Design, synthesis, and evaluation of substituted 2-acylamide-1,3-benzo[d]zole analogues as agents against MDR- and XDR-MTB

N-(5-Chlorobenzo[d]oxazol-2- yl)-4-methyl-1,2,3-thiadiazole-5-carboxamideox-amide has been identified as a potent inhibitor of Mtb H37Rv, with a minimum inhibitory concentration (MIC) of 0.42 mu M. In this study, a series of substituted 2-acylamide-1,3-zole analogues were designed and synthesized, and their anti-Mtb activities were analyzed. In total, 17 compounds were found to be potent anti-Mtb agents, especially against the MDR- and XDR-MTB strains, with MIC values < 10 mu M. These analogues can inhibit both drug-sensitive and drug-resistant Mtb. Four representative compounds were selected for further profiling, and the results indicate that compound 18 is acceptably safe and has favorable pharmacokinetic (PK) properties. In addition, this compound displays potent activity against Gram-positive bacteria, with MIC values in the range of 1.48-11.86 mu M. The data obtained herein suggest that promising anti-Mtb candidates may be developed via structural modification, and that further research is needed to explore other compounds. (c) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

A series of substituted 2-acylamide-1,3-thiazole analogues were designed and synthesized, with 17 compounds identified as potent anti-Mtb agents, especially against MDR- and XDR-MTB strains with MIC values < 10 mu M. One compound showed promising safety and pharmacokinetic properties, as well as potent activity against Gram-positive bacteria.