Keywords: Pyranopyrazole; molecular docking; Plasmodium falciparum; PfLDH; ADMET

Abstract

Plasmodium falciparum is the most virulent species of human malaria. Widespread resistance by Plasmodium parasites to quinolone based antimalarials and decreased efficacy of artemisinin-based combination therapy necessitates the discovery of new drugs. Malaria parasite enzyme in glycolytic pathway, Plasmodium falciparum lactate dehydrogenase (PfLDH) is specially targeted for anti-malarial drugs development as it an essentials enzyme for parasite survival. Five pyrano[2,3- c]pyrazole-3-carboxylates (1a-e) were synthesized and subjected to molecular docking studies to identify molecular interactions between the compounds and the Plasmodium falciparum lactate dehydrogenase (PfLDH) enzyme (PDB ID: 2A94). However, these compounds showed lower docking scores than the NADH cofactor, predicting its inefficiency in inhibiting PfLDH in the glycolysis reaction. The pharmacokinetics and drug-likeness of the test compounds were subsequently computed by ADMET prediction. Most of the compounds demonstrated low central nervous system side effects, absence of potential cardiac toxicity, and passing Lipinski's five rule. These in silico data suggest the potentiality of pyranopyrazole derivatives to be exploited as orally safe active drugs.