Synthesis, SAR, and Docking Studies Disclose 2-Arylfuran-1,4-naphthoquinones as Antiplasmodial Hits.

A total of 28 lapachol-related naphthoquinones with four different scaffolds were synthesized and spectroscopically characterized. antiplasmodial activity was assayed against the chloroquine-resistant W2 strain by the parasite lactate dehydrogenase (LDH) method. Cytotoxicity against Hep G2A16 cell was determined by the MTT assay. All compounds disclosed higher antiplasmodial activity than lapachol. and -naphthoquinones with a furan ring fused to the quinonoid moiety were more potent than 2-hydroxy-3-(1'-alkenyl)-1,4-naphthoquinones, while -furanonaphthoquinones were more cytotoxic. Molecular docking to targets cyt complex and DHOD enzyme showed that five out of the 28 naphthoquinones disclosed favorable binding energies. Furanonaphthoquinones endowed with an aryl moiety linked to the furan ring are highlighted as new antiplasmodial lead compounds and warrant further investigation.