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

2-Aminopyrimidine based 4-aminoquinolines were synthesized using an efficacious protocol. Some of the compounds showed in vitro anti-plasmodial activity against drug-sensitive CQS (3D7) and drug-resistant CQR (K1) strains of Plasmodium falciparum in the nM range. In particular, 5-isopropyloxycarbonyl-6-methyl-4-(2-nitrophenyl)-2-[(7-chloroquinolin-4-ylamino)butylamino] pyrimidine depicted the lowest IC50 (3.6 nM) value (56-fold less than CQ) against CQR 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 Pf DHFR allowed identification of stabilizing interactions.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► New antimalarial agents based on 2-aminopyrimidine have been synthesized. ► The synthesized compounds depict structure related activity profiles. ► Molecular docking with Pf DHFR identified stabilizing interactions. ► Compound 10r (IC50 = 3.6 nM) identified as most potent antimicrobial agent. ► Mechanism of binding of 10r was understood with heme, CT and pUC18 DNA.