Synthesis and Biological Screening of Thiazole-5-Carboxamide Derivatives

Abstract

Thiazole derivatives have been studied extensively because of their ready accessibility, diverse chemical activity. The chemistry of thiazole continues to draw the attention of synthetic organic chemists due to their varied biological activities, 1-5 such as antibacterial, antitubercular, anti-cancer, antifungal and anti-inflammatory activities. 6-9 Also 4-(4-aminophenyl)-thiazoles have been reported to exhibit antitubercular activity. 10 5-azole carboxamide derivatives show antianoxic activity. 11 The aryl imidazolyl carboxamide derivatives were shown to be cannabinoid CB1 receptor antagonist. 12,13 Based on these observations, substituted thiazole carboxamides were synthesized and subjected to microbial screening. Here in, we report a simple efficient and effective protocol for the synthesis of N-(4-(2-benzylthiazol-4-yl)phenyl)-2-benzyl-4-methylthiazole-5-carboxamide derivatives using EDC-HOBt coupling in DMF and their antimicrobial activities. The target compounds 5a-n were synthesized by reaction of 2-benzyl-4-methylthiazole-5-carboxylic acid 3a-c with 2-methyl/substitutedbenzyl-4-(4-aminophenyl) thiazoles 2a-f in the presence of EDC- HOBt in DMF in good yields (Scheme 1). The yields, melting points and molecular formula of carboxamide derivatives 5a-n are listed in Table 1. The reaction failed when ethyl 2-benzyl4-methylthiazole-5-carboxylate 1a-c was refluxed with 2methyl/substitutedbenzyl-4-(4-aminophenyl) thiazole 2af in absolute ethanol for 24 h. When the same reaction was carried out with acid chloride or mixed anhydride activation of the carboxylic acid, the yields were poor. The amino phenyl thiazole derivatives 2a-f were synthesized using literature protocol. 10,14 The target compounds were characterized by IR, 1 H NMR, 13 C NMR, mass and elemental analysis and all the spectral data are in accordance with the assumed structures. In additions to the signals for aromatic protons 1 H NMR spectra of the compounds 5a-n reveal singlet at 2.73-2.78 ppm for thiazole-CH3 protons. Furthermore, the spectra show singlet for methylene protons of benzylic carbon atoms in the range 3.73- 4.41 ppm. These compounds were found to be effective against the Gram-positive bacteria S. aureu and B. Subtilis and Gramnegative bacteria E. coli and P. aeruginosa. The zones of inhibition in mm, for the bioactive compounds against microorganisms tested are reported in Table 2. N-(4-(2-(4chlorobenzylthiazol-4-yl)phenyl)-2-(4-chlorobenzyl)-4methylthiazole-5-carboxamide (5k) is active against both gram positive and gram negative stains but looses activity on adding one chlorine at 3-position as in N-(4-(2-(3,4dichlorobenzylthiazol-4-yl)phenyl)-2-(4-chlorobenzyl)4-methylthiazole-5-carboxamide (5l). When chlorine in the first benzyl ring in 5l, was replaced by fluorine as in N(4-(2-(3,4-dichlorobenzylthiazol-4-yl)phenyl)-2-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide (5i), it showed antibacterial activity. N-(4-(2-(4-fluorobenzylthiazol-4-yl)phenyl)-2-(4-chlorobenzyl)-4-methylthiazole-5-carboxamide (5m) showed antifungal activity, but when one chlorine atom is added at 2-position as in N-(4-(2-(4-fluorobenzyl)thiazol-4-yl)phenyl)-2-(2,4-dichlorobenzyl)-4-methylthiazole-5-carboxamide (5c), it showed antibacterial activity with loss of antifungal activity. 2-methyl substituted carboxamide derivatives (5a, 5f) showed only antibacterial activity. The dimethoxy derivative 5n was found to be inactive against all stains.