Current drugs for TB primarily target cell wall biosynthesis or DNA/RNA synthesis. Rising number of resistant strains of MDR- and XDR-TB display an alarming need for new anti-tubercular agents with unique mode of action. FtsZ, a homolog of tubulin and a ubiquitous bacterial cytokinesis protein is a promising target. Inhibition of FtsZ assembly has shown to affect the cell division process. In our laboratory, we have successfully designed and synthesized novel series of trisubstituted benzimidazoles that displayed excellent antitubercular activity by inhibiting Ftsz. Hit to lead optimization studies resulted in the identification of compounds with good in vivo activities (up to 6.5 log10 reduction of CFU in lung and spleen) in the rapid mouse model of TB infection. The lead compounds were also found to be bactericidal and were active against Mtb grown under hypoxic conditions (LORA). Herein, we present the SAR study and biological evaluation of the lead compounds.                                                          

Trisubstituted benzimidazoles as a new class of antitubercular agents targeting FtsZ with high in vitro activity and in vivo efficacy

248th National Meeting (2014)

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