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Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies
- Source :
- Journal of Medicinal Chemistry
- Publication Year :
- 2021
-
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.
- Subjects :
- Male
Phenotypic screening
Iron
Mutant
Antitubercular Agents
Microbial Sensitivity Tests
Pyrimidinones
01 natural sciences
Article
Mycobacterium tuberculosis
03 medical and health sciences
Minimum inhibitory concentration
Mice
Structure-Activity Relationship
Bacterial Proteins
Microsomes
Drug Discovery
medicine
Structure–activity relationship
Animals
Humans
Mode of action
030304 developmental biology
0303 health sciences
biology
Chemistry
Membrane Transport Proteins
biology.organism_classification
In vitro
0104 chemical sciences
Rats
Mice, Inbred C57BL
010404 medicinal & biomolecular chemistry
Biochemistry
Mechanism of action
Mutation
Molecular Medicine
Pyrazoles
medicine.symptom
Half-Life
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 64
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....ff5eafa1e33ac7c64b2164da5d55d9f9