10.1021/acs.jmedchem.7b01839.s002 Shibin Chacko Shibin Chacko Helena I. M. Boshoff Helena I. M. Boshoff Vinayak Singh Vinayak Singh Davide M. Ferraris Davide M. Ferraris Deviprasad R. Gollapalli Deviprasad R. Gollapalli Minjia Zhang Minjia Zhang Ann P. Lawson Ann P. Lawson Michael J. Pepi Michael J. Pepi Andrzej Joachimiak Andrzej Joachimiak Menico Rizzi Menico Rizzi Valerie Mizrahi Valerie Mizrahi Gregory D. Cuny Gregory D. Cuny Lizbeth Hedstrom Lizbeth Hedstrom Expanding Benzoxazole-Based Inosine 5′-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents American Chemical Society 2018 17 b Mtb IMPDH 2 inhibitors SAR Mtb IMPDH 2 blocks guanine MIC Mtb IMPDH 2 Potential Antituberculosis Agents New drugs 2018-05-10 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Expanding_Benzoxazole-Based_Inosine_5_-Monophosphate_Dehydrogenase_IMPDH_Inhibitor_Structure_Activity_As_Potential_Antituberculosis_Agents/6394187 New drugs and molecular targets are urgently needed to address the emergence and spread of drug-resistant tuberculosis. <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) inosine 5′-monophosphate dehydrogenase 2 (<i>Mtb</i>IMPDH2) is a promising yet controversial potential target. The inhibition of <i>Mtb</i>IMPDH2 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 <i>Mtb</i>IMPDH2 inhibitors and demonstrate that minimum inhibitory concentrations (MIC) of ≤1 μM can be achieved. The antibacterial activity of the most promising compound, <b>17b</b> (<b>Q151</b>), is derived from the inhibition of <i>Mtb</i>IMPDH2 as demonstrated by conditional knockdown and resistant strains. Importantly, guanine does not change the MIC of <b>17b</b>, alleviating the concern that guanine salvage can protect <i>Mtb</i> in vivo. These findings suggest that <i>Mtb</i>IMPDH2 is a vulnerable target for tuberculosis.