Novel adamantyl clubbed iminothiazolidinones as promising elastase inhibitors: design, synthesis, molecular docking, ADMET and DFT studies

Abstract

Structurally diverse adamantyl-iminothiazolidinone conjugates were synthesized, evaluated for elastase inhibition, and subjected to in silico ADMET prediction. The inhibition studies revealed compounds 5a, 5f, 5g, and 5h to show significant activity. Porcine Pancreatic Elastase (PPE) is a serine protease that is homologous to trypsin and chymotrypsin that are involved in various pathologies like inflammatory disease, Chronic Obstructive Pulmonary Disease (COPD), acute respiratory distress syndrome, cystic fibrosis, and atherosclerosis. PPE if remained uninhibited would lead to digestion of important connective tissue. We developed new structurally diverse series of adamantyl-iminothiazolidinone hybrids to divulge elastase inhibition assay. To identify potent derivatives, in silico screening was conducted and in vitro studies disclosed that the compounds 5a, 5f, 5g, and 5h showed excellent binding energies and low IC 50 values. In silico studies including molecular docking, DFT studies (using the B3LYP/SVP basis set in the gas phase) drug likeness scores and molecular dynamic simulation studies were conducted to evaluate protein–ligand interactions and to determine the stability of top ranked conformation. In silico studies further supported the results of in vitro experiments and suggest these derivatives as novel inhibitors of elastase enzyme.