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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