Document Report Card

ID: ALA2169878

Journal: J Med Chem

Title: Optimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials: further structure-activity relationships, in vivo studies, and preliminary toxicity profiling.

Authors: Gemma S, Camodeca C, Sanna Coccone S, Joshi BP, Bernetti M, Moretti V, Brogi S, Bonache de Marcos MC, Savini L, Taramelli D, Basilico N, Parapini S, Rottmann M, Brun R, Lamponi S, Caccia S, Guiso G, Summers RL, Martin RE, Saponara S, Gorelli B, Novellino E, Campiani G, Butini S.

Abstract: Despite 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 parasite's '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.

CiteXplore: 22783984

DOI: 10.1021/jm300802s