Design, Synthesis, and Evaluation of New 1,4-Naphthoquinone-1,2,3-triazoles as Antimalarial Agents

The increasing resistance to existing antimalarial agents has prompted researchers to develop new therapeutic candidates. To address this, the hybridization of 1,4-naphthoquinone and 1,2,3-triazole yielded a new series of compounds evaluated as prospective in vitro antimalarial agents against the chloroquine-sensitive 3D7 and chloroquine-resistant K1 strains of Plasmodium falciparum. The target compounds were synthesized efficiently via a multistep route, involving the reaction of 1,4-naphthoquinone and p-aminobenzoic acid, followed by reactions with propargylamine and different prepared chlorides. The synthetic route was concluded using a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) "click" reaction. Based on structure-activity relationships (SAR), the compound bearing a 4-chloroaryl moiety (9g) was the most active against P. falciparum 3D7, exhibiting 60.00% growth inhibition at 25 µM. Furthermore, compound 9k bearing a 2-methylaryl moiety exhibited the most potent activity against P. falciparum K1, showing 64.52% growth inhibition at 50 µM. In silico simulations of compound 9g on thirteen protein targets in P. falciparum indicated strong interactions with the 1J3 and 1LDG targets. Also, the stability of the ligand-protein complexes was verified for 3FGO.