2. Academic Validation
  3. New synergistic benzoquinone scaffolds as inhibitors of mycobacterial cytochrome bc1 complex to treat multi-drug resistant tuberculosis

New synergistic benzoquinone scaffolds as inhibitors of mycobacterial cytochrome bc1 complex to treat multi-drug resistant tuberculosis

  • Eur J Med Chem. 2024 Jun 5:272:116479. doi: 10.1016/j.ejmech.2024.116479.
Naresh Babu Chilamakuru 1,  Azger Dusthackeer Vn 2,  Varadaraj Bhat G 3,  Nikhil Pallaprolu 4,  Aishwarya Dande 4,  Dina Nair 2,  Raghuveer Varma Pemmadi 5,  Padmanabha Reddy Y 6,  Ramalingam Peraman 7
Affiliations

Affiliations

  • 1 Research Scholar, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India; RERDS-CPR, Raghavendra Institute of Pharmaceutical Education and Research Campus, Ananthapuramu, 515721, Andhra Pradesh, India.
  • 2 ICMR-National Institute for Research in Tuberculosis (NIRT), Chennai, 600031, Tamil Nadu, India.
  • 3 Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
  • 4 Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hajipur 844102, Bihar, India.
  • 5 RERDS-CPR, Raghavendra Institute of Pharmaceutical Education and Research Campus, Ananthapuramu, 515721, Andhra Pradesh, India; Department of Pharmaceutical Chemistry, A.K.R.G College of Pharmacy, Nallajerla, Andhra Pradesh 534112. Electronic address: drraghuveervarma@gmail.com.
  • 6 RERDS-CPR, Raghavendra Institute of Pharmaceutical Education and Research Campus, Ananthapuramu, 515721, Andhra Pradesh, India.
  • 7 RERDS-CPR, Raghavendra Institute of Pharmaceutical Education and Research Campus, Ananthapuramu, 515721, Andhra Pradesh, India; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hajipur 844102, Bihar, India. Electronic address: drram@niperhajipur.ac.in.
PMID: 38733886 DOI: 10.1016/j.ejmech.2024.116479
Abstract

Through a comprehensive molecular docking study, a unique series of naphthoquinones clubbed azetidinone scaffolds was arrived with promising binding affinity to Mycobacterial Cytbc1 complex, a drug target chosen to kill multi-drug resistant Mycobacterium tuberculosis (MDR-Mtb). Five compounds from series-2, 2a, 2c, 2g, 2h, and 2j, showcased significant in vitro anti-tubercular activities against Mtb H37Rv and MDR clinical isolates. Further, synergistic studies of these compounds in combination with INH and RIF revealed a potent bactericidal effect of compound 2a at concentration of 0.39 μg/mL, and remaining (2c, 2g, 2h, and 2j) at 0.78 μg/mL. Exploration into the mechanism study through chemo-stress assay and proteome profiling uncovered the down-regulation of key proteins of electron-transport chain and Cytbc1 inhibition pathway. Metabolomics corroborated these proteome findings, and heightened further understanding of the underlying mechanism. Notably, in vitro and in vivo animal toxicity studies demonstrated minimal toxicity, thus underscoring the potential of these compounds as promising anti-TB agents in combination with RIF and INH. These active compounds adhered to Lipinski's Rule of Five, indicating the suitability of these compounds for drug development. Particular significance of molecules NQ02, 2a, and 2h, which have been patented (Published 202141033473).

Keywords

Chemo-proteomics; Cytochrome bc1 complex inhibitors; MDR-TB; Mycobacterium tuberculosis; Naphthoquinone.

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