Gemma, SandraCamodeca, CaterinaCoccone, Salvatore SannaJoshi, Bhupendra PBernetti, MatteoMoretti, VittoriaBrogi, Simonede Marcos, Maria Cruz BonacheSavini, LuisaTaramelli, DonatellaSummers, RobertMartin, Rowena2015-12-100022-2623http://hdl.handle.net/1885/65651Despite recent progress in the fight against malaria, the emergence and spread of drug-resistant parasites remains a serious obstacle to the treatment of infections. We recently reported the development of a novel antimalarial drug that combines the 4-aminoquinoline pharmacophore of chloroquine with that of clotrimazole-based antimalarials. Here we describe the optimization of this class of hybrid drug through in-depth structure-activity relationship studies. Antiplasmodial properties and mode of action were characterized in vitro and in vivo, and interactions with the parasites 'chloroquine resistance transporter' were investigated in a Xenopus laevis oocyte expression system. These tests indicated that piperazine derivatives 4b and 4d may be suitable for coadministration with chloroquine against chloroquine-resistant parasites. The potential for metabolism of the drugs by cytochrome P450 was determined in silico, and the lead compounds were tested for toxicity and mutagenicity. A preliminary pharmacokinetic analysis undertaken in mice indicated that compound 4b has an optimal half-life.Keywords: 4 aminoquinoline derivative; antimalarial agent; chloroquine; clotrimazole; cytochrome P450; hematin; n [(3 chlorophenyl)[3 chloro 4 (morpholin 4 ylmethyl)phenyl]methyl] 6 methoxy 4 aminoquinoline; n [(3 chlorophenyl)[3 chloro 4 (morpholin 4 ylmethyl)phen201210.1021/jm300802s2016-02-24