Chalcones as potential pepsin inhibitors: Synthesis, characterization, DFT and molecular docking studies

Pepsin, a unique protease activity at acidic environment in the stomach, can cause chronic inflammation in surrounding tissues after becoming hyperactive lead to enlarged tonsils, vocal fold polyps, laryngopharyngeal cancers, and other diseases. Therefore, design and development of new effective pepsin inhibitors becomes significant. In the present work, we synthesized, and characterized thiophene-based chalcones as anti-pepsin agents. The synthesized chalcones exhibited significantly better pepsin inhibition than commercially available drugs omeprazole and pantoprazole. The in-vitro screening revealed that the synthesized compounds exhibited pepsin inhibition in the range of 53.19-91.14 % at 3 × 10^-8 M concentration showing promising results controlling elevated pepsin levels. Compound 3p was found the best inhibitor with an IC50 value 1.02 × 10^-9 M. Molecular docking studies executed show the decrease in energy of interaction between pepsin and the synthesized compounds 3(a-t) varies from -69.104 to -83.124 kcal/mol and the highest decreased interaction energy with compound 3p. DFT analyses were conducted to gain a deeper understanding of the structural parameters. Energy minimization and quantum chemical parameters computed using Avagadro and ORCA software indicated ΔE values in the range 9.593-10.246 eV as per DFT calculations. The results obtained from the in vitro studies were supported with in silico studies.