title: Synthesis and biological evaluation of acridine derivatives as antimalarial agents.
abstract: New N-alkylaminoacridine derivatives attached to nitrogen heterocycles were synthesized, and their antimalarial potency was examined. They were tested in vitro against the growth of Plasmodium falciparum, including chloroquine (CQ)-susceptible and CQ-resistant strains. This biological evaluation has shown that the presence of a heterocyclic ring significantly increases the activity against P. falciparum. The best compound shows a nanomolar IC(50) value toward parasite proliferation on both CQ-susceptible and CQ-resistant strains. The antimalarial activity of these new acridine derivatives can be explained by the two mechanisms studied in this work. First, we showed the capacity of these compounds to inhibit heme biocrystallization, a detoxification process specific to the parasite and essential for its survival. Second, in our search for alternative targets, we evaluated the in vitro inhibitory activity of these compounds toward Sulfolobus shibatae topoisomerase VI-mediated DNA relaxation. The preliminary results obtained reveal that all tested compounds are potent DNA intercalators, and significantly inhibit the activity of S. shibatae topoisomerase VI at concentrations ranging between 2.0 and 2.5 μM.
authors.affiliation: Université Paris-Sud 11, Institut de Chimie Moléculaire et des Matériaux d'Orsay, Equipe de Chimie Bioorganique et Bioinorganique, Orsay 91405 CEDEX, France.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Yu
authors.forename: Florence
authors.initials: F
authors.lastname: Ramiandrasoa
authors.forename: Lucie
authors.initials: L
authors.lastname: Guetzoyan
authors.forename: Bruno
authors.initials: B
authors.lastname: Pradines
authors.forename: Edgar
authors.initials: E
authors.lastname: Quintino
authors.forename: Daniele
authors.initials: D
authors.lastname: Gadelle
authors.forename: Patrick
authors.initials: P
authors.lastname: Forterre
authors.forename: Thierry
authors.initials: T
authors.lastname: Cresteil
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Mahy
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Pethe
mesh_terms: D000166:Acridines / Q000737:chemistry*; D000585:Aminacrine / Q000737:chemistry; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004352:Drug Resistance, Microbial; D006418:Heme / Q000378:metabolism; D006420:Hemeproteins / Q000037:antagonists & inhibitors; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D007624:KB Cells / Q000187:drug effects; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development; D016944:Sulfolobus / Q000201:enzymology; D059003:Topoisomerase Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000166:Acridines; D000962:Antimalarials; D006420:Hemeproteins; D059003:Topoisomerase Inhibitors; C020753:hemozoin; D006418:Heme; D000585:Aminacrine; D002738:Chloroquine