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

Antimalarials can interact with heme covalently, by - interactions or hydrogen bonding. Consequently, the prototropy of 4-aminoquinolines and quinoline methanols was investigated using quantum mechanics. Calculations showed mefloquine protonated preferentially at the piperidine and was impeded at the endocyclic nitrogen due to 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, trifluromethyl groups buttressing quinolinyl nitrogen shifted binding of antimalarials to hematin, enabling switching from endocyclic to the exocyclic N. Both theoretical calculations (DFT calculations: B3LYP/6- 31+G*) and crystal structure of (±)-trans-N1,N2-bis-(2,8-ditrifluoromethylquinolin-4- yl)cyclohexane-1,2-diamine were used to reveal 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