Design, Synthesis, Molecular Docking, Drug-Likeness/ADMET and Molecular Dynamics Studies of Thiazolyl Benzenesulfonamide Carboxylates as Antimalarial Agents

In this work, nine novel thiazole derivatives of substituted benzenesulfonamide carboxylate were designed, synthesized and characterized (1H NMR, 13C NMR and Mass Spectra) for their possible development as antimalarial agents. All synthesized compounds were subjected to molecular docking, drug-likeness, ADMET properties and molecular dynamics studies by in silico methods using Biovia Discovery Studio (DS) 2020 software. The molecular docking study of all the synthesized compounds was carried out against Plasmodium falciparum cysteine protease falcipain 2 (FP-2, 3BPF) and falcipain 3 (FP-3, 3BPM) enzymes using the CDocker program of DS. Further, the best docked compound was studied by molecular dynamics simulation method followed by MM-PBSA calculation. In molecular docking studies, the synthesized thiazolyl benzenesulfonamides exhibited remarkable binding affinity against FP-2 and FP-3 enzymes. Molecular dynamics studies further confirmed the antimalarial potential of the compounds with the formation of well-defined and stable receptor-ligand interactions against both the falcipain enzymes. One derivative, ethyl 4-methyl-2-(4-methyl-2-(4-methylphenylsulfonamido)pentanamido) thiazole-5-carboxylate possesses promising inhibitory potential against both P. falciparum falcipain 2 and falcipain 3 enzymes. Based upon present findings, the thiazolyl benzenesulfonamide-5-carboxylates can be further evaluated for in vitro and in vivo antimalarial effectiveness towards possible development as antimalarial lead molecules and/ or potent antimalarial drug candidates.