Advanced
Synthesis and Biological Screening of Thiazole-5-Carboxamide Derivatives
Synthesis and Biological Screening of Thiazole-5-Carboxamide Derivatives
Journal of the Korean Chemical Society. 2011. Oct, 55(5): 882-886
Copyright © 2011, The Korean Chemical Society
  • Received : April 05, 2010
  • Accepted : September 15, 2010
  • Published : October 20, 2011
Download
PDF
e-PUB
PubReader
PPT
Export by style
Article
Author
Metrics
Cited by
TagCloud
About the Authors
Pravin C. Mhaske
Kamlesh S. Vadgaonkar
Department of Chemistry, HPT Arts and RYK Science College, Nashik India-422 005.
Rahul P. Jadhav
Department of Chemistry, HPT Arts and RYK Science College, Nashik India-422 005.
Vivek D. Bobade
Department of Chemistry, HPT Arts and RYK Science College, Nashik India-422 005.
v_bobade31@rediffmail.com

Abstract
Keywords
PPT Slide
Lager Image
PPT Slide
Lager Image
PPT Slide
Lager Image
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. 1 H-NMR and 13 C NMR spectra were recorded in CDCl 3 and DMSO- d 6 solution on a Varian Mercury YH-300 spectrometer operating at 300 MHz for 1 H and 75 MHz for 13 C. 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); 1 H NMR (CDCl 3 ): δ 2.74 (s, 3H, CH 3 ), 2.76 (s, 3H, CH 3 ), 4.39 (s, 2H, CH 2 -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 C 22 H 17 Cl 2 N 3 OS 2 : 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); 1 H NMR (CDCl 3 ): δ 2.75 (s, 3H, CH 3 ), 4.33 (s, 2H, CH 2 -Ph), 4.41 (s, 2H, CH 2 -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 C 28 H 20 BrCl 2 N 3 OS 2 : 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); 1 H NMR (CDCl 3 ): δ 2.75 (s, 3H, CH 3 ), 4.27 (s, 2H, CH 2 -Ph), 4.32 (s, 2H, CH 2 -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), 13 C NMR (CDCl3): δ 17.3 (Thiazole-CH 3 ), 36.9 (CH 2 -Ar), 38.9 (CH 2 -Ar), 112.5- 160.2 (24-C, Aromatic-C), 168.3 (CO-NH). Anal. Calcd. for C 28 H 20 Cl 2 FN 3 OS 2 : 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); 1 H NMR (CDCl 3 ): δ 2.73 (s, 3H, CH 3 ), 4.38 (s, 2H, CH 2 -Ph), 4.46 (s, 2H, CH 2 -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 C 28 H 19 Cl 4 N 3 OS 2 : 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); 1 H NMR (CDCl 3 ): δ 2.75 (s, 3H, CH 3 ), 3.87 (s, 3H, OCH 3 ), 3.88 (s, 3H, OCH 3 ), 4.32 (s, 2H, CH 2 -Ph), 4.41 (s, 2H, CH 2 -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 C 30 H 25 Cl 2 N 3 O 3 S 2 : 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); 1 H NMR (CDCl 3 ): δ 2.74 (s, 3H, CH 3 ), 2.76 (s, 3H, CH 3 ), 4.26 (s, 2H, CH 2 -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 C 22 H 18 FN 3 OS 2 : 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); 1 H NMR (CDCl 3 ): δ 2.73 (s, 3H, CH 3 ), 4.25 (s, 2H, CH 2 -Ph), 4.33 (s, 2H, CH 2 -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 C 28 H 21 ClFN 3 OS 2 : 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); 1 H NMR (CDCl 3 ): δ 2.75 (s, 3H, CH 3 ), 3.73 (s, 2H, CH 2 ), 4.34 (s, 2H, CH 2 ), 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 C 28 H 21 F 2 N 3 OS 2 : 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); 1 H NMR (CDCl 3 ): δ 2.74 (s, 3H, CH 3 ), 4.34 (s, 2H, CH 2 -Ph), 4.40 (s, 2H, CH 2 -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 C 28 H 20 Cl 2 FN 3 OS 2 : 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); 1 H NMR (CDCl 3 ): δ 2.75 (s, 3H, CH 3 ), 2.77 (s, 3H, CH 3 ), 4.26 (s, 2H, CH 2 -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 C 22 H 18 ClN 3 OS 2 : 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); 1 H NMR (CDCl 3 ): δ 2.78 (s, 3H, CH 3 ), 4.30 (s, 2H, CH 2 -Ph), 4.37 (s, 2H, CH 2 -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 C 28 H 21 Cl 2 N 3 OS 2 : 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); 1 H NMR (CDCl 3 ): δ 2.75 (s, 3H, CH 3 ), 4.27 (s, 2H, CH 2 -Ph), 4.47 (s, 2H, CH 2 -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 C 28 H 20 Cl 3 N 3 OS 2 : 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); 1 H NMR (CDCl 3 ): δ 2.75 (s, 3H, CH 3 ), 4.27 (s, 2H, CH 2 -Ph), 4.35 (s, 2H, CH 2 -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 C 28 H 21 ClFN 3 OS 2 : 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); 1 H NMR (CDCl 3 ): δ 2.76 (s, 3H, CH 3 ), 3.87 (s, 3H, O-CH 3 ), 3.89 (s, 3H, O-CH 3 ) 4.28 (s, 2H, CH 2 -Ph), 4.32 (s, 2H, CH 2 -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 C 30 H 26 ClN 3 O 3 S 2 : C, 62.54; H, 4.55; N, 7.29. Found: C, 62.35; H, 4.23; N, 7.33.
Acknowledgements
The authors are thankful to Garware Research Center, University of Pune and IIT Mumbai, India for providing facilities for spectral studies of compounds. Financial support from UGC, New Delhi is gratefully acknowledged.
References
Hargrave K. D. , Hess F. K. , Oliver J.T. 1983 J. Med. Chem. 23 1158 -    DOI : 10.1021/jm00362a014
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. 1992 J. Med. Chem. 35 2562 -    DOI : 10.1021/jm00092a006
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. 1988 J. Med. Chem. 31 1719 -    DOI : 10.1021/jm00117a010
Clemence F. , Martret O. L. , Delevallee F. , Benzoni J. , Jouanen A. , Jouquey S. , Mouren M. , Deraedt R. 1988 J. Med. Chem. 31 1453 -    DOI : 10.1021/jm00402a034
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. 1990 J. Med. Chem. 33 311 -    DOI : 10.1021/jm00163a051
Tsuji K. , Ishikawa H. 1994 Bioorg. Med. Chem. Lett. 4 1601 -    DOI : 10.1016/S0960-894X(01)80574-6
Bell F. W. , Cantrell A. S. , Hoberg M. , Jaskunas S. R. , Johansson N. G. , Jordon C. L. , Kinnick M. D. , Lind P. , 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. 1995 J. Med. Chem. 38 4929 -    DOI : 10.1021/jm00025a010
1962 Chem. Abstr. 54 22576 -
Manian A. K. , Khadse B. G. , Sengupta S. R. 1994 Indian drugs. 31 442 -
Kulkarni B. S. , Fernandez B. S. , Patel M. R. , Bellare R. A. , Deliwala C.V. 1969 J. Pharm. Sci. 58 852 -    DOI : 10.1002/jps.2600580713
Misturu O. , Atsushi K. , Hiroyoshi S. , Hisashi T. 1995 Chem. Pharma Bull. 43 947 -    DOI : 10.1248/cpb.43.947
Jong Y. K. , Hee J. S. , Sung H. L. , Myung E. J. , Kwangwoo A. , Jeongmin K. , Jinhwa L. 2009 Bioorg. Med. Chem. Lett. 19 142 -    DOI : 10.1016/j.bmcl.2008.10.130
Sidique S. , Ardecky R. , Su Y. , Narisawa S. , Brown B. , Millan J. L. , Sergienko E. , Cosford N. D. P. 2009 Bioorg. Med. Chem. Lett. 19 222 -    DOI : 10.1016/j.bmcl.2008.10.107
Rindhe S. S. , Mane R. A. , Ingle D. B. 1985 J. Indian Chem. Soc. 62 334 -