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Updated: Jan 18, 2026

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Indole-imidazolone derivatives as dual Mcl-1/COX-2 inhibitors: Design-oriented synthesis, molecular docking, and
Phoebe F Lamie1, Peter A Halim2, Ahmed M Sayed3
1Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Abstract:
A novel series of indole-imidazolone derivatives (6a-l) was synthesized and evaluated for Mcl-1 inhibition. Compounds 6c, 6 g, and 6 k showed strong binding affinities (Ki = 0.02-0.04 μM), significantly exceeding the reference compound gossypol. Among them, 6 g also demonstrated notable activity against Bcl-XL and Bcl-2, with Ki values (7.20 μM and 5.30 μM) comparable to or better than gossypol. The key target compounds 6c, 6 g, and 6 k demonstrated significant antiproliferative activity against MDA-MB-231, PC-3, and A-549 cancer cell lines, with the strongest effect observed in MDA-MB-231 cells. Their pro-apoptotic effects were confirmed by increased Bax and cytochrome c levels and validated through Annexin V/PI staining through flow cytometry. Additionally, they were evaluated for COX-1 and COX-2 inhibition, with 6c showing the highest COX-2 selectivity (S.I. = 28.44), surpassing celecoxib. Molecular docking and dynamics confirmed strong and stable binding to Mcl-1 and COX-2. In silico ADMET predictions indicated favorable drug-like and pharmacokinetic properties for the active compounds.
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