Antimalarial acridines: synthesis, in vitro activity against P. falciparum and interaction with hematin.
Identifieur interne : 000266 ( France/Analysis ); précédent : 000265; suivant : 000267Antimalarial acridines: synthesis, in vitro activity against P. falciparum and interaction with hematin.
Auteurs : Lucie Guetzoyan ; Xiao-Min Yu ; Florence Ramiandrasoa ; Stéphanie Pethe ; Christophe Rogier ; Bruno Pradines ; Thierry Cresteil [France] ; Martine Perrée-Fauvet ; Jean-Pierre MahySource :
- Bioorganic and Medicinal Chemistry [ 0968-0896 ] ; 2009-12-01.
Abstract
A series of acridine derivatives were synthesised and their in vitro antimalarial activity was evaluated against one chloroquine-susceptible strain (3D7) and three chloroquine-resistant strains (W2, Bre1 and FCR3) of Plasmodium falciparum. Structure-activity relationship showed that two positives charges as well as 6-chloro and 2-methoxy substituents on the acridine ring were required to exert a good antimalarial activity. The best compounds possessing these features inhibited the growth of the chloroquine-susceptible strain with an IC(50)0.07 microM, close to that of chloroquine itself, and that of the three chloroquine-resistant strains better than chloroquine with IC(50)0.3 microM. These acridine derivatives inhibited the formation of beta-hematin, suggesting that, like CQ, they act on the haem crystallization process. Finally, in vitro cytotoxicity was also evaluated upon human KB cells, which showed that one of them 9-(6-ammonioethylamino)-6-chloro-2-methoxyacridinium dichloride 1 displayed a promising antimalarial activity in vitro with a quite good selectivity index versus mammalian cell on the CQ-susceptible strain and promising selectivity on other strains.
Url:
DOI: 10.1016/j.bmc.2009.10.005
Affiliations:
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Hal:hal-00433243Le document en format XML
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first="Jean-Pierre" last="Mahy">Jean-Pierre Mahy</name></author></analytic><idno type="DOI">10.1016/j.bmc.2009.10.005</idno><series><title level="j">Bioorganic and Medicinal Chemistry</title><idno type="ISSN">0968-0896</idno><imprint><date type="datePub">2009-12-01</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"> <p>A series of acridine derivatives were synthesised and their in vitro antimalarial activity was evaluated against one chloroquine-susceptible strain (3D7) and three chloroquine-resistant strains (W2, Bre1 and FCR3) of Plasmodium falciparum. Structure-activity relationship showed that two positives charges as well as 6-chloro and 2-methoxy substituents on the acridine ring were required to exert a good antimalarial activity. The best compounds possessing these features inhibited the growth of the chloroquine-susceptible strain with an IC(50)0.07 microM, close to that of chloroquine itself, and that of the three chloroquine-resistant strains better than chloroquine with IC(50)0.3 microM. These acridine derivatives inhibited the formation of beta-hematin, suggesting that, like CQ, they act on the haem crystallization process. Finally, in vitro cytotoxicity was also evaluated upon human KB cells, which showed that one of them 9-(6-ammonioethylamino)-6-chloro-2-methoxyacridinium dichloride 1 displayed a promising antimalarial activity in vitro with a quite good selectivity index versus mammalian cell on the CQ-susceptible strain and promising selectivity on other strains.</p> </div></front></TEI><affiliations><list><country><li>France</li></country></list><tree><noCountry><name sortKey="Guetzoyan, Lucie" sort="Guetzoyan, Lucie" uniqKey="Guetzoyan L" first="Lucie" last="Guetzoyan">Lucie Guetzoyan</name><name sortKey="Mahy, Jean Pierre" sort="Mahy, Jean Pierre" uniqKey="Mahy J" first="Jean-Pierre" last="Mahy">Jean-Pierre Mahy</name><name sortKey="Perree Fauvet, Martine" sort="Perree Fauvet, Martine" uniqKey="Perree Fauvet M" first="Martine" last="Perrée-Fauvet">Martine Perrée-Fauvet</name><name sortKey="Pethe, Stephanie" sort="Pethe, Stephanie" uniqKey="Pethe S" first="Stéphanie" last="Pethe">Stéphanie Pethe</name><name sortKey="Pradines, Bruno" sort="Pradines, Bruno" uniqKey="Pradines B" first="Bruno" last="Pradines">Bruno Pradines</name><name sortKey="Ramiandrasoa, Florence" sort="Ramiandrasoa, Florence" uniqKey="Ramiandrasoa F" first="Florence" last="Ramiandrasoa">Florence Ramiandrasoa</name><name sortKey="Rogier, Christophe" sort="Rogier, Christophe" uniqKey="Rogier C" first="Christophe" last="Rogier">Christophe Rogier</name><name sortKey="Yu, Xiao Min" sort="Yu, Xiao Min" uniqKey="Yu X" first="Xiao-Min" last="Yu">Xiao-Min Yu</name></noCountry><country name="France"><noRegion><name sortKey="Cresteil, Thierry" sort="Cresteil, Thierry" uniqKey="Cresteil T" first="Thierry" last="Cresteil">Thierry Cresteil</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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