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

• Published in: ChemistrySelect (Weinheim) 2022-02, Vol.7 (5), p.n/a
• Main Authors: Ezugwu, James. A., Okoro, Uchechukwu. C., Ezeokonkwo, Mercy. A., Hariprasad, Kurma. S., Rudrapal, Mithun, Ugwu, David. I., Gogoi, Neelutpal, Chetia, Dipak, Celik, Ismail, Ekoh, Ogechi. C.
• Format: Article
• Language: English
• Subjects: ADMET; Antimalarial Dipeptide-Sulfonamide; Molecular Docking; Molecular Dynamics; P. berghei
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202103908

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. In this study, we synthesized and characterized new dipeptides bearing sulfonamide functionality. The protein‐ligand docking was performed to predict the binding affinity of the test compounds as possible novel antimalarial agents with inhibitory activity against P. falciparum cysteine protease FP‐2 (FP‐2) and FP‐3 (FP‐3) enzymes. And also evaluate in vivo antimalaral actvity of the dipeptide analogues.