Synthesis of Chromen–THP Hybrids as Dual Anticancer and Antioxidant Agents: In Silico and In Vitro Evaluation
摘要
Objective: This study evaluates the dual anticancer and antioxidant activities of the synthesized hybrids in both in vitro and in silico models. Methods: A series of chromen–tetrahydropyrimidine hybrids (4a–4f and 6a–6f) were synthesized via a one-pot Biginelli reaction using oxalic acid as a catalyst, combining substituted acetoacetates, aromatic aldehydes, and urea/thiourea. Characterization was performed using IR, NMR, and mass spectrometry. Anticancer activity was assessed against MCF-7 and MDA-MB-231 breast cancer cell lines using the SRB assay, while antioxidant activity was measured via the DPPH assay. In silico ADME properties were predicted using ADMETlab 2.0. Network pharmacology identified potential targets and pathways, supplemented by molecular docking and simulation studies to evaluate binding interactions and stability. Results and Discussion: Compounds 4d, 4e, 4f, 6b, and 6f showed potent cytotoxicity with GI50 values <10 μg/mL in both cell lines, with 6c selectively targeting MDA-MB-231. Compounds 4a, 4b, 6b, and 6f exhibited strong antioxidant activity, with IC50 values comparable to that of ascorbic acid (45.63 ± 0.20 μg/mL). Network pharmacology identified the top two hub genes STAT3 and AKT1, and KEGG pathway analysis revealed pathways in cancer, PI3K-Akt, and MAPK signaling as key contributors to anti-breast cancer effects. Molecular docking revealed high binding affinities, with 4d (−8.7 kcal/mol, AKT1) and 6b (−8.1 kcal/mol, STAT3). Molecular dynamic simulations confirmed stable protein-ligand complexes with minimal fluctuations. ADME analyses indicated favorable pharmacokinetics and low toxicity. Conclusions: These hybrids show promise as dual anticancer and antioxidant agents, warranting further development for breast cancer therapy.