Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of Mycobacterium tuberculosis

W. David Hong, Peter D. Gibbons, Suet C. Leung, Richard Amewu, Paul A. Stocks, Andrew Stachulski, Pedro Horta, Maria L.S. Cristiano, Alison E. Shone, Darren Moss, Alison Ardrey, Raman Sharma, Ashley J. Warman, Paul T.P. Bedingfield, Nicholas E. Fisher, Ghaith Aljayyoussi, Sally Mead, Maxine Caws, Neil G. Berry, Stephen A. WardGiancarlo A. Biagini, Paul M. O’Neill, Gemma L. Nixon

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

A high-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). The 11000 compounds were selected for the HTS based on the known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined HTS (11000 compounds) and in-house screening of a limited number of quinolones (50 compounds) identified ∼100 hits and four distinct chemotypes, the most promising of which contained the quinolone core. Subsequent Mtb screening of the complete in-house quinolone library (350 compounds) identified a further ∼90 hits across three quinolone subtemplates. Quinolones containing the amine-based side chain were selected as the pharmacophore for further modification, resulting in metabolically stable quinolones effective against multi drug resistant (MDR) Mtb. The lead compound, 42a (MTC420), displays acceptable antituberculosis activity (Mtb IC50 = 525 nM, Mtb Wayne IC50 = 76 nM, and MDR Mtb patient isolates IC50 = 140 nM) and favorable pharmacokinetic and toxicological profiles.

Original languageEnglish
Pages (from-to)3703-3726
Number of pages24
JournalJournal of Medicinal Chemistry
Volume60
Issue number9
DOIs
Publication statusPublished - 11 May 2017

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