Exploring sulfonamide carboxamides as promising leads for antimalarial drug development

Malaria remains a major global health challenge, compounded by the rapid emergence of drug-resistant Plasmodium strains. The development of new, effective antimalarial agents is therefore urgently needed. In this study, a series of novel carboxamide derivatives bearing a sulfonamide moiety were synthesized and structurally characterized using spectroscopic techniques. In vivo evaluation against Plasmodium berghei NK65 revealed that compounds 12e, 12f, and 12g exhibited significant parasitaemia suppression, with growth inhibition ranging from 48.0 to 66.8%. In silico ADMET analysis predicted favorable oral bioavailability and pharmacokinetic properties for all compounds. Molecular docking studies indicated that compound 12c binds strongly to Plasmodium falciparum plasmepsin II ( Pf PM2), forming key interactions with active site residues, although experimental activity suggests alternative mechanisms may contribute to antimalarial effects. These findings identify sulfonamide-based carboxamides, particularly 12e, 12f, and 12g , as promising scaffolds for further antimalarial drug development. Compound 12f exhibited the highest parasitaemia inhibition (66.8%), exceeding that of the reference drug artemisinin (59.0%), while compounds 12e and 12g showed moderate activity. Interestingly, compound 12c that displayed the highest binding affinity in the molecular docking study showed one of the least activities in the in vivo assay suggesting that the inhibition of Pf PM2 is not utilized by the compounds in expression of their biological activity.