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

Gemma, Sandra; Camodeca, Caterina; Coccone, Salvatore Sanna; Joshi, Bhupendra P; Bernetti, Matteo; Moretti, Vittoria; Brogi, Simone; de Marcos, Maria Cruz Bonache; Savini, Luisa; Taramelli, Donatella; Summers, Robert; Martin, Rowena

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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...[Show more]

dc.contributor.authorGemma, Sandra
dc.contributor.authorCamodeca, Caterina
dc.contributor.authorCoccone, Salvatore Sanna
dc.contributor.authorJoshi, Bhupendra P
dc.contributor.authorBernetti, Matteo
dc.contributor.authorMoretti, Vittoria
dc.contributor.authorBrogi, Simone
dc.contributor.authorde Marcos, Maria Cruz Bonache
dc.contributor.authorSavini, Luisa
dc.contributor.authorTaramelli, Donatella
dc.contributor.authorSummers, Robert
dc.contributor.authorMartin, Rowena
dc.date.accessioned2015-12-10T23:18:30Z
dc.identifier.issn0022-2623
dc.identifier.urihttp://hdl.handle.net/1885/65651
dc.description.abstractDespite 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.
dc.publisherAmerican Chemical Society
dc.sourceJournal of Medicinal Chemistry
dc.subjectKeywords: 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)phen
dc.titleOptimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials: Further structure-activity relationships, in vivo studies, and preliminary toxicity profiling
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume55
dc.date.issued2012
local.identifier.absfor060500 - MICROBIOLOGY
local.identifier.absfor060199 - Biochemistry and Cell Biology not elsewhere classified
local.identifier.ariespublicationf5625xPUB1138
local.type.statusPublished Version
local.contributor.affiliationGemma, Sandra, Università di Siena
local.contributor.affiliationCamodeca, Caterina, Università di Siena
local.contributor.affiliationCoccone, Salvatore Sanna, Università di Siena
local.contributor.affiliationJoshi, Bhupendra P, Università di Siena
local.contributor.affiliationBernetti, Matteo, Università di Siena
local.contributor.affiliationMoretti, Vittoria, Università di Siena
local.contributor.affiliationBrogi, Simone, Università di Siena
local.contributor.affiliationde Marcos, Maria Cruz Bonache, Università di Siena
local.contributor.affiliationSavini, Luisa, Università di Siena
local.contributor.affiliationTaramelli, Donatella, Università di Siena
local.contributor.affiliationSummers, Robert, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationMartin, Rowena, College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.issue15
local.bibliographicCitation.startpage6948
local.bibliographicCitation.lastpage6957
local.identifier.doi10.1021/jm300802s
dc.date.updated2016-02-24T08:38:30Z
local.identifier.scopusID2-s2.0-84864954364
local.identifier.thomsonID000307264100026
CollectionsANU Research Publications

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