Synthesis, Anti-Plasmodial Activities, and Mechanistic Insights of 4-Aminoquinoline-Triazolopyrimidine Hybrids

Abstract

In the search of new antiplasmodial agents, a multitargeted approach was used in the synthesis of triazolopyrimidine- and 4-aminoquinolines-based hybrids. In vitro antiplasmodial evaluation on chloroquine-sensitive (3D7) and -resistant (W2) P. falciparum strains identified triazolopyrimidine-4-aminoquinoline hybrids to be the most potent in the series, outperforming bis-triazolopyrimidines. The active compounds were subjected to mechanistic studies with the plausible and expected targets including heme, PfCRT, and PfDHODH, that eventually validated the biological data. The active compound surpassed the antimalarial drug CQ by inhibiting the parasite’s cellular process (hemozoin formation) and parasitic enzymes (PfCRT and PfDHODH), as confirmed by UV–vis and molecular modeling studies.