Design, Synthesis, Molecular Docking, Molecular Dynamics and In Vivo Antimalarial Activity of New Dipeptide-Sulfonamides

A new series of novel dipeptide sulfonamide analogues were designed, synthesized, and screened for their in silico studies and in vivo antimalarial activities. The synthesized compounds (50 mg/Kg) showed significant activity against P. berghei (NK65) with % inhibition values in (5.9 to 64.7 %) range in when compared with reference drug, artemisinin (66.7 %) in a four day suppressive assay. The in silico studies predicted favorable binding affinity of compounds with target protein residues with high dock score against P. falciparum falcipain 2 (FP-2) and falcipain 3 (FP-3) proteins in comparison with the reference ligands. The synthesized compounds showed druggable properties, and the predicted (absorption, distribution, metabolism, excretion and toxicities (ADMET) properties were within the acceptable limits. Molecular dynamics simulation study of the most active compound, 8 e was performed in order to further validate the stability of the protein-ligand complex and the protein-ligand interactions.

Automated summary

A new series of novel dipeptide sulfonamide analogues were designed and synthesized, and their in vitro and in vivo antimalarial activities were studied. The results showed significant antimalarial activity of these compounds. The in silico studies predicted high binding affinity of these compounds with the target proteins. The synthesized compounds exhibited drug-like properties, and their ADMET properties were within acceptable limits. Molecular dynamics simulation of the most active compound validated the stability of the protein-ligand complex and protein-ligand interactions.