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bioRxiv · 10.64898/2026.09.21.753226

Discovery and Optimization of Imidazothiazole Carboxamides as Novel Anti-Tuberculosis Agents

Meng, L.·Grant, D.·Xie, H.·Ford, R.·Webb, J.·McNamara, C. W.·Sukheja, P.·Yang, B.·Chatterjee, A. K.
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Abstract

Screening of the open-access CRESTdb small-molecule library identified the imidazothiazole carboxamide sCQG200 (1) as an initial hit, with activity against H37Rv and Erdman Mycobacterium tuberculosis strains in cholesterol-containing medium (MIC90= 6.88 uM and 4.48 uM, respectively) and against intracellular Mtb (EC50= 3.80 uM). sCQG200 retained activity against drug-resistant Mtb strains, including clinical MDR/XDR isolates. SAR optimization led to analogs 21 and 24 with substantially improved antimycobacterial potency. Mouse pharmacokinetic studies following oral and intravenous administration showed 62.1% and 29.5% oral bioavailability for 21 and 24, respectively. This structurally differentiated chemotype provides a promising starting point for further optimization as antitubercular agent.

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Meng, L., Grant, D., Xie, H., Ford, R., Webb, J., McNamara, C. W., Sukheja, P., Yang, B., Chatterjee, A. K.. 2026-09-24. Discovery and Optimization of Imidazothiazole Carboxamides as Novel Anti-Tuberculosis Agents. https://doi.org/10.64898/2026.09.21.753226

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