In Silico Evaluation of Novel 2-Pyrazoline Carboxamide Derivatives as Potential Protease Inhibitors Against Plasmodium Parasites

Malaria, a devastating disease caused by Plasmodium parasites, continues to pose a significant threat to global health, with increasing resistance to current antimalarial drugs. In this study, we employed an in silico approach to design and evaluate novel 2-pyrazoline carboxamide derivatives as potential protease inhibitors against Plasmodium falciparum. Our results show that all the designed ligands exhibit good drug-like properties, satisfying Lipinski’s rule of five, and have low toxicity profiles. Molecular docking studies revealed that five newly designed ligands (P5, P6, P7, P11, and P13) exhibit promising binding affinities and interactions with key protease enzymes involved in the hemoglobin degradation pathway, including Falcipain-2, Falcipain-3, and Plasmepsin-2 with PDB (Protein Data Bank) codes of 6JW9, 3BWK, and 1LF3, respectively. Notably, ligand P13 showed the strongest binding affinity with Falcipain-2, forming an additional hydrogen bond with CYS42, an essential residue for the enzyme’s catalytic activity. The interactions between the ligands and the enzymes suggest a competitive inhibition mechanism, with the potential to disrupt the hemoglobin degradation pathway and halt the parasite’s lifecycle. The biological implications of these findings are significant, as they suggest that these novel ligands could be effective against Plasmodium parasites, particularly in the context of increasing resistance to current antimalarial drugs. Overall, this study provides valuable insights into the potential of novel 2-pyrazoline carboxamide derivatives to serve as protease inhibitors against Plasmodium parasites, highlights their potential as a promising strategy for antimalarial drug development, and demonstrates the importance of in silico approaches in the discovery of novel therapeutics.