Thiophene-Pyridine Derivatives as Potential Anti-Proliferative and Anti-Inflammatory Apoptotic Agents: Synthesis, In Vitro Evaluation, Molecular Docking, and Dynamic Simulations

Theodor Bilharz Research Institute

Bibliographic Information

Authors: El-Bana G.G.; Salman F.H.; Mahmoud F.R.; F. El-Sayed A.; A. Ismail M.

Journal: Polycyclic Aromatic Compounds

Publisher: Taylor and Francis Ltd.

Publication Date: 29 January 2026

Volume / Issue: Volume 46 / Issue 5

Pages: 760–790

ISSN: 10406638

DOI: 10.1080/10406638.2026.2620419

Scopus: View on Scopus

Document Type: Article

Authors and Affiliations

El-Bana G.G., Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt, Mansoura University Student’s Hospital, Mansoura University, Mansoura, Egypt; Salman F.H., Biochemistry and Molecular Biology Department, Theodor Bilharz Research Institute (TBRI), Giza, Egypt; Mahmoud F.R., Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt; F. El-Sayed A., Microbial Genetics Department, Biotechnology Research Institute, National Research Centre, Giza, Egypt, Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, Egypt; A. Ismail M., Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt

Abstract

Inflammation is a key contributor to tumorigenesis and chemotherapy resistance. This underscores the need to develop monotherapeutic compounds with both anti-tumor and anti-inflammatory activities. To address this concern, a new series of thiophene derivatives linked to 1,2-dihydropyridine was prepared. These compounds were studied as promising dual-action compounds targeting apoptosis and inflammation. It was found that compound 5b showed notable cytotoxicity against human HepG2 liver cancer cells (IC50 = 20.4 μg/mL). It also had reduced cytotoxicity against normal human fibroblasts. Also, automated analysis showed that 5b induced apoptosis, confirmed by the overexpression of apoptosis-related proteins BAX and BID, and the downregulation of Bcl-2, as measured by flow cytometry. In anti-inflammatory studies, compound 5b dose-dependently inhibited protein denaturation by 94.3% and increased membrane stability by 78.0%. It also suppressed COX-2 gene expression. Molecular docking analyses revealed that compound 5b had a high binding affinity to BAX, Bcl-2, BID, and COX-2. Also, ADMET predictions and Molecular dynamics simulations over 100 ns showed improvements and confirmed the structural stability of the protein-ligand complexes, with Root Mean Square Deviation (RMSD) values below 0.35 nm and stable intermolecular hydrogen bonds. Unlike the other compounds, 5b had both anti-apoptotic and anti-inflammatory activities. Therefore, compound 5b is a promising candidate for treating inflammation-related hepatocellular carcinoma. © 2026 Taylor & Francis Group, LLC.

Keywords

ADMET; anti-inflammatory; cytotoxicity; dynamics simulations; molecular docking (MD); Thiophene–pyridine derivatives; Binding energy; Cell culture; Cell death; Chemotherapy; Chlorine compounds; Complexation; Gene expression; Hydrogen bonds; Molecular docking; Molecular dynamics; Molecular modeling; Pathology; Proteins; Pyridine; Stability; Tumors; Anti-inflammatories; Anti-inflammatory activity; Anti-proliferative; Apoptotic; Dynamics simulation; Pyridine derivatives; Thiophene–pyridine derivative; Thiophene

Citation Information

Scopus Citations: 2

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