2. Academic Validation
  3. N-Acyl phenothiazines as mycobacterial ATP synthase inhibitors: Rational design, synthesis and in vitro evaluation against drug sensitive, RR and MDR-TB

N-Acyl phenothiazines as mycobacterial ATP synthase inhibitors: Rational design, synthesis and in vitro evaluation against drug sensitive, RR and MDR-TB

  • Bioorg Chem. 2024 Oct:151:107702. doi: 10.1016/j.bioorg.2024.107702.
Rajkumar Reddyrajula 1,  Summaya Perveen 2,  Anjali Negi 2,  Umadevi Etikyala 3,  Vijjulatha Manga 3,  Rashmi Sharma 4,  Udaya Kumar Dalimba 5
Affiliations

Affiliations

  • 1 Central Research Facility, National Institute of Technology Karnataka, Surathkal, Mangalore 575 025, India; Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
  • 2 Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu 180 001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India.
  • 3 Medicinal Chemistry Laboratory, Department of Chemistry, Osmania University, Hyderabad 500 076, India.
  • 4 Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu 180 001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India. Electronic address: rashmi.sharma.09@iiim.res.in.
  • 5 Organic and Materials Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Surathkal, Mangalore 575 025, India. Electronic address: udayakumar@nitk.edu.in.
PMID: 39142196 DOI: 10.1016/j.bioorg.2024.107702
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 IC50 of 0.788 µM in M. smegmatis IMVs and was observed that it could deplete intracellular ATP levels, exhibiting an IC50 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.

Keywords

Molecular docking and DFT analysis; Mycobacterial F-ATP synthase; Mycobacterium tuberculosis; RR/MDR-TB.

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