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

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 SaponaraBeatrice Gorelli, Ettore Novellino, Giuseppe Campiani, Stefania Butini

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)6948-6957
Number of pages10
JournalJournal of Medicinal Chemistry
Volume55
Issue number15
DOIs
Publication statusPublished - Aug 9 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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