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Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor In Vivo Using Fluorinated Bisquinolines
Author(s) -
Fielding Alistair J.,
Lukinović Valentina,
Evans Philip G.,
AlizadehShekalgourabi Said,
Bisby Roger H.,
Drew Michael G. B.,
Male Verity,
Del Casino Alessio,
Dunn James F.,
Randle Laura E.,
Dempster Nicola M.,
Nahar Lutfun,
Sarker Satyajit D.,
Cantú Reinhard Fabián G.,
de Visser Sam P.,
Dascombe Mike J.,
Ismail Fyaz M. D.
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201605099
Subject(s) - chemistry , protonation , quinoline , substituent , stereochemistry , trifluoromethyl , steric effects , electronic effect , lipophilicity , hydrogen bond , medicinal chemistry , amine gas treating , organic chemistry , molecule , alkyl , ion
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 CF 3 groups simultaneously occupying the 2‐ and 8‐positions was recovered if the CF 3 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‐N 1 , N 2 ‐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.