N-Acyl phenothiazines as mycobacterial ATP synthase inhibitors: Rational design, synthesis and in vitro evaluation against drug sensitive, RR and MDR-TB
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Date
2024
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Academic Press Inc.
Abstract
The mycobacterial F-ATP synthase is responsible for the optimal growth, metabolism and viability of Mycobacteria, establishing it as a validated target for the development of anti-TB therapeutics. Herein, we report the discovery of an N-acyl phenothiazine derivative, termed PT6, targeting the mycobacterial F-ATP synthase. PT6 is bactericidal and active against the drug sensitive, Rifampicin-resistant as well as Multidrug-resistant tuberculosis strains. Compound PT6 showed noteworthy inhibition of F-ATP synthesis, exhibiting an IC<inf>50</inf> of 0.788 µM in M. smegmatis IMVs and was observed that it could deplete intracellular ATP levels, exhibiting an IC<inf>50</inf> of 30 µM. PT6 displayed a high selectivity towards mycobacterial ATP synthase compared to mitochondrial ATP synthase. Compound PT6 showed a minor synergistic effect in combination with Rifampicin and Isoniazid. PT6 demonstrated null cytotoxicity as confirmed by assessing its toxicity against VERO cell lines. Further, the binding mechanism and the activity profile of PT6 were validated by employing in silico techniques such as molecular docking, Prime MM/GBSA, DFT and ADMET analysis. These results suggest that PT6 presents an attractive lead for the discovery of a novel class of mycobacterial F-ATP synthase inhibitors. © 2024 Elsevier Inc.
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Keywords
5 chloro 1 [1 [2 oxo 2 (10h phenothiazin 10 yl)ethyl]piperidin 4 yl] 1,3 dihydro 2h benzo[d]imidazol 2 one, 5 chloro 3 (4 fluorobenzyl) 1 [1 [2 oxo 2 (10h phenothiazin 10 yl)ethyl]piperidin 4 yl] 1,3 dihydro 2h benzo[d]imidazol 2 one, bedaquiline, dicyclohexylcarbodiimide, isoniazid, phenothiazine, phenothiazine derivative, proton transporting adenosine triphosphate synthase, proton transporting adenosine triphosphate synthase inhibitor, rifampicin, tuberculostatic agent, unclassified drug, enzyme inhibitor, antibacterial activity, Article, binding affinity, cell viability, computer model, controlled study, drug binding, drug design, drug efficacy, drug potency, drug screening, drug synthesis, electrophilicity, enzyme inhibition, evaluation study, fractional inhibitory concentration, fractional inhibitory concentration index, hydrogen bond, IC50, in vitro study, membrane vesicle, minimum inhibitory concentration, molecular docking, multidrug resistance, multidrug resistant tuberculosis, Mycobacterium smegmatis, Mycobacterium tuberculosis, nonhuman, oral absorption, pharmacophore, rifampicin resistance, selectivity index, synergistic effect, Vero cell line, animal, chemical structure, chemistry, Chlorocebus aethiops, dose response, drug effect, drug therapy, enzymology, microbial sensitivity test, structure activity relation, synthesis, Animals, Antitubercular Agents, Dose-Response Relationship, Drug, Drug Design, Enzyme Inhibitors, Microbial Sensitivity Tests, Molecular Docking Simulation, Molecular Structure, Phenothiazines, Structure-Activity Relationship, Tuberculosis, Multidrug-Resistant, Vero Cells
Citation
Bioorganic Chemistry, 2024, 151, , pp. -