Ionic liquid promoted facile one-pot synthesis of phenothiazine-thiazolidin-4-ones as potent antitubercular agents via mycobacterial ATP synthase inhibition

Abstract

The mycobacterial 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 facile and efficient one-pot three component synthesis of 2-(10H-phenothiazin-3-yl)-3-substituted thiazolidin-4-one derivatives by using ionic liquid, 1?butyl?3-methylimidazolium bromide [Bmim]Br and their inhibitory potency against mycobacterium tuberculosis H37Rv strain (ATCC-27,294). Compound T27 exhibited the highest inhibition activity with an MIC of 0.78 ?g/mL, which is twofold and fourfold superior (in terms of the MIC values) to the standard first-line TB drugs isoniazid (MIC: 1.56 ?g/mL) and pyrazinamide (MIC: 3.12 ?g/mL) respectively. Two other compounds (T25 and T30) are equipotent as the isoniazid. The SAR studies revealed that insertion of 1,2,3-traizole and thiozolidine-2-one rings enhance the anti-TB activity in most of the tested compounds. Also, compound T27 was screened for mycobacterial ATP synthase inhibition activity and it exhibited an IC<inf>50</inf> of 0.735 µM in M. smegmatis IMVs. Further, toxicity evaluation against VERO cell lines confirmed null cytotoxicity (selectivity index > 70) of the potent analogues. The title compounds are highly specific towards to the M. tb strain, i.e., most of the compounds exhibited moderate inhibitory potency against the tested bacterial strains (MIC ? 6.25 ?g/mL). In addition, molecular docking was employed against the active site of the ATP synthase enzyme to validate the binding mechanism and in vitro activity profile of the phenothiazine derivatives. Furthermore, in silico ADME and pharmacokinetic parameters’ prediction indicated good oral bioavailability. © 2024 Elsevier B.V.