2. Academic Validation
  3. Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of Mycobacterium tuberculosis

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

  • J Med Chem. 2017 May 11;60(9):3703-3726. doi: 10.1021/acs.jmedchem.6b01718.
W David Hong 1,  Peter D Gibbons 1,  Suet C Leung 1,  Richard Amewu 2,  Paul A Stocks 1,  Andrew Stachulski 1,  Pedro Horta 3,  Maria L S Cristiano 3,  Alison E Shone 4,  Darren Moss 5,  Alison Ardrey 4,  Raman Sharma 4,  Ashley J Warman 4,  Paul T P Bedingfield 4,  Nicholas E Fisher 4,  Ghaith Aljayyoussi 4,  Sally Mead 4,  Maxine Caws 4,  Neil G Berry 1,  Stephen A Ward 4,  Giancarlo A Biagini 4,  Paul M O'Neill 1,  Gemma L Nixon 1
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, U.K.
  • 2 Department of Chemistry, University of Ghana , P.O. Box LG56, Legon-Accra, Ghana.
  • 3 CCMAR and Department of Chemistry and Pharmacy, University of Algarve , 8005-139 Faro, Portugal.
  • 4 Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, U.K.
  • 5 School of Pharmacy, Keele University , Keele ST5 5BG, U.K.
PMID: 28304162 DOI: 10.1021/acs.jmedchem.6b01718
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.

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