Hong, WD, Gibbons, PD, Leung, SC, Amewu, R, Stocks, PA, Stachulski, A, Horta, P, Cristiano, MLS, Shone, AE, Moss, D, Ardrey, A, Sharma, R, Warman, AJ, Bedingfield, PTP, Fisher, NE, Aljayyoussi, G, Mead, S, Caws, M, Berry, NG, Ward, SA, Biagini, GA, O'Neill, PM and Nixon, GL (2017) Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of Mycobacterium tuberculosis. Journal of Medicinal Chemistry. ISSN 1520-4804

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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.

Item Type: Article
Additional Information: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via American Chemical Society at http://dx.doi.org/10.1021/aacs.jmedchem.6b01718 - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: biomolecular chemistry, pharmaceutical sciences, pharmacology
Subjects: R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy
Related URLs:
Depositing User: Symplectic
Date Deposited: 18 May 2017 10:31
Last Modified: 02 Mar 2021 11:25
URI: https://eprints.keele.ac.uk/id/eprint/3475

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