Synthesis of New 4-Aminoquinolines and Evaluation of Their In Vitro Activity against Chloroquine-Sensitive and Chloroquine-Resistant Plasmodium falciparum.
Identifieur interne : 000E72 ( Main/Merge ); précédent : 000E71; suivant : 000E73Synthesis of New 4-Aminoquinolines and Evaluation of Their In Vitro Activity against Chloroquine-Sensitive and Chloroquine-Resistant Plasmodium falciparum.
Auteurs : Chandima S K. Rajapakse [États-Unis] ; Maryna Lisai [États-Unis] ; Christiane Deregnaucourt [France] ; Véronique Sinou [France] ; Christine Latour [France] ; Dipankar Roy [États-Unis] ; Joseph Schrével [France] ; Roberto A. Sánchez-Delgado [États-Unis]Source :
- PloS one [ 1932-6203 ] ; 2015.
Descripteurs français
- KwdFr :
- Animaux, Antipaludiques (), Antipaludiques (pharmacocinétique), Antipaludiques (pharmacologie), Antipaludiques (synthèse chimique), Chloroquine (), Chloroquine (pharmacocinétique), Chloroquine (pharmacologie), Humains, Lignée cellulaire, Modèles chimiques, Plasmodium falciparum (métabolisme), Rats, Résistance aux substances ().
- MESH :
- métabolisme : Plasmodium falciparum.
- pharmacocinétique : Antipaludiques, Chloroquine.
- pharmacologie : Antipaludiques, Chloroquine.
- synthèse chimique : Antipaludiques.
- Animaux, Antipaludiques, Chloroquine, Humains, Lignée cellulaire, Modèles chimiques, Rats, Résistance aux substances.
English descriptors
- KwdEn :
- Animals, Antimalarials (chemical synthesis), Antimalarials (chemistry), Antimalarials (pharmacokinetics), Antimalarials (pharmacology), Cell Line, Chloroquine (chemistry), Chloroquine (pharmacokinetics), Chloroquine (pharmacology), Drug Resistance (drug effects), Humans, Models, Chemical, Plasmodium falciparum (metabolism), Rats.
- MESH :
- chemical , chemical synthesis : Antimalarials.
- chemical , chemistry : Antimalarials, Chloroquine.
- chemical , pharmacokinetics : Antimalarials, Chloroquine.
- chemical , pharmacology : Antimalarials, Chloroquine.
- drug effects : Drug Resistance.
- metabolism : Plasmodium falciparum.
- Animals, Cell Line, Humans, Models, Chemical, Rats.
Abstract
The efficacy of chloroquine, once the drug of choice in the fight against Plasmodium falciparum, is now severely limited due to widespread resistance. Amodiaquine is one of the most potent antimalarial 4-aminoquinolines known and remains effective against chloroquine-resistant parasites, but toxicity issues linked to a quinone-imine metabolite limit its clinical use. In search of new compounds able to retain the antimalarial activity of amodiaquine while circumventing quinone-imine metabolite toxicity, we have synthesized five 4-aminoquinolines that feature rings lacking hydroxyl groups in the side chain of the molecules and are thus incapable of generating toxic quinone-imines. The new compounds displayed high in vitro potency (low nanomolar IC50), markedly superior to chloroquine and comparable to amodiaquine, against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum, accompanied by low toxicity to L6 rat fibroblasts and MRC5 human lung cells, and metabolic stability comparable or higher than that of amodiaquine. Computational studies indicate a unique mode of binding of compound 4 to heme through the HOMO located on a biphenyl moeity, which may partly explain the high antiplasmodial activity observed for this compound.
DOI: 10.1371/journal.pone.0140878
PubMed: 26473363
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pubmed:26473363Le document en format XML
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<term>Antimalarials (chemical synthesis)</term>
<term>Antimalarials (chemistry)</term>
<term>Antimalarials (pharmacokinetics)</term>
<term>Antimalarials (pharmacology)</term>
<term>Cell Line</term>
<term>Chloroquine (chemistry)</term>
<term>Chloroquine (pharmacokinetics)</term>
<term>Chloroquine (pharmacology)</term>
<term>Drug Resistance (drug effects)</term>
<term>Humans</term>
<term>Models, Chemical</term>
<term>Plasmodium falciparum (metabolism)</term>
<term>Rats</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Antipaludiques ()</term>
<term>Antipaludiques (pharmacocinétique)</term>
<term>Antipaludiques (pharmacologie)</term>
<term>Antipaludiques (synthèse chimique)</term>
<term>Chloroquine ()</term>
<term>Chloroquine (pharmacocinétique)</term>
<term>Chloroquine (pharmacologie)</term>
<term>Humains</term>
<term>Lignée cellulaire</term>
<term>Modèles chimiques</term>
<term>Plasmodium falciparum (métabolisme)</term>
<term>Rats</term>
<term>Résistance aux substances ()</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antimalarials</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antimalarials</term>
<term>Chloroquine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Antimalarials</term>
<term>Chloroquine</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antimalarials</term>
<term>Chloroquine</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Drug Resistance</term>
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<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Plasmodium falciparum</term>
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</keywords>
<keywords scheme="MESH" qualifier="pharmacocinétique" xml:lang="fr"><term>Antipaludiques</term>
<term>Chloroquine</term>
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<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antipaludiques</term>
<term>Chloroquine</term>
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<term>Models, Chemical</term>
<term>Rats</term>
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<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Antipaludiques</term>
<term>Chloroquine</term>
<term>Humains</term>
<term>Lignée cellulaire</term>
<term>Modèles chimiques</term>
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<front><div type="abstract" xml:lang="en">The efficacy of chloroquine, once the drug of choice in the fight against Plasmodium falciparum, is now severely limited due to widespread resistance. Amodiaquine is one of the most potent antimalarial 4-aminoquinolines known and remains effective against chloroquine-resistant parasites, but toxicity issues linked to a quinone-imine metabolite limit its clinical use. In search of new compounds able to retain the antimalarial activity of amodiaquine while circumventing quinone-imine metabolite toxicity, we have synthesized five 4-aminoquinolines that feature rings lacking hydroxyl groups in the side chain of the molecules and are thus incapable of generating toxic quinone-imines. The new compounds displayed high in vitro potency (low nanomolar IC50), markedly superior to chloroquine and comparable to amodiaquine, against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum, accompanied by low toxicity to L6 rat fibroblasts and MRC5 human lung cells, and metabolic stability comparable or higher than that of amodiaquine. Computational studies indicate a unique mode of binding of compound 4 to heme through the HOMO located on a biphenyl moeity, which may partly explain the high antiplasmodial activity observed for this compound. </div>
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