Kaur_2025_Future.Med.Chem__1

AIM: This study aimed to synthesize thiophene-based chalcones using green and conventional methods and evaluate their modulatory effects on key digestive enzymes-alpha-amylase, lipase, and trypsin for potential therapeutic applications in metabolic disorders. MATERIALS & METHODS: A series of twenty 2-acetylthiophene-based chalcones were synthesized via Claisen-Schmidt condensation using conventional, grinding, and ultrasonication methods. The compounds were characterized using FTIR, NMR, and melting point analysis. In vitro enzyme assays were conducted to assess activity against alpha-amylase, lipase, and trypsin. Molecular docking, drug-likeness, and ADMET profiling were performed in silico to predict binding interactions and pharmacokinetic properties. RESULTS: Ultrasonication offered the highest yield in the shortest time. Chalcones inhibited lipase (40.18-74.23%) and trypsin (40.86-73.91%), with compounds 3q and 3r showing the strongest inhibition (IC50 = 1.25 x 10(-8) M and 1.17 x 10(-8) M, respectively). Unexpectedly, alpha-amylase activation (50.18-75.18%) was observed, with compound 3g being the most effective. Docking studies supported enzyme binding, and ADMET analysis confirmed favorable safety profiles. CONCLUSIONS: Thiophene-based chalcones exhibit promising digestive enzyme modulatory properties, particularly as lipase and trypsin inhibitors, with potential application in managing obesity and related metabolic disorders.