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

Screening of the open-access CRESTdb small-molecule library identified the imidazothiazole carboxamide sCQG20 0 ( 1 ) as an initial hit, with activity against H37Rv and Erdman Mycobacterium tuberculosis strains in cholesterol-containing medium (MIC ₉₀ = 6.88 µM and 4.48 µM, respectively) and against intracellular Mtb (EC ₅₀ = 3.80 µM). 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.