Journal of the Korean Chemical Society (대한화학회지)

Korean Chemical Society (대한화학회)
권호 표지
DOI QR코드

DOI QR Code

Synthesis and Biological Screening of Thiazole-5-Carboxamide Derivatives

  • Mhaske, Pravin C. (Department of Chemistry, S. P. College) ;
  • Vadgaonkar, Kamlesh S. (Department of Chemistry, HPT Arts and RYK Science College) ;
  • Jadhav, Rahul P. (Department of Chemistry, HPT Arts and RYK Science College) ;
  • Bobade, Vivek D. (Department of Chemistry, HPT Arts and RYK Science College)
  • Received : 2010.04.05
  • Accepted : 2010.09.15
  • Published : 2011.10.20
Download PDF
⟨ Previous Next ⟩

Abstract

Keywords

EXPERIMENTAL

Melting points were determined in an open capillary on Veego melting point apparatus and are uncorrected. The purity of the compounds was checked on silica gel-G plates. The compounds 5a-n were purified on silica gel (100-200) column chromatography using ethyl acetate: hexane as eluent. Infrared spectra (cm-1) were recorded in KBr on a Shimadzu Model FTIR-435 spectrophotometer. 1H-NMR and 13C NMR spectra were recorded in CDCl3 and DMSO-d6 solution on a Varian Mercury YH-300 spectrometer operating at 300 MHz for 1H and 75 MHz for 13C. Chemical shifts are expressed relative to tetramethylsilane (TMS) and were reported as δ (ppm). Carbon, Hydrogen and Nitrogen analysis were performed with Perkin-Elmer 2400 series II instrument. Mass spectral (MS) measurements were made on a Jeol-JMS-DX 303 mass spectrometer. The isotopic peak at M+2 was observed in the mass spectrum of all the compounds due to S, Br and/or Cl.

The in vitro antibacterial activity was performed against Gram-positive bacteria including Staphylococcus aureus (NCIM 2079), Bacillus Subtilis (NCIM 2250) and Gramnegative bacteria including Escherichia coli (NCIM 2109), Pseudomonas aeruginosa (NCIM 2036). Yeast including Candida albicans (NCIM 3471) and fungi Aspergillus niger (NCIM 545) were used to test antifungal activity. Known antibiotics like Ciprofloxacin (the reference anti bacterial drugs) and Nystatin (the reference antifungal drug) were used for comparison.

General procedure for the synthesis of substituted 2-benzyl-4-methylthiazole-5-carboxylic acid. 1a-c. Mixture of 2-chloro-3-oxo ethylbutanoate (0.05 mol) and substituted benzyl thioamides (0.055 mol) in 50 mL of methanol was refluxed for 5-6 hours. After completion of the reaction, as monitored on TLC, 20 mL of 2N NaOH was added and refluxed further for 4 hours. Methanol was distilled off and the mixture acidified with 4N HCl to pH 2. The precipitated product was filtered, washed with water and recrystallized from aqueous ethanol.

Synthesis of amino phenylthiazole derivatives 2a-f. These compounds were prepared using the literature protocol.10,14

General procedure for the synthesis of N-(4-(2-methyl/benzylthiazol-4-yl) phenyl)-2-benzyl-4-methylthiazole-5-carboxamide 5a-n. A mixture of 2-benzyl-4-methylthiazole-5-carboxylic acid (1a-c) (1 mmol), DIPEA (0.35 mL, 2 mmol), HOBt (0.14 g, 1 mmol) in DMF (10 mL) was cooled to 0 ºC. To this 2-methyl/benzyl-4-(4-aminophenyl) thiazole (2a-f) (1mmol) was added followed by EDC. HCl (0.19 g, 1 mmol) at 0 ºC and stirred overnight at room temperature. The reaction was quenched with water and the product was filtered, washed with water. The spectral data of the purified compounds are as below:

N-(4-(2-Methylthiazol-4-yl)phenyl)-2-(2,4-dichlorobenzyl)-4-methylthiazole-5-carboxamide (5a). Solid, m.p. 179 ºC, IR(KBr, cm-1) 3440, 3262 (NH); 1646 (CO); 1593 (C=N); 1H NMR (CDCl3): δ 2.74 (s, 3H, CH3), 2.76 (s, 3H, CH3), 4.39 (s, 2H, CH2-Ph), 7.26-7.28 (m, 2H, Ar-H, Thiazole-H), 7.32 (d, J=8.3 Hz, 1H, Ar-H), 7.34 (bs, 1H, NH-CO), 7.45 (d, J=2Hz, 1H, Ar-H), 7.57 (d, J=8.6 Hz, 2H, Ar-H), 7.85 (d, J=8.6 Hz, 2H, Ar-H). LCMS: 474 (M+1). Anal. Calcd. for C22H17Cl2N3OS2: C, 55.70; H, 3.61; N, 8.86. Found: C, 55.31; H, 3.50; N, 8.84.

N-(4-(2-(4-Bromobenzyl)thiazol-4-yl)phenyl)-2-(2,4-dichlorobenzyl)-4-methylthiazole-5-carboxamide (5b). Solid, m.p. 141 ºC, IR(KBr, cm-1) 3448, 3292 (NH); 1652 (CO); 1598 (C=N); 1H NMR (CDCl3): δ 2.75 (s, 3H, CH3), 4.33 (s, 2H, CH2-Ph), 4.41 (s, 2H, CH2-Ph), 7.23-7.49 (m, 9H, Ar-H, Thiazole-H, NH-CO), 7.59 (d, J=8.5 Hz, 2H, Ar-H), 7.87 (d, J=8.5 Hz, 2H, Ar-H). Anal. Calcd. for C28H20BrCl2N3OS2: C, 53.43; H, 3.20; N, 6.68. Found: C, 53.08; H, 3.13; N, 6.33.

N-(4-(2-(4-Fluorobenzyl)thiazol-4-yl)phenyl)-2-(2,4-dichlorobenzyl)-4-methylthiazole-5-carboxamide (5c). Solid, m.p. 119 ºC, IR(KBr, cm-1) 3462, 3252 (NH); 1641 (CO); 1596 (C=N); 1H NMR (CDCl3): δ 2.75 (s, 3H, CH3), 4.27 (s, 2H, CH2-Ph), 4.32 (s, 2H, CH2-Ph), 7.03-7.46 (m, 9H, Ar-H, Thiazole-H, NH-CO), 7.58 (d, J=8.5 Hz, 2H, Ar-H), 7.86 (d, J=8.5 Hz, 2H, Ar-H), 13C NMR (CDCl3): δ 17.3 (Thiazole-CH3), 36.9 (CH2-Ar), 38.9 (CH2-Ar), 112.5- 160.2 (24-C, Aromatic-C), 168.3 (CO-NH). Anal. Calcd. for C28H20Cl2FN3OS2: C, 59.15; H, 3.55; N, 7.39. Found: C, 59.08; H, 3.33; N, 7.28.

N-(4-(2-(3,4-Dichlorobenzyl)thiazol-4-yl)phenyl)-2-(2,4-dichlorobenzyl)-4-methylthiazole-5-carboxamide (5d). Solid, m.p. 142 ºC, IR(KBr, cm-1) 3478, 3259 (NH); 1654 (CO); 1603 (C=N); 1H NMR (CDCl3): δ 2.73 (s, 3H, CH3), 4.38 (s, 2H, CH2-Ph), 4.46 (s, 2H, CH2-Ph), 7.21-7.45 (m, 8H, Ar-H, Thiazole-H, NH-CO) 7.57 (d, J=9 Hz, 2H, Ar-H), 7.85 (d, J=9 Hz, 2H, Ar-H), Anal. Calcd. for C28H19Cl4N3OS2: C, 54.29; H, 3.09; N, 6.38. Found: C, 54.08; H, 3.03; N, 6.35.

N-(4-(2-(3,4-Dimethoxybenzyl)thiazol-4-yl)phenyl)-2-(2,4-dichlorobenzyl)-4-methylthiazole-5-carboxamide (5e). Solid, m.p. 113 ºC, IR(KBr, cm-1) 3455, 3248 (NH); 1642 (CO); 1595 (C=N); 1H NMR (CDCl3): δ 2.75 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.32 (s, 2H, CH2-Ph), 4.41 (s, 2H, CH2-Ph), 6.84-7.47 (m, 8H, Ar-H, Thiazole-H, NH-CO) 7.68 (d, J=8.7 Hz, 2H, Ar-H), 7.88 (d, J=8.7 Hz, 2H, Ar-H). Anal. Calcd. for C30H25Cl2N3O3S2: C, 59.01; H, 4.13; N, 6.88. Found: C, 58.72; H, 3.94; N, 6.58.

N-(4-(2-Methylthiazol-4-yl)phenyl)-2-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide (5f). Solid, m.p. 152 ºC, IR(KBr, cm-1) 3444, 3256 (NH); 1660 (CO); 1599 (C=N); 1H NMR (CDCl3): δ 2.74 (s, 3H, CH3), 2.76 (s, 3H, CH3), 4.26 (s, 2H, CH2-Ph), 7.03-7.35 (m, 6H, Ar-H, Thiazole-H, NH-CO), 7.56 (d, J=8.6 Hz, 2H, Ar-H), 7.84 (d, J=8.6 Hz, 2H, Ar-H), LCMS: 423.8 (M+1). Anal. Calcd. for C22H18FN3OS2: C, 62.39; H, 4.28; N, 9.92. Found: C, 61.99; H, 3.95; N, 9.61.

N-(4-(2-(4-Chlorobenzylthiazol-4-yl)phenyl)-2-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide (5g). Solid, m.p. 171 ºC, IR(KBr, cm-1) 3449, 3232 (NH); 1651 (CO); 1595 (C=N); 1H NMR (CDCl3): δ 2.73 (s, 3H, CH3), 4.25 (s, 2H, CH2-Ph), 4.33 (s, 2H, CH2-Ph), 7.02-7.33 (m, 9H, Ar-H, NH-CO), 7.45 (s, IH, Thiazole-H), 7.57 (d, J=8.7 Hz, 2H, Ar-H), 7.85 (d, J=8.7 Hz, 2H, Ar-H), 13C NMR (CDCl3): δ 17.31 (Thiazole-CH3), 39.01 (2 x CH2-Ar), 112.58-169.64 (24-C, Aromatic-C), 170.69 (CO-NH), LCMS: 423.8 (M+1). Anal. Calcd. for C28H21ClFN3OS2: C, 62.97; H, 3.96; N, 7.87. Found: C, 62.59; H, 3.87; N, 7.53.

N-(4-(2-(4-Fluorobenzylthiazol-4-yl)phenyl)-2-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide (5h). Solid, m.p. 140 ºC, IR(KBr, cm-1) 3441, 3242 (NH); 1647 (CO); 1601 (C=N); 1H NMR (CDCl3): δ 2.75 (s, 3H, CH3), 3.73 (s, 2H, CH2), 4.34 (s, 2H, CH2), 7.00-7.32 (m, 10H, Ar-H, Thiazole-H, NH-CO), 7.49 (d, J=8.4 Hz, 2H, Ar-H), 7.82 (d, J=8.4 Hz, 2H, Ar-H). Anal. Calcd. for C28H21F2N3OS2: C, 64.97; H, 4.09; N, 8.12. Found: C, 64.69; H, 3.97; N, 8.01.

N-(4-(2-(3,4-Dichlorobenzylthiazol-4-yl)phenyl)-2-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide (5i). Solid, m.p. 158 ºC, IR(KBr, cm-1) 3472, 3264 (NH); 1641 (CO); 1598 (C=N); 1H NMR (CDCl3): δ 2.74 (s, 3H, CH3), 4.34 (s, 2H, CH2-Ph), 4.40 (s, 2H, CH2-Ph), 7.02-7.60 (m, 9H, Ar-H, Thiazole-H, NH-CO), 7.58 (d, J=9.0 Hz, 2H, Ar-H), 7.86 (d, J=9.0 Hz, 2H, Ar-H), 13C NMR (CDCl3): δ 17.3 (Thiazole-CH3), 36.9 (CH2-Ar), 38.9 (CH2-Ar), 112.5- 159.7 (24-C, Aromatic-C), 168.4 (CO-NH). Anal. Calcd. for C28H20Cl2FN3OS2: C, 59.15; H, 3.55; N, 7.39. Found: C, 58.88; H, 3.38; N, 7.28.

N-(4-(2-Methylthiazol-4-yl)phenyl)-2-(4-chlorobenzyl)-4-methylthiazole-5-carboxamide (5j). Solid, m.p. 142 ºC, IR(KBr, cm-1) 3439, 3255 (NH); 1644 (CO); 1596 (C=N); 1H NMR (CDCl3): δ 2.75 (s, 3H, CH3), 2.77 (s, 3H, CH3), 4.26 (s, 2H, CH2-Ph), 7.25-7.42 (m, 6H, Ar-H, Thiazole-H, NH-CO), 7.58 (d, J=8.7 Hz, 2H, Ar-H), 7.85 (d, J=8.7 Hz, 2H, Ar-H). Anal. Calcd. for C22H18ClN3OS2: C, 60.06; H, 4.12; N, 9.55. Found: C, 59.86; H, 3.92; N, 9.43.

N-(4-(2-(4-Chlorobenzylthiazol-4-yl)phenyl)-2-(4-chlorobenzyl)-4-methylthiazole-5-carboxamide (5k). Solid, m.p. 186 ºC, IR(KBr, cm-1) 3472, 3222 (NH); 1655 (CO); 1594 (C=N); 1H NMR (CDCl3): δ 2.78 (s, 3H, CH3), 4.30 (s, 2H, CH2-Ph), 4.37 (s, 2H, CH2-Ph), 7.29-7.39 (m, 10H, Ar-H, Thiazole-H, NH-CO), 7.62 (d, J=8.7 Hz, 2H, Ar-H), 7.90 (d, J=8.7 Hz, 2H, Ar-H). Anal. Calcd. for C28H21Cl2N3OS2: C, 62.97; H, 3.96; N, 7.87. Found: C, 62.65; H, 3.78; N, 7.81.

N-(4-(2-(3,4-Dichlorobenzylthiazol-4-yl)phenyl)-2-(4-chlorobenzyl)-4-methylthiazole-5-carboxamide (5l). Solid, m.p. 170 ºC, IR(KBr, cm-1) 3471, 3233 (NH); 1649 (CO); 1589 (C=N); 1H NMR (CDCl3): δ 2.75 (s, 3H, CH3), 4.27 (s, 2H, CH2-Ph), 4.47 (s, 2H, CH2-Ph), 7.22-7.46 (m, 9H, Ar-H, Thiazole-H, NH-CO), 7.58 (d, J=8.5 Hz, 2H, Ar-H), 7.86 (d, J=8.5 Hz, 2H, Ar-H). Anal. alcd. for C28H20Cl3N3OS2: C, 62.97; H, 3.96; N, 7.87. Found: C, 62.59; H, 3.87; N, 7.53.

N-(4-(2-(4-Fluorobenzylthiazol-4-yl)phenyl)-2-(4-chlorobenzyl)-4-methylthiazole-5-carboxamide (5m). Solid, m.p. 155 ºC, IR(KBr, cm-1) 3449, 3258 (NH); 1651 (CO); 1594 (C=N); 1H NMR (CDCl3): δ 2.75 (s, 3H, CH3), 4.27 (s, 2H, CH2-Ph), 4.35 (s, 2H, CH2-Ph), 7.01-7.38 (m, 10H, Ar-H, Thiazole-H, NH-CO), 7.58 (d, J=8.7 Hz, 2H, Ar-H), 7.87 (d, J=8.7 Hz, 2H, Ar-H). Anal. Calcd. for C28H21ClFN3OS2: C, 62.97; H, 3.96; N, 7.87. Found: C, 62.69; H, 3.84; N, 7.79.

N-(4-(2-(3,4-Dimethoxybenzylthiazol-4-yl)phenyl)-2-(4-chlorobenzyl)-4-methylthiazole-5-carboxamide (5n). Solid, m.p. 160 ºC, IR(KBr, cm-1) 3448, 3268 (NH); 1647 (CO); 1597 (C=N); 1H NMR (CDCl3): δ 2.76 (s, 3H, CH3), 3.87 (s, 3H, O-CH3), 3.89 (s, 3H, O-CH3) 4.28 (s, 2H, CH2-Ph), 4.32 (s, 2H, CH2-Ph), 6.84-7.37 (m, 9H, Ar-H, Thiazole-H, NH-CO), 7.59 (d, J=8.5 Hz, 2H, Ar-H), 7.88 (d, J=8.5 Hz, 2H, Ar-H), LCMS: 575 (M+), 577 (M+2). Anal. Calcd. for C30H26ClN3O3S2: C, 62.54; H, 4.55; N, 7.29. Found: C, 62.35; H, 4.23; N, 7.33.

References

  1. Hargrave, K. D.; Hess, F. K.; Oliver, J.T. J. Med. Chem. 1983, 23, 1158.
  2. Patt, W. C.; Hammilton, H. W.; Teller, M. D.; Ryan, M. J.; Taylor, D. G.; Connolly, C. J.; Doherty, A. M.; Klutchko, S. R.; Sircar, I.; Steinbaugh, B. A.; Batley, B. L.; Painchaud, C.A.; Rapundalo, S.T.; Michniewicz, B.M.; Olson, S.C. J. Med. Chem. 1992, 35, 2562. https://doi.org/10.1021/jm00092a006
  3. Haviv, F.; Ratajczyk, J. D.; DeNet, R. W.; Kerdesky, F. A.; Waltwers, R. L.; Schmidt, S. P.; Holmes, J. H.; Young, P. R.; Carter, G. W. J. Med. Chem. 1988, 31, 1719. https://doi.org/10.1021/jm00117a010
  4. Clemence, F.; Martret, O. L.; Delevallee, F.; Benzoni, J.; Jouanen, A.; Jouquey, S.; Mouren, M.; Deraedt, R. J. Med. Chem. 1988, 31, 1453. https://doi.org/10.1021/jm00402a034
  5. Jaen, J. C.; Wise, L. D.; Caprathe, B. W.; Tecle, H.; Bergmeier, S.; Humblet, C. C.; Heffner, T. G.; Meltzner, L. T.; Pugsley, T. A. J. Med. Chem. 1990, 33, 311. https://doi.org/10.1021/jm00163a051
  6. Tsuji, K.; Ishikawa, H. Bioorg. Med. Chem. Lett. 1994, 4, 1601. https://doi.org/10.1016/S0960-894X(01)80574-6
  7. Bell, F. W.; Cantrell, A. S.; Hoberg, M.; Jaskunas, S. R.; Johansson, N. G.; Jordon, C. L.; Kinnick, M. D.; Lind, P.; Jr. Morin, J. M.; Noreen, R.; Oberg, B.; Palkowitz, J. A.; Parrish, C. A.; Pranc, P.; Sahlberg, C.; Ternansky, R. J.; Vasileff, R. T.; Vrang, L.; West, S. J.; Zhang, H.; Zhou, X. X. J. Med. Chem. 1995, 38, 4929. https://doi.org/10.1021/jm00025a010
  8. Chem. Abstr. 1962, 54, 22576.
  9. Manian, A. K.; Khadse, B. G.; Sengupta, S. R. Indian drugs. 1994, 31, 442.
  10. Kulkarni, B. S.; Fernandez, B. S.; Patel, M. R.; Bellare, R. A.; Deliwala, C.V. J. Pharm. Sci. 1969, 58, 852. https://doi.org/10.1002/jps.2600580713
  11. Misturu O.; Atsushi K.; Hiroyoshi S.; Hisashi, T. Chem. Pharma Bull. 1995, 43, 947. https://doi.org/10.1248/cpb.43.947
  12. Jong, Y. K.; Hee, J. S.; Sung, H. L.; Myung, E. J.; Kwangwoo, A.; Jeongmin, K. Jinhwa, L. Bioorg. Med. Chem. Lett. 2009, 19, 142. https://doi.org/10.1016/j.bmcl.2008.10.130
  13. Sidique, S.; Ardecky, R.; Su, Y.; Narisawa, S.; Brown, B.; Millan, J. L.; Sergienko, E.; Cosford, N. D. P. Bioorg. Med. Chem. Lett. 2009, 19, 222. https://doi.org/10.1016/j.bmcl.2008.10.107
  14. Rindhe, S. S.; Mane, R. A.; Ingle, D. B. J. Indian Chem. Soc. 1985, 62, 334.

Cited by

  1. Synthesis and Antimicrobial Activities of Novel Series of 3-(4-(2-substituted thiazol-4-yl)phenyl)-2-(4-methyl-2-substituted thiazol-5-yl)thiazolidin-4-one Derivatives vol.51, pp.4, 2014, https://doi.org/10.1002/jhet.1789
  2. Facile synthesis of novel (1-Aryl/alkyl-1H-1,2,3-triazol- 4-yl)methyl-2-bromo-4-methylthiazole-5-carboxylates by Cu(I) catalyzed click reaction vol.86, pp.7, 2016, https://doi.org/10.1134/S1070363216070306
  3. 2-Benzamido-4-methylthiazole-5-carboxylic Acid Derivatives as Potential Xanthine Oxidase Inhibitors and Free Radical Scavengers vol.350, pp.2, 2017, https://doi.org/10.1002/ardp.201600313
  4. Efficient one-pot synthesis of ethyl 2-substitued-4-methylthiazole-5-carboxylates vol.7, pp.1, 2014, https://doi.org/10.1080/17518253.2014.895858
  5. Synthesis and Antimicrobial Activities of Novel Series of 1-((4-Methyl-2-Substituted Thiazol-5-yl)Methyleneam INO)-2-Substituted Isothiourea Derivatives vol.188, pp.9, 2013, https://doi.org/10.1080/10426507.2012.745542
  6. Synthesis and pharmacological evaluation of a novel series of 3-aryl-2-(2-substituted-4-methylthiazole-5-yl)thiazolidin-4-one as possible anti-inflammatory and antimicrobial agents vol.22, pp.20, 2012, https://doi.org/10.1016/j.bmcl.2012.08.073
  7. Development of Thiazole-5-carboxylate Derivatives as Selective Inhibitors of Monoacylglycerol Lipase as Target in Cancer vol.19, pp.5, 2011, https://doi.org/10.2174/1389557518666180702103542
  8. Synthesis, antimicrobial screening, and docking study of new 2‐(2‐ethylpyridin‐4‐yl)‐ 4‐METHYL‐ N ‐phenylthiazole‐5 vol.68, pp.2, 2011, https://doi.org/10.1002/jccs.202000174