Synthesis, Screening and Docking Analysis of Novel Benzimidazolium and Benzotriazolium Compounds as Potent Anti Tubercular Agents

Introduction: Tuberculosis is an infectious bacterial disease that mainly affects the lungs. Globally, there are about 10.5 million new cases and about 1.5 million deaths reported each year as per science daily research news in 2017.

Objective: One of the biggest problems of Tuberculosis is the lack of effective treatments. Bedaquiline (2013) and Delaminid (2014) are the only two agents approved for TB after Rifampicin. This clearly shows the need for new lead molecules to fight against TB.

Methodology: A series of benzimidazolium and benzotriazolium derivatives were synthesized and the structures were confirmed by their IR, 1H NMR,13C NMR and mass spectral data. They were tested for in vitro antitubercular activity by MABA Assay, MTT Assay and axenic culture assay. To determine selective TB activity, they were also tested for antimicrobial activity and cytotoxicity. Docking simulations and drug-inhibitor combination studies were conducted to know the probable mechanism of action.

Results: Among the synthesized compounds B10, B11, B13, B14, B22, B23, B24, B25, B26 and B27 showed excellent anti TB activity with an MIC 3.12-0.8 μg/mL. Among these, compound 1,3- bis(4-chlorobenzyl)-1H-benzo[d]imidazol-3-ium chloride (B11) has shown selective anti TB activity against Mycobacterium tuberculosis H37Rv (0.8μg/mL) in MABA assay. This compound hasn't shown any antimicrobial (at 100μg/mL) and cytotoxicity (at 10μM). Docking studies and drug-inhibitor combination studies indicated that the compounds might act via enzymes involved in the cell division process.

Conclusion: In conclusion, we synthesized molecules with potent and selective anti TB activity.