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Hit discovery of Mycobacterium tuberculosis inosine 5'-monophosphate dehydrogenase, GuaB2, inhibitors
Sahu, N.U Singh, V Ferraris, D.M Rizzi, M Kharkar, P.S
Sahu, N.U
Singh, V
Ferraris, D.M
Rizzi, M
Kharkar, P.S
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Abstract
Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis (Mtb). Inosine 5'-monophosphate dehydrogenase (IMPDH), guaB2, of Mtb, required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive MtbH37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb-GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb, followed by cross-resistance to IMPDH inhibitor-resistant SRMV2.6 strain of Mtb, and activity on human IMPDH2 isoform. One of the hits, 13, a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb-GuaB2 enzyme. The hit, 13, is a promising molecule with potential for further development as an antitubercular agent.
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Date
2018-04-18
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Publisher
Elsevier
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Keywords
1,2,3-Triazole,Anti-tubercular,GuaB2,IMPDH,Mycobacterium tuberculosis,Tuberculosis
Citation
Sahu NU, Singh V, Ferraris DM, Rizzi M, Kharkar PS. Hit discovery of Mycobacterium tuberculosis inosine 5'-monophosphate dehydrogenase, GuaB2, inhibitors. Bioorg Med Chem Lett. 2018 Jun 1;28(10):1714-1718. doi: 10.1016/j.bmcl.2018.04.045.