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 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. © 2012 American Chemical Society.
Gemma, S., Camodeca, C., SANNA COCCONE, S., Bhupendra P., J., Bernetti, M., Moretti, V., et al. (2012). Optimization of 4-Aminoquinoline/Clotrimazole-Based Hybrid Antimalarials: Further Structure-Activity Relationships, in vivo Studies, and Preliminary Toxicity Profiling. JOURNAL OF MEDICINAL CHEMISTRY, 55(15), 6948-6967 [10.1021/jm300802s].
Optimization of 4-Aminoquinoline/Clotrimazole-Based Hybrid Antimalarials: Further Structure-Activity Relationships, in vivo Studies, and Preliminary Toxicity Profiling
GEMMA, SANDRA;CAMODECA, CATERINA;SANNA COCCONE, SALVATORE;BERNETTI, MATTEO;SAVINI, LUISA;LAMPONI, STEFANIA;SAPONARA, SIMONA;GORELLI, BEATRICE;CAMPIANI, GIUSEPPE;BUTINI, STEFANIA
2012-01-01
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 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. © 2012 American Chemical Society.File | Dimensione | Formato | |
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https://hdl.handle.net/11365/33712
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