Design, Synthesis, Biological Evaluation and Molecular Docking of Novel Isatin-Oxime Ether Derivatives as Potential IDH1 Inhibitors

Design, Synthesis, Biological Evaluation and Molecular Docking of Novel Isatin-Oxime Ether Derivatives as Potential IDH1 Inhibitors | 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 Design, Synthesis, Biological Evaluation and Molecular Docking of Novel Isatin-Oxime Ether Derivatives as Potential IDH1 Inhibitors Kangning Wei, Kaige Guo, Ye Tao, Xuanming Gong, Liangliang Wang, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5266541/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Jan, 2025 Read the published version in Molecular Diversity → Version 1 posted 4 You are reading this latest preprint version Graphical Abstract Abstract A series of novel isatin-oxime ether derivatives were designed, synthesized and characterized by 1H NMR and 13C NMR and HRMS. These compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (A549, HepG2 and Hela) by MTT assay. According to the experimental results, compounds 6a (IC50=0.34μM), 6c (IC50=14nM) and 6r (IC50=45nM) were found as the excellent selectivity and high activity against A549, whereas compounds 6m (IC50=12nM) and 6n(IC50=25nM) displayed the significant activity for HepG2, respectively. Compound 6f (IC50=30nM), 6n (IC50=9nM) and 6o(IC50=20nM) also showed the excellent activity against Hela. From the experiments of cell migration and colony formation assays, the findings demonstrated that 6m can effectively suppress the migration and growth of HepG2 cells. In addition, the results of molecular docking studies determined the strong binding interactions between the potential active compounds 6m and 6n and the active sites of isocitrate dehydrogenase 1 (IDH1) with the lowest binding affinity energy. Isatin Oxime ether Anticancer activity Isocitrate dehydrogenase 1 Molecular docking Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Cancer is a serious health problem in the world, which has increasingly caused high morbidity and mortality rates in the past decades [ 1 – 2 ]. The activation of oncogenes and the inactivation of tumor suppressor genes cause uncontrolled cell growth and spreading [ 3 – 5 ]. In addition, cancer cells often typically have high levels of replication stress [ 6 – 8 ]. Surgery and radiotherapy are two main treatment methods for patients [ 9 – 11 ]. However, these traditional therapies suffer from some issues, such as high risk and difficult curability. Recently, chemotherapy interfering with biological molecules has become one of the most effective means in the treatment of cancer by inhibiting cancer cell proliferation. Therefore, the development of highly efficient and novel targeting drugs for chemotherapy is desirable. Isocitrate dehydrogenases (IDHs) play important roles in cellular metabolism and cancer as the key enzymes, which catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) [ 12 ]. The IDH family includes three isoforms (IDH1, IDH2, and IDH3) in humans [ 13 ]. IDH1 has attracted a lot of attention as a hot target for research, due to the high mutation frequency. Ivosidenib (AG-120) is a first-in-class isocitrate dehydrogenase 1 (IDH1) inhibitor granted approval by the FDA in 2018 for the treatment of relapsed of refractory acute myeloid leukemia in adults, which has been introduced to treat leukemia and cholangiocarcinoma approved by the EMA in 2023. Up to date, numerous research teams are devoted to developing high efficient inhibitors for targeted therapy for diseases caused by IDH1 mutations. Isatin (indole-1H-2,3-dione) represents one of the most prevalent heterocyclic compounds, which has been found in pharmaceuticals, agrochemicals and natural products [ 14 ]. Isatin and its derivatives exhibit a broad spectrum of pharmacological and biological activities, such as anticancer [ 15 ], antibacterial [ 16 ] antiviral [ 17 ], anti-inflammatory [ 18 ], antifungal [ 19 ], anticonvulsant [ 20 ], anti-HIV [ 21 ]. Especially, several commercial anticancer drugs containing isatin backbone, such as Semaxanib (SU5416), Sunitinib (SU11248), and Nintedanib ( I - III , Fig. 1 ), were approved by the Food and Drug Administration (FDA) [ 22 ]. Numerous isatin derivatives have been explored through the modification based on C-3 carbonyl group in the past decades. For examples, isatin oxime ether derivatives display antiviral activity ( I V, Fig. 1 ) [ 23 ]. Isatin-hydrazone derivatives have been reported to exhibit a-glucosidase inhibitory activity ( V-VI , Fig. 1 ) [ 24 – 25 ]. Isatin moiety using as a pharmacophore has received widespread attention in the discovery of new drugs. On the other hand, oxime ethers are a class of important organic compounds, which have been widely used in designing pharmaceutical and agrochemical molecules [ 26 – 27 ]. For examples, Fenpyroximate ( VII , Fig. 2 ) with two important moieties of pyrazole ring and oxime ethers in the structure displays excellent acaricidal properties, which was launched in most European countries from 1995 [ 28 ]. As an antifungal drug in the form of a nitrate salt, Oxiconazole ( VIII , Fig. 2 ) was spreadly applied to the skin in the form of an ointment, cream or powder [ 29 ]. Fluvoxamine ( IX , Fig. 2 ) used as an antidepressant drug, which displayed pharmacological activity as a selective serotonin reuptake inhibitor [ 30 ]. Due to its significant biological activities, oxime ether derivatives have gained overwhelming attention [ 31 – 36 ]. In view of their biological activities, we integrated the structural features of isatin backbone and oxime ether moiety to design some novel isatin-oxime ether hybrid scaffolds with potential bioactivities as shown in Fig. 3 . Results and discussion Chemistry The hybrid compounds need to be carried out in three steps and the synthetic route is shown in Fig. 4 . The nucleophilic substitution reaction of benzyl bromides with 2-hydroxyisoindoline-1,3-dione provides 2-(benzyloxy)isoindoline-1,3-diones, then reduced with hydrazine hydrate to give O -benzylhydroxylamines. Finally, dehydration condensation of isatin derivatives and O -benzylhydroxylamines delivers the target molecules. Biology Results of MTT From these results, substitution groups on isatin backbone and benzene ring of oxime ether moiety have a significant impact on biological activity. Firstly, based on 5-fluoro isatin-oxime ether hybrids 6a-6f , it was found that substitution groups on oxime ether moiety have an important effect on selectivity and activity. For examples, compounds 6a displayed biological activity against A549 (IC 50 = 0.34µM) and Hela (IC 50 = 6.69µM) cancer cells. Introduction of a fluorine atom in the benzene ring of oxime ether moiety 6c resulted in different selectivity and relatively high activity, such as against A549 (IC 50 = 14nM) and HepG2 (IC 50 = 2.01µM) cancer cells, whereas chlorine 6b and bromine atom 6d can lead to lower activity. Interestingly, compounds 6e and 6f showed high selectivity and activity against HepG2 (IC 50 = 1.31µM) and hela (IC 50 = 30nM), respectively, when the benzene ring changed to the pyridine ring 6e , and fluorine atom was replaced by tertbutyl ester group 6f . Secondly, the different substitution groups on the isatin backbone were also explored for the influence of activity 6g - 6s , mainly based on the unchanged structure of oxime ether moiety with tertbutyl ester group. 5-bromo and 7-fluoro N -free isatin-oxime ether hybrids 6h and 6m exhibited the high activity against Hela (IC 50 = 2.38µM) and HepG2 (IC 50 = 12nM) cells, respectively. N -substituted isatin-oxime ether hybrids 6o and 6r showed high selectivity and activity against Hela (IC 50 = 20nM) and A549 (IC 50 = 45nM) cells, respectively. It is also interesting to note that 7-bromo- N -meyhyl satin-oxime ether hybrids 6n displayed the significant activity against Hela (IC 50 = 9nM) and HepG2(IC 50 = 25nM) cells. These results possibly indicated that the N -substitution groups in the isatin moiety is critical for the activity against Hela ( 6n and 6o ), whereas the introduction of a fluorine atom into isatin backbone and the substituted position on benzene ring have a significant effect on the activity against A549, HepG2 and Hela ( 6j-m ). These comprehensive factors may be attributed to its drastically conformational change and steric requirement of isatin-oxime ether hybrids. Table 1 IC 50 (µM) value of isatin-oxime ether hybrids. Isatin-oxime ether hybrids IC 50 (µM) a ± SD b Comp. R 1 R 2 R 3 A549 HepG2 Hela 6a H 5-F H 0.34 ± 0.06 > 100 6.69 ± 0.24 6b 4-Cl 5-F H 42.25 ± 0.09 45.38 ± 0.21 > 100 6c 4-F 5-F H 0.014 ± 0.05 2.01 ± 0.24 > 100 6d 2-Br 5-F H > 100 > 100 23.36 ± 0.20 6e Pyridyl c 5-F H 47.55 ± 0.20 1.31 ± 0.28 21.48 ± 0.16 6f 4-CO 2 t Bu 5-F H > 100 99.51 ± 0.29 0.03 ± 0.22 6g 4-CO 2 t Bu 5-CH 3 H 37.43 ± 0.08 18.03 ± 0.14 > 100 6h 4-CO 2 t Bu 5-Br H > 100 28.96 ± 0.34 2.38 ± 0.28 6i 4-CO 2 t Bu 5-OCH 3 H 44.50 ± 0.05 55.64 ± 0.26 > 100 6j 4-CO 2 t Bu 6-Cl H > 100 > 100 > 100 6k 4-CO 2 t Bu 6-F H 22.34 ± 0.14 13.96 ± 0.15 14.00 ± 0.14 6l 4-CO 2 t Bu 7-Cl H > 100 29.16 ± 0.18 > 100 6m 4-CO 2 t Bu 7-F H > 100 0.012 ± 0.10 32.92 ± 0.18 6n 4-CO 2 t Bu 7-Br CH 3 > 100 0.025 ± 0.20 0.009 ± 0.12 6o 4-CO 2 t Bu H Bn > 100 > 100 0.020 ± 0.24 6p 4-CO 2 t Bu H 4-MeC 6 H 4 CH 2 > 100 > 100 53.52 ± 0.23 6q 4-CO 2 t Bu H 4-FC 6 H 4 CH 2 > 100 > 100 59.64 ± 0.20 6r 4-CO 2 t Bu H 4-ClC 6 H 4 CH 2 0.045 ± 0.04 > 100 18.79 ± 0.21 6s 4-CO 2 t Bu H H 13.21 ± 0.27 15.58 ± 0.22 14.92 ± 0.28 a All IC 50 values are reported as means of values from at three determinations. b SD: standard deviation. c (6-chloropyridin-3-yl)methyl. Results of Cell migration Cancer mortality and prognosis are often linked to the metastatic potential of tumors, as cancer cells exhibit a high capacity for migration. To explore the effect of 6m on cell migration, we employed the wound healing assay. In this experiment, HepG2 cells were exposed to 6m following the creation of a scratch in the confluent monolayer of the cultured cells. Images of the wound area were taken at 0 h and 48 h post-treatment. As illustrated in Fig. 5 , the wound in the DMSO-treated control group had nearly fully healed by 48h, whereas treatment with 6m led to a concentration-dependent inhibition of wound closure. These findings demonstrate that 6m can effectively suppress the migration of HepG2 cells. Results of Colony formation To assess the inhibitory effects of 6m on cell proliferation, a colony formation assay was conducted to evaluate its impact on HepG2 cells. Cells were exposed to 6m at different concentrations (20 µmol, 20/3 µmol, and 20/9 µmol). As depicted in Fig. 6 , treatment with 6m led to a pronounced reduction in viable cell numbers in a dose-dependent fashion when compared with the DMSO control. These results clearly indicate that 6m is capable of significantly suppressing HepG2 cell growth. Results of Molecular docking studies From the results shown in Table 2 , the binding energies between compounds and IDH1 were relatively reasonable, compared with that of co-crystal compound (ivosidenib, AG-120). The compound 6m has the best binding affinity with − 11.8 kcal/mol of the binding energy. Table 2 The binding affinity energies between isatin-oxime ether hybrids and IDH1. Comp. Affinity. Kcal/mol Comp. Affinity. Kcal/mol Comp. Affinity. Kcal/mol 6a -11.3 6h -11.4 6n -11.0 6b -11.7 6i -11.2 6o -11.6 6c -11.5 6j -11.5 6p -11.3 6d -11.3 6k -11.5 6q -11.2 6e -11.2 6l -11.4 6r -11.4 6f -11.6 6m -11.8 6s -11.0 6g -11.7 Ivosidenib -13.5 We also investigated the binding interaction between high active compounds 6m , 6n and the active sites of IDH1 shown in Fig. 7 – 8 . As shown in Fig. 7 , the binding mode of compound 6m included four hydrogen bonds formation between Leu120 with NH, fluorine atom of isatin, between Ala111 with nitrogen of oxime ether, and between Arg119 with fluorine atom of isatin. The amino acid residues Trp124 and Tyr285 showed π-π stacked and π-π T-shaped hydrophobic interactions with benzene ring, whereas π-sigma interactions were observed between benzene ring and Val281, Ile130 and Ile113 residues. In addition, hydrophobic interactions like alkyl, π-alkyl and van der Waals, also play an essential role in the inhibitory activity. As for compound 6n shown in Fig. 8 , the typical binding mode consists of three hydrogen bonds between Ala111, Arg109 with nitrogen atom of oxime ether moiety, between Ser280 with oxygen atom of tert-butyl ester. The amino acid residues Ile130 showed π-sigma hydrophobic interactions with benzene ring of oxime ether moiety. The hydrophobic interactions of alkyl, π-alkyl with Trp267, Leu120 and Arg119 were observed. However, unfavourable bump between 6n and amino acid residues was also obvious, such as Ile128, Val281,Tyr285, Trp124, Pro127. Conclusion We have designed and synthesized isatin-oxime ether hybrids as potential IDH1 inhibitors. The in vitro bioassay of these compounds against A549, HepG2 and Hela cancer cells revealed that compounds 6c , 6m , 6n had significant biological activity. In addition, the colony formation and wound healing assays demonstrated that 6m exhibited strong anti-proliferative and anti-migratory properties. The reasonable interactions in molecular docking study make them good lead compounds for the development of IDH1 inhibitors. Experimental Materials Reagents and instruments All chemicals were purchased from Alfa Aesar and Shaoyuan Webstore. Chloroform-d and Methyl sulfoxide-d6 were purchased from Cambridge Isotope Laboratories. CDCl 3 was used as solvent with tetramethylsilane (TMS) as internal standard. All solvents were distilled prior to use. All reactions with air- and moisture-sensitive components were performed under a nitrogen atmosphere in a flame-dried reaction flask. For chromatography, 200–300 mesh silica gel (Qingdao, China) was employed. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were measure on Bruker 400 M spectrometers. High Resolution Mass Spectrometry (HRMS) were all recorded on an ABI/Sciex QStar Mass Spectrometer using a positive electrospray ionization (ESI+). RPMI Medium 1640 basic was purchased from Shanghai Lifei Biotechnology Co., Ltd. Dulbecco's Modifed Eagle Medium was purchased from Thermo Fisher Scientific (Suzhou) Instruments Co., Ltd. Fetal Bovine Serum (FBS) and streptomycin mixture (100X) were purchased from Gibco. PBS, trypsin, DMSO, and MTT powder were purchased from sigma company. Culture dishes (100 mm) and 6/96-well plates were purchased from NEST. Cell mix device, cell climbing sheet, sealing membrane, frozen storage tube, electric heating thermostatic water bath (XMTD were purchased Shanghai Jinghong Experimental Equipment Co., Ltd.). Cells were purchased from the national experimental cell resource sharing platform. Synthesis of compounds General procedure for the synthesis of 2-(benzyloxy)isoindoline-1,3-diones ( 3a-f ) To a solution of 2-hydroxyisoindoline-1,3-dione 1a (4 mmol) and K 2 CO 3 (4 mmol) in anhydrous dimethyl formamide (DMF) (20 mL), (bromomethyl)arenes 2a-f (4.8 mmol, 1.2 equiv) was added under inert gas at room temperature. After the reaction mixture was stirred for 24 h, and monitored by TLC. When the reaction was completed, the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over MgSO 4 and evaporated to leave a residue, which was purified by column chromatography using the indicated eluent to give the solid products of 2-(benzyloxy)isoindoline-1,3-dione 3a-f . General procedure for the synthesis of O-benzylhydroxylamines ( 4a-f ) To a solution of 2-(benzyloxy)isoindoline-1,3-diones 3a-f (2 mmol) in absolute ethanol (EtOH, 10 mL), 80% hydrazine hydrate (2.4 mmol, 1.2 equiv) was added under inert gas at room temperature for 2 h, and monitored by TLC. When the reaction was completed, ice water (20 mL) was added in the reaction. The mixture was stirred vigorously until a large amount of solid was precipitated. After filtration, the filtrate was extracted with ethyl acetate. The combined organic layer was dried over MgSO 4 and evaporated to leave a residue, which was purified by column chromatography using the indicated eluent to the product of O -benzylhydroxylamines 4a-f . General procedure for the synthesis of (Z)-3-((benzyloxy)imino)indolin-2-one ( 6a-s ) To a solution of O -benzylhydroxylamines 4a-f (1.2 mmol 1.2 equiv) in absolute ethanol (EtOH, 10 mL), isatin derivatives 5a-s (1 mmol) and acetic acid (1.0% mmol) was added. The reaction mixture was refluxed for 2–3 h. Then the mixture was allowed to cool to room temperature. The crystalline products 6a-s were collected by filtration and washed thoroughly with cold ether. Structure determination of isatin-oxime ether hybrids All the hybrid compounds were characterized by 1 H NMR, 13 C NMR and HRMS spectroscopic techniques. (Z)-3-((benzyloxy)imino)-5-fluoroindolin-2-one ( 6a ) Yellow Solid; Yield: 87%; 1 H NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H, NH), 7.58 (dd, J = 8.0, 4.0Hz, 1H), 7.47 ~ 7.35 (m, 5H), 7.23 (ddd, J = 12.0, 8.0, 4.0Hz, 1H), 6.91 ~ 6.85(m, 1H), 5.73 (s, 2H); 13 C NMR (100 MHz, DMSO-d6): δ 164.1, 156.9, 144.8, 140.2, 130.50 ,129.50, 129.1, 128.9, 119.9(d, J CF =23Hz), 116.5 (d, J CF =9Hz), 114.8(d, J CF =26Hz), 112.1(d, J CF =8Hz), 78.7; 19 F NMR (377 MHz, DMSO-d6): δ -120.56~-121.18(m,1F); HRMS calcd for C 15 H 11 FN 2 O 2 [M + Na] + : 293.0701, found: 293.0702. (Z)-3-(((4-chlorobenzyl)oxy)imino)-5-fluoroindolin-2-one ( 6b ) Yellow Solid; Yield: 79%; 1 H NMR (400 MHz DMSO-d6): δ 10.80 (s, 1H, NH), 7.58 (dd, J = 8.0, 4.0Hz, 1H), 7.48 ~ 7.43 (m, 4H), 7.23 (ddd, J = 12.0, 8.0, 4.0Hz, 1H), 6.85(dd, J = 8.0, 4.0Hz, 1H), 5.44 (s, 2H); 13 C NMR (100 MHz, DMSO-d6): δ 164.0, 159.3, 145.0(d, J CF =2Hz), 140.3(d, J CF =2Hz), 136.3, 133.5, 130.7(d, J CF =7Hz), 129.1(d, J CF =11Hz), 120.1(d, J CF =24Hz), 116.4, 115.0(d, J CF =25Hz), 112.1(d, J CF =8Hz), 77.7; 19 F NMR (377 MHz, DMSO-d6): δ -121.10~-121.13(d,1F); HRMS calcd for C 15 H 10 ClFN 2 O 2 [M + Na] + : 327.0312, found: 327.0313. -5-fluoro-3-(((4-fluorobenzyl)oxy)imino)indolin-2-one ( 6c ) Yellow Solid; Yield: 73%; 1 H NMR (400 MHz DMSO-d6): δ 10.81 (s, 1H, NH), 7.59 (dd, J = 8.0, 4.0Hz, 1H), 7.52 (dd, J = 8.0, 4.0Hz, 1H), 7.27 ~ 7.21 (m, 4H), 6.87(dd, J = 8.0, 4.0Hz, 1H), 5.74 (s, 2H); 13 C NMR (100 MHz, DMSO-d6): δ 164.1(d, J CF =23Hz), 161.4, 159.2, 156.9, 144.8(d, J CF =3Hz), 140.2(d, J CF =2Hz), 133.4(d, J CF =3Hz), 131.3, 120.1(d, J CF =24Hz), 116.5, 116.1, 114.9(d, J CF =27Hz), 112.1(d, J CF =8Hz), 77.9; 19 F NMR (377 MHz, DMSO-d6): δ -113.51~-113.54(d,1F), -121.14~-121.17(d,1F); HRMS calcd for C 15 H 10 F 2 N 2 O 2 [M + Na] + : 311.0607, found: 311.0608. (Z)-3-(((2-bromobenzyl)oxy)imino)-5-fluoroindolin-2-one ( 6d ) Yellow Solid; Yield: 72%; 1 H NMR (400 MHz DMSO-d6): δ 10.79 (s, 1H, NH), 7.66 (dd, J = 8.0, 4.0Hz, 1H), 7.59(dd, J = 8.0, 4.0Hz, 1H), 7.51 (dd, J = 8.0, 4.0Hz, 1H), 7.40(td, J = 8.0, 4.0Hz, 1H), 7.30(ddd, J = 12.0, 8.0, 4.0Hz, 1H), 7.23(ddd, J = 12.0, 8.0, 4.0Hz, 1H), 5.5 (s, 2H); 13 C NMR (100 MHz, DMSO-d6): δ 164.0, 159.8, 156.8, 145.2(d, J CF =2Hz), 140.3(d, J CF =2Hz), 136.2, 133.3, 131.6, 131.2, 128.6, 123.9, 120.2(d, J CF =24Hz), 116.4, 115.0(d, J CF =26Hz), 112.2, 78.3; 19 F NMR (377 MHz, DMSO-d6): δ -121.05~-121.11(t,1F); HRMS calcd for C 15 H 10 BrFN 2 O 2 [M + Na] + : 370.9807, found: 370.9807. (Z)-3-(((6-chloropyridin-3-yl)methoxy)imino)-5-fluoroindolin-2-one ( 6e ) Yellow Solid; Yield: 67%; 1 H NMR (400 MHz DMSO-d6): δ 10.79 (s, 1H, NH), 8.49 (dd, J = 8.0, 4.0Hz, 1H), 7.93(dd, J = 8.0, 4.0Hz, 1H), 7.61 (dd, J = 8.0, 4.0Hz, 1H), 7.53(dd, J = 8.0, 4.0Hz, 1H), 7.22(ddd, J = 12.0, 8.0, 4.0Hz, 1H), 6.84(dd, J = 8.0, 4.0Hz, 1H), 5.48 (s, 2H); 13 C NMR (100 MHz, DMSO-d6): δ 164.0, 159.3, 156.9, 150.8, 145.3(d, J CF =3Hz), 140.6, 140.3(d, J CF =2Hz), 132.5, 124.9, 120.3(d, J CF =23Hz), 115.2, 115.0, 112.1(d, J CF =8Hz), 75.1; 19 F NMR (377 MHz, DMSO-d6): δ -121.07~-121.10(d,1F); HRMS calcd for C 14 H 9 ClFN 3 O 2 [M + Na] + : 328.0264, found: 328.0265. tert-butyl (Z)-4-((((5-fluoro-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6f ) Yellow Solid; Yield: 75%; 1 H NMR (400 MHz CDCl 3 -d1): δ 9.48 (s, 1H, NH), 8.00(m, 2H), 7.61(dd, J = 8.0, 4.0Hz, 1H), 7.46 (m, 2H), 7.03(td, J = 8.0, 4.0Hz, 1H), 6.84(dd, J = 12.0, 4.0Hz, 1H), 5.56 (s, 2H), 1.58(s, 9H); 13 C NMR (100 MHz, CDCl 3 -d1): δ 165.9 (C = O), 165.5(C = O), 160.1, 157.7, 144.5, 138.2(d, J CF =3Hz), 132.3, 129.9, 128.0, 119.57(d, J CF =24Hz), 116.7(d, J CF =9Hz), 115.5(d, J = 1.6(d, J = 7.0 Hz ), 81.3, 79.1, 28.3; 19 F NMR (377 MHz, CDCl 3 -d1): δ -119.3~-119.26 (d,1F); HRMS calcd for C 20 H 19 FN 2 O 4 [M + Na] + : 393.1226, found: 393.1227. tert-butyl (Z)-4-((((5-methyl-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6g ) Yellow Solid; Yield: 73%; 1 H NMR (400 MHz CDCl 3 -d1): δ 9.50 (s, 1H, NH), 7.99(d, J = 8.0Hz, 2H), 7.71(dd, J = 8.0, 4.0Hz, 1H), 7.47 (d, J = 8.0Hz, 2H), 7.11(ddd, J = 12.0, 8.0, 4.0Hz, 1H), 6.79(d, J = 8.0Hz, 1H), 5.55(s, 2H), 2.27(s, 3H), 1.58(s, 9H); 13 C NMR (100 MHz, CDCl 3 -d1): δ 166.1, 165.5, 145.0, 141.1, 141.0, 133.5, 132.8, 129.8, 128.7, 127.8, 116.3, 110.8, 81.3, 78.6, 28.3, 21.1; HRMS calcd for C 21 H 22 N 2 O 4 [M + Na] + : 389.1476, found: 389.1477. tert-butyl (Z)-4-((((5-bromo-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6h ) Yellow Solid; Yield: 78%; 1 H NMR (400 MHz DMSO-d6): δ 10.9 (s, 1H, NH), 7.93(m, 3H), 7.53(m, 3H), 6.82(d, J = 8.0Hz, 1H), 5.52(s, 2H), 1.50(s, 9H); 13 C NMR (100 MHz, DMSO-d6): δ 165.2, 163.6, 146.2, 143.5, 142.3, 136.0, 131.7, 130.1, 129.8, 128.6, 117.8, 114.7, 113.2, 81.3, 77.9, 28.3; HRMS calcd for C 20 H 19 BrN 2 O 4 [M + Na] + : 453.0425, found: 453.0426. tert-butyl (Z)-4-((((5-methoxy-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6i ) Yellow Solid; Yield: 76%; 1 H NMR (400 MHz CDCl 3 -d1): δ 9.42(s, 1H, NH), 7.99(m, 2H), 7.51(d, J = 4.0Hz, 1H), 7.46 (m, 2H), 6.87(dd, J = 8.0, 4.0Hz, 1H), 6.81(dd, J = 8.0, 4.0Hz, 1H), 5.55(s, 2H), 3.73(s, 3H), 1.58(s, 9H); 13 C NMR (100 MHz, CDCl 3 -d1): δ 166.0 (C = O), 165.5, 155.91, 145.2, 140.8, 135.9, 132.1, 129.9, 127.8, 118.1, 116.9, 114.5, 111.4, 81.3, 78.7, 56.0, 28.3; HRMS calcd for C 21 H 22 N 2 O 5 [M + Na] + : 405.1425, found: 405.1426. tert-butyl (Z)-4-((((6-chloro-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6j ) Yellow Solid; Yield: 74%; 1 H NMR (400 MHz CDCl 3 -d1): δ 9.45(s, 1H, NH), 7.99(m, 2H), 7.78(d, J = 12.0Hz, 1H), 7.45 (m, 2H), 6.95(m, 2H), 5.54(s, 2H), 1.58(s, 9H); 13 C NMR (100 MHz, CDCl 3 -d1): δ 166.8, 165.5, 143.8, 143.2, 140.5, 138.8, 132.3, 129.9, 129.0, 128.0, 123.4, 114.8, 111.7, 81.4, 79.9, 28.3; HRMS calcd for C 20 H 19 ClN 2 O 4 [M + Na] + : 409.0930, found: 409.0931. tert-butyl (Z)-4-((((6-fluoro-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6k ) Yellow Solid; Yield: 72%; 1 H NMR (400 MHz CDCl 3 -d1): δ 9.51(s, 1H, NH), 7.99(m, 2H), 7.86(m, 1H), 7.46 (m, 2H), 6.67(m, 2H), 5.53(s, 2H), 1.58(s, 9H); 13 C NMR (100 MHz, CDCl 3 -d1): δ 166.7, 165.3, 165.4, 164.2, 144.3, 143.7, 141.4, 132.2, 130.1 (d, J CF =11Hz), 128.0, 112.7, 110.0 (d, J CF =23Hz), 99.8(d, J CF =27Hz), 81.9, 78.8, 28.3; 19 F NMR (377 MHz, CDCl 3 -d1): δ -102.47~-102.49(d, 1F); HRMS calcd for C 21 H 22 N 2 O 5 [M + Na] + : 405.1425, found: 405.1426. HRMS calcd for C 20 H 19 FN 2 O 4 [M + Na] + : 393.1226, found: 393.1227. tert-butyl (Z)-4-((((7-chloro-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6l ) Yellow Solid; Yield: 77%; 1 H NMR (400 MHz CDCl 3 -d1): δ 8.68(s, 1H, NH), 7.99(d, J = 8.0Hz, 2H), 7.78(dd, J = 8.0, 4.0Hz, 1H), 7.46 (d, J = 8.0Hz, 2H), 7.30(dt, J = 8.0Hz, 4.0Hz, 1H), 6.95(m, 1H), 5.55(s, 2H), 1.58(s, 9H); 13 C NMR (100 MHz, CDCl 3 -d1): δ 165.5, 164.2, 144.2, 140.4, 139.6, 132.5, 132.3, 129.9, 128.1, 126.4, 124.1, 117.5, 116.0, 81.3, 79.0, 28.3; HRMS calcd for C 20 H 19 ClN 2 O 4 [M + Na] + : 409.0930, found: 409.0931. tert-butyl (Z)-4-((((7-fluoro-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6m ) Yellow Solid; Yield: 73%; 1 H NMR (400 MHz CDCl 3 -d1): δ 8.91(s, 1H, NH), 8.0(m, 2H), 7.69(dt, J = 8.0, 4.0Hz, 1H), 7.46 (m, 2H), 7.11(ddd, J = 12.0, 8.0, 4.0Hz, 1H), 6.96(ddd, J = 12.0, 8.0, 4.0Hz, 1H), 5.56(s, 2H), 1.58(s, 9H); 13 C NMR (100 MHz, CDCl 3 -d1): δ 165.5, 164.4, 148.3, 145.8, 143.9, 141.7, 132.2, 129.9, 128.1, 123.9(q, J CF =4Hz), 119.9(d, J CF =17Hz), 118.5(d, J CF =4Hz), 81.3, 79.0, 28.3; 19 F NMR (377 MHz, CDCl 3 -d1): δ -133.21(s, 1F); HRMS calcd for C 20 H 19 FN 2 O 4 [M + Na] + : 393.1226, found: 393.1227. tert-butyl(Z)-4-((((7-bromo-1-methyl-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6n ) Yellow Solid; Yield: 66%; 1 H NMR (400 MHz CDCl 3 -d1): δ 7.96(d, J = 8.0Hz, 2H), 7.85(dd, J = 8.0, 4.0Hz, 1H), 7.41 (m, 3H), 6.88(dd, J = 8.0, 4.0Hz, 1H), 5.51(s, 2H), 3.55(s, 3H),1.58(s, 9H); 13 C NMR (100 MHz, CDCl 3 -d1): δ 166.6, 163.8, 143.1, 141.8, 140.5, 138.1, 132.2, 129.9, 128.0, 127.8, 127.1, 124.3, 118.4, 103.2, 81.2, 79.0, 29.8, 28.3; HRMS calcd for C 21 H 21 BrN 2 O 4 [M + Na] + : 467.0582, found: 467.0582. tert-butyl (Z)-4-((((1-benzyl-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6o ) Yellow Solid; Yield: 79%; 1 H NMR (400 MHz CDCl 3 -d1): δ 8.01(m, 2H), 7.91(m, 1H), 7.49 (m, 2H), 7.28(m, 4H), 7.23(m, 2H), 6.97(td, J = 8.0, 4.0Hz, 1H), 6.68(dt, J = 8.0, 4.0Hz, 1H), 5.56(s, 2H), 4.90(s, 2H),1.58(s, 9H); 13 C NMR (100 MHz, CDCl 3 -d1): δ 166.6, 163.7, 144.4, 143.8, 140.9, 135.4, 132.8, 129.9, 129.0, 127.9, 127.4, 123.3, 116.8, 115.6, 109.7, 81.1, 78.7, 43.8, 28.3; HRMS calcd for C 27 H 26 N 2 O 4 [M + Na] + : 465.1789, found: 465.1790. tert-butyl(Z)-4-((((1-(4-methylbenzyl)-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6p ) Yellow Solid; Yield: 75%; 1 H NMR (400 MHz CDCl 3 -d1): δ 8.01(m, 2H), 7.91(ddd, J = 12.0, 8.0, 4.0Hz,1H), 7.49 (m, 2H), 7.25(td, 1H), 7.19(m, 2H), 7.10(m, 2H), 6.97(td, J = 8.0, 4.0Hz, 1H), 6.71(dt, J = 8.0, 4.0Hz, 1H), 5.57(s, 2H), 4.89(s, 2H), 2.29(s, 3H), 1.59(s, 9H); 13 C NMR (100 MHz, CDCl 3 -d1): δ 165.5, 163.6, 144.5, 143.9, 140.8, 137.6, 132.7, 132.4, 129.9, 129.6, 128.1, 128.0, 127.5, 123.2, 115.9, 109.7, 83.0, 78.7, 43.6, 28.3, 21.2; HRMS calcd for C 28 H 28 N 2 O 4 [M + Na] + : 479.1947, found: 479.1947. tert-butyl(Z)-4-((((1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6q ) Yellow Solid; Yield: 76%; 1 H NMR (400 MHz CDCl 3 -d1): δ 8.00(m, 2H), 7.92(ddd, J = 12.0, 8.0, 4.0Hz,1H), 7.48 (m, 2H), 7.27(m, 3H), 6.98(m, 3H), 6.69(dt, J = 8.0, 4.0Hz, 1H), 5.56(s, 2H), 4.89(s, 2H), 2.29(s, 3H), 1.58(s, 9H); 13 C NMR (100 MHz, CDCl 3 -d1): δ 165.5, 163.6, 161.2, 144.2, 143.6, 140.7, 132.8, 132.2, 131.2(d, J CF =4Hz), 129.9, 129.30, 128.2, 128.0, 127.5, 123.4, 116.0(d, J CF =4Hz), 109.4, 81.3, 78.8, 43.1, 28.3; 19 F NMR (377 MHz, CDCl 3 -d1): δ -114.14(s, 1F); HRMS calcd for C 27 H 25 FN 2 O 4 [M + Na] + : 483.1694, found: 483.1696. tert-butyl(Z)-4-((((1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6r ) Yellow Solid; Yield: 72%; 1 H NMR (400 MHz CDCl 3 -d1): δ 8.01(m, 2H), 7.92(m,1H), 7.48 (d, J = 8.0Hz, 2H), 7.25(m, 5H), 7.00(td, J = 8.0, 4.0Hz, 1H), 6.66(dt, J = 8.0, 4.0Hz, 1H), 5.57(s, 2H), 4.90(s, 2H), 1.58(s, 9H); 13 C NMR (100 MHz, CDCl 3 -d1): δ 165.5, 163.6, 143.5, 140.7, 133.9, 133.8, 132.8, 132.2, 129.9, 129.7, 129.1, 128.8, 128.3, 128.1, 123.4, 109.4, 82.4, 78.8, 43.2, 28.3; HRMS calcd for C 27 H 25 ClN 2 O 4 [M + Na] + : 499.1400, found: 499.1401. tert-butyl (Z)-4-((((2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate ( 6s ) Yellow Solid; Yield: 85%; 1 H NMR (400 MHz CDCl 3 -d1): δ 9.89(s, 1H, NH), 7.96(d, J = 8.0Hz, 2H), 7.81 (d, J = 8.0Hz, 1H), 7.43(d, J = 8.0Hz, 2H), 7.23(d, J = 12.0Hz, 1H),, 6.91(m, 2H), 5.50(s, 2H), 1.55(s, 9H); 13 C NMR (100 MHz, CDCl 3 -d1): δ 166.1, 165.6, 145.0, 142.5, 140.9, 133.0, 132.0, 129.8, 128.1, 127.9, 123.2, 116.2, 111.2, 81.3, 78.6, 28.3; HRMS calcd for C 20 H 20 N 2 O 4 [M + Na] + : 375.1320, found: 375.1321. Biology MTT assay The antitumour activity of isatin-oxime ether hybrids ( 6a-s ) was evaluated using on human cancer cells A549, HepG2 and Hela by MTT assay in vitro. These cancer cells were cultivated in RPMI medium plates containing 10% fetal bovine serum and 2 mM L-glutamine for 24 h at 37 0 C. The percentage of growth inhibition was calculated using the formula [Ti/C] x 100% [ 37 ]. Cell migration assay HepG2 cells were seeded in a 6-well plate at a concentration of 5x10 5 cells/well, which were allowed to reach 90% confluence in complete medium after 24h of growth. A single scratch wound of cell cultures was created with a 200 µL sterile pipette tip using the designed mold [ 38 ]. The wounded monolayers were washed three times with phosphate buffer saline (PBS) to remove the detached cells. The various concentrations of 6m were added to its corresponding wells. After 48h of incubation, each well was washed several times with PBS to remove the medium. Images of the wound area were taken at 0 h and 48 h post-treatment. Colony formation assay HepG2 cells were seeded in 6-well plates at a density of 1.25×10 4 cells per well and incubated for 24 hours. The cells were then treated with 6m and vehicle (DMSO) for 6 days, with the medium refreshed every 3 days [ 39 – 40 ].The culture medium was replaced by the fresh RPMI 1640 medium, aspirated the medium, washed twice with PBS, fixed with 4% paraformaldehyde for 30 min, washed with PBS three times, and finally stained with crystal violet 15 min, PBS washed twice. All experiments were conducted in triplicate to ensure the reliability of the results. Molecular docking simulation Molecular docking studies based on autodock 4.0 were carried out to investigate the binding affinity energies between compounds 6a-s and the active sites of isocitrate dehydrogenase 1 (IDH1). PDB ID: 6U4J with the high-resolution structure of 2.11Å has been selected from RCSB Protein Data Bank (RCSB PDB). 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Pest Manag Sci 70(8):1207–1214. https://doi.org/10.1002/ps.3672 Wu J, Wu S, Shi L, Zhang S, Ren J, Yao S, Yun D, Huang L, Wang J, Li W, Wu X, Qiu P, Liang G (2017) Design, synthesis, and evaluation of asymmetric EF24 analogues as potential anti-cancer agents for lung cancer. Eur J Med Chem 125:1321–1331. https://doi.org/10.1016/j.ejmech.2016.10.027 Zhu S, Huo X, Ma Q, Chen W, Zhang J, Guo L (2022) Design, synthesis, and antitumor activity of β-carbolinebenzimidazole hybrids. Chin J Org Chem 42(4):1129–1135. https://doi.org/10.6023/cjoc202110025 Mogavero A, Maiorana MV, Zanutto S et al (2017) Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production. Sci Rep 7:15992. https://doi.org/10.1038/s41598-017-16149-z Xie T, Hu W, You L, Wang X (2024) Design, synthesis and biological evaluation of thienopyridine derivatives as c-Met kinase inhibitors. Mol Divers. https://doi.org/10.1007/s11030-024-10998-3 Additional Declarations No competing interests reported. Supplementary Files SI.doc Cite Share Download PDF Status: Published Journal Publication published 02 Jan, 2025 Read the published version in Molecular Diversity → Version 1 posted Editorial decision: Revision requested 23 Oct, 2024 Editor assigned by journal 16 Oct, 2024 Submission checks completed at journal 16 Oct, 2024 First submitted to journal 15 Oct, 2024 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. 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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-5266541","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":369391799,"identity":"56d677ab-da6d-489b-bfb9-e83ab97e841c","order_by":0,"name":"Kangning Wei","email":"","orcid":"","institution":"Zhejiang A\u0026F University","correspondingAuthor":false,"prefix":"","firstName":"Kangning","middleName":"","lastName":"Wei","suffix":""},{"id":369391801,"identity":"b82f5476-749f-4618-acb4-8c7adceb3d31","order_by":1,"name":"Kaige Guo","email":"","orcid":"","institution":"Zhejiang A\u0026F University","correspondingAuthor":false,"prefix":"","firstName":"Kaige","middleName":"","lastName":"Guo","suffix":""},{"id":369391804,"identity":"58eb5a4a-55cf-42dd-865c-3f0bcf1452d5","order_by":2,"name":"Ye Tao","email":"","orcid":"","institution":"Zhejiang A\u0026F University","correspondingAuthor":false,"prefix":"","firstName":"Ye","middleName":"","lastName":"Tao","suffix":""},{"id":369391807,"identity":"f2f2ece6-bde0-4805-b75d-eeb6498ec409","order_by":3,"name":"Xuanming Gong","email":"","orcid":"","institution":"Zhejiang A\u0026F University","correspondingAuthor":false,"prefix":"","firstName":"Xuanming","middleName":"","lastName":"Gong","suffix":""},{"id":369391810,"identity":"d18f7f0a-db0d-4477-993b-4ea3bcbc33fb","order_by":4,"name":"Liangliang Wang","email":"","orcid":"","institution":"Lishui University","correspondingAuthor":false,"prefix":"","firstName":"Liangliang","middleName":"","lastName":"Wang","suffix":""},{"id":369391813,"identity":"2a21f2b2-9409-4916-89bf-e1bdfd69819a","order_by":5,"name":"Ming Guo","email":"","orcid":"","institution":"Zhejiang A\u0026F University","correspondingAuthor":false,"prefix":"","firstName":"Ming","middleName":"","lastName":"Guo","suffix":""},{"id":369391814,"identity":"7bbecf27-725e-4b2a-88db-71f7c1230550","order_by":6,"name":"Guobing Yan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYDACCRBRwcDA3gCkeYjXcgao+gBJWhjbSNEiH91j+LlwXp08j0QC44O3bQzy5oS0GN45Yyw9cxubYY9EArPh3DYGw50NhLTMyDGQ5t3Gw7hfIoFNmreNIcHgAGEtxr9550jYA21h/02UFnmJHDNp3gaDRKAWNmaitBjIHCuz5jmWkNzD87BZcs45CcMNBG2Z3bz5Nk9NnW0Pe/LBD2/KbOQJ23KAwwDKZGxggMYsAVsa2B8QVjUKRsEoGAUjGwAAkwk539ECbw4AAAAASUVORK5CYII=","orcid":"","institution":"Zhejiang A\u0026F University","correspondingAuthor":true,"prefix":"","firstName":"Guobing","middleName":"","lastName":"Yan","suffix":""}],"badges":[],"createdAt":"2024-10-15 07:38:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5266541/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5266541/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11030-024-11084-4","type":"published","date":"2025-01-02T15:57:15+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":68261292,"identity":"a6ca7375-a361-4f4b-a17f-9c0218fae805","added_by":"auto","created_at":"2024-11-05 12:02:51","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":38274,"visible":true,"origin":"","legend":"\u003cp\u003eSeveral examples of isatin derivatives with biological activities.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5266541/v1/5833a412fb5c8ed0335de542.jpg"},{"id":68261029,"identity":"6a8d3e74-9881-4897-be59-3bb4412d19ab","added_by":"auto","created_at":"2024-11-05 11:54:51","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":16937,"visible":true,"origin":"","legend":"\u003cp\u003eSeveral examples of oxime ether derivatives with biological activities.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5266541/v1/4f3a6a9c7b979717c9bb1dca.jpg"},{"id":68261032,"identity":"db7ee5dd-cc23-4a36-89b7-111b3e5c646f","added_by":"auto","created_at":"2024-11-05 11:54:51","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":20011,"visible":true,"origin":"","legend":"\u003cp\u003eSynthetic route for isatin-oxime ether hybrids and the reaction conditions: (i) K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e, DMF, rt, 24 h; (ii) NH\u003csub\u003e2\u003c/sub\u003eNH\u003csub\u003e2 · \u003c/sub\u003eH\u003csub\u003e2\u003c/sub\u003eO, EtOH, rt 2 h; (iii) AcOH, EtOH, Reflux, 2-3 h.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5266541/v1/f29bf2d8ce72c13e88444c02.jpg"},{"id":68261034,"identity":"467f7784-f3e6-43f7-90de-038303cc5c3e","added_by":"auto","created_at":"2024-11-05 11:54:52","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":54355,"visible":true,"origin":"","legend":"\u003cp\u003eThe effect of \u003cstrong\u003e6m\u003c/strong\u003e on the migration of HepG2 cells. Phase-contrast microscopy was used to capture images of the cells before treatment (0h) and 48 hours after treatment with \u003cstrong\u003e6m\u003c/strong\u003e and DMSO.Compared with DMSO group,*p\u0026lt;0.05,**p\u0026lt;0.01.\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5266541/v1/964223fe7b4afcd16b7e4345.jpg"},{"id":68261028,"identity":"a47f1d2c-5c16-46f3-b871-1e498d00543d","added_by":"auto","created_at":"2024-11-05 11:54:51","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":57352,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative images of HepG2 cell colonies after treatment with different concentrations of \u003cstrong\u003e6m\u003c/strong\u003e. The HepG2 cells were exposed to \u003cstrong\u003e6m\u003c/strong\u003e, then transferred to fresh medium and allowed to form colonies. The colonies were subsequently stained using crystal violet and photographed.\u003c/p\u003e","description":"","filename":"Picture5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5266541/v1/3f20bc8f29d9dc3427537b0a.jpg"},{"id":68261030,"identity":"d6436209-3dea-41ab-af57-a3199e0e7cb9","added_by":"auto","created_at":"2024-11-05 11:54:51","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":60551,"visible":true,"origin":"","legend":"\u003cp\u003e2D(Left), 3D(Right) binding interaction between compound \u003cstrong\u003e6m\u003c/strong\u003e and active sites of IDH1 (PDB: 6U4J ).\u003c/p\u003e","description":"","filename":"Picture6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5266541/v1/b6ec05b7b191f3c9b1864b1f.jpg"},{"id":68261293,"identity":"d8b14788-fef9-43c3-a839-765938d5bf47","added_by":"auto","created_at":"2024-11-05 12:02:51","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":64259,"visible":true,"origin":"","legend":"\u003cp\u003e2D(Left), 3D(Right) binding interaction between compound \u003cstrong\u003e6n\u003c/strong\u003e and active sites of IDH1 (PDB: 6U4J ).\u003c/p\u003e","description":"","filename":"Picture7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5266541/v1/0cdaa8c5dd105c0e226d4166.jpg"},{"id":68261035,"identity":"5ff46e89-8721-4440-9687-5fe293e75c10","added_by":"auto","created_at":"2024-11-05 11:54:52","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"graphical-abstract","size":25505,"visible":true,"origin":"","legend":"A series of novel isatin-oxime ether derivatives were designed, synthesized and characterized by H NMR and C NMR and HRMS. These compounds were evaluated for their cytotoxicity against three human cancer cell lines (A549, HepG2 and Hela) by MTT assay. According to the experimental results, compounds (IC\u0026thinsp;=\u0026thinsp;0.34\u0026micro;M), (IC\u0026thinsp;=\u0026thinsp;14nM) and (IC\u0026thinsp;=\u0026thinsp;45nM) were found as the excellent selectivity and high activity against A549, whereas compounds (IC\u0026thinsp;=\u0026thinsp;12nM) and (IC\u0026thinsp;=\u0026thinsp;25nM) displayed the significant activity for HepG2, respectively. Compound (IC\u0026thinsp;=\u0026thinsp;30nM), (IC\u0026thinsp;=\u0026thinsp;9nM) and (IC\u0026thinsp;=\u0026thinsp;20nM) also showed the excellent activity against Hela. From the experiments of cell migration and colony formation assays, the findings demonstrated that can effectively suppress the migration and growth of HepG2 cells. In addition, the results of molecular docking studies determined the strong binding interactions between the potential active compounds and and the active sites of isocitrate dehydrogenase 1 (IDH1) with the lowest binding affinity energy.","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5266541/v1/7cb51fcaaabaf20e555032b4.png"},{"id":73094402,"identity":"5c3c34d3-1b26-48e0-9d40-a00d3ab438e5","added_by":"auto","created_at":"2025-01-06 16:23:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1140014,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5266541/v1/111806bc-99d1-41e0-99c0-b5b06ed3183c.pdf"},{"id":68261037,"identity":"9ecc5e85-2f8b-46fe-9b25-636834b01d0c","added_by":"auto","created_at":"2024-11-05 11:54:52","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":12589568,"visible":true,"origin":"","legend":"","description":"","filename":"SI.doc","url":"https://assets-eu.researchsquare.com/files/rs-5266541/v1/bfa0db6f71fd24e4eb93cf81.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Design, Synthesis, Biological Evaluation and Molecular Docking of Novel Isatin-Oxime Ether Derivatives as Potential IDH1 Inhibitors","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCancer is a serious health problem in the world, which has increasingly caused high morbidity and mortality rates in the past decades [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The activation of oncogenes and the inactivation of tumor suppressor genes cause uncontrolled cell growth and spreading [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In addition, cancer cells often typically have high levels of replication stress [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Surgery and radiotherapy are two main treatment methods for patients [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, these traditional therapies suffer from some issues, such as high risk and difficult curability. Recently, chemotherapy interfering with biological molecules has become one of the most effective means in the treatment of cancer by inhibiting cancer cell proliferation. Therefore, the development of highly efficient and novel targeting drugs for chemotherapy is desirable.\u003c/p\u003e \u003cp\u003eIsocitrate dehydrogenases (IDHs) play important roles in cellular metabolism and cancer as the key enzymes, which catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The IDH family includes three isoforms (IDH1, IDH2, and IDH3) in humans [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. IDH1 has attracted a lot of attention as a hot target for research, due to the high mutation frequency. Ivosidenib (AG-120) is a first-in-class isocitrate dehydrogenase 1 (IDH1) inhibitor granted approval by the FDA in 2018 for the treatment of relapsed of refractory acute myeloid leukemia in adults, which has been introduced to treat leukemia and cholangiocarcinoma approved by the EMA in 2023. Up to date, numerous research teams are devoted to developing high efficient inhibitors for targeted therapy for diseases caused by IDH1 mutations.\u003c/p\u003e \u003cp\u003eIsatin (indole-1H-2,3-dione) represents one of the most prevalent heterocyclic compounds, which has been found in pharmaceuticals, agrochemicals and natural products [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Isatin and its derivatives exhibit a broad spectrum of pharmacological and biological activities, such as anticancer [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], antibacterial [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] antiviral [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], anti-inflammatory [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], antifungal [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], anticonvulsant [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], anti-HIV [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Especially, several commercial anticancer drugs containing isatin backbone, such as Semaxanib (SU5416), Sunitinib (SU11248), and Nintedanib (\u003cb\u003eI\u003c/b\u003e-\u003cb\u003eIII\u003c/b\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), were approved by the Food and Drug Administration (FDA) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Numerous isatin derivatives have been explored through the modification based on C-3 carbonyl group in the past decades. For examples, isatin oxime ether derivatives display antiviral activity (\u003cb\u003eI\u003c/b\u003eV, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Isatin-hydrazone derivatives have been reported to exhibit a-glucosidase inhibitory activity (\u003cb\u003eV-VI\u003c/b\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Isatin moiety using as a pharmacophore has received widespread attention in the discovery of new drugs.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOn the other hand, oxime ethers are a class of important organic compounds, which have been widely used in designing pharmaceutical and agrochemical molecules [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. For examples, Fenpyroximate (\u003cb\u003eVII\u003c/b\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) with two important moieties of pyrazole ring and oxime ethers in the structure displays excellent acaricidal properties, which was launched in most European countries from 1995 [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. As an antifungal drug in the form of a nitrate salt, Oxiconazole (\u003cb\u003eVIII\u003c/b\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) was spreadly applied to the skin in the form of an ointment, cream or powder [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Fluvoxamine (\u003cb\u003eIX\u003c/b\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) used as an antidepressant drug, which displayed pharmacological activity as a selective serotonin reuptake inhibitor [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Due to its significant biological activities, oxime ether derivatives have gained overwhelming attention [\u003cspan additionalcitationids=\"CR32 CR33 CR34 CR35\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn view of their biological activities, we integrated the structural features of isatin backbone and oxime ether moiety to design some novel isatin-oxime ether hybrid scaffolds with potential bioactivities as shown in \u003cb\u003eFig.\u0026nbsp;3\u003c/b\u003e.\u003c/p\u003e"},{"header":"Results and discussion","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eChemistry\u003c/h2\u003e \u003cp\u003eThe hybrid compounds need to be carried out in three steps and the synthetic route is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The nucleophilic substitution reaction of benzyl bromides with 2-hydroxyisoindoline-1,3-dione provides 2-(benzyloxy)isoindoline-1,3-diones, then reduced with hydrazine hydrate to give \u003cem\u003eO\u003c/em\u003e-benzylhydroxylamines. Finally, dehydration condensation of isatin derivatives and \u003cem\u003eO\u003c/em\u003e-benzylhydroxylamines delivers the target molecules.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eBiology\u003c/h3\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eResults of MTT\u003c/h2\u003e \u003cp\u003eFrom these results, substitution groups on isatin backbone and benzene ring of oxime ether moiety have a significant impact on biological activity. Firstly, based on 5-fluoro isatin-oxime ether hybrids \u003cb\u003e6a-6f\u003c/b\u003e, it was found that substitution groups on oxime ether moiety have an important effect on selectivity and activity. For examples, compounds \u003cb\u003e6a\u003c/b\u003e displayed biological activity against A549 (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.34\u0026micro;M) and Hela (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;6.69\u0026micro;M) cancer cells. Introduction of a fluorine atom in the benzene ring of oxime ether moiety \u003cb\u003e6c\u003c/b\u003e resulted in different selectivity and relatively high activity, such as against A549 (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;14nM) and HepG2 (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.01\u0026micro;M) cancer cells, whereas chlorine \u003cb\u003e6b\u003c/b\u003e and bromine atom \u003cb\u003e6d\u003c/b\u003e can lead to lower activity. Interestingly, compounds \u003cb\u003e6e\u003c/b\u003e and \u003cb\u003e6f\u003c/b\u003e showed high selectivity and activity against HepG2 (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.31\u0026micro;M) and hela (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;30nM), respectively, when the benzene ring changed to the pyridine ring \u003cb\u003e6e\u003c/b\u003e, and fluorine atom was replaced by tertbutyl ester group \u003cb\u003e6f\u003c/b\u003e. Secondly, the different substitution groups on the isatin backbone were also explored for the influence of activity \u003cb\u003e6g\u003c/b\u003e-\u003cb\u003e6s\u003c/b\u003e, mainly based on the unchanged structure of oxime ether moiety with tertbutyl ester group. 5-bromo and 7-fluoro \u003cem\u003eN\u003c/em\u003e-free isatin-oxime ether hybrids \u003cb\u003e6h\u003c/b\u003e and \u003cb\u003e6m\u003c/b\u003e exhibited the high activity against Hela (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.38\u0026micro;M) and HepG2 (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;12nM) cells, respectively. \u003cem\u003eN\u003c/em\u003e-substituted isatin-oxime ether hybrids \u003cb\u003e6o\u003c/b\u003e and \u003cb\u003e6r\u003c/b\u003e showed high selectivity and activity against Hela (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;20nM) and A549 (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;45nM) cells, respectively. It is also interesting to note that 7-bromo-\u003cem\u003eN\u003c/em\u003e-meyhyl satin-oxime ether hybrids \u003cb\u003e6n\u003c/b\u003e displayed the significant activity against Hela (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;9nM) and HepG2(IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;25nM) cells. These results possibly indicated that the \u003cem\u003eN\u003c/em\u003e-substitution groups in the isatin moiety is critical for the activity against Hela (\u003cb\u003e6n\u003c/b\u003e and \u003cb\u003e6o\u003c/b\u003e), whereas the introduction of a fluorine atom into isatin backbone and the substituted position on benzene ring have a significant effect on the activity against A549, HepG2 and Hela (\u003cb\u003e6j-m\u003c/b\u003e). These comprehensive factors may be attributed to its drastically conformational change and steric requirement of isatin-oxime ether hybrids.\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\u003eIC\u003csub\u003e50\u003c/sub\u003e (\u0026micro;M) value of isatin-oxime ether hybrids.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eIsatin-oxime ether hybrids\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eIC\u003csub\u003e50\u003c/sub\u003e(\u0026micro;M)\u003csup\u003ea\u003c/sup\u003e \u0026plusmn; SD\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComp.\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eR\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA549\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHepG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHela\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5-F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6b\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-Cl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5-F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e42.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6c\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5-F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.014\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6d\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2-Br\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5-F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e23.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6e\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePyridyl \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5-F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47.55\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6f\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5-F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e99.51\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6g\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5-CH\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e18.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5-Br\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28.96\u0026thinsp;\u0026plusmn;\u0026thinsp;0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6i\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5-OCH\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e55.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6j\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6-Cl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6k\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6-F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.96\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6l\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7-Cl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6m\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7-F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.012\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e32.92\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6n\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7-Br\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCH\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.025\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.009\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6o\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBn\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.020\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6p\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4-MeC\u003csub\u003e6\u003c/sub\u003eH\u003csub\u003e4\u003c/sub\u003eCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e53.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6q\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4-FC\u003csub\u003e6\u003c/sub\u003eH\u003csub\u003e4\u003c/sub\u003eCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e59.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6r\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4-ClC\u003csub\u003e6\u003c/sub\u003eH\u003csub\u003e4\u003c/sub\u003eCH\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.045\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18.79\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6s\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4-CO\u003csub\u003e2\u003c/sub\u003e\u003csup\u003et\u003c/sup\u003eBu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14.92\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\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\u003eAll IC\u003csub\u003e50\u003c/sub\u003e values are reported as means of values from at three determinations.\u003c/p\u003e \u003cp\u003e \u003csup\u003eb\u003c/sup\u003e SD: standard deviation.\u003c/p\u003e \u003cp\u003e \u003csup\u003ec\u003c/sup\u003e (6-chloropyridin-3-yl)methyl.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eResults of Cell migration\u003c/h3\u003e\n\u003cp\u003eCancer mortality and prognosis are often linked to the metastatic potential of tumors, as cancer cells exhibit a high capacity for migration. To explore the effect of 6m on cell migration, we employed the wound healing assay. In this experiment, HepG2 cells were exposed to 6m following the creation of a scratch in the confluent monolayer of the cultured cells. Images of the wound area were taken at 0 h and 48 h post-treatment. As illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e, the wound in the DMSO-treated control group had nearly fully healed by 48h, whereas treatment with \u003cb\u003e6m\u003c/b\u003e led to a concentration-dependent inhibition of wound closure. These findings demonstrate that 6m can effectively suppress the migration of HepG2 cells.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eResults of Colony formation\u003c/h3\u003e\n\u003cp\u003eTo assess the inhibitory effects of \u003cb\u003e6m\u003c/b\u003e on cell proliferation, a colony formation assay was conducted to evaluate its impact on HepG2 cells. Cells were exposed to \u003cb\u003e6m\u003c/b\u003e at different concentrations (20 \u0026micro;mol, 20/3 \u0026micro;mol, and 20/9 \u0026micro;mol). As depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e, treatment with \u003cb\u003e6m\u003c/b\u003e led to a pronounced reduction in viable cell numbers in a dose-dependent fashion when compared with the DMSO control. These results clearly indicate that \u003cb\u003e6m\u003c/b\u003e is capable of significantly suppressing HepG2 cell growth.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eResults of Molecular docking studies\u003c/h2\u003e \u003cp\u003eFrom the results shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the binding energies between compounds and IDH1 were relatively reasonable, compared with that of co-crystal compound (ivosidenib, AG-120). The compound \u003cb\u003e6m\u003c/b\u003e has the best binding affinity with \u0026minus;\u0026thinsp;11.8 kcal/mol of the binding energy.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe binding affinity energies between isatin-oxime ether hybrids and IDH1.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComp.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAffinity. Kcal/mol\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eComp.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAffinity. Kcal/mol\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComp.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAffinity. Kcal/mol\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e6h\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-11.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e6n\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-11.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6b\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-11.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e6i\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-11.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e6o\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-11.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6c\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-11.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e6j\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-11.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e6p\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-11.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6d\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e6k\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-11.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e6q\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-11.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6e\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-11.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e6l\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-11.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e6r\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-11.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6f\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-11.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e6m\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-11.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e6s\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-11.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6g\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-11.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eIvosidenib\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-13.5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe also investigated the binding interaction between high active compounds \u003cb\u003e6m\u003c/b\u003e, \u003cb\u003e6n\u003c/b\u003e and the active sites of IDH1 shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e8\u003c/span\u003e. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e, the binding mode of compound \u003cb\u003e6m\u003c/b\u003e included four hydrogen bonds formation between Leu120 with NH, fluorine atom of isatin, between Ala111 with nitrogen of oxime ether, and between Arg119 with fluorine atom of isatin. The amino acid residues Trp124 and Tyr285 showed π-π stacked and π-π T-shaped hydrophobic interactions with benzene ring, whereas π-sigma interactions were observed between benzene ring and Val281, Ile130 and Ile113 residues. In addition, hydrophobic interactions like alkyl, π-alkyl and van der Waals, also play an essential role in the inhibitory activity.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAs for compound \u003cb\u003e6n\u003c/b\u003e shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e8\u003c/span\u003e, the typical binding mode consists of three hydrogen bonds between Ala111, Arg109 with nitrogen atom of oxime ether moiety, between Ser280 with oxygen atom of tert-butyl ester. The amino acid residues Ile130 showed π-sigma hydrophobic interactions with benzene ring of oxime ether moiety. The hydrophobic interactions of alkyl, π-alkyl with Trp267, Leu120 and Arg119 were observed. However, unfavourable bump between \u003cb\u003e6n\u003c/b\u003e and amino acid residues was also obvious, such as Ile128, Val281,Tyr285, Trp124, Pro127.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe have designed and synthesized isatin-oxime ether hybrids as potential IDH1 inhibitors. The in vitro bioassay of these compounds against A549, HepG2 and Hela cancer cells revealed that compounds \u003cb\u003e6c\u003c/b\u003e, \u003cb\u003e6m\u003c/b\u003e, \u003cb\u003e6n\u003c/b\u003e had significant biological activity. In addition, the colony formation and wound healing assays demonstrated that \u003cb\u003e6m\u003c/b\u003e exhibited strong anti-proliferative and anti-migratory properties. The reasonable interactions in molecular docking study make them good lead compounds for the development of IDH1 inhibitors.\u003c/p\u003e"},{"header":"Experimental","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMaterials\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003eReagents and instruments\u003c/h2\u003e \u003cp\u003eAll chemicals were purchased from Alfa Aesar and Shaoyuan Webstore. Chloroform-d and Methyl sulfoxide-d6 were purchased from Cambridge Isotope Laboratories. CDCl\u003csub\u003e3\u003c/sub\u003e was used as solvent with tetramethylsilane (TMS) as internal standard. All solvents were distilled prior to use. All reactions with air- and moisture-sensitive components were performed under a nitrogen atmosphere in a flame-dried reaction flask. For chromatography, 200\u0026ndash;300 mesh silica gel (Qingdao, China) was employed. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were measure on Bruker 400 M spectrometers. High Resolution Mass Spectrometry (HRMS) were all recorded on an ABI/Sciex QStar Mass Spectrometer using a positive electrospray ionization (ESI+).\u003c/p\u003e \u003cp\u003eRPMI Medium 1640 basic was purchased from Shanghai Lifei Biotechnology Co., Ltd. Dulbecco's Modifed Eagle Medium was purchased from Thermo Fisher Scientific (Suzhou) Instruments Co., Ltd. Fetal Bovine Serum (FBS) and streptomycin mixture (100X) were purchased from Gibco. PBS, trypsin, DMSO, and MTT powder were purchased from sigma company. Culture dishes (100 mm) and 6/96-well plates were purchased from NEST. Cell mix device, cell climbing sheet, sealing membrane, frozen storage tube, electric heating thermostatic water bath (XMTD were purchased Shanghai Jinghong Experimental Equipment Co., Ltd.). Cells were purchased from the national experimental cell resource sharing platform.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSynthesis of compounds\u003c/h2\u003e \u003cp\u003eGeneral procedure for the synthesis of 2-(benzyloxy)isoindoline-1,3-diones (\u003cb\u003e3a-f\u003c/b\u003e)\u003c/p\u003e \u003cp\u003eTo a solution of 2-hydroxyisoindoline-1,3-dione \u003cb\u003e1a\u003c/b\u003e (4 mmol) and K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (4 mmol) in anhydrous dimethyl formamide (DMF) (20 mL), (bromomethyl)arenes \u003cb\u003e2a-f\u003c/b\u003e (4.8 mmol, 1.2 equiv) was added under inert gas at room temperature. After the reaction mixture was stirred for 24 h, and monitored by TLC. When the reaction was completed, the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over MgSO\u003csub\u003e4\u003c/sub\u003e and evaporated to leave a residue, which was purified by column chromatography using the indicated eluent to give the solid products of 2-(benzyloxy)isoindoline-1,3-dione \u003cb\u003e3a-f\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eGeneral procedure for the synthesis of O-benzylhydroxylamines (\u003cb\u003e4a-f\u003c/b\u003e)\u003c/p\u003e \u003cp\u003eTo a solution of 2-(benzyloxy)isoindoline-1,3-diones \u003cb\u003e3a-f\u003c/b\u003e (2 mmol) in absolute ethanol (EtOH, 10 mL), 80% hydrazine hydrate (2.4 mmol, 1.2 equiv) was added under inert gas at room temperature for 2 h, and monitored by TLC. When the reaction was completed, ice water (20 mL) was added in the reaction. The mixture was stirred vigorously until a large amount of solid was precipitated. After filtration, the filtrate was extracted with ethyl acetate. The combined organic layer was dried over MgSO\u003csub\u003e4\u003c/sub\u003e and evaporated to leave a residue, which was purified by column chromatography using the indicated eluent to the product of \u003cem\u003eO\u003c/em\u003e-benzylhydroxylamines \u003cb\u003e4a-f\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eGeneral procedure for the synthesis of (Z)-3-((benzyloxy)imino)indolin-2-one (\u003cb\u003e6a-s\u003c/b\u003e)\u003c/p\u003e \u003cp\u003eTo a solution of \u003cem\u003eO\u003c/em\u003e-benzylhydroxylamines \u003cb\u003e4a-f\u003c/b\u003e (1.2 mmol 1.2 equiv) in absolute ethanol (EtOH, 10 mL), isatin derivatives \u003cb\u003e5a-s\u003c/b\u003e (1 mmol) and acetic acid (1.0% mmol) was added. The reaction mixture was refluxed for 2\u0026ndash;3 h. Then the mixture was allowed to cool to room temperature. The crystalline products \u003cb\u003e6a-s\u003c/b\u003e were collected by filtration and washed thoroughly with cold ether.\u003c/p\u003e \u003cp\u003eStructure determination of isatin-oxime ether hybrids\u003c/p\u003e \u003cp\u003eAll the hybrid compounds were characterized by \u003csup\u003e1\u003c/sup\u003eH NMR, \u003csup\u003e13\u003c/sup\u003eC NMR and HRMS spectroscopic techniques.\u003c/p\u003e \u003cp\u003e(Z)-3-((benzyloxy)imino)-5-fluoroindolin-2-one (\u003cb\u003e6a\u003c/b\u003e) Yellow Solid; Yield: 87%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H, NH), 7.58 (dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.47\u0026thinsp;~\u0026thinsp;7.35 (m, 5H), 7.23 (ddd, J\u0026thinsp;=\u0026thinsp;12.0, 8.0, 4.0Hz, 1H), 6.91\u0026thinsp;~\u0026thinsp;6.85(m, 1H), 5.73 (s, 2H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO-d6): δ 164.1, 156.9, 144.8, 140.2, 130.50 ,129.50, 129.1, 128.9, 119.9(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e=23Hz), 116.5 (d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =9Hz), 114.8(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =26Hz), 112.1(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e=8Hz), 78.7; \u003csup\u003e19\u003c/sup\u003eF NMR (377 MHz, DMSO-d6): δ -120.56~-121.18(m,1F); HRMS calcd for C\u003csub\u003e15\u003c/sub\u003eH\u003csub\u003e11\u003c/sub\u003eFN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 293.0701, found: 293.0702.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e(Z)-3-(((4-chlorobenzyl)oxy)imino)-5-fluoroindolin-2-one (\u003cb\u003e6b\u003c/b\u003e) Yellow Solid; Yield: 79%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz DMSO-d6): δ 10.80 (s, 1H, NH), 7.58 (dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.48\u0026thinsp;~\u0026thinsp;7.43 (m, 4H), 7.23 (ddd, J\u0026thinsp;=\u0026thinsp;12.0, 8.0, 4.0Hz, 1H), 6.85(dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 5.44 (s, 2H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO-d6): δ 164.0, 159.3, 145.0(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =2Hz), 140.3(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =2Hz), 136.3, 133.5, 130.7(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =7Hz), 129.1(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =11Hz), 120.1(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e=24Hz), 116.4, 115.0(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e=25Hz), 112.1(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =8Hz), 77.7; \u003csup\u003e19\u003c/sup\u003eF NMR (377 MHz, DMSO-d6): δ -121.10~-121.13(d,1F); HRMS calcd for C\u003csub\u003e15\u003c/sub\u003eH\u003csub\u003e10\u003c/sub\u003eClFN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 327.0312, found: 327.0313.\u003c/p\u003e \u003cp\u003e-5-fluoro-3-(((4-fluorobenzyl)oxy)imino)indolin-2-one (\u003cb\u003e6c\u003c/b\u003e) Yellow Solid; Yield: 73%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz DMSO-d6): δ 10.81 (s, 1H, NH), 7.59 (dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.52 (dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.27\u0026thinsp;~\u0026thinsp;7.21 (m, 4H), 6.87(dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 5.74 (s, 2H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO-d6): δ 164.1(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =23Hz), 161.4, 159.2, 156.9, 144.8(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =3Hz), 140.2(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =2Hz), 133.4(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =3Hz), 131.3, 120.1(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e=24Hz), 116.5, 116.1, 114.9(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e=27Hz), 112.1(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =8Hz), 77.9; \u003csup\u003e19\u003c/sup\u003eF NMR (377 MHz, DMSO-d6): δ -113.51~-113.54(d,1F), -121.14~-121.17(d,1F); HRMS calcd for C\u003csub\u003e15\u003c/sub\u003eH\u003csub\u003e10\u003c/sub\u003eF\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 311.0607, found: 311.0608.\u003c/p\u003e \u003cp\u003e(Z)-3-(((2-bromobenzyl)oxy)imino)-5-fluoroindolin-2-one (\u003cb\u003e6d\u003c/b\u003e) Yellow Solid; Yield: 72%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz DMSO-d6): δ 10.79 (s, 1H, NH), 7.66 (dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.59(dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.51 (dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.40(td, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.30(ddd, J\u0026thinsp;=\u0026thinsp;12.0, 8.0, 4.0Hz, 1H), 7.23(ddd, J\u0026thinsp;=\u0026thinsp;12.0, 8.0, 4.0Hz, 1H), 5.5 (s, 2H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO-d6): δ 164.0, 159.8, 156.8, 145.2(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =2Hz), 140.3(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =2Hz), 136.2, 133.3, 131.6, 131.2, 128.6, 123.9, 120.2(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =24Hz), 116.4, 115.0(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e=26Hz), 112.2, 78.3; \u003csup\u003e19\u003c/sup\u003eF NMR (377 MHz, DMSO-d6): δ -121.05~-121.11(t,1F); HRMS calcd for C\u003csub\u003e15\u003c/sub\u003eH\u003csub\u003e10\u003c/sub\u003eBrFN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 370.9807, found: 370.9807.\u003c/p\u003e \u003cp\u003e(Z)-3-(((6-chloropyridin-3-yl)methoxy)imino)-5-fluoroindolin-2-one (\u003cb\u003e6e\u003c/b\u003e) Yellow Solid; Yield: 67%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz DMSO-d6): δ 10.79 (s, 1H, NH), 8.49 (dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.93(dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.61 (dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.53(dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.22(ddd, J\u0026thinsp;=\u0026thinsp;12.0, 8.0, 4.0Hz, 1H), 6.84(dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 5.48 (s, 2H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO-d6): δ 164.0, 159.3, 156.9, 150.8, 145.3(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =3Hz), 140.6, 140.3(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =2Hz), 132.5, 124.9, 120.3(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =23Hz), 115.2, 115.0, 112.1(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =8Hz), 75.1; \u003csup\u003e19\u003c/sup\u003eF NMR (377 MHz, DMSO-d6): δ -121.07~-121.10(d,1F); HRMS calcd for C\u003csub\u003e14\u003c/sub\u003eH\u003csub\u003e9\u003c/sub\u003eClFN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 328.0264, found: 328.0265.\u003c/p\u003e \u003cp\u003etert-butyl (Z)-4-((((5-fluoro-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6f\u003c/b\u003e) Yellow Solid; Yield: 75%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 9.48 (s, 1H, NH), 8.00(m, 2H), 7.61(dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.46 (m, 2H), 7.03(td, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 6.84(dd, J\u0026thinsp;=\u0026thinsp;12.0, 4.0Hz, 1H), 5.56 (s, 2H), 1.58(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 165.9 (C\u0026thinsp;=\u0026thinsp;O), 165.5(C\u0026thinsp;=\u0026thinsp;O), 160.1, 157.7, 144.5, 138.2(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =3Hz), 132.3, 129.9, 128.0, 119.57(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =24Hz), 116.7(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =9Hz), 115.5(d, J\u0026thinsp;=\u0026thinsp;1.6(d, J\u0026thinsp;=\u0026thinsp;7.0 Hz ), 81.3, 79.1, 28.3; \u003csup\u003e19\u003c/sup\u003eF NMR (377 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ -119.3~-119.26 (d,1F); HRMS calcd for C\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eFN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 393.1226, found: 393.1227.\u003c/p\u003e \u003cp\u003etert-butyl (Z)-4-((((5-methyl-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6g\u003c/b\u003e) Yellow Solid; Yield: 73%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 9.50 (s, 1H, NH), 7.99(d, J\u0026thinsp;=\u0026thinsp;8.0Hz, 2H), 7.71(dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.47 (d, J\u0026thinsp;=\u0026thinsp;8.0Hz, 2H), 7.11(ddd, J\u0026thinsp;=\u0026thinsp;12.0, 8.0, 4.0Hz, 1H), 6.79(d, J\u0026thinsp;=\u0026thinsp;8.0Hz, 1H), 5.55(s, 2H), 2.27(s, 3H), 1.58(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 166.1, 165.5, 145.0, 141.1, 141.0, 133.5, 132.8, 129.8, 128.7, 127.8, 116.3, 110.8, 81.3, 78.6, 28.3, 21.1; HRMS calcd for C\u003csub\u003e21\u003c/sub\u003eH\u003csub\u003e22\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 389.1476, found: 389.1477.\u003c/p\u003e \u003cp\u003etert-butyl (Z)-4-((((5-bromo-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6h\u003c/b\u003e)\u003c/p\u003e \u003cp\u003eYellow Solid; Yield: 78%; \u003csup\u003e1\u003c/sup\u003e H NMR (400 MHz DMSO-d6): δ 10.9 (s, 1H, NH), 7.93(m, 3H), 7.53(m, 3H), 6.82(d, J\u0026thinsp;=\u0026thinsp;8.0Hz, 1H), 5.52(s, 2H), 1.50(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, DMSO-d6): δ 165.2, 163.6, 146.2, 143.5, 142.3, 136.0, 131.7, 130.1, 129.8, 128.6, 117.8, 114.7, 113.2, 81.3, 77.9, 28.3; HRMS calcd for C\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eBrN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 453.0425, found: 453.0426.\u003c/p\u003e \u003cp\u003etert-butyl (Z)-4-((((5-methoxy-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6i\u003c/b\u003e) Yellow Solid; Yield: 76%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 9.42(s, 1H, NH), 7.99(m, 2H), 7.51(d, J\u0026thinsp;=\u0026thinsp;4.0Hz, 1H), 7.46 (m, 2H), 6.87(dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 6.81(dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 5.55(s, 2H), 3.73(s, 3H), 1.58(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 166.0 (C\u0026thinsp;=\u0026thinsp;O), 165.5, 155.91, 145.2, 140.8, 135.9, 132.1, 129.9, 127.8, 118.1, 116.9, 114.5, 111.4, 81.3, 78.7, 56.0, 28.3; HRMS calcd for C\u003csub\u003e21\u003c/sub\u003eH\u003csub\u003e22\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 405.1425, found: 405.1426.\u003c/p\u003e \u003cp\u003etert-butyl (Z)-4-((((6-chloro-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6j\u003c/b\u003e) Yellow Solid; Yield: 74%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 9.45(s, 1H, NH), 7.99(m, 2H), 7.78(d, J\u0026thinsp;=\u0026thinsp;12.0Hz, 1H), 7.45 (m, 2H), 6.95(m, 2H), 5.54(s, 2H), 1.58(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 166.8, 165.5, 143.8, 143.2, 140.5, 138.8, 132.3, 129.9, 129.0, 128.0, 123.4, 114.8, 111.7, 81.4, 79.9, 28.3; HRMS calcd for C\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eClN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 409.0930, found: 409.0931.\u003c/p\u003e \u003cp\u003etert-butyl (Z)-4-((((6-fluoro-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6k\u003c/b\u003e) Yellow Solid; Yield: 72%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 9.51(s, 1H, NH), 7.99(m, 2H), 7.86(m, 1H), 7.46 (m, 2H), 6.67(m, 2H), 5.53(s, 2H), 1.58(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 166.7, 165.3, 165.4, 164.2, 144.3, 143.7, 141.4, 132.2, 130.1 (d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =11Hz), 128.0, 112.7, 110.0 (d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =23Hz), 99.8(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =27Hz), 81.9, 78.8, 28.3; \u003csup\u003e19\u003c/sup\u003eF NMR (377 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ -102.47~-102.49(d, 1F); HRMS calcd for C\u003csub\u003e21\u003c/sub\u003eH\u003csub\u003e22\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e5\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 405.1425, found: 405.1426. HRMS calcd for C\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eFN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 393.1226, found: 393.1227.\u003c/p\u003e \u003cp\u003etert-butyl (Z)-4-((((7-chloro-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6l\u003c/b\u003e) Yellow Solid; Yield: 77%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 8.68(s, 1H, NH), 7.99(d, J\u0026thinsp;=\u0026thinsp;8.0Hz, 2H), 7.78(dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.46 (d, J\u0026thinsp;=\u0026thinsp;8.0Hz, 2H), 7.30(dt, J\u0026thinsp;=\u0026thinsp;8.0Hz, 4.0Hz, 1H), 6.95(m, 1H), 5.55(s, 2H), 1.58(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 165.5, 164.2, 144.2, 140.4, 139.6, 132.5, 132.3, 129.9, 128.1, 126.4, 124.1, 117.5, 116.0, 81.3, 79.0, 28.3; HRMS calcd for C\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eClN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 409.0930, found: 409.0931.\u003c/p\u003e \u003cp\u003etert-butyl (Z)-4-((((7-fluoro-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6m\u003c/b\u003e) Yellow Solid; Yield: 73%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 8.91(s, 1H, NH), 8.0(m, 2H), 7.69(dt, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.46 (m, 2H), 7.11(ddd, J\u0026thinsp;=\u0026thinsp;12.0, 8.0, 4.0Hz, 1H), 6.96(ddd, J\u0026thinsp;=\u0026thinsp;12.0, 8.0, 4.0Hz, 1H), 5.56(s, 2H), 1.58(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 165.5, 164.4, 148.3, 145.8, 143.9, 141.7, 132.2, 129.9, 128.1, 123.9(q, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =4Hz), 119.9(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =17Hz), 118.5(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =4Hz), 81.3, 79.0, 28.3; \u003csup\u003e19\u003c/sup\u003eF NMR (377 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ -133.21(s, 1F); HRMS calcd for C\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eFN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 393.1226, found: 393.1227.\u003c/p\u003e \u003cp\u003etert-butyl(Z)-4-((((7-bromo-1-methyl-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6n\u003c/b\u003e) Yellow Solid; Yield: 66%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 7.96(d, J\u0026thinsp;=\u0026thinsp;8.0Hz, 2H), 7.85(dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 7.41 (m, 3H), 6.88(dd, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 5.51(s, 2H), 3.55(s, 3H),1.58(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 166.6, 163.8, 143.1, 141.8, 140.5, 138.1, 132.2, 129.9, 128.0, 127.8, 127.1, 124.3, 118.4, 103.2, 81.2, 79.0, 29.8, 28.3; HRMS calcd for C\u003csub\u003e21\u003c/sub\u003eH\u003csub\u003e21\u003c/sub\u003eBrN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 467.0582, found: 467.0582.\u003c/p\u003e \u003cp\u003etert-butyl (Z)-4-((((1-benzyl-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6o\u003c/b\u003e) Yellow Solid; Yield: 79%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 8.01(m, 2H), 7.91(m, 1H), 7.49 (m, 2H), 7.28(m, 4H), 7.23(m, 2H), 6.97(td, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 6.68(dt, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 5.56(s, 2H), 4.90(s, 2H),1.58(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 166.6, 163.7, 144.4, 143.8, 140.9, 135.4, 132.8, 129.9, 129.0, 127.9, 127.4, 123.3, 116.8, 115.6, 109.7, 81.1, 78.7, 43.8, 28.3; HRMS calcd for C\u003csub\u003e27\u003c/sub\u003eH\u003csub\u003e26\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 465.1789, found: 465.1790.\u003c/p\u003e \u003cp\u003etert-butyl(Z)-4-((((1-(4-methylbenzyl)-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6p\u003c/b\u003e) Yellow Solid; Yield: 75%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 8.01(m, 2H), 7.91(ddd, J\u0026thinsp;=\u0026thinsp;12.0, 8.0, 4.0Hz,1H), 7.49 (m, 2H), 7.25(td, 1H), 7.19(m, 2H), 7.10(m, 2H), 6.97(td, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 6.71(dt, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 5.57(s, 2H), 4.89(s, 2H), 2.29(s, 3H), 1.59(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 165.5, 163.6, 144.5, 143.9, 140.8, 137.6, 132.7, 132.4, 129.9, 129.6, 128.1, 128.0, 127.5, 123.2, 115.9, 109.7, 83.0, 78.7, 43.6, 28.3, 21.2; HRMS calcd for C\u003csub\u003e28\u003c/sub\u003eH\u003csub\u003e28\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 479.1947, found: 479.1947.\u003c/p\u003e \u003cp\u003etert-butyl(Z)-4-((((1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6q\u003c/b\u003e) Yellow Solid; Yield: 76%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 8.00(m, 2H), 7.92(ddd, J\u0026thinsp;=\u0026thinsp;12.0, 8.0, 4.0Hz,1H), 7.48 (m, 2H), 7.27(m, 3H), 6.98(m, 3H), 6.69(dt, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 5.56(s, 2H), 4.89(s, 2H), 2.29(s, 3H), 1.58(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 165.5, 163.6, 161.2, 144.2, 143.6, 140.7, 132.8, 132.2, 131.2(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =4Hz), 129.9, 129.30, 128.2, 128.0, 127.5, 123.4, 116.0(d, J\u003csub\u003e\u003cem\u003eCF\u003c/em\u003e\u003c/sub\u003e =4Hz), 109.4, 81.3, 78.8, 43.1, 28.3; \u003csup\u003e19\u003c/sup\u003eF NMR (377 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ -114.14(s, 1F); HRMS calcd for C\u003csub\u003e27\u003c/sub\u003eH\u003csub\u003e25\u003c/sub\u003eFN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 483.1694, found: 483.1696.\u003c/p\u003e \u003cp\u003etert-butyl(Z)-4-((((1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6r\u003c/b\u003e) Yellow Solid; Yield: 72%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 8.01(m, 2H), 7.92(m,1H), 7.48 (d, J\u0026thinsp;=\u0026thinsp;8.0Hz, 2H), 7.25(m, 5H), 7.00(td, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 6.66(dt, J\u0026thinsp;=\u0026thinsp;8.0, 4.0Hz, 1H), 5.57(s, 2H), 4.90(s, 2H), 1.58(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 165.5, 163.6, 143.5, 140.7, 133.9, 133.8, 132.8, 132.2, 129.9, 129.7, 129.1, 128.8, 128.3, 128.1, 123.4, 109.4, 82.4, 78.8, 43.2, 28.3; HRMS calcd for C\u003csub\u003e27\u003c/sub\u003eH\u003csub\u003e25\u003c/sub\u003eClN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 499.1400, found: 499.1401.\u003c/p\u003e \u003cp\u003etert-butyl (Z)-4-((((2-oxoindolin-3-ylidene)amino)oxy)methyl)benzoate (\u003cb\u003e6s\u003c/b\u003e) Yellow Solid; Yield: 85%; \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 9.89(s, 1H, NH), 7.96(d, J\u0026thinsp;=\u0026thinsp;8.0Hz, 2H), 7.81 (d, J\u0026thinsp;=\u0026thinsp;8.0Hz, 1H), 7.43(d, J\u0026thinsp;=\u0026thinsp;8.0Hz, 2H), 7.23(d, J\u0026thinsp;=\u0026thinsp;12.0Hz, 1H),, 6.91(m, 2H), 5.50(s, 2H), 1.55(s, 9H); \u003csup\u003e13\u003c/sup\u003eC NMR (100 MHz, CDCl\u003csub\u003e3\u003c/sub\u003e-d1): δ 166.1, 165.6, 145.0, 142.5, 140.9, 133.0, 132.0, 129.8, 128.1, 127.9, 123.2, 116.2, 111.2, 81.3, 78.6, 28.3; HRMS calcd for C\u003csub\u003e20\u003c/sub\u003eH\u003csub\u003e20\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e [M\u0026thinsp;+\u0026thinsp;Na]\u003csup\u003e+\u003c/sup\u003e : 375.1320, found: 375.1321.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eBiology\u003c/h2\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003eMTT assay\u003c/h2\u003e \u003cp\u003eThe antitumour activity of isatin-oxime ether hybrids (\u003cb\u003e6a-s\u003c/b\u003e) was evaluated using on human cancer cells A549, HepG2 and Hela by MTT assay in vitro. These cancer cells were cultivated in RPMI medium plates containing 10% fetal bovine serum and 2 mM L-glutamine for 24 h at 37\u003csup\u003e0\u003c/sup\u003eC. The percentage of growth inhibition was calculated using the formula [Ti/C] x 100% [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eCell migration assay\u003c/h2\u003e \u003cp\u003eHepG2 cells were seeded in a 6-well plate at a concentration of 5x10\u003csup\u003e5\u003c/sup\u003e cells/well, which were allowed to reach 90% confluence in complete medium after 24h of growth. A single scratch wound of cell cultures was created with a 200 \u0026micro;L sterile pipette tip using the designed mold [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The wounded monolayers were washed three times with phosphate buffer saline (PBS) to remove the detached cells. The various concentrations of \u003cb\u003e6m\u003c/b\u003e were added to its corresponding wells. After 48h of incubation, each well was washed several times with PBS to remove the medium. Images of the wound area were taken at 0 h and 48 h post-treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eColony formation assay\u003c/h2\u003e \u003cp\u003eHepG2 cells were seeded in 6-well plates at a density of 1.25\u0026times;10\u003csup\u003e4\u003c/sup\u003e cells per well and incubated for 24 hours. The cells were then treated with \u003cb\u003e6m\u003c/b\u003e and vehicle (DMSO) for 6 days, with the medium refreshed every 3 days [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].The culture medium was replaced by the fresh RPMI 1640 medium, aspirated the medium, washed twice with PBS, fixed with 4% paraformaldehyde for 30 min, washed with PBS three times, and finally stained with crystal violet 15 min, PBS washed twice. All experiments were conducted in triplicate to ensure the reliability of the results.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eMolecular docking simulation\u003c/h2\u003e \u003cp\u003eMolecular docking studies based on autodock 4.0 were carried out to investigate the binding affinity energies between compounds \u003cb\u003e6a-s\u003c/b\u003e and the active sites of isocitrate dehydrogenase 1 (IDH1). PDB ID: 6U4J with the high-resolution structure of 2.11\u0026Aring; has been selected from RCSB Protein Data Bank (RCSB PDB).\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003e\"K.N. and K.G. wrote the main manuscript text and Y. and X.M. prepared the molucular docking. All authors reviewed the manuscript.\"\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank the Project Sponsored of Advanced Talents by Zhejiang A\u0026amp;F University (No. 04251700031) and Zhejiang University Student Science and Technology Innovation Activity Plan（New Seedling talent Plan subsidy project，2024R412B039）for financial support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J (2016) Cancer statistics in China. 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Mol Divers. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s11030-024-10998-3\u003c/span\u003e\u003cspan address=\"10.1007/s11030-024-10998-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-diversity","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"modi","sideBox":"Learn more about [Molecular Diversity](http://link.springer.com/journal/11030)","snPcode":"11030","submissionUrl":"https://submission.nature.com/new-submission/11030/3","title":"Molecular Diversity","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Isatin, Oxime ether, Anticancer activity, Isocitrate dehydrogenase 1, Molecular docking","lastPublishedDoi":"10.21203/rs.3.rs-5266541/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5266541/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA series of novel isatin-oxime ether derivatives were designed, synthesized and characterized by 1H NMR and 13C NMR and HRMS. These compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (A549, HepG2 and Hela) by MTT assay. According to the experimental results, compounds 6a (IC50=0.34μM), 6c (IC50=14nM) and 6r (IC50=45nM) were found as the excellent selectivity and high activity against A549, whereas compounds 6m (IC50=12nM) and 6n(IC50=25nM) displayed the significant activity for HepG2, respectively. Compound 6f (IC50=30nM), 6n (IC50=9nM) and 6o(IC50=20nM) also showed the excellent activity against Hela. From the experiments of cell migration and colony formation assays, the findings demonstrated that 6m can effectively suppress the migration and growth of HepG2 cells. In addition, the results of molecular docking studies determined the strong binding interactions between the potential active compounds 6m and 6n and the active sites of isocitrate dehydrogenase 1 (IDH1) with the lowest binding affinity energy.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Design, Synthesis, Biological Evaluation and Molecular Docking of Novel Isatin-Oxime Ether Derivatives as Potential IDH1 Inhibitors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-05 11:54:47","doi":"10.21203/rs.3.rs-5266541/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-23T07:16:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-16T18:42:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-16T06:48:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Diversity","date":"2024-10-15T07:30:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-diversity","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"modi","sideBox":"Learn more about [Molecular Diversity](http://link.springer.com/journal/11030)","snPcode":"11030","submissionUrl":"https://submission.nature.com/new-submission/11030/3","title":"Molecular Diversity","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"1cdc235d-7cc1-4962-b9ad-ea2ccdfdab8e","owner":[],"postedDate":"November 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-06T16:21:51+00:00","versionOfRecord":{"articleIdentity":"rs-5266541","link":"https://doi.org/10.1007/s11030-024-11084-4","journal":{"identity":"molecular-diversity","isVorOnly":false,"title":"Molecular Diversity"},"publishedOn":"2025-01-02 15:57:15","publishedOnDateReadable":"January 2nd, 2025"},"versionCreatedAt":"2024-11-05 11:54:47","video":"","vorDoi":"10.1007/s11030-024-11084-4","vorDoiUrl":"https://doi.org/10.1007/s11030-024-11084-4","workflowStages":[]},"version":"v1","identity":"rs-5266541","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5266541","identity":"rs-5266541","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}