- Optimization of 4-aminoquinoline/clotrimazole-based hybrid antimalarials: Further structure-activity relationships, in vivo studies, and preliminary toxicity profiling
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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 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.
- Gemma, Sandra,Camodeca, Caterina,Sanna Coccone, Salvatore,Joshi, Bhupendra P.,Bernetti, Matteo,Moretti, Vittoria,Brogi, Simone,De Marcos, Maria Cruz Bonache,Savini, Luisa,Taramelli, Donatella,Basilico, Nicoletta,Parapini, Silvia,Rottmann, Matthias,Brun, Reto,Lamponi, Stefania,Caccia, Silvio,Guiso, Giovanna,Summers, Robert L.,Martin, Rowena E.,Saponara, Simona,Gorelli, Beatrice,Novellino, Ettore,Campiani, Giuseppe,Butini, Stefania
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p. 6948 - 6957
(2012/11/07)
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- Clotrimazole scaffold as an innovative pharmacophore towards potent antimalarial agents: Design, synthesis, and biological and structure-activity relationship studies
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We describe herein the design, synthesis, biological evaluation, and structure-activity relationship (SAR) studies of an innovative class of antimalarial agents based on a polyaromatic pharmacophore structurally related to clotrimazole and easy to synthesize by low-cost synthetic procedures. SAR studies delineated a number of structural features able to modulate the in vitro and in vivo antimalarial activity. A selected set of antimalarials was further biologically investigated and displayed low in vitro toxicity on a panel of human and murine cell lines. In vitro, the novel compounds proved to be selective for free heme, as demonstrated in the β-hematin inhibitory activity assay, and did not show inhibitory activity against 14-α-lanosterol demethylase (a fungal P450 cytochrome). Compounds 2, 4e, and 4n exhibited in vivo activity against P. chabaudi after oral administration and thus represent promising antimalarial agents for further preclinical development.
- Gemma, Sandra,Campiani, Giuseppe,Butini, Stefania,Kukreja, Gagan,Coccone, Salvatore Sanna,Joshi, Bhupendra P.,Persico, Marco,Nacci, Vito,Fiorini, Isabella,Novellino, Ettore,Fattorusso, Ernesto,Taglialatela-Scafati, Orazio,Savini, Luisa,Taramelli, Donatella,Basilico, Nicoletta,Parapini, Silvia,Morace, Giulia,Yardley, Vanessa,Croft, Simon,Coletta, Massimiliano,Marini, Stefano,Fattorusso, Caterina
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p. 1278 - 1294
(2008/09/20)
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- ANTIMALARIAL AGENTS HAVING POLYAROMATIC STRUCTURE
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Antimalarial agents having a novel pharmacophore of formula (I) are herein described. These polycyclic compounds are able to inhibit chloroquine-sensitive and chloroquine-resistant strains ofPlasmodium falciparum (Pf). Furthermore, the synthesis of these compounds involves few steps from commercial products with low cost of production.Λa présente invention concerne des agents antimalariaux comportant un nouveau pharmacophore de formule (I). Ces composés polycycliques sont susceptibles d''inhiber les souches sensibles à la chloroquine et résistantes à la chloroquine de Plasmodium falciparum (Pf). En outre, la synthèse de ces composés est peu onéreuse et implique peu d''étapes à partir des produits commerciaux.
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