Investigation of the Anti-Plasmodial Properties of N-2-Oxo Pyrrolidine Pentanamide-Based Sulfonamides: Experimental and Theoretical Approach

The study aimed to investigate novel pyrrolidine-pentanamide derivatives of sulfonamides as potential anti-malaria agents through a comprehensive approach involving experimental, theoretical, and in silico evaluations. The compounds were synthesized using standard methods and characterized using NMR, FT-IR, and HRMS techniques. The molecular properties of the compounds were investigated using density functional theory (DFT) at the B3LYP-D3 meta-functional/GenECP theoretical level. The calculated vibrational frequencies of the compounds showed good agreement with experimental results, validating the accuracy of the theoretical approach in capturing the behavior of different functional groups. Molecular docking simulations were performed to assess the binding affinity of the compounds to the amino acid residues binding sites of two target proteins: farnesyl pyrophosphate synthase (PDB ID: 1RQJ) and Plasmodium falciparum 80S ribosome (PDB ID: 3J7A). Substantially, the results of the docking simulations demonstrated that three compounds, namely 3-Methyl-2-(4-methylphenylsulfonamido)-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pentanamide (MMOPEP), 3-Methyl-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2-(phenylsulfonamido)pentanamide (MOPEPP), and 3-Methyl-2-(4-nitrophenylsulfonamido)-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pentanamide (MNOPEP), exhibited tight binding to the target proteins. These compounds showed favorable docking scores compared to standard drugs, indicating their potential as anti-malaria agents. Additionally, the high electrophilicity index recorded for the three compounds further supports their suitability as anti-malaria agents. The results collectively suggest that the pyrrolidine-pentanamide derivatives of sulfonamides have promising interactions with the target proteins, indicating their potential effectiveness against malaria. This study provides valuable insights into the molecular properties and binding affinities of the synthesized compounds, contributing to the development of new anti-malaria therapies.