New sulphonamide pyrolidine carboxamide derivatives: Synthesis, molecular docking, antiplasmodial and antioxidant activities.

Abstract

Carboxamides bearing sulphonamide functionality have been shown to exhibit significant lethal effect on Plasmodium falciparum, the causative agent of human malaria. Here we report the synthesis of thirty-two new drug-like sulphonamide pyrolidine carboxamide derivatives and their antiplasmodial and antioxidant capabilities. In addition, molecular docking was used to check their binding affinities for homology modelled P. falciparum N-myristoyltransferase, a confirmed drug target in the pathogen. Results revealed that sixteen new derivatives killed the parasite at single-digit micromolar concentration (IC50 = 2.40-8.30 μM) and compounds 10b, 10c, 10d, 10j and 10o scavenged DPPH radicals at IC50s (6.48, 8.49, 3.02, 6.44 and 4.32 μg/mL respectively) comparable with 1.06 μg/mL for ascorbic acid. Compound 10o emerged as the most active of the derivatives to bind to the PfNMT with theoretical inhibition constant (Ki = 0.09 μM) comparable to the reference ligand pyrazole-sulphonamide (Ki = 0.01 μM). This study identifies compound 10o, and this series in general, as potential antimalarial candidate with antioxidant activity which requires further attention to optimise activity.