2. Academic Validation
  3. Discovery of 1-hydroxy-2-methylquinolin-4(1H)-one derivatives as new cytochrome bd oxidase inhibitors for tuberculosis therapy

Discovery of 1-hydroxy-2-methylquinolin-4(1H)-one derivatives as new cytochrome bd oxidase inhibitors for tuberculosis therapy

  • Eur J Med Chem. 2023 Jan 5;245(Pt 1):114896. doi: 10.1016/j.ejmech.2022.114896.
Yang Zhou 1,  Min Shao 1,  Weiwei Wang 2,  Chen-Yi Cheung 3,  Yu Wu 1,  Hang Yu 1,  Xianglong Hu 1,  Gregory M Cook 3,  Hongri Gong 4,  Xiaoyun Lu 5
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 855 Xingye Avenue, Guangzhou, 510632, China.
  • 2 State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300071, China.
  • 3 Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, 9054, New Zealand.
  • 4 State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, 300071, China. Electronic address: [email protected].
  • 5 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 855 Xingye Avenue, Guangzhou, 510632, China. Electronic address: [email protected].
PMID: 36370551 DOI: 10.1016/j.ejmech.2022.114896
Abstract

The cytochrome bcc-aa3 oxidase (Cyt-bcc) of Mycobacterium tuberculosis (Mtb) is a promising anti-tuberculosis target. However, when Cyt-bcc is inhibited, cytochrome bd terminal oxidase (Cyt-bd) can still maintain the activity of the respiratory chain and drive ATP synthesis. Through virtual screening and biological validation, we discovered two FDA-approved drugs, ivacaftor and roquinimex, exhibited moderate binding affinity to Cyt-bd. Structural modifications of them led to 1-hydroxy-2-methylquinolin-4(1H)-one derivatives as potent new Cyt-bd inhibitors. Compound 8d binds to Cyt-bd with a Kd value of 4.17 μM and inhibits the growth of the Cyt-bcc knock-out strain (ΔqcrCAB, Cyt-bd+) with a MIC value of 6.25 μM. The combination of 8d with the Cyt-bcc inhibitor Q203 completely inhibited oxygen consumption of the wild-type strain and the inverted-membrane vesicles expressing M. tuberculosis Cyt-bd (ΔcydAB::MtbCydAB+). Our study provides a promising starting point for the development of novel dual chemotherapies for tuberculosis.

Keywords

Combinational therapy; Cytochrome bd oxidase; Inhibitors; Tuberculosis.

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