Design, Synthesis and Biological Evaluation of Novel Trisubstituted-Benzimidazoles as a New Class of Antitubercular Agents, Targeting FtsZ
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Despite extensive research in last 40 years, the treatment of TB is still limited to a cocktail of classical drugs that mostly target cell wall biosynthesis, DNA coiling, transcription, translation. Knowing the bacterial ability to develop resistance, there is a dire need for the discovery of new cellular targets to develop novel antitubercular agents which can surpass the resistance. In this context, FtsZ, a highly conserved and ubiquitous cytokinesis protein, offers an extremely promising therapeutic target. It has been observed that inhibition of FtsZ assembly leads to absence of septum formation, eventually causing cell lethality. Hence, compounds targeting FtsZ can be developed as novel anti-tubercular agents. Libraries of novel trisubstituted benzimidazoles were created through rational drug design. A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5-6 Μg/mL (2-15 ¶æM) against Mtb H37Rv strain with no appreciable cytotoxicity (IC50 >200 ΜM) against Vero cells. Moreover, five of the lead compounds also exhibited excellent activity against clinical Mtb strains with different drug-resistance profiles. In the light scattering experiments, the lead compounds clearly showed inhibition of FtsZ assembly in a dose dependent manner while enhancing the GTPase activity of Mtb FtsZ by 3-4 folds. Transmission electron microscopy (TEM) images of Mtb FtsZ treated with lead compound revealed an impressive dose-dependent inhibition of FtsZ assembly and a remarkable reduction in FtsZ protofilament formation. A unique Mtb cell morphology was observed under Scanning electron microscopy (SEM). Mtb cells were shorter in length with increased circumferences and altered polar caps. The TEM and SEM analyses strongly suggest that lead benzimidazoles have a novel mechanism of action on the inhibition of Mtb FtsZ assembly and Z-ring formation. Furthermore, as FtsZ is highly conserved in different pathogens, we also identified several hit compounds against F. tularensis, B. thailandensis and Y. pestis. Design, synthesis, optimization and biological evaluation of novel trisubstituted-benzimidazoles are presented.