Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor in vivo Using Fluorinated Bisquinolines

Alistair Fielding, Valentina Lukinović, Philip G. Evans, Said Alizadeh-Shekalgourabi, Roger H. Bisby, Michael G B Drew, Alessio ADel Casino, James F. Dunn, Laura E. Randle, Nicola M. Dempster, Lutfun Nahar, Satyajit D. Sarker, Fabian Cantu Reinhard, Samuel De Visser, Michael Dascombe, Fyaz M. D. Ismail

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    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 CF3 groups simultaneously occupying the 2- and 8-positions was recovered if the CF3 group 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.
    Original languageEnglish
    Pages (from-to)6811-6828
    Number of pages18
    JournalChemistry: A European Journal
    Issue number28
    Early online date21 Apr 2017
    Publication statusPublished - 18 May 2017


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