Optimization of 4-Aminoquinoline/Clotrimazole-Based Hybrid Antimalarials: Further Structure鈥揂ctivity Relationships, in Vivo Studies, and Preliminary Toxicity Profiling
详细信息 查看全文
- 作者：Sandra Gemma ; Caterina Camodeca ; Salvatore Sanna Coccone ; Bhupendra P. Joshi ; Matteo Bernetti ; Vittoria Moretti ; Simone Brogi ; Maria Cruz Bonache de Marcos ; Luisa Savini ; Donatella Taramelli ; Nicoletta Basilico ; Silvia Parapini ; Matthias Rottmann ; Reto Brun ; Stefania Lamponi ; Silvio Caccia ; Giovanna Guiso ; Robert L. Summers ; Rowena E. Martin ; Simona Saponara ; Beatrice Gorelli ; Ettore Novellino ; Giuseppe Campiani ; Stefania Butini
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：August 9, 2012
- 年：2012
- 卷：55
- 期：15
- 页码：6948-6967
- 全文大小：845K
- 年卷期：v.55,no.15(August 9, 2012)
- ISSN：1520-4804
文摘
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鈥揳ctivity relationship studies. Antiplasmodial properties and mode of action were characterized in vitro and in vivo, and interactions with the parasite鈥檚 '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.