Repurposing of a drug scaffold: Identification of novel sila analogues of rimonabant as potent antitubercular agents

•The antitubercular activity of diaryl pyrazoles (rimonabant analogues) was investigated as part of drug scaffold repurposing.•From SAR analysis, silicon incorporation increased the anti-TB potential of the series.•The sila analogue 18a was the most potent compound (MIC 31 ng/mL, H37Rv).•Compound 18e (MIC 390 ng/mL) was the best in terms of in vitro pharmacokinetics.

The structural similarity between an MmpL3 inhibitor BM212, and a cannabinoid receptor modulator rimonabant, prompted us to investigate the anti-tubercular activity of rimonabant and its analogues. Further optimization, particularly through incorporation of silicon into the scaffold, resulted in new compounds with significant improvement in anti-tubercular activity against Mycobacterium tuberculosis (H37Rv). The sila analogue 18a was found to be the most potent antimycobacterial compound (MIC, 31 ng/mL) from this series with an excellent selectivity index.

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