003cstrong\u003e12\u0026nbsp;\u003c/strong\u003eto\u003cstrong\u003e\u0026nbsp;17\u0026nbsp;\u003c/strong\u003ewith \u003cem\u003eO\u003c/em\u003e-benzylhydroxylamine.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiological activity and structure-activity relationships\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEvaluations of algicidal and herbicidal activity focused on discovering compounds that strongly inhibited Scero, a green alga, and showed high selectivity against different strains of microalgae, but had no or low inhibitory effect on LEMPA, a lower plant. We determined the algicidal activity against Scero, and also of the herbicidal activity against LEMPA, of each of the synthesized phenyl oxime derivatives by using a UV/VIS spectrophotometer to measure the \u003cem\u003ein vivo\u003c/em\u003e chlorophyll absorption. The absorbance values were converted into percentage growth inhibition.\u003c/p\u003e\n\u003cp\u003eFirst, the effect of the functional group, R, of \u003cstrong\u003eKH01-19\u003c/strong\u003e on algicidal activity was examined (Table 2). \u003cstrong\u003eKH01\u003c/strong\u003e, which had no functional group substitution, exhibited moderate efficacy, inhibiting Scero by 95% at 2.0 \u0026mu;M. It showed no herbicidal effect on LEMPA, even at 20.0 \u0026mu;M, thus demonstrating exceptional selectivity. Next, compounds in which R was substituted with aliphatic groups were synthesized and their algicidal activities investigated. \u003cstrong\u003eKH02\u003c/strong\u003e (methyl substitution) exhibited higher algicidal activity against Scero (16.5% inhibition at 0.2 \u0026mu;M) than \u003cstrong\u003eKH01\u003c/strong\u003e (4.4% inhibition at 0.2 \u0026mu;M). However, \u003cstrong\u003eKH02\u003c/strong\u003e showed herbicidal activity against LEMPA (72.7% inhibition at 20.0 \u0026mu;M), in contrast to the lack of herbicidal activity of \u003cstrong\u003eKH01\u003c/strong\u003e at 20.0 \u0026mu;M. \u003cstrong\u003eKH03\u003c/strong\u003e (\u003cem\u003en\u003c/em\u003e-butyl substitution) exhibited high algicidal activity (75.7% inhibition at 0.2 \u0026mu;M), but herbicidal activity against LEMPA was not observed (0% inhibition at 20 \u0026mu;M). \u003cstrong\u003eKH04\u003c/strong\u003e (\u003cem\u003et\u003c/em\u003e-butyl substitution) demonstrated the highest algicidal activity of the synthesized derivatives (95.4% inhibition at 0.2 \u0026mu;M). However, it also showed a low level of herbicidal activity against LEMPA (8.8% inhibition at 20 \u0026mu;M). \u003cstrong\u003eKH05 (\u003c/strong\u003epropylene substitution) exhibited a relatively high algicidal activity (76.4% inhibition at 0.2 \u0026mu;M) but had herbicidal activity at high concentration (26.0% inhibition at 2.0 \u0026mu;M). \u003cstrong\u003eKH06 (\u003c/strong\u003ecyclopropyl substitution) demonstrated high algicidal activity (73.7% inhibition at 0.2 \u0026mu;M) but no herbicidal activity (0% inhibition at 20 \u0026mu;M), indicating good selectivity.\u003c/p\u003e\n\u003cp\u003eAs the next step in the optimization, the R group was replaced with an aromatic ring. \u003cstrong\u003eKH07\u003c/strong\u003e (substitution with phenyl moiety) exhibited lower algicidal activity (30.2% inhibition at 0.2\u0026nbsp;\u0026mu;M) than derivatives \u003cstrong\u003eKH03\u003c/strong\u003e to \u003cstrong\u003eKH06\u0026nbsp;\u003c/strong\u003ethat had aliphatic substitutions at R, although \u003cstrong\u003eKH07\u003c/strong\u003e had no observable herbicidal effects on LEMPA (0% inhibition at 20.0\u0026nbsp;\u0026mu;M). \u003cstrong\u003eKH08 (\u003c/strong\u003esubstitution\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ewith benzyl moiety) was the compound with third highest algicidal activity (85.5% inhibition at 0.2\u0026nbsp;\u0026mu;M). Additionally, \u003cstrong\u003eKH08\u003c/strong\u003e exhibited remarkable selectivity, as it showed no herbicidal activity (0% inhibition at 20\u0026nbsp;\u0026mu;M).\u003c/p\u003e\n\u003cp\u003eThe R group was further optimized by modifying the substituents on the aromatic ring. \u003cstrong\u003eKH09\u003c/strong\u003e, \u003cstrong\u003eKH10\u003c/strong\u003e and \u003cstrong\u003eKH11\u003c/strong\u003e were synthesized by substituting, respectively, the \u003cem\u003eortho\u003c/em\u003e-, \u003cem\u003emeta\u003c/em\u003e- and \u003cem\u003epara\u003c/em\u003e- positions of the benzyl group in \u003cstrong\u003eKH08\u0026nbsp;\u003c/strong\u003ewith fluorine. All three compounds had relatively high algicidal activities (34-78% inhibition at 0.2\u0026nbsp;\u0026mu;M) and also exhibited some level of herbicidal activity (\u0026gt;10% inhibition at 20.0\u0026nbsp;\u0026mu;M). \u003cstrong\u003eKH12\u003c/strong\u003e, \u003cstrong\u003eKH13\u003c/strong\u003e and \u003cstrong\u003eKH14\u003c/strong\u003e were similarly synthesized from \u003cstrong\u003eKH08\u003c/strong\u003e by substituting chlorine at the \u003cem\u003eortho\u003c/em\u003e-, \u003cem\u003emeta\u003c/em\u003e- and \u003cem\u003epara\u003c/em\u003e- positions, respectively, of the aromatic ring. Algicidal activity decreased slightly when the benzyl group of \u003cstrong\u003eKH08\u003c/strong\u003e was substituted with chlorine (27%-62% inhibition at 0.2\u0026nbsp;\u0026mu;M) rather than fluorine (34-78% inhibition at 0.2\u0026nbsp;\u0026mu;M). By contrast, herbicidal activities of the chlorinated compounds (0-12% inhibition at 20.0\u0026nbsp;\u0026mu;M) were comparable with those of the fluorinated compounds (0-7% inhibition at 20.0\u0026nbsp;\u0026mu;M).\u003c/p\u003e\n\u003cp\u003eAs the next stage in optimizing the aromatic ring, an electron-withdrawing group, CF\u003csub\u003e3\u003c/sub\u003e, was substituted at the \u003cem\u003emeta\u003c/em\u003e- and \u003cem\u003epara\u003c/em\u003e- positions of the benzyl group in \u003cstrong\u003eKH08\u0026nbsp;\u003c/strong\u003eto synthesize, respectively, \u003cstrong\u003eKH15\u003c/strong\u003e and \u003cstrong\u003eKH16\u003c/strong\u003e. \u003cstrong\u003eKH15\u0026nbsp;\u003c/strong\u003eand \u003cstrong\u003eKH16\u003c/strong\u003e showed reduced algicidal activities (15-38% inhibition at 0.2\u0026nbsp;\u0026mu;M) compared with the \u003cstrong\u003eKH08\u003c/strong\u003e derivatives that contained halogen substitutions. The herbicidal activities of \u003cstrong\u003eKH15\u003c/strong\u003e and \u003cstrong\u003eKH16\u003c/strong\u003e (12-14% inhibition at 20\u0026nbsp;\u0026mu;M) were higher, however, than those of the derivatives containing halogen substitutions.\u003c/p\u003e\n\u003cp\u003eNext, an electron-donating group, methoxy, was introduced at the \u003cem\u003emeta\u003c/em\u003e- and \u003cem\u003epara\u003c/em\u003e- positions of the benzyl group in \u003cstrong\u003eKH08\u003c/strong\u003e to synthesize, respectively, \u003cstrong\u003eKH17\u003c/strong\u003e and \u003cstrong\u003eKH18\u003c/strong\u003e. These compounds showed relatively inferior algicidal activities (33%-46% inhibition at 0.2\u0026nbsp;\u0026mu;M) when compared with the other derivatives. On the other hand, these compounds had no herbicidal activity (0% inhibition at 20.0\u0026nbsp;\u0026mu;M).\u003c/p\u003e\n\u003cp\u003eFinally, the effects on biological activity of substituting pyridyl at the R group were investigated. \u003cstrong\u003eKH19\u003c/strong\u003e was synthesized by substituting a 3-pyridyl group. It exhibited moderate algicidal activities (57% inhibition at 0.2\u0026nbsp;\u0026mu;M) and herbicidal activities (34% inhibition at 20.0\u0026nbsp;\u0026mu;M).\u003c/p\u003e\n\u003cp\u003eIn summary, we synthesized 19 derivatives with substitutions at the R group. Most exhibited a higher level of algicidal activity than the reference compound glutaraldehyde, as well as low herbicidal activity. Additionally, these compounds showed superior efficacy, in terms of activity and selectivity, than loreclezole, which had been identified previously as a promising active compound (Kim et al. 2021). \u003cstrong\u003eKH04\u003c/strong\u003e and \u003cstrong\u003eKH08\u003c/strong\u003e could be considered the \u0026ldquo;best\u0026rdquo; of the synthesized derivatives. Both exhibited high activities with over 85% inhibiton of Scero at 0.2 \u0026mu;M. \u003cstrong\u003eKH04\u003c/strong\u003e was not suitable as an algicide for environmental use, however, because of its herbicidal effect on LEMPA. Therefore, \u003cstrong\u003eKH08\u003c/strong\u003e was tentatively designated our lead compound and taken forward for further optimization.\u003c/p\u003e\n\u003cp\u003eSubsequent modifications of \u003cstrong\u003eKH08\u003c/strong\u003e focused on optimizing the triazole moiety (Table 3). Although the five-membered ring comprising 1,2,4-triazole was retained, further iterations of \u003cstrong\u003eKH08\u003c/strong\u003e were derived through slight modifications of the position and number of the heteroatom, N. \u003cstrong\u003eKH20\u0026nbsp;\u003c/strong\u003ewas\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eobtained by substituting 1,2,4-triazole with 1,2-diazole. This compound exhibited inferior algicidal activity (26.6% inhibition) and did not show any herbicidal activity (0% inhibition at 20 \u0026mu;M). By contrast, \u003cstrong\u003eKH21\u003c/strong\u003e, a \u003cstrong\u003eKH08\u003c/strong\u003e derivative in which 1,3-diazole, which has a different N position from 1,2-diazole, was substituted, showed greatly improved algicidal activity (96.5% inhibition at 0.2 \u0026mu;M) and relatively low herbicidal activity (25.6% inhibition at 20.0 \u0026mu;M).\u003c/p\u003e\n\u003cp\u003eThe next step of heterocyclic ring optimization involved substituting 1,2,3-triazole and 1,2,5-triazole to synthesize \u003cstrong\u003eKH22\u003c/strong\u003e and \u003cstrong\u003eKH23\u003c/strong\u003e, respectively. Both compounds had inferior algicidal activity (15-26% inhibition at 20 \u0026mu;M) and lacked any herbicidal activity (0% inhibition). Finally, we synthesized \u003cstrong\u003eKH24\u003c/strong\u003e and \u003cstrong\u003eKH25\u003c/strong\u003e by substituting with 1,2,3,4-tetrazole and 1,2,3,5-tetrazole, respectively. These compounds also showed inferior algicidal activity (20-40% inhibition at 20 \u0026mu;M) with no herbicidal activity (0% inhibition).\u003c/p\u003e\n\u003cp\u003eTo summarize, all compounds with modifications within the five-membered heterocyclic ring, other than \u003cstrong\u003eKH21\u003c/strong\u003e, showed weaker activity than the reference compounds. Although \u003cstrong\u003eKH21\u003c/strong\u003e exhibited the highest algicidal activity, it was unsuitable for use in the environment due to its herbicidal activity. \u003cstrong\u003eKH08\u003c/strong\u003e therefore retained its status as the most promising lead compound.\u003c/p\u003e\n\u003cp\u003eIn our final optimization stage, an aromatic ring in the biphenyl group of the phenyl oxime derivative was substituted with an electron-withdrawing group, an electron-donating, and a halogen group (Table 4). The biological properties of \u003cstrong\u003eKH08\u003c/strong\u003e, in which Br was substituted at the \u003cem\u003epara\u003c/em\u003e-position of the aromatic ring, were compared with those of the newly synthesized compounds \u003cstrong\u003eKH26\u003c/strong\u003e and \u003cstrong\u003eKH27\u003c/strong\u003e, in which Br was substituted at \u003cem\u003eortho-\u003c/em\u003e and \u003cem\u003emeta-\u003c/em\u003e positions, respectively. Both \u003cstrong\u003eKH26\u003c/strong\u003e and \u003cstrong\u003eKH27\u0026nbsp;\u003c/strong\u003edemonstrated inferior algicidal activity (0-20.2% inhibition at 0.2\u0026nbsp;\u0026mu;M).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKH28\u003c/strong\u003e was synthesized by substituting an electron-withdrawing group, CF\u003csub\u003e3\u003c/sub\u003e, at the \u003cem\u003epara\u003c/em\u003e-position of the aromatic ring in the biphenyl group. This compound showed reduced algicidal activity (19.4% inhibition at 0.2\u0026nbsp;\u0026mu;M). Moreover, as shown in Table 4, \u003cstrong\u003eKH29\u003c/strong\u003e, in which an electron-donating group, methyl, was substituted at the \u003cem\u003eortho\u003c/em\u003e-position of the aromatic ring in the biphenyl group, showed a considerable decrease in algicidal activity (8.7% inhibition at 0.2\u0026nbsp;\u0026mu;M).\u003c/p\u003e\n\u003cp\u003eTo determine the effect on the biological activities of substituting a halogen in the aromatic ring, \u003cstrong\u003eKH30\u003c/strong\u003e and \u003cstrong\u003eKH31\u003c/strong\u003e were synthesized by substituting F or Cl, respectively. Both compounds exhibited negligible or low algicidal activity (0-36.2% inhibition at 0.2 \u0026mu;M). Furthermore, these compounds showed relatively low herbicidal activities (10-30% inhibition at 20 \u0026mu;M). Taken together, the studies of the effect of modifying functional groups in the biphenyl ring revealed that \u003cstrong\u003eKH08\u003c/strong\u003e, which had a Br substitution at the \u003cem\u003epara\u003c/em\u003e-position, had the highest level of algicidal activity, as well as high microalgal selectivity.\u003c/p\u003e\n\u003cp\u003eTo discover a novel compound that had high algicidal activity, but was not toxic to aquatic ecosystems, we synthesized 31 phenyl oxime derivatives and investigated the relationship between their structure and their algicidal activity. \u003cstrong\u003eKH04\u003c/strong\u003e, \u003cstrong\u003eKH08\u003c/strong\u003e, and \u003cstrong\u003eKH21\u003c/strong\u003e all showed excellent algicidal activity, as they inhibited growth of a green alga, Scero, by more than 85% when tested at a concentration of 0.2 \u0026mu;M. At a higher concentration (20 \u0026mu;M), \u003cstrong\u003eKH04\u003c/strong\u003e and \u003cstrong\u003eKH21\u003c/strong\u003e inhibited growth of an aquatic plant, LEMPA, by 8.8% and 25.6%, respectively, but \u003cstrong\u003eKH08\u003c/strong\u003e did not inhibit plant growth at all. \u003cstrong\u003eKH08\u003c/strong\u003e was therefore selected as a candidate for further investigations due to its excellent activity against green algae and minimal toxicity to lower plants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAlgicidal spectra of KH08\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe algicidal activity spectra of the lead compound \u003cstrong\u003eKH08\u003c/strong\u003e were determined by measuring its effects on different species of green and cyanobacteria. The algicidal activity spectra of \u003cstrong\u003eKH08\u003c/strong\u003e were compared with those of glutaraldehyde, a conventional algicide.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKH08\u003c/strong\u003e had high algicidal activity against green algae but showed relatively low algicidal activity against cyanobacteria. A concentration of 0.16 \u0026mu;M \u003cstrong\u003eKH08\u003c/strong\u003e inhibited growth of green algae Scenedesmus rotundus (Scero), \u003cem\u003eDesmodesmus asymmetricus\u003c/em\u003e (Desas) and \u003cem\u003eChlorella vulgaris\u003c/em\u003e (Cv-K) by 60% - 70%; in addition, 1.25 \u0026mu;M \u003cstrong\u003eKH08\u003c/strong\u003e inhibited growth of the green alga, \u003cem\u003eRaphidocelis subcapitata\u003c/em\u003e (Rs), by 48.7% (Fig. 2A). However, although 0.63 \u0026mu;M\u003cstrong\u003e\u0026nbsp;KH08\u003c/strong\u003e inhibited growth of the cyanobacteria, \u003cem\u003eMicrocystis aeruginosa\u003c/em\u003e (Ma-F), by 60%, concentrations of up to 5.0 \u0026mu;M \u003cstrong\u003eKH08\u003c/strong\u003e did not inhibit growth of the cyanobacteria, \u003cem\u003eMicrocystis aeruginosa\u003c/em\u003e (Ma-K), \u003cem\u003eAnabaena affinis\u003c/em\u003e (Ana) and \u003cem\u003eOscillatoria spp.\u003c/em\u003e (Osc), by more than 20% (Fig. 2B).\u003c/p\u003e\n\u003cp\u003eThe algicidal activity spectra of glutaraldehyde contrasted with those of \u003cstrong\u003eKH08\u003c/strong\u003e. Glutaraldehyde inhibited growth of glutaraldehyde-sensitive microalgae species by more than 30% at 10.0\u0026nbsp;\u0026mu;M, but inhibited the growth of glutaraldehyde-insensitive microalgae species by less than 60%, even at 40.0 \u0026mu;M. Specifically, 10.0 \u0026mu;M glutaraldehyde inhibited growth of the green algae, Scero and Desar, by 40%-60%, and 40.0 \u0026mu;M glutaraldehyde inhibited growth of the green algae, Cv-K and Rs, by about 60% (Fig. 2C). A concentration of 10 \u0026mu;M glutaraldehyde inhibited growth of the cyanobacteria, Ma-F, Ana and Osc by 35.9%, 26.9%, and 50.0%, respectively. However, growth of a cyanobacteria, Ma-K, was only inhibited by 45.6% by 40.0 \u0026mu;M glutaraldehyde (Fig. 2D).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Under matched assay conditions, \u003cstrong\u003eKH08\u003c/strong\u003e inhibited green microalgae at lower \u0026mu;M concentrations than glutaraldehyde, while activity toward cyanobacteria was comparatively weak.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcute toxicity of KH08\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo investigate the toxicity of \u003cstrong\u003eKH08\u003c/strong\u003e, to different animal species, acute toxicity tests of the compound were conducted on a water flea (\u003cem\u003eDaphnia magna\u003c/em\u003e), two freshwater fish species (\u003cem\u003eOryzias latipes\u003c/em\u003e and \u003cem\u003eDanio rerio\u003c/em\u003e), and ICR mice.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWater flea (Daphnia magna)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eObservations of immobilization and abnormal behavior of \u003cem\u003eD. magna\u003c/em\u003e exposed to \u003cstrong\u003eKH08\u003c/strong\u003e indicated that the EC\u003csub\u003e50\u003c/sub\u003e of \u003cstrong\u003eKH08\u003c/strong\u003e was 4.800 mg/L after 24 h and 3.107 mg/L after 48 h. These values were, respectively, 2.88\u0026times; and 2.94\u0026times; higher than the EC\u003csub\u003e50\u003c/sub\u003e of potassium dichromate, a positive control compound (Table 5). The NOEC of \u003cstrong\u003eKH08\u003c/strong\u003e, that is, the maximum concentration at which \u003cstrong\u003eKH08\u003c/strong\u003e had no observable effect on \u003cem\u003eD. magna\u003c/em\u003e, was 1.000 mg/mL over observation periods of 24 h and 48 h.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFreshwater fish\u003c/em\u003e (\u003cem\u003eOryzias latipes\u003c/em\u003e and \u003cem\u003eDanio rerio)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTo evaluate the acute toxicity of \u003cstrong\u003eKH08\u003c/strong\u003e to \u003cem\u003eO. latipes\u0026nbsp;\u003c/em\u003eand \u003cem\u003eD. rerio\u003c/em\u003e, test groups of fish were treated with 2.0 mg/L of \u003cstrong\u003eKH08\u003c/strong\u003e. A negative control group was treated with fresh water, and a solvent control group with 0.01% acetone aqueous solution. None of these treatments caused death or abnormal symptoms during the acute toxicity test periods of 48 h and 96 h (Table 6). Therefore, the LC\u003csub\u003e50\u003c/sub\u003e of \u003cstrong\u003eKH08\u003c/strong\u003e for \u003cem\u003eO. latipes\u003c/em\u003e and \u003cem\u003eD. rerio\u003c/em\u003e was concluded to exceed 2.0 mg/L.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eICR mice\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKH08\u003c/strong\u003e, orally administered at a dose of 2,000 mg/kg BW, did not cause death of ICR mice, nor were symptoms of general poisoning observed (Table7). The BW of the mice increased over the test period following \u003cstrong\u003eKH08\u003c/strong\u003e administration. Necropsy after the test was completed did not reveal any abnormal findings in animals that had received oral \u003cstrong\u003eKH08\u003c/strong\u003e. The LD\u003csub\u003e50\u003c/sub\u003e of \u003cstrong\u003eKH08\u0026nbsp;\u003c/strong\u003efor ICR mice thus appeared to be greater than 2,000 mg/kg BW.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThirty-one phenyl-oxime derivatives were synthesized and evaluated for algicidal activity against the green microalga \u003cem\u003eScenedesmus rotundus\u003c/em\u003e (Scero) and herbicidal activity against \u003cem\u003eLemna paucicostata\u003c/em\u003e (LEMPA), enabling identification of selective compounds. The lead, (\u003cem\u003eE\u003c/em\u003e)-1-(4′-bromo-[1,1′-biphenyl]-4-yl)-2-(1\u003cem\u003eH\u003c/em\u003e-1,2,4-triazol-1-yl)ethan-1-one \u003cem\u003eO\u003c/em\u003e-benzyl oxime (\u003cstrong\u003eKH08\u003c/strong\u003e), strongly inhibited \u003cem\u003eS. rotundus\u003c/em\u003e while showing no measurable activity toward \u003cem\u003eL. paucicostata\u003c/em\u003e. Under matched assay conditions, \u003cstrong\u003eKH08\u003c/strong\u003e achieved comparable or greater inhibition of green microalgae at lower μM concentrations than glutaraldehyde, whereas activity toward cyanobacteria was modest. Acute-toxicity tests indicated low toxicity under our test conditions (\u003cem\u003eDaphnia magna\u003c/em\u003e EC₅₀ = 3.11–4.80 mg L⁻¹; fish LC₅₀ \u0026gt; 2.0 mg L⁻¹; mouse LD₅₀ \u0026gt; 2000 mg kg⁻¹). Collectively, these findings position \u003cstrong\u003eKH08\u003c/strong\u003e as a selective algicide candidate with practical relevance for microalgal control.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s Contribution\u0026nbsp;\u003c/strong\u003eJun Young Lee: Conceptualization, Data Curation, Investigation, Visualization, Writing \u0026ndash; Original Draft, Writing \u0026ndash; Review and Editing. Yeo Jin Kim: Data Curation, Investigation, Methodology. Bong Gyu Choi: Investigation, Validation. Jin-Seog Kim: Investigation, Validation, Visualization. Hasoo Seong: Data Curation, Writing \u0026ndash; Review and Editing. Chul Min Park: Methodology, Resources. Hyun Suk Yeom: Data curation, Formal Analysis. Seok Ki Min: Data Curation, Formal Analysis. Hyeung-geun Park: Resources, Supervision, Writing \u0026ndash; Review and Editing. Joon Ho Lee: Funding Acquisition, Project Administration, Supervision, Writing \u0026ndash; Review and Editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eThis research was supported by grants from the Korea Environmental Industry \u0026amp; Technology Institute, funded by the Ministry of Environment (RS-2022-KE002109). Partial funding was provided by Korea Research Institute Chemical Technology intramural funding (Grant Number KK2532-10).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003eThe datasets and analysis sheets that support the findings of this study are provided in the Supplementary Information; additional raw data are available from the corresponding authors upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003eThe authors declare no competing financial interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBalaji Prasath, B.; Wang, Y.; Su, Y.P.; Hamilton, D.P.; Lin, H.; Zheng, L.; Zhang, Y. (2022). Methods to control harmful algal blooms: a review. \u003cem\u003eEnvironmental Chemistry Letters\u003c/em\u003e, \u003cem\u003e20\u003c/em\u003e, 3133-3152.\u003c/li\u003e\n\u003cli\u003eCho, I.K.; Seol, J.U.; Rahman, M.M.; Lee, D.-G.; Son, H.; Cho, H. 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A review on control of harmful algal blooms by plant-derived allelochemicals. \u003cem\u003eJournal of Hazardous Materials\u003c/em\u003e, \u003cem\u003e401\u003c/em\u003e, 123403.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Scheme","content":"\u003cp\u003eScheme 1 is available in the Supplementary Files section.\u003c/p\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 2 to 7 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"algal growth inhibition, applied phycology, chlorophyll-based assay, Lemna paucicostata, non-target toxicity, phenyl-oxime, selective algicide, Scenedesmus rotundus","lastPublishedDoi":"10.21203/rs.3.rs-7558839/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7558839/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHarmful algal blooms (HABs) impair water quality and threaten aquatic life, while common chemical controls (e.g., cooper salts, glutaraldehyde) raise non-target toxicity concerns. We synthesized 31 phenyl-oxime derivatives and quantified algicidal activity as \u003cem\u003ein vivo\u003c/em\u003e chlorophyll-reduction in standardized microalgal assays, alongside non-target acute toxicity tests. A lead compound, (\u003cem\u003eE\u003c/em\u003e)-1-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-(1\u003cem\u003eH\u003c/em\u003e-1,2,4-triazol-1-yl)ethan-1-one \u003cem\u003eO\u003c/em\u003e-benzyl oxime (\u003cb\u003eKH08\u003c/b\u003e), strongly inhibited green microalgae (notably \u003cem\u003eScenedesmus rotundus\u003c/em\u003e) while showing minimal activity toward \u003cem\u003eLemna paucicostata\u003c/em\u003e. Under matched conditions, \u003cb\u003eKH08\u003c/b\u003e achieved comparable or greater inhibition of green microalgae versus glutaraldehyde, whereas activity against cyanobacteria was modest. Acute-toxicity studies indicated low toxicity to \u003cem\u003eDaphnia magna\u003c/em\u003e, \u003cem\u003eOryzias latipes\u003c/em\u003e, \u003cem\u003eDanio rerio\u003c/em\u003e, and mice. These data position \u003cb\u003eKH08\u003c/b\u003e as a selective algicide candidate with practical relevance for microalgal control.\u003c/p\u003e","manuscriptTitle":"Selective phenyl-oxime algicides with low non-target acute toxicity: efficacy against green microalgae vs glutaraldehyde","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-17 14:34:26","doi":"10.21203/rs.3.rs-7558839/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"718eeff7-d142-4e56-b1ff-2eceeef01548","owner":[],"postedDate":"September 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-02T03:08:10+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-17 14:34:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7558839","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7558839","identity":"rs-7558839","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}