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.
Highlights
Malaria is a human parasitic disease that is caused by some species of Plasmodium in which Plasmodium falciparum is the deadliest [1, 2]
Synthesis and characterization of new dipeptide derivatives Pyrrolidine moiety was introduced into the sulphonamide dicarboxamides because it occurs frequently in synthetic and isolated natural peptides that have antimalarial activity [35, 36]
We presented the synthesis and full characterization of 32 new druglike sulphonamide-carboxamide derivatives and explored their antimalaria and antioxidant properties
Summary
Malaria is a human parasitic disease that is caused by some species of Plasmodium in which Plasmodium falciparum is the deadliest [1, 2]. In spite of extensive measures to combat the disease [3, 4], 214 million new cases and more than 400,000 deaths were reported in 2018 [5]. The emergence of drug-resistance strains of P. falciparum, which are no longer susceptible to even frontline drugs such as artemisinin, and cross-resistance, where resistance to one drug confers resistance to other chemically similar drugs or those that share mode of action, are blamed for the persistent devastation [6] and raises the dire need to discover new drugs to check the rate of malaria morbidity as well as mortality [7, 8].
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