Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies
Open Access
- 14 January 2021
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 64 (1), 719-740
- https://doi.org/10.1021/acs.jmedchem.0c01727
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.Funding Information
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Bill and Melinda Gates Foundation (OPP1024038, OPP1066878)
- Department of Science and Technology, Republic of South Africa
- National Research Foundation
- South African Medical Research Council
- Strategic Health Innovation Partnerships (SHIP) unit of the South African Medical Research Council (SAMRC)
This publication has 49 references indexed in Scilit:
- The ESX-3 Secretion System Is Necessary for Iron and Zinc Homeostasis in Mycobacterium tuberculosisPLOS ONE, 2013
- Identification of New Drug Targets and Resistance Mechanisms in Mycobacterium tuberculosisPLOS ONE, 2013
- A Dual Read-Out Assay to Evaluate the Potency of Compounds Active against Mycobacterium tuberculosisPLOS ONE, 2013
- Synthesis and Evaluation of α-Thymidine Analogues as Novel AntimalarialsJournal of Medicinal Chemistry, 2012
- High-Resolution Phenotypic Profiling Defines Genes Essential for Mycobacterial Growth and Cholesterol CatabolismPLoS Pathogens, 2011
- Discovery and characterization of a unique mycobacterial heme acquisition systemProceedings of the National Academy of Sciences of the United States of America, 2011
- Bis{tris[3-(2-pyridyl)-1H-pyrazole]nickel(II)} dodecamolybdo(V,VI)phosphate hexahydrateActa Crystallographica Section E: Crystallographic Communications, 2010
- Mycobacterial Esx-3 is required for mycobactin-mediated iron acquisitionProceedings of the National Academy of Sciences of the United States of America, 2009
- Characterization of aMycobacterium tuberculosisESX-3 Conditional Mutant: Essentiality and Rescue by Iron and ZincJournal of Bacteriology, 2009
- Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequenceNature, 1998