Structure-activity relationship studies on 2,5,6-trisubstituted benzimidazoles targeting Mtb-FtsZ as antitubercular agents

Filamenting temperature sensitive protein Z (FtsZ) is an essential bacterial cell division protein and a promising target for the development of new antibacterial therapeutics. As a part of our ongoing SAR studies on 2,5,6-trisubstituted benzimidazoles as antitubercular agents targeting Mtb-FtsZ, a new library of compounds with modifications at the 2 position was designed, synthesized and evaluated for their activity against Mtb-H37Rv. This new library of trisubstituted benzimidazoles exhibited MIC values in the range of 0.004-50 mu g mL(-1). Compounds 6b, 6c, 20f and 20g showed excellent growth inhibitory activities ranging from 0.004-0.08 mu g mL(-1). This SAR study has led to the discovery of a remarkably potent compound 20g (MIC 0.0039 mu g mL(-1); normalized MIC 0.015 mu g mL(-1)). Our 3DQSAR model predicted 20g as the most potent compound in the library.

Automated summary

A new library of compounds targeting Mtb-FtsZ was designed, synthesized, and evaluated, with compound 20g showing the highest potency against Mtb-H37Rv. The SAR study led to the discovery of remarkably potent compounds, with 20g predicted as the most effective in the library by the 3DQSAR model.