Synthesis of Novel Acetamidobenzanilides Derivatives as Potencial Trypanocidal Agents

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Ortellado, Carlos U. Molfesa Kaczoruk, Lucio A. Guaymas, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4415338/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract A simple synthesis of novel N -(2-[ N ’-acetamidomethyl])benzanilides derivatives from 2-nitrobenzaldehyde in a four steps process is described. The 1 H-NMR and 13 C-NMR spectra were meticulously analyzed to characterize their structure and it was observed that derivatives with an ortho-substituted phenyl group exhibited detectable atropisomerism. The ADME/toxicity analyses was performed and several of these acetamidobenzanilides were tested in vitro against the epimastigote form of Trypanosoma cruzi , demonstrating significant activity. Acetamidobenzanilides Antichagasic activity NMR diamides Atropisomerism Figures Figure 1 Figure 2 INTRODUCTION Chagas’ disease (also known as American trypanosomiasis) is a zoonosis caused by the flagellated protozoan Trypanosoma cruzi and is the most widespread parasitic disease in Latin America affecting at least 6–7 million of human beings all over the world [ 1 ]. The available drugs for the treatment of this condition are Benznidazole and Nifurtimox, both are associated with a high frequency of adverse events and exhibit variable efficacy [ 2 ]. As a consequence, several investigations were conducted in order to broaden the molecular diversity of bioactive compounds against the parasite. The trypanocidal activities of various compounds, such as acridines, phenothiazines, benzazepines, imidazoisoquinolinones, quinazolines, and pyridoquinolines, have been studied [ 3 ]. While many of these compounds exhibit promising bioactive properties, further investigations in this field are deemed necessary. In the literature, exist substances derived from amides, polyamides, and polyamines that act as inhibitors of trypanothione reductase (TryR), an enzyme exclusive to trypanosomatids (Fig. 1 ) [ 4 ]. A paradigmatic example of such compounds is suramin, a symmetrical polyamide approved for the treatment of Trypanosoma brucei infection (Fig. 2 ) [ 5 ]. Although suramin has a proven therapeutic effect, its neurotoxicity, potentially severe and dose-limiting, impedes the drug's clinical utility. Moreover, Suramin and other polyamides present multi-step and complex organic syntheses, leading to expensive preparation procedures. Other diamides derivatives compounds have shown biological activity as insecticide [ 6 ] or as antimicrobial [ 7 ]. Also, one bisamide derivative of 1,4-benzodioxane was reported as an HSF1 pathway inhibitor that showed growth inhibitory activities in the human ovarian carcinoma xenograft model [ 8 ]. Additionally, anthranilic acid diamides have been evaluated as cholecystokinin receptor antagonists [ 9 ] and antispasmodics [ 10 ]. Due to the significance of suramin and other diamides or bisamides in the study of Chagas’ disease, we decided to investigate the preparation and biological activity of a series of acetamidobenzanilide derivatives. Hence, we designed a synthesis strategy for preparing new N -(2-[ N ’-acetamidomethyl])benzanilides derivatives through a four-step process. The synthetic precursors employed had been previously studied in our laboratory as intermediates in the synthesis of 1,4-benzodiazepin-3-ones [ 11 ]. In a preliminary study, we decided to synthesize four acetamidobenzanilides to evaluate their in vitro activity (CC 50 and IC 50 ) against T. cruzi . As the results were promising, a battery of 18 of these compounds was prepared. RESULTS AND DISCUSSION Synthesis The synthesis of these novel acetamidobenzanilides is described in Scheme 1 . In the initial step, N -(2-nitrobenzyl)anilines 2 were prepared by reductive amination of o -nitrobenzaldehyde 1 with anilines using a standard method and NaBH 4 as a reduction agent [ 11 ]. These substituted anilines were obtained in good yields and subsequently underwent amidation with acetyl chloride in toluene at reflux to afford acetamides 3 . In the third step process, the nitro group was reduced to amino group using iron dust in a solution of ammonium chloride with ethanol-water as solvent at reflux to afford acetamides 4 [ 11 ]. The final diamides ( 5 ) were obtained with a benzoylation of the amino group using benzoyl chlorides in toluene at 110°C. Diamides 5 were prepared in good to very good yields with the exception of compounds bearing R 2 = NO 2 ( 5m , 5o and 5r were obtained with lower yields) and were characterized by elemental analysis, 1 H NMR, and 13 C NMR. Yields of the final step and melting points of the white or pale yellow solid products are listed in Table 1 . Table 1 Yields and melting points of products 5 . Compounds 5 Final step yield (%) Melting point (°C) 5a (R 1 = p -Br; R 2 = H) 81 203–204 5b (R 1 = o -Cl; R 2 = H) 72 160–161 5c (R 1 = p -Cl; R 2 = H) 78 202–203 5d (R 1 = o -F; R 2 = H) 76 112–113 5e (R 1 = p -F; R 2 = H) 62 179–180 5f (R 1 = p- I; R 2 = H) 46 178–179 5g (R 1 = p -Br; R 2 = o -Cl) 89 154–155 5h (R 1 = o -Cl; R 2 = o -Cl) 69 112–113 5i (R 1 = p -Cl; R 2 = o -Cl) 54 162–163 5j (R 1 = o -F; R 2 = o -Cl) 75 62–63 5k (R 1 = p -F; R 2 = o -Cl) 65 135–136 5l (R 1 = p -I; R 2 = o -Cl) 68 143–144 5m (R 1 = p -Br; R 2 = o -NO 2 ) 33 185–186 5n (R 1 = o -Cl; R 2 = o -NO 2 ) 60 114–115 5o (R 1 = p -Cl; R 2 = o -NO 2 ) 31 174–175 5p (R 1 = o -F; R 2 = o -NO 2 ) 40 160–161 5q (R 1 = p -F; R 2 = o -NO 2 ) 69 173–174 5r (R 1 = p -I; R 2 = o -NO 2 ) 32 183–184 NMR study As bioactive organic molecules interact with their biological receptors in a particular and finely tuned manner a thorough analysis of their structures and conformations is imperative to get reliable information that may contribute to the knowledge of the biological molecular mechanisms and structure-activity relationships [ 12 ]. In recent decades, atropisomerism has gained increased attention owing to its significance in investigations concerning natural products and bioactive molecules as both isomers often manifest distinct pharmacological activities [ 13 ]. While the conformational rigidity of bicyclic moieties is extensively documented in the literatura [ 14 ], recent interest in drug discovery science has focused investigations of atropisomerism around the C-N axis in cases where the nitrogen atom is acyclic [ 15 ]. Upon analyzing the structures of the synthesized acetamidobenzanilides, we identified an atropisomeric scaffold characterized by axial chirality along the C-N bond axis in several examples, as illustrated in Scheme 2 . As shown in Scheme 2 , benzanilides exhibit the presence of two stereogenic C-N axes, with their conformational flexibility modulated by neighboring aryl substituents. It has been previously reported that the C-NHR moiety lacks atropisomeric properties, the racemization process occurs too rapid to be detected by 1 H-NMR spectroscopy. Therefore, isomerism arises from the C-NRR’ axis, wherein the presence of an ortho substituent (R 1 ) in the second aryl group is associated with the atropisomerism, as evidenced by the distinctive pattern observed in the methylene 1 H NMR spectra as two diastereotopic hydrogens. In Table 2 , we summarize the 1 H NMR details of the CH 2 signal of compounds 5 with high level of configuration stability that generates detectable atropisomerism in all compounds with R 1 = o -X. As an example, 1 H NMR of compund 5b is shown in Scheme 3 . Table 2 1 H-NMR CH 2 signals for compounds 5 Compounds 5 CH 2 1 H-NMR chemical shifts δ, ppm ( J , Hz) 5a (R 1 = p -Br; R 2 = H) 4.80 (s, 2H) 5b (R 1 = o -Cl; R 2 = H) 5.23 (d, J = 14.7, 1H); 4.31 (d, J = 14.7, 1H) 5c (R 1 = p -Cl; R 2 = H) 4.80 (s, 2H) 5d (R 1 = o -F; R 2 = H) 5.03 (d, J = 14.6, 1H); 4.56 (d, J = 14.6, 1H) 5e (R 1 = p -F; R 2 = H) 4.80 (s, 2H) 5f (R 1 = p- I; R 2 = H) 4.79 (s, 2H) 5g (R 1 = p -Br; R 2 = o -Cl) 4.81 (s, 2H) 5h (R 1 = o -Cl; R 2 = o -Cl) 5.26 (d, J = 14.8, 1H); 4.32 (d, J = 14.8, 1H) 5i (R 1 = p -Cl; R 2 = o -Cl) 4.82 (s, 2H) 5j (R 1 = o -F; R 2 = o -Cl) 5.07 (d, J = 14.7, 1H); 4.55 (d, J = 14.7, 1H) 5k (R 1 = p -F; R 2 = o -Cl) 4.81 (s, 2H) 5l (R 1 = p -I; R 2 = o -Cl) 4.81 (s, 2H) 5m (R 1 = p -Br; R 2 = o -NO 2 ) 4.77 (s, 2H) 5n (R 1 = o -Cl; R 2 = o -NO 2 ) 5.23 (d, J = 14.8, 1H); 4.26 (d, J = 14.8, 1H) 5o (R 1 = p -Cl; R 2 = o -NO 2 ) 4.77 (s, 2H) 5p (R 1 = o -F; R 2 = o -NO 2 ) 5.10 (d, J = 14.8, 1H); 4.44 (d, J = 14.8, 1H) 5q (R 1 = p -F; R 2 = o -NO 2 ) 4.77 (s, 2H) 5r (R 1 = p -I; R 2 = o -NO 2 ) 4.76 (s, 2H) ADME predictions To select target molecules in the early stages of drug development, predicting ADME profiles has been proven to be a reliable and valuable tool [ 16 ]. We calculate the physicochemical properties, lipophilicity, and drug likeness of the prepared compounds [ 17 ]. The complete results are summarized in the supporting information section. The drug likeness evaluation of most compounds are deemed acceptable according to Lipinski's rule of five, as well as the parameters considered by Ghose, Veber, Egan, and Muegge. In R 2 : -H or -X derivatives, the topological polar surface area (TPSA) suggests a likely favorable intestinal adsorption of the molecule. However, a TPSA value below 60 Å indicates potential penetration of the blood-brain barrier, as observed in the BBB permeability results. On the other hand, benzanilides derived from R 2 : -NO 2 exhibit an optimal TPSA value ranging between 60 and 140 Å. Consequently, the pharmacokinetic profile, including blood-brain barrier permeability and CYP1A2 inhibition, is superior to those described for the aforementioned compounds. The compounds shown in 1.2. SI table (demonstrate a favorable bioavailability score of 0.55, acceptable skin permeation values ranging between − 8 to -1, and reasonable synthetic accessibility (< 3.1). In vitro biological evaluation The in vitro activity of 5a-d showed a dose-response inhibitory effect in their activity against T. cruzi epimastigotes, with half-maximum inhibitory concentration (IC 50 ) values less than 15 mM. The evaluated compounds were selected to perform a first screening analyzing the influence of three electron-withdrawing groups in different positions. The IC 50 results of these compounds suggest that they are active ( 5a and 5c ) and moderately active ( 5b and 5d ) against T. cruzi in this parasitic stage. On the other hand, cytotoxicity is determined in the VERO cell line, it can be observed that none of the compounds evaluated presents cytotoxicity, in particular compounds 5b and 5d stand out for their CC 50 value (CC 50 > 500 µM) (Table 3 ). SI was also calculated. Table 3 In vitro anti- T. cruzi activity and cytotoxic activity of selected compounds. BNZ was used as reference drug Compound IC 50 (µM) CC 50 (µM) SI 5a 6.9 ± 0.3 35.2 ± 2.1 5.1 5b 14.5 ± 0.4 > 500 - 5c 8.0 ± 0.6 52.7 ± 8.3 6.6 5d 9.4 ± 0.9 > 500 - BNZ 6.1 ± 0.5 > 500 - CONCLUSION In conclusión, we have designed and implemented a facile and efficient synthesis of new N -(2-[ N ’-acetamidomethyl])benzanilides derivatives through a four-step process. All 18 final compounds were synthesized with satisfactory yields. It was observed that compounds 5 bearing an ortho substituent (R 1 ) in the phenyl group of the acetanilide moeity, exhibited atropisomerism attributable to the axial chirality along the C-N bond axis. The manifestation of this phenomenon is evidenced by the presence of a doublet signal in the 1 H NMR spectrum for each diastereotopic hydrogen within the CH 2 moiety. Several of these diamides ( 5a - d ) exhibited inhibitory effects against T. cruzi epimastigote forms, with compounds 5a and 5c demonstrating significant activity, while compounds 5b and 5d showed moderate activity as determined by the evaluation of IC 50 values. Cytotoxicity was also assessed, and none of the analyzed compounds exhibited cytotoxic effects. A complete biological study (cytotoxicity, in vitro and in vivo assays with T. cruzi epi and trypomastigote forms) and computational studies with all 18 new compounds will be carried out in a subsequent work. EXPERIMENTAL SECTION General methods and materials Melting points were determined with a Büchi apparatus and were uncorrected. 1 H NMR and 13 C NMR spectra were recorded on a Brucker Avance Neo 500, 11.75 T spectrometer operated at 500 MHz ( 1 H) and 126 MHz ( 13 C). Liquid column chromatography separations were achieved on silica gel Grace Davison 60- 200 mesh or Sigma-Aldrich 230–400 mesh. Thin-layer chromatography (TLC) was performed on silica gel 60 F254 sheets (Merck). Elemental analyses for C, H, N, and S were performed using a Carlo Erba EA 1108 analyzer. o- Nitrobenzaldehyde, anilines, acetyl chloride, benzoyl chloride, triethylamine (TEA) and sodium borohydride were purchased from Aldrich. 2-Chloro and 2-nitrobenzoyl chlorides were prepared by a standard method [ 18 ]. Synthesis of N -(2-nitrobenzyl)anilines ( 2 ) As a general procedure, to a solution of 1 (10 mmol) in 10 ml of methanol was added the primary aniline (10 mmol) and heated at reflux for 2 h. The mixture was cooled at 0°C and NaBH 4 (10 mmol) was added, stirred for 2–24 h and evaporated. The resulting solid was dissolved in CH 2 Cl 2 (10 ml), washed with water (5 ml), dried over sodium sulfate and the solvent was removed under reduced pressure to afford the N- (2-nitrobenzyl)anilines that were used without further purification. Synthesis of N -phenyl- N -(2-nitrobenzyl)acetamides ( 3 ) N -(2-nitrobenzyl)aniline ( 2 ) (5 mmol) and 5 mmol of TEA were dissolved in toluene (10 ml) and a solution of 5 mmol of acetyl chloride in 10 ml of toluene was added. The mixture was heated to reflux for 2–24 hs, cooled and washed with water (10 ml), HCl 10% (10 ml) and water (2 x 10 ml). Solution was dried over sodium sulfate and concentrated to dryness at reduced pressure to obtain crude N -phenyl- N -(2-nitrobenzyl)acetamides ( 3 ) that were purified by column chromatography (hexane-EtOAc 8:2). Synthesis of N -phenyl- N -(2-aminobenzyl)acetamides ( 4 ) N -phenyl- N -(2-nitrobenzyl)acetamides ( 3 ) (3 mmol) were disolved in 30 ml of metanol and 15 mmol of iron dust was added. The mixture was energetically stirred and a solution of 30 mmol of NH 4 Cl in 15 ml of water was added and then heated at reflux until complete reaction. The mixture was filtered over celite, washed with metanol and the solvente removed at reduced pressure. The residue was disolved with 30 ml of CH 2 Cl 2 , washed with water, and the solution dried over sodium sulfate. The solvent was evaporated and the product purified by silica column cromatography (hexane-EtOAc 7:3) affording acetamides 4 . Synthesis of N -(2-[ N’ -acetamidomethyl])benzanilides ( 5 ) N -phenyl- N -(2-aminobenzyl)acetamides ( 4 ) (2 mmol) and 2 mmol of TEA were dissolved in toluene (5 ml) and a solution of 2 mmol of the proper benzoyl chloride in 5 ml of toluene was added. The mixture was heated to reflux for 2–24 hs, cooled and washed with water (10 ml), HCl 10% (10 ml) and water (2 x 10 ml). Solution was dried over sodium sulfate and concentrated to dryness at reduced pressure to obtain crude N -(2-[ N ’-acetamidomethyl])benzanilides ( 5 ) that were purified by crystallization of ethanol. N -(2-( N’ -(4-bromophenyl)acetamidomethyl)benzanilide 5a Yield: 81%. Mp = 203–204°C. C 22 H 19 BrN 2 O 2 ; found C, 62.46; H, 4.55; N, 6.63%; requires C, 62.42; H, 4.52; Br, 18.88; N, 6.62; O, 7.56%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.71 (s, 1H), 8.20 (dd, J = 7.8, 1.8 Hz, 2H), 8.13 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.56–7.51 (m, 3H), 7.37 (m, 1H), 7.00–6.94 (m, 3H), 6.71 (d, J = 7.6 Hz, 1H), 4.80 (s, 2H), 1.83 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ) δ 171.33, 166.59, 141.70, 136.93, 135.01, 133.38, 131.80, 131.39, 130.23, 129.13, 128.62, 128.00, 127.12, 125.32, 124.37, 122.71, 50.43, 22.66. N -(2-( N ’-(2-chlorophenyl)acetamidomethyl)benzanilide 5b Yield: 72%. Mp = 160–161°C. C 22 H 19 ClN 2 O 2 ; found C, 69.66; H, 5.08; N, 7.40%; requires C, 69.75; H, 5.06; Cl, 9.36; N, 7.39; O, 8.45%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.74 (s, 1H), 8.25–8.19 (m, 2H), 8.16 (dd, J = 8.3, 1.2 Hz, 1H), 7.60–7.50 (m, 4H), 7.38 (dtd, J = 9.4, 7.7, 1.6 Hz, 2H), 7.32 (td, J = 7.6, 1.5 Hz, 1H), 7.02 (dd, J = 7.8, 1.6 Hz, 1H), 6.97 (td, J = 7.4, 1.2 Hz, 1H), 6.69 (dd, J = 7.6, 1.6 Hz, 1H), 5.23 (d, J = 14.7 Hz, 1H), 4.31 (d, J = 14.7 Hz, 1H), 1.82 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 171.81, 166.67, 139.69, 137.20, 135.09, 133.11, 131.77, 131.51, 131.27, 131.07, 130.26, 129.06, 128.60, 128.19, 128.05, 126.98, 125.10, 124.24, 49.19, 22.23. N -(2-( N ’-(4-chlorophenyl)acetamidomethyl)benzanilide 5c Yield: 78%. Mp = 202–203°C. C 22 H 19 ClN 2 O 2 ; found C, 69.72; H, 5.01; N, 7.36%; requires C, 69.75; H, 5.06; Cl, 9.36; N, 7.39; O, 8.45%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.72 (s, 1H), 8.20 (dd, J = 7.9, 1.5 Hz, 2H), 8.13 (d, J = 8.1 Hz, 1H), 7.61–7.49 (m, 3H), 7.42 (d, J = 8.6 Hz, 2H), 7.39–7.33 (m, 1H), 7.01 (d, J = 8.6 Hz, 2H), 6.98 (t, J = 7.6 Hz, 1H), 6.71 (dd, J = 7.6, 1.6 Hz, 1H), 4.80 (s, 2H), 1.83 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 171.40, 166.59, 141.17, 136.94, 135.00, 134.69, 131.80, 131.39, 130.36, 129.90, 129.12, 128.61, 128.00, 127.13, 125.30, 124.35, 50.46, 22.64. N -(2-( N ’-(2-fluorophenyl)acetamidomethyl)benzanilide 5d Yield: 76%. Mp = 112–113°C. C 22 H 19 FN 2 O 2 ; found C, 73.10; H, 5.22; N, 7.45%; requires C, 72.91; H, 5.28; F, 5.24; N, 7.73; O, 8.83%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.70 (s, 1H), 8.22 (dd, J = 7.7, 1.8 Hz, 2H), 8.14 (d, J = 8.1 Hz, 1H), 7.59–7.51 (m, 3H), 7.45–7.39 (m, 1H), 7.36 (ddd, J = 8.6, 7.6, 1.6 Hz, 1H), 7.25–7.19 (m, 2H), 7.08 (td, J = 7.7, 1.7 Hz, 1H), 6.97 (td, J = 7.5, 1.3 Hz, 1H), 6.71 (dd, J = 7.7, 1.6 Hz, 1H), 5.03 (d, J = 14.6 Hz, 1H), 4.56 (d, J = 14.6 Hz, 1H), 1.86 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 171.95, 166.61, 159.03, 157.04, 136.98, 135.07, 131.78, 131.15, 130.72, 130.69, 130.66, 129.07, 128.62, 128.02, 127.25, 125.32, 125.28, 125.18, 124.37, 117.35, 117.19, 49.76, 22.08. N -(2-( N ’-(4-fluorophenyl)acetamidomethyl)benzanilide 5e Yield: 62%. Mp = 179–180°C. C 22 H 19 FN 2 O 2 ; found C, 73.09; H, 5.20; N, 7.60%; requires C, 72.91; H, 5.28; F, 5.24; N, 7.73; O, 8.83%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.74 (s, 1H), 8.21 (dd, J = 7.8, 1.8 Hz, 2H), 8.13 (dd, J = 8.3, 1.2 Hz, 1H), 7.60–7.49 (m, 3H), 7.37 (td, J = 7.8, 1.6 Hz, 1H), 7.13 (m, 2H), 7.08–7.01 (m, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.71 (dd, J = 7.7, 1.6 Hz, 1H), 4.80 (s, 2H), 1.82 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 171.63, 166.62, 163.29, 161.31, 138.69, 138.66, 136.95, 135.01, 131.79, 131.42, 130.34, 130.27, 129.07, 128.61, 128.01, 127.19, 125.27, 124.31, 117.16, 116.97, 50.53, 22.62. N -(2-( N ’-(4-yodophenyl)acetamidomethyl)benzanilide 5f Yield: 46%. Mp = 178–179°C. C 22 H 19 IN 2 O 2 ; found C, 56.25; H, 4.10; N, 5.97%; requires C, 56.18; H, 4.07; I, 26.98; N, 5.96; O, 6.80%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.72 (s, 1H), 8.23–8.17 (m, 2H), 8.12 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.57–7.50 (m, 3H), 7.36 (t, J = 7.4 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 7.4 Hz, 1H), 4.79 (s, 2H), 1.83 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 171.27, 166.56, 142.38, 139.35, 136.89, 134.98, 131.78, 131.36, 130.43, 129.09, 128.60, 127.98, 127.14, 125.29, 124.36, 94.15, 50.38, 22.64. 2-Chloro -N -(2-( N’ -(4-bromophenyl)acetamidomethyl)benzanilide 5g Yield: 94%. Mp = 154–155°C. C 22 H 18 ClBrN 2 O 2 ; found C, 57.80; H, 4.00; N, 6.19%; requires C, 57.73; H, 3.96; Br, 17.46; Cl, 7.74; N, 6.12; O, 6.99%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.27 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.66 (dd, J = 6.7, 2.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.48 (dd, J = 7.2, 2.1 Hz, 1H), 7.43–7.34 (m, 3H), 6.96 (td, J = 7.5, 1.2 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 6.69 (dd, J = 7.6, 1.6 Hz, 1H), 4.81 (s, 2H), 1.74 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 171.37, 166.12, 141.18, 136.70, 136.66, 133.29, 131.58, 131.28, 131.18, 130.25, 130.12, 129.37, 129.24, 127.01, 126.28, 124.36, 123.62, 122.67, 50.37, 22.49. 2-Chloro- N -(2-( N ’-(2-chlorophenyl)acetamidomethyl)benzanilide 5h Yield: 69%. Mp = 112–113°C. C 22 H 18 Cl 2 N 2 O 2 ; found C, 63.80; H, 4.48; N, 6.77%; requires C, 63.93; H, 4.39; Cl, 17.15; N, 6.78; O, 7.74%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.32 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 7.71–7.65 (m, 1H), 7.52 (dd, J = 8.0, 1.4 Hz, 1H), 7.50–7.46 (m, 1H), 7.43–7.32 (m, 4H), 7.29–7.24 (m, 1H), 6.97–6.88 (m, 2H), 6.66 (dd, J = 7.6, 1.6 Hz, 1H), 5.26 (d, J = 14.8 Hz, 1H), 4.32 (d, J = 14.8 Hz, 1H), 1.72 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 171.88, 166.20, 139.17, 137.05, 136.73, 133.09, 131.64, 131.40, 131.16, 131.13, 130.98, 130.28, 130.23, 129.35, 129.28, 128.17, 126.98, 126.15, 124.23, 123.43, 49.13, 22.04. 2-Chloro- N -(2-( N ’-(4-chlorophenyl)acetamidomethyl)benzanilide 5i Yield: 54%. Mp = 162–163°C. C 22 H 18 Cl 2 N 2 O 2 ; found C, 63.85; H, 4.45; N, 6.83%; requires C, 63.93; H, 4.39; Cl, 17.15; N, 6.78; O, 7.74%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.27 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.48 (d, J = 7.1 Hz, 1H), 7.45–7.32 (m, 5H), 7.01–6.90 (m, 3H), 6.69 (d, J = 7.3 Hz, 1H), 4.82 (s, 2H), 1.74 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 171.50, 166.18, 140.66, 136.72, 136.68, 134.68, 131.62, 131.31, 131.21, 130.31, 130.28, 129.87, 129.40, 129.36, 127.07, 126.32, 124.38, 123.68, 50.57, 22.61. 2-Chloro -N -(2-( N ’-(2-fluorophenyl)acetamidomethyl)benzanilide 5j Yield: 75%. Mp = 62–63°C. C 22 H 18 ClFN 2 O 2 ; found C, 66.51; H, 4.55; N, 7.02%; requires C, 66.59; H, 4.57; Cl, 8.93; F, 4.79; N, 7.06; O, 8.06%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.25 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.70–7.66 (m, 1H), 7.50–7.46 (m, 1H), 7.43–7.33 (m, 4H), 7.20–7.13 (m, 2H), 6.98 (td, J = 7.5, 1.7 Hz, 1H), 6.94 (td, J = 7.5, 1.2 Hz, 1H), 6.68 (dd, J = 7.5, 1.6 Hz, 1H), 5.07 (d, J = 14.7 Hz, 1H), 4.55 (d, J = 14.7 Hz, 1H), 1.76 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 172.00, 166.16, 159.02, 157.02, 136.79, 131.32, 131.16, 130.69, 130.63, 130.59, 130.28, 129.32, 129.27, 126.98, 126.43, 125.25, 125.22, 124.33, 123.56, 117.24, 117.08, 49.64, 21.90. 2-Chloro -N -(2-( N ’-(4-fluorophenyl)acetamidomethyl)benzanilide 5k Yield: 65%. Mp = 135–136°C. C 22 H 18 ClFN 2 O 2 ; found C, 66.50; H, 4.51; N, 7.09%; requires C, 66.59; H, 4.57; Cl, 8.93; F, 4.79; N, 7.06; O, 8.06%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.30 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 7.69–7.65 (m, 1H), 7.48 (dd, J = 7.0, 2.1 Hz, 1H), 7.44–7.34 (m, 3H), 7.08 (t, J = 8.5 Hz, 2H), 6.99–6.93 (m, 3H), 6.68 (dd, J = 7.6, 1.6 Hz, 1H), 4.81 (s, 2H), 1.73 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 171.69, 166.16, 163.25, 161.27, 138.17, 138.14, 136.71, 136.68, 131.62, 131.17, 130.25, 130.23, 130.16, 129.34, 129.23, 127.00, 126.36, 124.30, 123.59, 117.08, 116.90, 50.50, 22.45. 2-Chloro -N -(2-( N ’-(4-yodophenyl)acetamidomethyl)benzanilide 5l Yield: 68%. Mp = 143–144°C. C 22 H 18 ClIN 2 O 2 ; found C, 52.24; H, 3.66; N, 5.60%; requires C, 52.35; H, 3.59; Cl, 7.02; I, 25.14; N, 5.55; O, 6.34%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.27 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.66 (dd, J = 6.9, 2.0 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.39 (m, 3H), 6.97 (t, J = 7.5 Hz, 1H), 6.74 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 7.4 Hz, 1H), 4.81 (s, 2H), 1.74 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 171.33, 166.12, 141.91, 139.29, 136.70, 136.67, 131.58, 131.29, 131.18, 130.34, 130.26, 129.37, 129.24, 127.01, 126.32, 124.37, 123.65, 94.17, 50.35, 22.51. 2-Nitro -N -(2-( N’ -(4-bromophenyl)acetamidomethyl)benzanilide 5m Yield: 33%. Mp = 185–186°C. C 22 H 18 BrN 3 O 4 ; found C, 56.44; H, 3.87; N, 8.99%; requires C, 56.42; H, 3.87; Br, 17.06; N, 8.97; O, 13.67%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.43 (s, 1H), 8.41 (dd, J = 8.2, 1.1 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.81–7.72 (m, 2H), 7.63 (ddd, J = 8.6, 6.4, 2.4 Hz, 1H), 7.42–7.32 (m, 3H), 6.97–6.89 (m, 3H), 6.64 (dd, J = 7.6, 1.5 Hz, 1H), 4.77 (s, 2H), 1.70 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 171.93, 165.39, 146.32, 140.28, 136.84, 134.73, 134.04, 133.62, 131.73, 130.57, 130.30, 129.74, 129.63, 129.23, 125.66, 124.63, 124.27, 123.01, 50.51, 22.31. 2-Nitro -N -(2-( N ’-(2-chlorophenyl)acetamidomethyl)benzanilide 5n Yield: 60%. Mp = 114–115°C. C 22 H 18 ClN 3 O 4 ; found C, 62.28; H, 4.25; N, 9.99%; requires C, 62.34; H, 4.28; Cl, 8.36; N, 9.91; O, 15.10%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.49 (s, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 4.4 Hz, 2H), 7.64 (dt, J = 8.5, 4.4 Hz, 1H), 7.52 (dd, J = 8.0, 1.4 Hz, 1H), 7.36 (dtd, J = 15.4, 8.2, 1.5 Hz, 2H), 7.28–7.23 (m, 1H), 6.93 (t, J = 7.4 Hz, 1H), 6.88 (dd, J = 7.8, 1.6 Hz, 1H), 6.61 (dd, J = 7.6, 1.5 Hz, 1H), 5.23 (d, J = 14.8 Hz, 1H), 4.26 (d, J = 14.8 Hz, 1H), 1.68 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 172.37, 165.41, 146.46, 138.78, 137.16, 134.01, 133.66, 132.90, 131.75, 131.19, 130.93, 130.56, 130.31, 129.61, 129.28, 128.23, 125.58, 124.64, 124.17, 122.86, 49.17, 21.87. 2-Nitro -N -(2-( N ’-(4-chlorophenyl)acetamidomethyl)benzanilide 5o Yield: 31%. Mp = 174–175°C. C 22 H 18 ClN 3 O 4 ; found C, 62.30; H, 4.20; N, 9.84%; requires C, 62.34; H, 4.28; Cl, 8.36; N, 9.91; O, 15.10%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.42 (s, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.81–7.72 (m, 2H), 7.63 (ddd, J = 8.6, 6.5, 2.2 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.41–7.34 (m, 1H), 6.95 (td, J = 7.5, 1.2 Hz, 1H), 6.86 (d, J = 8.5 Hz, 2H), 6.64 (dd, J = 7.6, 1.5 Hz, 1H), 4.77 (s, 2H), 1.70 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 171.86, 165.39, 146.32, 140.81, 136.84, 134.05, 133.63, 133.32, 131.74, 130.57, 130.13, 130.07, 129.65, 129.24, 125.64, 124.65, 124.29, 123.02, 50.49, 22.34. 2-Nitro -N -(2-( N ’-(2-fluorophenyl)acetamidomethyl)benzanilide 5p Yield: 40%. Mp = 160–161°C. C 22 H 18 FN 3 O 4 ; found C, 64.87; H, 4.48; N, 10.39%; requires C, 64.86; H, 4.45; F, 4.66; N, 10.31; O, 15.71%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.43 (s, 1H), 8.39 (d, J = 8.2 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 4.4 Hz, 2H), 7.66–7.61 (m, 1H), 7.38 (m, 2H), 7.23–7.11 (m, 2H), 6.98–6.90 (m, 2H), 6.64 (d, J = 7.5 Hz, 1H), 5.10 (d, J = 14.8 Hz, 1H), 4.44 (d, J = 14.8 Hz, 1H), 1.73 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 172.48, 165.38, 158.93, 156.94, 146.45, 136.91, 134.00, 133.66, 131.48, 130.76, 130.57, 129.60, 129.26, 125.90, 125.26, 124.67, 124.29, 123.07, 117.21, 117.06, 49.66, 21.79. 2-Nitro -N -(2-( N ’-(4-fluorophenyl)acetamidomethyl)benzanilide 5q Yield: 69%. Mp = 173–174°C. C 22 H 18 FN 3 O 4 ; found C, 64.77; H, 4.50; N, 10.46%; requires C, 64.86; H, 4.45; F, 4.66; N, 10.31; O, 15.71%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.45 (s, 1H), 8.41 (d, J = 8.2 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.80–7.72 (m, 2H), 7.63 (ddd, J = 8.7, 6.3, 2.6 Hz, 1H), 7.38 (td, J = 7.8, 1.6 Hz, 1H), 7.07 (m, 2H), 6.98–6.91 (m, 3H), 6.63 (dd, J = 7.6, 1.5 Hz, 1H), 4.77 (s, 2H), 1.69 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 172.18, 165.42, 163.30, 161.32, 146.32, 137.77, 136.86, 134.05, 133.64, 131.76, 130.57, 130.19, 130.12, 129.61, 129.24, 125.74, 124.64, 124.23, 122.99, 117.11, 116.93, 50.62, 22.29. 2-Nitro -N -(2-( N ’-(4-yodophenyl)acetamidomethyl)benzanilide 5r Yield: 32%. Mp = 183–184°C. C 22 H 18 IN 3 O 4 ; found C, 51.36; H, 3.55; N, 8.23%; requires C, 51.28; H, 3.52; I, 24.63; N, 8.15; O, 12.42%. Spectral Data: 1 H NMR (500 MHz, Chloroform- d ): δ 10.43 (s, 1H), 8.40 (d, J = 8.2 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.80–7.72 (m, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.63 (ddd, J = 8.6, 6.7, 2.4 Hz, 1H), 7.38 (td, J = 7.6, 1.5 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 6.8 Hz, 1H), 4.76 (s, 2H), 1.69 (s, 3H). 13 C NMR (126 MHz, Chloroform- d ): δ 171.80, 165.38, 141.52, 139.31, 136.83, 134.04, 133.63, 131.74, 130.56, 130.29, 129.63, 129.23, 128.33, 125.68, 124.64, 124.30, 123.04, 94.28, 50.45, 22.34. Epimastigote proliferation inhibition assay Parasites belonging to the virulent RA strain (DTU VI), were employed. Parasites (1.5 x 10 6 /mL) were cultured in the presence of either 0, 1, 3, 10, 30 or 100 µg/mL each compound. Benznidazole (BNZ, Elea Laboratory, Argentina) was used as positive control. A Neubauer hemocytometer was employed for parasite counts. The concentration that inhibited 50% of parasite growth (IC 50 ) was determined after 72 h of co-culture by regression analysis with the Prism 5.0 software. Three independent experiments were carried out in duplicate. Cytotoxicity assay The toxicity of each compound was determined on Vero cells. Cell viability was determined by the MTT assay. Cells were cultured in a 96-well flat-bottom plate in the presence of increasing concentrations of each compound (0, 31.2, 62.5, 125, 250, 500 mM) at 37º C and 5% CO 2 for 48 h. Viability was determined by adding 20 mL/well of an MTT solution (1.5 mg/mL in complete RPMI medium without phenol red (Gibco)) for 4 h allowing purple formazan crystals to form. Crystals were completely dissolved with ethanol and the absorbance was read at 570 nm in a microplate reader (Bio-Rad Laboratories). The selectivity index was calculated as CC 50 /IC 50 for epimastigote parasite stage. Declarations Author Contribution V.I.A. synthesized the productsC.U.M.K. synthesized the productsL.A.G. synthesized the productsE.P. synthesized the productsG.G.F. synthesized the productsG.C.M. Analized and wrote biological evaluationF.M.A. provided fund for biological evaluation, made the in vitro analysis and supervised the related paragraphsA.M.B. was part of the conceptualization of the work, supervision and reviewA.P. was part of the methodology of the work, made the NMR and computational studies. Wrote and reviewed part of the manuscript. He made part of supplementary dataL.D.S provided fund for products synthesis and synthesized and supervised the experimental part. He was part of methodology of the work and analized NMR spectra. Wrote and reviewed part of the manuscript and made schemes and tables. Wrote conclusions and references. He directed the work. Acknowledgement This work was generously supported by funds provided by Universidad Nacional de La Plata, Argentina (Proyecto I + D EX001) and Universidad de Buenos Aires (20020190100199BA). Authors wish to thank Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CICPBA), UNLP, UBA and CONICET for their active support to the present work. We express deep thanks to Lic. Omar E. Guaymas (CICPBA) for assistance in the preparation and characterization of some compounds, Tec. Melani Walker (IMPaM, UBA-CONICET) for the technical assistance in antiparasite activity determination and Prof. Dra. Alicia Cánepa (UNLP) for valuable advice. Data Availability Data is provided within the manuscript and the supplementary information files References WORLD HEALTH ORGANIZATION, https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis ). 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Chem. 34:752–757. https://doi.org/10.1021/jm00106a041 Scheme Schemes 1-3 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files diamidassuppinfo.docx Scheme1.docx Scheme2.docx Scheme3.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4415338","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":306912325,"identity":"471bce9a-f81c-4797-94e2-f63614878ae3","order_by":0,"name":"Valentín I. Ortellado","email":"","orcid":"","institution":"Universidad Nacional de La Plata","correspondingAuthor":false,"prefix":"","firstName":"Valentín","middleName":"I.","lastName":"Ortellado","suffix":""},{"id":306912326,"identity":"4af2f53f-ef50-4acd-bf60-e26ca73eba50","order_by":1,"name":"Carlos U. Molfesa Kaczoruk","email":"","orcid":"","institution":"Universidad Nacional de La Plata","correspondingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"U. Molfesa","lastName":"Kaczoruk","suffix":""},{"id":306912327,"identity":"f731873e-44de-42df-b892-9099c9e3d9b7","order_by":2,"name":"Lucio A. Guaymas","email":"","orcid":"","institution":"Universidad Nacional de La Plata","correspondingAuthor":false,"prefix":"","firstName":"Lucio","middleName":"A.","lastName":"Guaymas","suffix":""},{"id":306912328,"identity":"05c59cee-b1d1-4f67-8860-5b2ee2760acf","order_by":3,"name":"Ezequiel Parisi","email":"","orcid":"","institution":"Universidad Nacional de La Plata","correspondingAuthor":false,"prefix":"","firstName":"Ezequiel","middleName":"","lastName":"Parisi","suffix":""},{"id":306912329,"identity":"39267152-4427-46fb-abcc-33de939f6e59","order_by":4,"name":"Guido G. Fraga","email":"","orcid":"","institution":"Universidad Nacional de La Plata","correspondingAuthor":false,"prefix":"","firstName":"Guido","middleName":"G.","lastName":"Fraga","suffix":""},{"id":306912330,"identity":"8d1e91f6-7718-40c2-9a8d-6a506c41cd6e","order_by":5,"name":"Gisela C. Muscia","email":"","orcid":"","institution":"Universidad de Buenos Aires","correspondingAuthor":false,"prefix":"","firstName":"Gisela","middleName":"C.","lastName":"Muscia","suffix":""},{"id":306912331,"identity":"e28ccd3e-b036-482e-98a2-34c339401b43","order_by":6,"name":"Fernanda M. Frank","email":"","orcid":"","institution":"Universidad de Buenos Aires","correspondingAuthor":false,"prefix":"","firstName":"Fernanda","middleName":"M.","lastName":"Frank","suffix":""},{"id":306912332,"identity":"060f29e1-66c2-4d91-8e0b-e070c23d7fdc","order_by":7,"name":"Ana M. Bruno","email":"","orcid":"","institution":"Universidad de Buenos Aires","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"M.","lastName":"Bruno","suffix":""},{"id":306912333,"identity":"f48d0880-06c4-440e-a543-7ee849b3e187","order_by":8,"name":"Agustín Ponzinibbio","email":"","orcid":"","institution":"Universidad Nacional de La Plata","correspondingAuthor":false,"prefix":"","firstName":"Agustín","middleName":"","lastName":"Ponzinibbio","suffix":""},{"id":306912334,"identity":"3f7ab1c6-7ae7-4694-93f6-670312ad7dbf","order_by":9,"name":"Leandro D. Sasiambarrena","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABHElEQVRIiWNgGAWjYJCCAyDED2YYgAUYD4CIBkJaJBsQWhgIaoGYfwDVENxa5NuPPzzwM+eOvPHxHMNDNwrs5Bkkcg8cLmCwkd1wgPnZByxaDM7kGBzs3fbMcNuZNwaHcwySDRsk8hIOz2BIM95wgM14BjYtDDkMB3i3HWbcdiMHpOUAY4MEkMHDcDhxwwEGY6wO63/+4ODfbYftN8+AaLGHavkP1ML+GatnbiQYHAbakrhBAqIlEarlAFALD1ZbDG4AvSC77VnyjDPPCkB+SW7jAYrMMEg2nnmYpxi7w9Iff3y77Y5tf3vy5s85f+xs+9lzDB8XVNjJ9h1v34wjnGEgAUKxATEzOE6ZCWiAa2EgSvEoGAWjYBSMJAAAm1FzOfnVMHgAAAAASUVORK5CYII=","orcid":"","institution":"Universidad Nacional de La Plata","correspondingAuthor":true,"prefix":"","firstName":"Leandro","middleName":"D.","lastName":"Sasiambarrena","suffix":""}],"badges":[],"createdAt":"2024-05-13 21:38:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4415338/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4415338/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57200818,"identity":"9ee2de20-9d58-4b0c-823d-ed46741502cb","added_by":"auto","created_at":"2024-05-27 09:53:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":30160,"visible":true,"origin":"","legend":"\u003cp\u003eTrypanothione reductase inhibitors di and polyamides\u003c/p\u003e","description":"","filename":"F1.png","url":"https://assets-eu.researchsquare.com/files/rs-4415338/v1/68b06cbd8a492fcb6be4d14e.png"},{"id":57201545,"identity":"b2e5019e-938e-4316-a094-f5fba9e45411","added_by":"auto","created_at":"2024-05-27 10:01:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":11466,"visible":true,"origin":"","legend":"\u003cp\u003eSuramine\u003c/p\u003e","description":"","filename":"F2.png","url":"https://assets-eu.researchsquare.com/files/rs-4415338/v1/9d3c2751b196e23ac2850195.png"},{"id":60710311,"identity":"954f0ee9-460e-45fe-ad68-7b7bb99cd3d7","added_by":"auto","created_at":"2024-07-19 20:01:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":960844,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4415338/v1/6261ecc8-85e8-4624-8d38-746ab9240b79.pdf"},{"id":57201547,"identity":"61e5ee98-8149-4803-95b7-d5d0a8ea4098","added_by":"auto","created_at":"2024-05-27 10:01:41","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14639584,"visible":true,"origin":"","legend":"","description":"","filename":"diamidassuppinfo.docx","url":"https://assets-eu.researchsquare.com/files/rs-4415338/v1/6f4621f273ea6acb10f5b4fc.docx"},{"id":57200819,"identity":"92fb51a8-7ce0-49fc-9453-7b0357e7433d","added_by":"auto","created_at":"2024-05-27 09:53:41","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":43340,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4415338/v1/4e84d45f828c04b2a6b76160.docx"},{"id":57200823,"identity":"4c0e5139-b1d5-4507-be0b-154cfa3a0774","added_by":"auto","created_at":"2024-05-27 09:53:41","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":37244,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme2.docx","url":"https://assets-eu.researchsquare.com/files/rs-4415338/v1/ea9eef6e5316742e1b4610ae.docx"},{"id":57200821,"identity":"bddfc3e4-cb53-4794-8923-1a43de18d726","added_by":"auto","created_at":"2024-05-27 09:53:41","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":659724,"visible":true,"origin":"","legend":"","description":"","filename":"Scheme3.docx","url":"https://assets-eu.researchsquare.com/files/rs-4415338/v1/70799c840ae4f312355e80f3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSynthesis of Novel Acetamidobenzanilides Derivatives as Potencial Trypanocidal Agents\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eChagas\u0026rsquo; disease (also known as American trypanosomiasis) is a zoonosis caused by the flagellated protozoan \u003cem\u003eTrypanosoma cruzi\u003c/em\u003e and is the most widespread parasitic disease in Latin America affecting at least 6\u0026ndash;7\u0026nbsp;million of human beings all over the world [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The available drugs for the treatment of this condition are Benznidazole and Nifurtimox, both are associated with a high frequency of adverse events and exhibit variable efficacy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. As a consequence, several investigations were conducted in order to broaden the molecular diversity of bioactive compounds against the parasite. The trypanocidal activities of various compounds, such as acridines, phenothiazines, benzazepines, imidazoisoquinolinones, quinazolines, and pyridoquinolines, have been studied [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. While many of these compounds exhibit promising bioactive properties, further investigations in this field are deemed necessary.\u003c/p\u003e \u003cp\u003eIn the literature, exist substances derived from amides, polyamides, and polyamines that act as inhibitors of trypanothione reductase (TryR), an enzyme exclusive to trypanosomatids (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. A paradigmatic example of such compounds is suramin, a symmetrical polyamide approved for the treatment of \u003cem\u003eTrypanosoma brucei\u003c/em\u003e infection (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Although suramin has a proven therapeutic effect, its neurotoxicity, potentially severe and dose-limiting, impedes the drug's clinical utility. Moreover, Suramin and other polyamides present multi-step and complex organic syntheses, leading to expensive preparation procedures.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOther diamides derivatives compounds have shown biological activity as insecticide [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] or as antimicrobial [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Also, one bisamide derivative of 1,4-benzodioxane was reported as an HSF1 pathway inhibitor that showed growth inhibitory activities in the human ovarian carcinoma xenograft model [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, anthranilic acid diamides have been evaluated as cholecystokinin receptor antagonists [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and antispasmodics [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDue to the significance of suramin and other diamides or bisamides in the study of Chagas\u0026rsquo; disease, we decided to investigate the preparation and biological activity of a series of acetamidobenzanilide derivatives. Hence, we designed a synthesis strategy for preparing new \u003cem\u003eN\u003c/em\u003e-(2-[\u003cem\u003eN\u003c/em\u003e\u0026rsquo;-acetamidomethyl])benzanilides derivatives through a four-step process. The synthetic precursors employed had been previously studied in our laboratory as intermediates in the synthesis of 1,4-benzodiazepin-3-ones [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn a preliminary study, we decided to synthesize four acetamidobenzanilides to evaluate their \u003cem\u003ein vitro\u003c/em\u003e activity (CC\u003csub\u003e50\u003c/sub\u003e and IC\u003csub\u003e50\u003c/sub\u003e) against \u003cem\u003eT. cruzi\u003c/em\u003e. As the results were promising, a battery of 18 of these compounds was prepared.\u003c/p\u003e"},{"header":"RESULTS AND DISCUSSION","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eSynthesis\u003c/h2\u003e\n \u003cp\u003eThe synthesis of these novel acetamidobenzanilides is described in Scheme \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003eIn the initial step, \u003cem\u003eN\u003c/em\u003e-(2-nitrobenzyl)anilines \u003cstrong\u003e2\u003c/strong\u003e were prepared by reductive amination of \u003cem\u003eo\u003c/em\u003e-nitrobenzaldehyde \u003cstrong\u003e1\u003c/strong\u003e with anilines using a standard method and NaBH\u003csub\u003e4\u003c/sub\u003e as a reduction agent [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]. These substituted anilines were obtained in good yields and subsequently underwent amidation with acetyl chloride in toluene at reflux to afford acetamides \u003cstrong\u003e3\u003c/strong\u003e.\u003c/p\u003e\n \u003cp\u003eIn the third step process, the nitro group was reduced to amino group using iron dust in a solution of ammonium chloride with ethanol-water as solvent at reflux to afford acetamides \u003cstrong\u003e4\u003c/strong\u003e [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]. The final diamides (\u003cstrong\u003e5\u003c/strong\u003e) were obtained with a benzoylation of the amino group using benzoyl chlorides in toluene at 110\u0026deg;C. Diamides \u003cstrong\u003e5\u003c/strong\u003e were prepared in good to very good yields with the exception of compounds bearing R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;NO\u003csub\u003e2\u003c/sub\u003e (\u003cstrong\u003e5m\u003c/strong\u003e, \u003cstrong\u003e5o\u003c/strong\u003e and \u003cstrong\u003e5r\u003c/strong\u003e were obtained with lower yields) and were characterized by elemental analysis, \u003csup\u003e1\u003c/sup\u003eH NMR, and \u003csup\u003e13\u003c/sup\u003eC NMR. Yields of the final step and melting points of the white or pale yellow solid products are listed in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eYields and melting points of products \u003cstrong\u003e5\u003c/strong\u003e.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCompounds 5\u003c/p\u003e\n \u003cp\u003e\u003cimg 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\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFinal step yield (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMelting point (\u0026deg;C)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5a\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-Br; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;H)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e203\u0026ndash;204\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5b\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;H)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e160\u0026ndash;161\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5c\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-Cl; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;H)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e202\u0026ndash;203\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5d\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-F; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;H)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e112\u0026ndash;113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5e\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-F; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;H)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e179\u0026ndash;180\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5f\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep-\u003c/em\u003eI; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;H)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e178\u0026ndash;179\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5g\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-Br; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e154\u0026ndash;155\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5h\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e112\u0026ndash;113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5i\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-Cl; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e162\u0026ndash;163\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5j\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-F; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e62\u0026ndash;63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5k\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-F; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e135\u0026ndash;136\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5l\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-I; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e143\u0026ndash;144\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5m\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-Br; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-NO\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e185\u0026ndash;186\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5n\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-NO\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e114\u0026ndash;115\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5o\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-Cl; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-NO\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e174\u0026ndash;175\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5p\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-F; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-NO\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e160\u0026ndash;161\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5q\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-F; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-NO\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e173\u0026ndash;174\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5r\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-I; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-NO\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e183\u0026ndash;184\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eNMR study\u003c/h2\u003e\n \u003cp\u003eAs bioactive organic molecules interact with their biological receptors in a particular and finely tuned manner a thorough analysis of their structures and conformations is imperative to get reliable information that may contribute to the knowledge of the biological molecular mechanisms and structure-activity relationships [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. In recent decades, atropisomerism has gained increased attention owing to its significance in investigations concerning natural products and bioactive molecules as both isomers often manifest distinct pharmacological activities [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\n \u003cp\u003eWhile the conformational rigidity of bicyclic moieties is extensively documented in the literatura [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e], recent interest in drug discovery science has focused investigations of atropisomerism around the C-N axis in cases where the nitrogen atom is acyclic [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]. Upon analyzing the structures of the synthesized acetamidobenzanilides, we identified an atropisomeric scaffold characterized by axial chirality along the C-N bond axis in several examples, as illustrated in Scheme \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003eAs shown in Scheme \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, benzanilides exhibit the presence of two stereogenic C-N axes, with their conformational flexibility modulated by neighboring aryl substituents. It has been previously reported that the C-NHR moiety lacks atropisomeric properties, the racemization process occurs too rapid to be detected by \u003csup\u003e1\u003c/sup\u003eH-NMR spectroscopy. Therefore, isomerism arises from the C-NRR\u0026rsquo; axis, wherein the presence of an ortho substituent (R\u003csup\u003e1\u003c/sup\u003e) in the second aryl group is associated with the atropisomerism, as evidenced by the distinctive pattern observed in the methylene \u003csup\u003e1\u003c/sup\u003eH NMR spectra as two diastereotopic hydrogens. In Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, we summarize the \u003csup\u003e1\u003c/sup\u003eH NMR details of the CH\u003csub\u003e2\u003c/sub\u003e signal of compounds \u003cstrong\u003e5\u003c/strong\u003e with high level of configuration stability that generates detectable atropisomerism in all compounds with R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-X. As an example, \u003csup\u003e1\u003c/sup\u003eH NMR of compund \u003cstrong\u003e5b\u003c/strong\u003e is shown in Scheme \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003eH-NMR CH\u003csub\u003e2\u003c/sub\u003e signals for compounds \u003cstrong\u003e5\u003c/strong\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCompounds 5\u003c/p\u003e\n \u003cp\u003e\u003cimg 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+tmnJkP4uhEnwzAMsBq2bRuGMb1yaL1YLC789OsjPQLiZIDNGI1Gtm3DvWz61nWJawiIk4E2A97Y0I9Cr7WgI4kRkEAG/LzI1ePPxMPPV0ZBMmazGRoJGJDrutpUZORWkIyMrerioQhoMkJhWU+iJmM9uIe2+j9mkBeD3o2P/QAAAABJRU5ErkJggg==\"\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCH\u003csub\u003e2\u003c/sub\u003e \u003csup\u003e1\u003c/sup\u003eH-NMR chemical shifts \u0026delta;, ppm (\u003cem\u003eJ\u003c/em\u003e, Hz)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5a\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-Br; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;H)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.80 (s, 2H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5b\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;H)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.23 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.7, 1H); 4.31 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.7, 1H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5c\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-Cl; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;H)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.80 (s, 2H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5d\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-F; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;H)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.03 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.6, 1H); 4.56 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.6, 1H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5e\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-F; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;H)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.80 (s, 2H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5f\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep-\u003c/em\u003eI; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;H)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.79 (s, 2H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5g\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-Br; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.81 (s, 2H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5h\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.26 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.8, 1H); 4.32 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.8, 1H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5i\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-Cl; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.82 (s, 2H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5j\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-F; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.07 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.7, 1H); 4.55 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.7, 1H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5k\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-F; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.81 (s, 2H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5l\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-I; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.81 (s, 2H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5m\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-Br; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-NO\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.77 (s, 2H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5n\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-Cl; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-NO\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.23 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.8, 1H); 4.26 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.8, 1H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5o\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-Cl; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-NO\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.77 (s, 2H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5p\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-F; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-NO\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.10 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.8, 1H); 4.44 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.8, 1H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5q\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-F; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-NO\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.77 (s, 2H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5r\u003c/strong\u003e (R\u003csup\u003e1\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003ep\u003c/em\u003e-I; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;\u003cem\u003eo\u003c/em\u003e-NO\u003csub\u003e2\u003c/sub\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.76 (s, 2H)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003ch3\u003eADME predictions\u003c/h3\u003e\n\u003cp\u003eTo select target molecules in the early stages of drug development, predicting ADME profiles has been proven to be a reliable and valuable tool [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. We calculate the physicochemical properties, lipophilicity, and drug likeness of the prepared compounds [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. The complete results are summarized in the supporting information section. The drug likeness evaluation of most compounds are deemed acceptable according to Lipinski\u0026apos;s rule of five, as well as the parameters considered by Ghose, Veber, Egan, and Muegge. In R\u003csup\u003e2\u003c/sup\u003e: -H or -X derivatives, the topological polar surface area (TPSA) suggests a likely favorable intestinal adsorption of the molecule. However, a TPSA value below 60 \u0026Aring; indicates potential penetration of the blood-brain barrier, as observed in the BBB permeability results. On the other hand, benzanilides derived from R\u003csup\u003e2\u003c/sup\u003e: -NO\u003csub\u003e2\u003c/sub\u003e exhibit an optimal TPSA value ranging between 60 and 140 \u0026Aring;. Consequently, the pharmacokinetic profile, including blood-brain barrier permeability and CYP1A2 inhibition, is superior to those described for the aforementioned compounds. The compounds shown in 1.2. SI table (demonstrate a favorable bioavailability score of 0.55, acceptable skin permeation values ranging between \u0026minus;\u0026thinsp;8 to -1, and reasonable synthetic accessibility (\u0026lt;\u0026thinsp;3.1).\u003c/p\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eIn vitro biological evaluation\u003c/h2\u003e\n \u003cp\u003eThe \u003cem\u003ein vitro\u003c/em\u003e activity of \u003cstrong\u003e5a-d\u003c/strong\u003e showed a dose-response inhibitory effect in their activity against \u003cem\u003eT. cruzi\u003c/em\u003e epimastigotes, with half-maximum inhibitory concentration (IC\u003csub\u003e50\u003c/sub\u003e) values less than 15 mM. The evaluated compounds were selected to perform a first screening analyzing the influence of three electron-withdrawing groups in different positions. The IC\u003csub\u003e50\u003c/sub\u003e results of these compounds suggest that they are active (\u003cstrong\u003e5a\u003c/strong\u003e and \u003cstrong\u003e5c\u003c/strong\u003e) and moderately active (\u003cstrong\u003e5b\u003c/strong\u003e and \u003cstrong\u003e5d\u003c/strong\u003e) against \u003cem\u003eT. cruzi\u003c/em\u003e in this parasitic stage. On the other hand, cytotoxicity is determined in the VERO cell line, it can be observed that none of the compounds evaluated presents cytotoxicity, in particular compounds \u003cstrong\u003e5b\u003c/strong\u003e and \u003cstrong\u003e5d\u003c/strong\u003e stand out for their CC\u003csub\u003e50\u003c/sub\u003e value (CC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;500 \u0026micro;M) (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). SI was also calculated.\u003c/p\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u003cem\u003eIn vitro\u003c/em\u003e anti-\u003cem\u003eT. cruzi\u003c/em\u003e activity and cytotoxic activity of selected compounds. BNZ was used as reference drug\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCompound\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIC\u003csub\u003e50\u003c/sub\u003e (\u0026micro;M)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCC\u003csub\u003e50\u003c/sub\u003e (\u0026micro;M)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSI\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5a\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.9 \u0026plusmn; 0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35.2 \u0026plusmn; 2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5b\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.5 \u0026plusmn; 0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5c\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.0 \u0026plusmn; 0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52.7 \u0026plusmn; 8.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5d\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.4 \u0026plusmn; 0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBNZ\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.1 \u0026plusmn; 0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n\u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusi\u0026oacute;n, we have designed and implemented a facile and efficient synthesis of new \u003cem\u003eN\u003c/em\u003e-(2-[\u003cem\u003eN\u003c/em\u003e\u0026rsquo;-acetamidomethyl])benzanilides derivatives through a four-step process. All 18 final compounds were synthesized with satisfactory yields. It was observed that compounds \u003cb\u003e5\u003c/b\u003e bearing an ortho substituent (R\u003csup\u003e1\u003c/sup\u003e) in the phenyl group of the acetanilide moeity, exhibited atropisomerism attributable to the axial chirality along the C-N bond axis. The manifestation of this phenomenon is evidenced by the presence of a doublet signal in the \u003csup\u003e1\u003c/sup\u003eH NMR spectrum for each diastereotopic hydrogen within the CH\u003csub\u003e2\u003c/sub\u003e moiety. Several of these diamides (\u003cb\u003e5a\u003c/b\u003e-\u003cb\u003ed\u003c/b\u003e) exhibited inhibitory effects against \u003cem\u003eT. cruzi\u003c/em\u003e epimastigote forms, with compounds \u003cb\u003e5a\u003c/b\u003e and \u003cb\u003e5c\u003c/b\u003e demonstrating significant activity, while compounds \u003cb\u003e5b\u003c/b\u003e and \u003cb\u003e5d\u003c/b\u003e showed moderate activity as determined by the evaluation of IC\u003csub\u003e50\u003c/sub\u003e values. Cytotoxicity was also assessed, and none of the analyzed compounds exhibited cytotoxic effects. A complete biological study (cytotoxicity, \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e assays with \u003cem\u003eT. cruzi\u003c/em\u003e epi and trypomastigote forms) and computational studies with all 18 new compounds will be carried out in a subsequent work.\u003c/p\u003e"},{"header":"EXPERIMENTAL SECTION","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eGeneral methods and materials\u003c/h2\u003e \u003cp\u003eMelting points were determined with a B\u0026uuml;chi apparatus and were uncorrected. \u003csup\u003e1\u003c/sup\u003eH NMR and \u003csup\u003e13\u003c/sup\u003eC NMR\u003c/p\u003e \u003cp\u003espectra were recorded on a Brucker Avance Neo 500, 11.75 T spectrometer operated at 500 MHz (\u003csup\u003e1\u003c/sup\u003eH) and\u003c/p\u003e \u003cp\u003e126 MHz (\u003csup\u003e13\u003c/sup\u003eC). Liquid column chromatography separations were achieved on silica gel Grace Davison 60-\u003c/p\u003e \u003cp\u003e200 mesh or Sigma-Aldrich 230\u0026ndash;400 mesh. Thin-layer chromatography (TLC) was performed on silica gel 60 F254 sheets (Merck). Elemental analyses for C, H, N, and S were performed using a Carlo Erba EA 1108 analyzer. \u003cem\u003eo-\u003c/em\u003eNitrobenzaldehyde, anilines, acetyl chloride, benzoyl chloride, triethylamine (TEA) and sodium borohydride were purchased from Aldrich. 2-Chloro and 2-nitrobenzoyl chlorides were prepared by a standard method [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cb\u003eSynthesis of\u003c/b\u003e \u003cb\u003eN\u003c/b\u003e\u003cb\u003e-(2-nitrobenzyl)anilines\u003c/b\u003e (\u003cb\u003e2\u003c/b\u003e)\u003c/p\u003e \u003cp\u003eAs a general procedure, to a solution of \u003cb\u003e1\u003c/b\u003e (10 mmol) in 10 ml of methanol was added the primary aniline (10 mmol) and heated at reflux for 2 h. The mixture was cooled at 0\u0026deg;C and NaBH\u003csub\u003e4\u003c/sub\u003e (10 mmol) was added, stirred for 2\u0026ndash;24 h and evaporated. The resulting solid was dissolved in CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e (10 ml), washed with water (5 ml), dried over sodium sulfate and the solvent was removed under reduced pressure to afford the \u003cem\u003eN-\u003c/em\u003e(2-nitrobenzyl)anilines that were used without further purification.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSynthesis of\u003c/b\u003e \u003cb\u003eN\u003c/b\u003e\u003cb\u003e-phenyl-\u003c/b\u003e\u003cb\u003eN\u003c/b\u003e\u003cb\u003e-(2-nitrobenzyl)acetamides\u003c/b\u003e (\u003cb\u003e3\u003c/b\u003e)\u003c/p\u003e \u003cp\u003e \u003cem\u003eN\u003c/em\u003e-(2-nitrobenzyl)aniline (\u003cb\u003e2\u003c/b\u003e) (5 mmol) and 5 mmol of TEA were dissolved in toluene (10\u003c/p\u003e \u003cp\u003eml) and a solution of 5 mmol of acetyl chloride in 10 ml of toluene was added. The mixture was\u003c/p\u003e \u003cp\u003eheated to reflux for 2\u0026ndash;24 hs, cooled and washed with water (10 ml), HCl 10% (10 ml) and water (2 x 10\u003c/p\u003e \u003cp\u003eml). Solution was dried over sodium sulfate and concentrated to dryness at reduced pressure to obtain\u003c/p\u003e \u003cp\u003ecrude \u003cem\u003eN\u003c/em\u003e-phenyl-\u003cem\u003eN\u003c/em\u003e-(2-nitrobenzyl)acetamides (\u003cb\u003e3\u003c/b\u003e) that were purified by column chromatography (hexane-EtOAc 8:2).\u003c/p\u003e \u003cp\u003e \u003cb\u003eSynthesis of\u003c/b\u003e \u003cb\u003eN\u003c/b\u003e\u003cb\u003e-phenyl-\u003c/b\u003e\u003cb\u003eN\u003c/b\u003e\u003cb\u003e-(2-aminobenzyl)acetamides\u003c/b\u003e (\u003cb\u003e4\u003c/b\u003e)\u003c/p\u003e \u003cp\u003e \u003cem\u003eN\u003c/em\u003e-phenyl-\u003cem\u003eN\u003c/em\u003e-(2-nitrobenzyl)acetamides (\u003cb\u003e3\u003c/b\u003e) (3 mmol) were disolved in 30 ml of metanol and 15 mmol of iron dust was added. The mixture was energetically stirred and a solution of 30 mmol of NH\u003csub\u003e4\u003c/sub\u003eCl in 15 ml of water was added and then heated at reflux until complete reaction. The mixture was filtered over celite, washed with metanol and the solvente removed at reduced pressure. The residue was disolved with 30 ml of CH\u003csub\u003e2\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003e, washed with water, and the solution dried over sodium sulfate. The solvent was evaporated and the product purified by silica column cromatography (hexane-EtOAc 7:3) affording acetamides \u003cb\u003e4\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSynthesis of\u003c/b\u003e \u003cb\u003eN\u003c/b\u003e\u003cb\u003e-(2-[\u003c/b\u003e\u003cb\u003eN\u0026rsquo;\u003c/b\u003e\u003cb\u003e-acetamidomethyl])benzanilides\u003c/b\u003e (\u003cb\u003e5\u003c/b\u003e)\u003c/p\u003e \u003cp\u003e \u003cem\u003eN\u003c/em\u003e-phenyl-\u003cem\u003eN\u003c/em\u003e-(2-aminobenzyl)acetamides (\u003cb\u003e4\u003c/b\u003e) (2 mmol) and 2 mmol of TEA were dissolved in toluene (5 ml) and a solution of 2 mmol of the proper benzoyl chloride in 5 ml of toluene was added. The mixture was heated to reflux for 2\u0026ndash;24 hs, cooled and washed with water (10 ml), HCl 10% (10 ml) and water (2 x 10\u003c/p\u003e \u003cp\u003eml). Solution was dried over sodium sulfate and concentrated to dryness at reduced pressure to obtain\u003c/p\u003e \u003cp\u003ecrude \u003cem\u003eN\u003c/em\u003e-(2-[\u003cem\u003eN\u003c/em\u003e\u0026rsquo;-acetamidomethyl])benzanilides (\u003cb\u003e5\u003c/b\u003e) that were purified by crystallization of ethanol.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u0026rsquo;\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(4-bromophenyl)acetamidomethyl)benzanilide\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e5a\u003c/span\u003e\u003c/p\u003e \u003cp\u003eYield: 81%. Mp\u0026thinsp;=\u0026thinsp;203\u0026ndash;204\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eBrN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e; found C, 62.46; H, 4.55; N, 6.63%; requires C, 62.42; H, 4.52; Br, 18.88; N, 6.62; O, 7.56%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.71 (s, 1H), 8.20 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.8, 1.8 Hz, 2H), 8.13 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 1H), 7.58 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 2H), 7.56\u0026ndash;7.51 (m, 3H), 7.37 (m, 1H), 7.00\u0026ndash;6.94 (m, 3H), 6.71 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6 Hz, 1H), 4.80 (s, 2H), 1.83 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e) δ 171.33, 166.59, 141.70, 136.93, 135.01, 133.38, 131.80, 131.39, 130.23, 129.13, 128.62, 128.00, 127.12, 125.32, 124.37, 122.71, 50.43, 22.66.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(2-chlorophenyl)acetamidomethyl)benzanilide\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e5b\u003c/span\u003e\u003c/p\u003e \u003cp\u003eYield: 72%. Mp\u0026thinsp;=\u0026thinsp;160\u0026ndash;161\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eClN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e; found C, 69.66; H, 5.08; N, 7.40%; requires C, 69.75; H, 5.06; Cl, 9.36; N, 7.39; O, 8.45%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.74 (s, 1H), 8.25\u0026ndash;8.19 (m, 2H), 8.16 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.3, 1.2 Hz, 1H), 7.60\u0026ndash;7.50 (m, 4H), 7.38 (dtd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.4, 7.7, 1.6 Hz, 2H), 7.32 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6, 1.5 Hz, 1H), 7.02 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.8, 1.6 Hz, 1H), 6.97 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.4, 1.2 Hz, 1H), 6.69 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6, 1.6 Hz, 1H), 5.23 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.7 Hz, 1H), 4.31 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.7 Hz, 1H), 1.82 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 171.81, 166.67, 139.69, 137.20, 135.09, 133.11, 131.77, 131.51, 131.27, 131.07, 130.26, 129.06, 128.60, 128.19, 128.05, 126.98, 125.10, 124.24, 49.19, 22.23.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(4-chlorophenyl)acetamidomethyl)benzanilide 5c\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 78%. Mp\u0026thinsp;=\u0026thinsp;202\u0026ndash;203\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eClN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e; found C, 69.72; H, 5.01; N, 7.36%; requires C, 69.75; H, 5.06; Cl, 9.36; N, 7.39; O, 8.45%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.72 (s, 1H), 8.20 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.9, 1.5 Hz, 2H), 8.13 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 1H), 7.61\u0026ndash;7.49 (m, 3H), 7.42 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.6 Hz, 2H), 7.39\u0026ndash;7.33 (m, 1H), 7.01 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.6 Hz, 2H), 6.98 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6 Hz, 1H), 6.71 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6, 1.6 Hz, 1H), 4.80 (s, 2H), 1.83 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 171.40, 166.59, 141.17, 136.94, 135.00, 134.69, 131.80, 131.39, 130.36, 129.90, 129.12, 128.61, 128.00, 127.13, 125.30, 124.35, 50.46, 22.64.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(2-fluorophenyl)acetamidomethyl)benzanilide 5d\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 76%. Mp\u0026thinsp;=\u0026thinsp;112\u0026ndash;113\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eFN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e; found C, 73.10; H, 5.22; N, 7.45%; requires C, 72.91; H, 5.28; F, 5.24; N, 7.73; O, 8.83%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.70 (s, 1H), 8.22 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.7, 1.8 Hz, 2H), 8.14 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 1H), 7.59\u0026ndash;7.51 (m, 3H), 7.45\u0026ndash;7.39 (m, 1H), 7.36 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.6, 7.6, 1.6 Hz, 1H), 7.25\u0026ndash;7.19 (m, 2H), 7.08 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.7, 1.7 Hz, 1H), 6.97 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.5, 1.3 Hz, 1H), 6.71 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.7, 1.6 Hz, 1H), 5.03 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.6 Hz, 1H), 4.56 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.6 Hz, 1H), 1.86 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 171.95, 166.61, 159.03, 157.04, 136.98, 135.07, 131.78, 131.15, 130.72, 130.69, 130.66, 129.07, 128.62, 128.02, 127.25, 125.32, 125.28, 125.18, 124.37, 117.35, 117.19, 49.76, 22.08.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(4-fluorophenyl)acetamidomethyl)benzanilide 5e\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 62%. Mp\u0026thinsp;=\u0026thinsp;179\u0026ndash;180\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eFN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e; found C, 73.09; H, 5.20; N, 7.60%; requires C, 72.91; H, 5.28; F, 5.24; N, 7.73; O, 8.83%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.74 (s, 1H), 8.21 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.8, 1.8 Hz, 2H), 8.13 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.3, 1.2 Hz, 1H), 7.60\u0026ndash;7.49 (m, 3H), 7.37 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.8, 1.6 Hz, 1H), 7.13 (m, 2H), 7.08\u0026ndash;7.01 (m, 2H), 6.98 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.4 Hz, 1H), 6.71 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.7, 1.6 Hz, 1H), 4.80 (s, 2H), 1.82 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 171.63, 166.62, 163.29, 161.31, 138.69, 138.66, 136.95, 135.01, 131.79, 131.42, 130.34, 130.27, 129.07, 128.61, 128.01, 127.19, 125.27, 124.31, 117.16, 116.97, 50.53, 22.62.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(4-yodophenyl)acetamidomethyl)benzanilide 5f\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 46%. Mp\u0026thinsp;=\u0026thinsp;178\u0026ndash;179\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e19\u003c/sub\u003eIN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e; found C, 56.25; H, 4.10; N, 5.97%; requires C, 56.18; H, 4.07; I, 26.98; N, 5.96; O, 6.80%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.72 (s, 1H), 8.23\u0026ndash;8.17 (m, 2H), 8.12 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 7.78 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 7.57\u0026ndash;7.50 (m, 3H), 7.36 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.4 Hz, 1H), 6.98 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.5 Hz, 1H), 6.82 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 6.71 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.4 Hz, 1H), 4.79 (s, 2H), 1.83 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 171.27, 166.56, 142.38, 139.35, 136.89, 134.98, 131.78, 131.36, 130.43, 129.09, 128.60, 127.98, 127.14, 125.29, 124.36, 94.15, 50.38, 22.64.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e2-Chloro\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003e-N\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u0026rsquo;\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(4-bromophenyl)acetamidomethyl)benzanilide 5g\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 94%. Mp\u0026thinsp;=\u0026thinsp;154\u0026ndash;155\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eClBrN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e; found C, 57.80; H, 4.00; N, 6.19%; requires C, 57.73; H, 3.96; Br, 17.46; Cl, 7.74; N, 6.12; O, 6.99%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.27 (s, 1H), 8.34 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 7.66 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.7, 2.5 Hz, 1H), 7.53 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 2H), 7.48 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.2, 2.1 Hz, 1H), 7.43\u0026ndash;7.34 (m, 3H), 6.96 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.5, 1.2 Hz, 1H), 6.87 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 2H), 6.69 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6, 1.6 Hz, 1H), 4.81 (s, 2H), 1.74 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 171.37, 166.12, 141.18, 136.70, 136.66, 133.29, 131.58, 131.28, 131.18, 130.25, 130.12, 129.37, 129.24, 127.01, 126.28, 124.36, 123.62, 122.67, 50.37, 22.49.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e2-Chloro-\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(2-chlorophenyl)acetamidomethyl)benzanilide 5h\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 69%. Mp\u0026thinsp;=\u0026thinsp;112\u0026ndash;113\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e; found C, 63.80; H, 4.48; N, 6.77%; requires C, 63.93; H, 4.39; Cl, 17.15; N, 6.78; O, 7.74%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.32 (s, 1H), 8.38 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 7.71\u0026ndash;7.65 (m, 1H), 7.52 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.0, 1.4 Hz, 1H), 7.50\u0026ndash;7.46 (m, 1H), 7.43\u0026ndash;7.32 (m, 4H), 7.29\u0026ndash;7.24 (m, 1H), 6.97\u0026ndash;6.88 (m, 2H), 6.66 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6, 1.6 Hz, 1H), 5.26 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.8 Hz, 1H), 4.32 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.8 Hz, 1H), 1.72 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 171.88, 166.20, 139.17, 137.05, 136.73, 133.09, 131.64, 131.40, 131.16, 131.13, 130.98, 130.28, 130.23, 129.35, 129.28, 128.17, 126.98, 126.15, 124.23, 123.43, 49.13, 22.04.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e2-Chloro-\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(4-chlorophenyl)acetamidomethyl)benzanilide 5i\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 54%. Mp\u0026thinsp;=\u0026thinsp;162\u0026ndash;163\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eCl\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e; found C, 63.85; H, 4.45; N, 6.83%; requires C, 63.93; H, 4.39; Cl, 17.15; N, 6.78; O, 7.74%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.27 (s, 1H), 8.35 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.8 Hz, 1H), 7.67 (s, 1H), 7.48 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.1 Hz, 1H), 7.45\u0026ndash;7.32 (m, 5H), 7.01\u0026ndash;6.90 (m, 3H), 6.69 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.3 Hz, 1H), 4.82 (s, 2H), 1.74 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 171.50, 166.18, 140.66, 136.72, 136.68, 134.68, 131.62, 131.31, 131.21, 130.31, 130.28, 129.87, 129.40, 129.36, 127.07, 126.32, 124.38, 123.68, 50.57, 22.61.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e2-Chloro\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003e-N\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(2-fluorophenyl)acetamidomethyl)benzanilide 5j\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 75%. Mp\u0026thinsp;=\u0026thinsp;62\u0026ndash;63\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eClFN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e; found C, 66.51; H, 4.55; N, 7.02%; requires C, 66.59; H, 4.57; Cl, 8.93; F, 4.79; N, 7.06; O, 8.06%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.25 (s, 1H), 8.34 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 7.70\u0026ndash;7.66 (m, 1H), 7.50\u0026ndash;7.46 (m, 1H), 7.43\u0026ndash;7.33 (m, 4H), 7.20\u0026ndash;7.13 (m, 2H), 6.98 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.5, 1.7 Hz, 1H), 6.94 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.5, 1.2 Hz, 1H), 6.68 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.5, 1.6 Hz, 1H), 5.07 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.7 Hz, 1H), 4.55 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.7 Hz, 1H), 1.76 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 172.00, 166.16, 159.02, 157.02, 136.79, 131.32, 131.16, 130.69, 130.63, 130.59, 130.28, 129.32, 129.27, 126.98, 126.43, 125.25, 125.22, 124.33, 123.56, 117.24, 117.08, 49.64, 21.90.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e2-Chloro\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003e-N\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(4-fluorophenyl)acetamidomethyl)benzanilide 5k\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 65%. Mp\u0026thinsp;=\u0026thinsp;135\u0026ndash;136\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eClFN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e; found C, 66.50; H, 4.51; N, 7.09%; requires C, 66.59; H, 4.57; Cl, 8.93; F, 4.79; N, 7.06; O, 8.06%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.30 (s, 1H), 8.35 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 7.69\u0026ndash;7.65 (m, 1H), 7.48 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.0, 2.1 Hz, 1H), 7.44\u0026ndash;7.34 (m, 3H), 7.08 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 2H), 6.99\u0026ndash;6.93 (m, 3H), 6.68 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6, 1.6 Hz, 1H), 4.81 (s, 2H), 1.73 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 171.69, 166.16, 163.25, 161.27, 138.17, 138.14, 136.71, 136.68, 131.62, 131.17, 130.25, 130.23, 130.16, 129.34, 129.23, 127.00, 126.36, 124.30, 123.59, 117.08, 116.90, 50.50, 22.45.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e2-Chloro\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003e-N\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(4-yodophenyl)acetamidomethyl)benzanilide 5l\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 68%. Mp\u0026thinsp;=\u0026thinsp;143\u0026ndash;144\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eClIN\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e; found C, 52.24; H, 3.66; N, 5.60%; requires C, 52.35; H, 3.59; Cl, 7.02; I, 25.14; N, 5.55; O, 6.34%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.27 (s, 1H), 8.34 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 7.73 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 7.66 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.9, 2.0 Hz, 1H), 7.47 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.2 Hz, 1H), 7.39 (m, 3H), 6.97 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.5 Hz, 1H), 6.74 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.3 Hz, 2H), 6.69 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.4 Hz, 1H), 4.81 (s, 2H), 1.74 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 171.33, 166.12, 141.91, 139.29, 136.70, 136.67, 131.58, 131.29, 131.18, 130.34, 130.26, 129.37, 129.24, 127.01, 126.32, 124.37, 123.65, 94.17, 50.35, 22.51.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e2-Nitro\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003e-N\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u0026rsquo;\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(4-bromophenyl)acetamidomethyl)benzanilide 5m\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 33%. Mp\u0026thinsp;=\u0026thinsp;185\u0026ndash;186\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eBrN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e; found C, 56.44; H, 3.87; N, 8.99%; requires C, 56.42; H, 3.87; Br, 17.06; N, 8.97; O, 13.67%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.43 (s, 1H), 8.41 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2, 1.1 Hz, 1H), 8.17 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 7.81\u0026ndash;7.72 (m, 2H), 7.63 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.6, 6.4, 2.4 Hz, 1H), 7.42\u0026ndash;7.32 (m, 3H), 6.97\u0026ndash;6.89 (m, 3H), 6.64 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6, 1.5 Hz, 1H), 4.77 (s, 2H), 1.70 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 171.93, 165.39, 146.32, 140.28, 136.84, 134.73, 134.04, 133.62, 131.73, 130.57, 130.30, 129.74, 129.63, 129.23, 125.66, 124.63, 124.27, 123.01, 50.51, 22.31.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e2-Nitro\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003e-N\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(2-chlorophenyl)acetamidomethyl)benzanilide 5n\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 60%. Mp\u0026thinsp;=\u0026thinsp;114\u0026ndash;115\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eClN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e; found C, 62.28; H, 4.25; N, 9.99%; requires C, 62.34; H, 4.28; Cl, 8.36; N, 9.91; O, 15.10%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.49 (s, 1H), 8.43 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 8.17 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 7.78 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.4 Hz, 2H), 7.64 (dt, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5, 4.4 Hz, 1H), 7.52 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.0, 1.4 Hz, 1H), 7.36 (dtd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;15.4, 8.2, 1.5 Hz, 2H), 7.28\u0026ndash;7.23 (m, 1H), 6.93 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.4 Hz, 1H), 6.88 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.8, 1.6 Hz, 1H), 6.61 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6, 1.5 Hz, 1H), 5.23 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.8 Hz, 1H), 4.26 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.8 Hz, 1H), 1.68 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 172.37, 165.41, 146.46, 138.78, 137.16, 134.01, 133.66, 132.90, 131.75, 131.19, 130.93, 130.56, 130.31, 129.61, 129.28, 128.23, 125.58, 124.64, 124.17, 122.86, 49.17, 21.87.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e2-Nitro\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003e-N\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(4-chlorophenyl)acetamidomethyl)benzanilide 5o\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 31%. Mp\u0026thinsp;=\u0026thinsp;174\u0026ndash;175\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eClN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e; found C, 62.30; H, 4.20; N, 9.84%; requires C, 62.34; H, 4.28; Cl, 8.36; N, 9.91; O, 15.10%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.42 (s, 1H), 8.40 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 1H), 8.17 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 7.81\u0026ndash;7.72 (m, 2H), 7.63 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.6, 6.5, 2.2 Hz, 1H), 7.52 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 2H), 7.41\u0026ndash;7.34 (m, 1H), 6.95 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.5, 1.2 Hz, 1H), 6.86 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 2H), 6.64 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6, 1.5 Hz, 1H), 4.77 (s, 2H), 1.70 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 171.86, 165.39, 146.32, 140.81, 136.84, 134.05, 133.63, 133.32, 131.74, 130.57, 130.13, 130.07, 129.65, 129.24, 125.64, 124.65, 124.29, 123.02, 50.49, 22.34.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e2-Nitro\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003e-N\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(2-fluorophenyl)acetamidomethyl)benzanilide 5p\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 40%. Mp\u0026thinsp;=\u0026thinsp;160\u0026ndash;161\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eFN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e; found C, 64.87; H, 4.48; N, 10.39%; requires C, 64.86; H, 4.45; F, 4.66; N, 10.31; O, 15.71%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.43 (s, 1H), 8.39 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 8.17 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 7.77 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.4 Hz, 2H), 7.66\u0026ndash;7.61 (m, 1H), 7.38 (m, 2H), 7.23\u0026ndash;7.11 (m, 2H), 6.98\u0026ndash;6.90 (m, 2H), 6.64 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.5 Hz, 1H), 5.10 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.8 Hz, 1H), 4.44 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.8 Hz, 1H), 1.73 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 172.48, 165.38, 158.93, 156.94, 146.45, 136.91, 134.00, 133.66, 131.48, 130.76, 130.57, 129.60, 129.26, 125.90, 125.26, 124.67, 124.29, 123.07, 117.21, 117.06, 49.66, 21.79.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e2-Nitro\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003e-N\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(4-fluorophenyl)acetamidomethyl)benzanilide 5q\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 69%. Mp\u0026thinsp;=\u0026thinsp;173\u0026ndash;174\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eFN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e; found C, 64.77; H, 4.50; N, 10.46%; requires C, 64.86; H, 4.45; F, 4.66; N, 10.31; O, 15.71%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.45 (s, 1H), 8.41 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 8.17 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 7.80\u0026ndash;7.72 (m, 2H), 7.63 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.7, 6.3, 2.6 Hz, 1H), 7.38 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.8, 1.6 Hz, 1H), 7.07 (m, 2H), 6.98\u0026ndash;6.91 (m, 3H), 6.63 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6, 1.5 Hz, 1H), 4.77 (s, 2H), 1.69 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 172.18, 165.42, 163.30, 161.32, 146.32, 137.77, 136.86, 134.05, 133.64, 131.76, 130.57, 130.19, 130.12, 129.61, 129.24, 125.74, 124.64, 124.23, 122.99, 117.11, 116.93, 50.62, 22.29.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e2-Nitro\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003e-N\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e-(2-(\u003c/span\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e\u0026rsquo;-(4-yodophenyl)acetamidomethyl)benzanilide 5r\u003c/span\u003e \u003c/p\u003e \u003cp\u003eYield: 32%. Mp\u0026thinsp;=\u0026thinsp;183\u0026ndash;184\u0026deg;C. C\u003csub\u003e22\u003c/sub\u003eH\u003csub\u003e18\u003c/sub\u003eIN\u003csub\u003e3\u003c/sub\u003eO\u003csub\u003e4\u003c/sub\u003e; found C, 51.36; H, 3.55; N, 8.23%; requires C, 51.28; H, 3.52; I, 24.63; N, 8.15; O, 12.42%. Spectral Data: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 10.43 (s, 1H), 8.40 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 8.17 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 1H), 7.80\u0026ndash;7.72 (m, 2H), 7.72 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 7.63 (ddd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.6, 6.7, 2.4 Hz, 1H), 7.38 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.6, 1.5 Hz, 1H), 6.95 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.4 Hz, 1H), 6.73 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 6.65 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.8 Hz, 1H), 4.76 (s, 2H), 1.69 (s, 3H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, Chloroform-\u003cem\u003ed\u003c/em\u003e): δ 171.80, 165.38, 141.52, 139.31, 136.83, 134.04, 133.63, 131.74, 130.56, 130.29, 129.63, 129.23, 128.33, 125.68, 124.64, 124.30, 123.04, 94.28, 50.45, 22.34.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eEpimastigote proliferation inhibition assay\u003c/h2\u003e \u003cp\u003eParasites belonging to the virulent RA strain (DTU VI), were employed. Parasites (1.5 x 10\u003csup\u003e6\u003c/sup\u003e/mL) were cultured in the presence of either 0, 1, 3, 10, 30 or 100 \u0026micro;g/mL each compound. Benznidazole (BNZ, Elea Laboratory, Argentina) was used as positive control. A Neubauer hemocytometer was employed for parasite counts. The concentration that inhibited 50% of parasite growth (IC\u003csub\u003e50\u003c/sub\u003e) was determined after 72 h of co-culture by regression analysis with the Prism 5.0 software. Three independent experiments were carried out in duplicate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCytotoxicity assay\u003c/h2\u003e \u003cp\u003eThe toxicity of each compound was determined on Vero cells. Cell viability was determined by the MTT assay. Cells were cultured in a 96-well flat-bottom plate in the presence of increasing concentrations of each compound (0, 31.2, 62.5, 125, 250, 500 mM) at 37\u0026ordm; C and 5% CO\u003csub\u003e2\u003c/sub\u003e for 48 h. Viability was determined by adding 20 mL/well of an MTT solution (1.5 mg/mL in complete RPMI medium without phenol red (Gibco)) for 4 h allowing purple formazan crystals to form. Crystals were completely dissolved with ethanol and the absorbance was read at 570 nm in a microplate reader (Bio-Rad Laboratories). The selectivity index was calculated as CC\u003csub\u003e50\u003c/sub\u003e/IC\u003csub\u003e50\u003c/sub\u003e for epimastigote parasite stage.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eV.I.A. synthesized the productsC.U.M.K. synthesized the productsL.A.G. synthesized the productsE.P. synthesized the productsG.G.F. synthesized the productsG.C.M. Analized and wrote biological evaluationF.M.A. provided fund for biological evaluation, made the in vitro analysis and supervised the related paragraphsA.M.B. was part of the conceptualization of the work, supervision and reviewA.P. was part of the methodology of the work, made the NMR and computational studies. Wrote and reviewed part of the manuscript. He made part of supplementary dataL.D.S provided fund for products synthesis and synthesized and supervised the experimental part. He was part of methodology of the work and analized NMR spectra. Wrote and reviewed part of the manuscript and made schemes and tables. Wrote conclusions and references. He directed the work.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThis work was generously supported by funds provided by Universidad Nacional de La Plata, Argentina (Proyecto I + D EX001) and Universidad de Buenos Aires (20020190100199BA). Authors wish to thank Comisi\u0026oacute;n de Investigaciones Cient\u0026iacute;ficas de la Provincia de Buenos Aires (CICPBA), UNLP, UBA and CONICET for their active support to the present work. We express deep thanks to Lic. Omar E. Guaymas (CICPBA) for assistance in the preparation and characterization of some compounds, Tec. Melani Walker (IMPaM, UBA-CONICET) for the technical assistance in antiparasite activity determination and Prof. Dra. Alicia C\u0026aacute;nepa (UNLP) for valuable advice.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData is provided within the manuscript and the supplementary information files\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWORLD HEALTH ORGANIZATION, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis\u003c/span\u003e\u003cspan address=\"https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJackson Y, Wyssa B, Chappuis (2020) Tolerance to nifurtimox and benznidazole in adult patients with chronic Chagas' disease. J. Antimicrob. 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Chem. 34:752\u0026ndash;757. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1021/jm00106a041\u003c/span\u003e\u003cspan address=\"10.1021/jm00106a041\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Scheme ","content":"\u003cp\u003eSchemes 1-3 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Acetamidobenzanilides, Antichagasic activity, NMR diamides, Atropisomerism","lastPublishedDoi":"10.21203/rs.3.rs-4415338/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4415338/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA simple synthesis of novel \u003cem\u003eN\u003c/em\u003e-(2-[\u003cem\u003eN\u003c/em\u003e\u0026rsquo;-acetamidomethyl])benzanilides derivatives from 2-nitrobenzaldehyde in a four steps process is described. The \u003csup\u003e1\u003c/sup\u003eH-NMR and \u003csup\u003e13\u003c/sup\u003eC-NMR spectra were meticulously analyzed to characterize their structure and it was observed that derivatives with an ortho-substituted phenyl group exhibited detectable atropisomerism. The ADME/toxicity analyses was performed and several of these acetamidobenzanilides were tested \u003cem\u003ein vitro\u003c/em\u003e against the epimastigote form of \u003cem\u003eTrypanosoma cruzi\u003c/em\u003e, demonstrating significant activity.\u003c/p\u003e","manuscriptTitle":"Synthesis of Novel Acetamidobenzanilides Derivatives as Potencial Trypanocidal Agents","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-27 09:53:36","doi":"10.21203/rs.3.rs-4415338/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"08106abb-6658-4bb5-9763-8154ed6135a7","owner":[],"postedDate":"May 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-19T19:53:27+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-27 09:53:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4415338","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4415338","identity":"rs-4415338","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}