Synthesis and Biological Evaluation of Coumarin Derivatives with Promising Anti-Cancer Activity: Computational Kinase Profiling and Molecular Modeling Analysis.

The growing resistance and toxicity associated with current cancer treatments highlight the urgent need for novel therapeutic agents. In this study, we synthesized a series of pyrazolopyrimidine-coumarin derivatives (10a-d) and evaluated their anti-cancer activity using the NCI-60 cell line panel, representing nine cancer types. Among the compounds, 10c demonstrated the most potent activity, achieving a mean growth inhibition of 50% across the entire cell lines' panel. To investigate its mechanism of action, we performed molecular docking studies against 18 kinases, identifying JAK1 and CDK2 as primary potential targets with binding affinities comparable to the ligands co-crystallized with the PDB protein complexes. Pharmacokinetic and toxicity predictions using ADMETLab 3.0, OSIRIS Property Explorer, and ProTox-III confirmed compound 10c as a promising drug-like candidate. These findings position 10c as a potential lead compound for developing next-generation anti-cancer agents. Future efforts will focus on optimizing this scaffold to combat resistance and toxicity, particularly enhancing JAK1 and CDK2 inhibition. This study underscores the potential of coumarin-based derivatives in advancing cancer therapeutics.