Design, synthesis, and biological evaluation of 1‐ethyl‐3‐(thiazol‐2‐yl)urea derivatives as Escherichia coli DNA gyrase inhibitors

Discovery of novel DNA gyrase B inhibitors remains an attractive field in the search for new antibacterial drugs to overcome the known bacterial resistance mechanisms. In the present study, we designed and synthesized novel ethylurea derivatives of 4,5,6,7‐tetrahydrobenzo[1,2‐d]thiazole‐2,6‐diamine, 2‐(2‐aminothiazol‐4‐yl)acetic acid, and benzo[1,2‐d]thiazole‐2,6‐diamine and evaluated their Escherichia coli DNA gyrase inhibition. The most potent DNA gyrase inhibitors in the prepared library of compounds were benzo[1,2‐d]thiazoles 32–34, 36, and 37 with IC50 values in the low micromolar range. The most promising inhibitors identified were evaluated against selected Gram‐positive and Gram‐negative bacterial strains. Compound 33 showed a MIC of 50 μM against an E. coli efflux pump‐defective strain, which suggests that efflux decreases the on‐target concentrations of these compounds. A series of new thiazole‐based ethylureas were prepared as DNA gyrase inhibitors. Among these, tert‐butyl (4‐(2‐((2‐(3‐ethylureido)benzo[1,2‐d]thiazol‐6‐yl)amino)‐2‐oxoethyl)thiazol‐2‐yl)carbamate (33) was found to be the most potent inhibitor of E. coli DNA gyrase (IC50 = 3.9 µM). It also displayed antibacterial activity against an efflux pump‐deficient strain of E. coli (MIC = 50 µM).