2-Aminopyrimidine based 4-aminoquinoline anti-plasmodial agents. Synthesis biological activity structure–activity relationship and mode of action studies

摘要

2-Aminopyrimidine based 4-aminoquinolines were synthesized using an efficacious protocol. Some of the compounds showed anti-plasmodial activity against drug-sensitive CQ (3D7) and drug-resistant CQ (K1) strains of in the nM range. In particular, 5-isopropyloxycarbonyl-6-methyl-4-(2-nitrophenyl)-2-[(7-chloroquinolin-4-ylamino)butylamino] pyrimidine depicted the lowest IC (3.6 nM) value (56-fold less than CQ) against CQ strain. Structure–activity profile and binding with heme, μ-oxo-heme have been studied. Binding assays with DNA revealed better binding with target parasite type AT rich pUC18 DNA. Most compounds were somewhat cytotoxic, but especially cytostatic. Molecular docking analysis with DHFR allowed identification of stabilizing interactions.