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.