title: Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of Mycobacterium tuberculosis.
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.
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, U.K.
authors.forename: W David
authors.initials: WD
authors.lastname: Hong
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, U.K.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gibbons
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, U.K.
authors.forename: Suet C
authors.initials: SC
authors.lastname: Leung
authors.affiliation: Department of Chemistry, University of Ghana , P.O. Box LG56, Legon-Accra, Ghana.
authors.forename: Richard
authors.initials: R
authors.lastname: Amewu
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, U.K.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Stocks
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, U.K.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stachulski
authors.affiliation: CCMAR and Department of Chemistry and Pharmacy, University of Algarve , 8005-139 Faro, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Horta
authors.affiliation: CCMAR and Department of Chemistry and Pharmacy, University of Algarve , 8005-139 Faro, Portugal.
authors.forename: Maria L S
authors.initials: MLS
authors.lastname: Cristiano
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, U.K.
authors.forename: Alison E
authors.initials: AE
authors.lastname: Shone
authors.affiliation: School of Pharmacy, Keele University , Keele ST5 5BG, U.K.
authors.forename: Darren
authors.initials: D
authors.lastname: Moss
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, U.K.
authors.forename: Alison
authors.initials: A
authors.lastname: Ardrey
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, U.K.
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, U.K.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Warman
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, U.K.
authors.forename: Paul T P
authors.initials: PTP
authors.lastname: Bedingfield
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, U.K.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Fisher
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, U.K.
authors.forename: Ghaith
authors.initials: G
authors.lastname: Aljayyoussi
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, U.K.
authors.forename: Sally
authors.initials: S
authors.lastname: Mead
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, U.K.
authors.forename: Maxine
authors.initials: M
authors.lastname: Caws
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, U.K.
authors.forename: Neil G
authors.initials: NG
authors.lastname: Berry
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, U.K.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.affiliation: Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, U.K.
authors.forename: Giancarlo A
authors.initials: GA
authors.lastname: Biagini
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, U.K.
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, U.K.
authors.forename: Gemma L
authors.identifier: 0000-0002-9730-0960
authors.initials: GL
authors.lastname: Nixon
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D015195:Drug Design; D004579:Electron Transport / Q000187:drug effects; D056945:Hep G2 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D066244:Proton Magnetic Resonance Spectroscopy; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D018675:Toxicity Tests
chemical_list: D015363:Quinolones