4-Aminoquinoline derivatives and benzoxaborole-4-aminoquinoline hybrids: synthesis, antiplasmodial evaluation, heme-inhibition and in silico studies
TL;DR
UV-visible spectroscopic titrations demonstrated that compound 8b binds monomeric heme more selectively than CQ at both physiological and digestive vacuole pH, supporting inhibition of hemozoin formation as its primary mode of action.
Abstract
A library of 4-aminoquinoline derivatives and benzoxaborole-4-aminoquinoline hybrids, linked through amide and 1H-1,2,3-triazole spacers, was synthesized and evaluated against both chloroquine-sensitive (3D7) and -resistant (W2) strains of Plasmodium falciparum. Structure–activity relationship studies revealed that antiplasmodial potency was strongly influenced by the length of the alkyl chain and by the nature of the terminal functional group (azido, aldehyde, or benzyl alcohol). Notably, incorporation of the benzoxaborole core significantly enhanced activity relative to the parent 4-aminoquinoline derivatives. Among the series, hybrid 8b emerged as the most potent analogue, displaying superior activity against the CQ-resistant W2 strain compared with the reference antimalarials quinine and chloroquine. The hybrids exhibited negligible cytotoxicity toward HEK-293 cells, affording selectivity indices of up to ∼700. UV-visible spectroscopic titrations demonstrated that compound 8b binds monomeric heme more selectively than CQ at both physiological and digestive vacuole pH, supporting inhibition of hemozoin formation as its primary mode of action. Furthermore, homology modelling, induced-fit docking, and molecular dynamics simulations with both wild-type and benzoxaborole-resistant (H36Y/D470N) PfCPSF3 suggested that the scaffold can maintain a stable Zn2+-coordinated binding mode in both protein variants. These findings indicate a potential dual mechanism involving hemozoin inhibition and PfCPSF3 targeting, warranting further experimental validation.