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

Autor: Chilamakuru NB; 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., Vn AD; ICMR-National Institute for Research in Tuberculosis (NIRT), Chennai, 600031, Tamil Nadu, India., G VB; Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India., Pallaprolu N; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hajipur 844102, Bihar, India., Dande A; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hajipur 844102, Bihar, India., Nair D; ICMR-National Institute for Research in Tuberculosis (NIRT), Chennai, 600031, Tamil Nadu, India., Pemmadi RV; 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., Reddy Y P; RERDS-CPR, Raghavendra Institute of Pharmaceutical Education and Research Campus, Ananthapuramu, 515721, Andhra Pradesh, India., Peraman R; 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.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Jun 05; Vol. 272, pp. 116479. Date of Electronic Publication: 2024 May 07.
DOI: 10.1016/j.ejmech.2024.116479
Abstrakt: 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 H 37 Rv 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).
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Ramalingam Peraman reports financial support was provided by DST - Science and Engineering Research Board, Government of India. Ramalingam Peraman has patent #202141033473 pending to Ramalingam Peraman. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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