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

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Computational Chemistry

Background:

• Pepsin's hyperactivity in acidic environments causes chronic inflammation and diseases like vocal fold polyps and laryngopharyngeal cancers.
• Effective pepsin inhibitors are crucial for managing these pepsin-associated pathologies.
• Current treatments like omeprazole and pantoprazole have limitations in pepsin inhibition.

Purpose of the Study:

• To synthesize and characterize novel thiophene-based chalcones as potential anti-pepsin agents.
• To evaluate the in vitro and in silico efficacy of these synthesized compounds against pepsin.
• To identify lead compounds with superior pepsin inhibitory activity.

Main Methods:

• Synthesis and characterization of a series of thiophene-based chalcones (compounds 3a-t).
• In vitro pepsin inhibition assays to determine percentage inhibition and IC50 values.
• Molecular docking and Density Functional Theory (DFT) analyses to understand binding interactions and electronic properties.

Main Results:

• Synthesized chalcones demonstrated significantly higher pepsin inhibition compared to omeprazole and pantoprazole.
• In vitro screening showed inhibition ranging from 53.19% to 91.14% at 3 × 10⁻⁸ M.
• Compound 3p exhibited the highest potency with an IC50 value of 1.02 × 10⁻⁹ M.
• Molecular docking revealed strong binding interactions, with compound 3p showing the lowest interaction energy (-83.124 kcal/mol).
• DFT calculations provided insights into the electronic structure and stability of the compounds.

Conclusions:

• Thiophene-based chalcones are effective inhibitors of pepsin.
• Compound 3p represents a highly promising candidate for developing new anti-pepsin therapies.
• The study validates the potential of these novel compounds for treating pepsin-related disorders.
• Integrated in vitro and in silico approaches confirm the efficacy of the designed chalcones.