Design, Synthesis, and Anti-Melanoma Activity Study of Cinnamaldehyde Derivatives Targeting ENO1

Melanoma, a highly invasive malignant skin tumor, has a steadily increasing incidence rate, with poor prognosis and high mortality among advanced-stage patients. This study targeted ENO1 and used rational drug design strategies. While maintaining CA's key pharmacophore—the α,β-unsaturated aldehyde structure—the benzene ring core was chemically modified. Substituents with different electronic and steric properties, such as methyl groups, halogens, and complex aromatic rings, were introduced. A series of derivatives was designed through molecular docking-based virtual screening. Twenty-five target compounds (CAA-1 to CAA-25) were synthesized organically. Their inhibitory activity against two melanoma cell lines (A375 and C918) was tested using cytotoxicity assays (CCK-8 method), along with drug-like property predictions via the Swiss ADME online platform. Results show that CAA-23 has optimal anti-melanoma activity, providing vital experimental evidence for developing new ENO1-targeted anti-melanoma drugs, with plans to further explore its mechanisms of action in vivo and in vitro.