Premium
Synthesis and Biological Evaluation of Acridine Derivatives as Antimalarial Agents
Author(s) -
Yu XiaoMin,
Ramiandrasoa Florence,
Guetzoyan Lucie,
Pradines Bruno,
Quintino Edgar,
Gadelle Daniele,
Forterre Patrick,
Cresteil Thierry,
Mahy JeanPierre,
Pethe Stéphanie
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100554
Subject(s) - plasmodium falciparum , acridine , topoisomerase , in vitro , chloroquine , chemistry , biological activity , potency , biochemistry , heme , pharmacophore , pharmacology , biology , stereochemistry , malaria , enzyme , immunology , organic chemistry
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 μ M .