Sahu, N.USingh, VFerraris, D.MRizzi, MKharkar, P.S2024-08-032024-08-032018-04-18Sahu 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.https://pubmed.ncbi.nlm.nih.gov/29699922/https://doi.org/10.1016/j.bmcl.2018.04.045https://hdl.handle.net/11288/597096Tuberculosis 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.en1,2,3-TriazoleAnti-tubercularGuaB2IMPDHMycobacterium tuberculosisTuberculosisArticle