Synthesis and biological evaluation of acridine derivatives as antimalarial agents

ChemMedChem
Xiao-Min YuStéphanie Pethe

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.

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Citations

Oct 21, 2014·Chemical Reviews·Cátia TeixeiraPaula Gomes
Jun 7, 2013·Medicinal Research Reviews·Ling ZhangCheng-He Zhou
May 13, 2015·Organic & Biomolecular Chemistry·Kathleen SolmontDamien Prim
Oct 16, 2015·Antimicrobial Agents and Chemotherapy·Esther JortzikKatja Becker
Jan 28, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mélanie FonteCátia Teixeira

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