Expanding Benzoxazole-Based Inosine 5′-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents

New drugs and molecular targets are
urgently needed to address
the emergence and spread of drug-resistant tuberculosis. Mycobacterium
tuberculosis (Mtb) inosine 5′-monophosphate
dehydrogenase 2 (MtbIMPDH2) is a promising yet controversial
potential target. The inhibition of MtbIMPDH2 blocks
the biosynthesis of guanine nucleotides, but high concentrations of
guanine can potentially rescue the bacteria. Herein we describe an
expansion of the structure–activity relationship (SAR) for
the benzoxazole series of MtbIMPDH2 inhibitors and
demonstrate that minimum inhibitory concentrations (MIC) of ≤1
μM can be achieved. The antibacterial activity of the most promising
compound, 17b (Q151), is derived from the
inhibition of MtbIMPDH2 as demonstrated by conditional
knockdown and resistant strains. Importantly, guanine does not change
the MIC of 17b, alleviating the concern that guanine
salvage can protect Mtb in vivo. These findings suggest
that MtbIMPDH2 is a vulnerable target for tuberculosis.