Design, synthesis and molecular docking of novel 4-chloro-2-(4-(4-(sulfonyl)piperazin-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one for the evaluation anti-cancer activity

Abstract

A series of novel 4-chloro-2-(4-(4-(sulfonyl)piperazin-1-yl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one derivatives (9a-n) were rationally designed, synthesized, and evaluated for their anticancer activity against MCF-7 and A-549 cancer cell lines. The synthesis followed a stepwise approach involving crucial steps such as cyclization, esterification, reduction, benzylic bromination, Boc-protection, and the final formation of the target compounds. In vitro cytotoxicity assays revealed that six compounds (9a, 9b, 9d, 9f, 9g, and 9n) exhibited significant potency compared to the reference drug doxorubicin. Notably, compound 9a showed exceptional activity with IC₅₀ values of 23.1 μM and 10.6 μM against A-549 and MCF-7 cells, respectively. Molecular docking studies were performed against EGFR tyrosine kinase (PDB: 4HJO) and estrogen receptor (PDB: 1ERR) to elucidate potential mechanisms of action. Compounds 9a and 9f demonstrated strong binding affinities with docking scores of 11.25 and 11.21 kcal/mol, respectively, against EGFR, and 10.41 and 10.29 kcal/mol, respectively, against estrogen receptor. A structure-activity relationship analysis revealed that electron-withdrawing and hydrophobic substituents enhanced cytotoxic efficacy. In silico ADME and toxicity predictions indicated that all compounds met Lipinski's rule of five, suggesting good oral bioavailability. These findings highlight the potential of these novel piperazinyl-pyridinone derivatives as promising anticancer agents targeting EGFR and estrogen receptor pathways. Further in vivo validation and mechanistic studies are warranted to establish their clinical relevance and optimize their pharmacological properties.