Zaki, Magdi E. A.Alhilal, MohammadRiyadh, Sayed M.Alhilal, SuzanAhmed, Mohamed S. M.Gomha, Sobhi M.El-Naggar, Mohamed2026-04-162026-04-1620260272-43911098-2299https://hdl.handle.net/20.500.12514/10670https://doi.org/10.1002/ddr.70272A series of unsymmetrical azine-linked thiazolo[3,2-a]benzimidazole derivatives (4a-r) was synthesized and structurally characterized. Density functional theory (DFT) calculations, including frontier molecular orbital (FMO) analysis and global reactivity descriptors, supported the preferential formation of the E-isomeric forms. In silico target prediction prioritized cyclin-dependent kinase 2 (CDK2), and molecular docking of representative active members (4b, 4 d, 4p, and 4r) revealed key contacts around Arg83/Pro84 and favorable binding energies ( - 3.91 to -6.20 kcal/mol). In vitro antiproliferative activity against human colon carcinoma (HCT-116) and human hepatocellular carcinoma (HepG2) cell lines identified 4r as the most potent compound (half-maximal inhibitory concentration, IC50 = 5.26 +/- 0.37 and 5.03 +/- 0.42 & micro;M, respectively), surpassing doxorubicin (IC50 = 7.05 +/- 0.49 and 6.42 +/- 0.31 & micro;M). Absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction indicated high gastrointestinal (GI) absorption, no blood-brain barrier (BBB) permeation, no P-glycoprotein (P-gp) substrate liability, a bioavailability score of 0.55, and zero pan-assay interference compounds (PAINS) alerts. Overall, the integrated synthetic, computational, and biological results highlight azine-linked thiazolo[3,2-a]benzimidazoles, particularly 4r, as promising CDK2-directed anticancer leads.en10.1002/ddr.70272info:eu-repo/semantics/closedAccessMolecular Docking StudiesDensity Functional Theory CalculationsUnsymmetrical AzinesDrug-Likeness EvaluationAnticancer AgentsThiazolo[3,2-a]benzimidazoleArticle2-s2.0-105034817852