Phenotypic-Based Discovery and Exploration of a Resorufin Scaffold with Activity against Mycobacterium tuberculosis.

Autor: Tran E; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia., Cheung CY; Department of Microbiology and Immunology, Otago School of Medical Sciences, University of Otago, Dunedin, 9054, New Zealand., Li L; Department of Microbiology & Immunology, The University of Melbourne at The Peter Doherty Institute for Infection & Immunity, Melbourne, Victoria, 3000, Australia., Carter GP; Department of Microbiology & Immunology, The University of Melbourne at The Peter Doherty Institute for Infection & Immunity, Melbourne, Victoria, 3000, Australia., Gable RW; School of Chemistry, University of Melbourne, Parkville, Victoria, 3010, Australia., West NP; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, 4072, Australia., Kaur A; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Monash University, Melbourne, Victoria, 3052, Australia., Gee YS; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia., Cook GM; Department of Microbiology and Immunology, Otago School of Medical Sciences, University of Otago, Dunedin, 9054, New Zealand., Baell JB; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia., Jörg M; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.; Chemistry-School of Natural & Environmental Sciences, Newcastle University Centre for Cancer, Newcastle University, Bedson Building, Newcastle Upon Tyne, NE1 7RU, UK.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2024 Dec 16; Vol. 19 (24), pp. e202400482. Date of Electronic Publication: 2024 Oct 25.
DOI: 10.1002/cmdc.202400482
Abstrakt: Tuberculosis remains a leading cause of death by infectious disease. The long treatment regimen and the spread of drug-resistant strains of the causative agent Mycobacterium tuberculosis (Mtb) necessitates the development of new treatment options. In a phenotypic screen, nitrofuran-resorufin conjugate 1 was identified as a potent sub-micromolar inhibitor of whole cell Mtb. Complete loss of activity was observed for this compound in Mtb mutants affected in enzyme cofactor F 420 biosynthesis (fbiC), suggesting that 1 undergoes prodrug activation in a manner similar to anti-tuberculosis prodrug pretomanid. Exploration of the structure-activity relationship led to the discovery of novel resorufin analogues that do not rely on the deazaflavin-dependent nitroreductase (Ddn) bioactivation pathway for their antimycobacterial activity. These analogues are of interest as they work through an alternative, currently unknown mechanism that may expand our chemical arsenal towards the treatment of this devastating disease.
(© 2024 The Author(s). ChemMedChem published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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