Antitubercular 2-Pyrazolylpyrimidinones: Structure–Activity Relationship and Mode-of-Action Studies
Year: 2021
Type: article
Abstract: Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure–activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
Source: Journal of Medicinal Chemistry
Authors: Candice Soares de Melo, Vinayak Singh, Alissa Myrick, Sandile B. Simelane, Dale Taylor, Christel Brunschwig, Nina Lawrence, Dirk Schnappinger, Curtis A. Engelhart, Anuradha Kumar, Tanya Parish, Qin Su, Timothy G. Myers, Helena I. M. Boshoff, Clifton E. Barry, Frederick A. Sirgel, Paul D. van Helden, Kirsteen I. Buchanan, Tracy Bayliss, Simon R. Green, Peter C. Ray, Paul G. Wyatt, Gregory S. Basarab, Charles J. Eyermann, Kelly Chibale, Sandeep R. Ghorpade
Institutions: University of Cape Town, South African Medical Research Council, Institute of Infectious Disease and Molecular Medicine, Cornell University, Weill Cornell Medicine, Infectious Disease Research Institute, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Stellenbosch University, University of Dundee
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $2,640
Funders: Bill and Melinda Gates Foundation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Wellcome Trust, National Research Foundation, South African Medical Research Council, Department of Science and Technology, Republic of South Africa, National Institutes of Health, Medical Research Council, National Institute of Allergy and Infectious Diseases, NHLBI Division of Intramural Research
OpenAlex ID: W3120699211