title: Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor In Vivo Using Fluorinated Bisquinolines.
abstract: Antimalarials can interact with heme covalently, by π⋅⋅⋅π interactions or by hydrogen bonding. Consequently, the prototropy of 4-aminoquinolines and quinoline methanols was investigated by using quantum mechanics. Calculations showed mefloquine protonated preferentially at the piperidine and was impeded at the endocyclic nitrogen because of electronic rather than steric factors. In gas-phase calculations, 7-substituted mono- and bis-4-aminoquinolines were preferentially protonated at the endocyclic quinoline nitrogen. By contrast, compounds with a trifluoromethyl substituent on both the 2- and 8-positions, reversed the order of protonation, which now favored the exocyclic secondary amine nitrogen at the 4-position. Loss of antimalarial efficacy by CF3groups simultaneously occupying the 2- and 8-positions was recovered if the CF3group occupied the 7-position. Hence, trifluoromethyl groups buttressing the quinolinyl nitrogen shifted binding of antimalarials to hematin, enabling switching from endocyclic to the exocyclic N. Both theoretical calculations (DFT calculations: B3LYP/BS1) and crystal structure of (±)-trans-N1,N2-bis-(2,8-ditrifluoromethylquinolin-4-yl)cyclohexane-1,2-diamine were used to reveal the preferred mode(s) of interaction with hematin. The order of antimalarial activity in vivo followed the capacity for a redox change of the iron(III) state, which has important implications for the future rational design of 4-aminoquinoline antimalarials.
authors.affiliation: School of Chemistry and the Photon Science Institute, The University of Manchester, Manchester, M13 9PL, UK.
authors.forename: Alistair J
authors.identifier: http://orcid.org/0000-0002-4437-9791
authors.initials: AJ
authors.lastname: Fielding
authors.affiliation: School of Chemistry and the Photon Science Institute, The University of Manchester, Manchester, M13 9PL, UK.
authors.forename: Valentina
authors.identifier: http://orcid.org/0000-0002-5206-2452
authors.initials: V
authors.lastname: Lukinović
authors.affiliation: Peakdale Molecular Limited, Discovery Park, Sandwich, Kent, CT13 9FF, UK.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Evans
authors.affiliation: Department of Pharmacy, University of Hertfordshire, Hatfield, Hertfordshire, AL10 9AB, UK.
authors.forename: Said
authors.initials: S
authors.lastname: Alizadeh-Shekalgourabi
authors.affiliation: Biomedical Sciences Research Institute, University of Salford, Salford, M5 4WT, UK.
authors.forename: Roger H
authors.identifier: http://orcid.org/0000-0002-5069-0498
authors.initials: RH
authors.lastname: Bisby
authors.affiliation: School of Chemistry, The University of Reading, Whiteknights, Reading, RG6 6AD, UK.
authors.forename: Michael G B
authors.initials: MGB
authors.lastname: Drew
authors.affiliation: School of Chemistry, The University of Reading, Whiteknights, Reading, RG6 6AD, UK.
authors.forename: Verity
authors.initials: V
authors.lastname: Male
authors.affiliation: Medicinal Chemistry and Natural Products Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
authors.forename: Alessio
authors.initials: A
authors.lastname: Del Casino
authors.affiliation: Medicinal Chemistry and Natural Products Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
authors.forename: James F
authors.initials: JF
authors.lastname: Dunn
authors.affiliation: Medicinal Chemistry and Natural Products Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Randle
authors.affiliation: Medicinal Chemistry and Natural Products Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
authors.forename: Nicola M
authors.initials: NM
authors.lastname: Dempster
authors.affiliation: Medicinal Chemistry and Natural Products Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
authors.forename: Lutfun
authors.initials: L
authors.lastname: Nahar
authors.affiliation: Medicinal Chemistry and Natural Products Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
authors.forename: Satyajit D
authors.initials: SD
authors.lastname: Sarker
authors.affiliation: Manchester Institute of Biotechnology, School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.
authors.forename: Fabián G
authors.identifier: http://orcid.org/0000-0002-0916-6758
authors.initials: FG
authors.lastname: Cantú Reinhard
authors.affiliation: Manchester Institute of Biotechnology, School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.
authors.forename: Sam P
authors.identifier: http://orcid.org/0000-0002-2620-8788
authors.initials: SP
authors.lastname: de Visser
authors.affiliation: Faculty of Biology, Medicine and Health, Stopford Building 1.124, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Dascombe
authors.affiliation: Medicinal Chemistry and Natural Products Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
authors.forename: Fyaz M D
authors.identifier: http://orcid.org/0000-0002-3595-6665
authors.initials: FMD
authors.lastname: Ismail
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D015195:Drug Design; D004578:Electron Spin Resonance Spectroscopy; D005290:Ferric Compounds / Q000737:chemistry; D054879:Halogenation; D006427:Hemin / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D007536:Isomerism; D008124:Locomotion / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D010962:Plasmodium berghei / Q000187:drug effects / Q000472:pathogenicity; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D013816:Thermodynamics
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D005290:Ferric Compounds; D011804:Quinolines; D006427:Hemin; C001920:4-aminoquinoline
keywords: density functional calculations; drug design; drug discovery; molecular modeling; receptors