Design, synthesis, and in-silico studies of hydrazide-hydrazone linked coumarin glycoconjugates with possible...

Coumarins, known for their broad-spectrum bioactivity, continue to serve as versatile scaffolds in drug design and development. Given the recent advancements in coumarin-based anticancer therapeutics, the design of novel coumarin derivatives has garnered significant attention for the development of multifunctional drug candidates. In this study, we designed and synthesized a series of novel hydrazide-hydrazone anchored coumarin-glycohybrids (1-8) using acetyl-protected β-C-glycopyranosyl propanone (11a and 11b) as starting materials. The glycosyl ketones were first converted into the corresponding hydrazones of cyanoacetohydrazide (13a and 13b) via reaction with cyanoacetohydrazide. Subsequent Knoevenagel condensation of 13a and 13b with salicylaldehyde derivatives, followed by hydrolysis, yielded the target compounds (1-8). The synthesized compounds were structurally characterized using spectroscopic techniques, including ¹H and ¹³C NMR, FT-IR, and mass spectrometry. The binding interactions of the synthesized glycohybrids were investigated through molecular docking studies targeting key cancer-related kinases, including EGFR, VEGFR-2, and CDK2. Docking results demonstrated strong binding affinities in compounds, particularly towards EGFR and CDK2 proteins, when compared with their known inhibitors. Molecular dynamics (MD) simulation studies predicted stable binding for the selected compounds 7 and 5 within the binding pocket of EGFR and VEGFR-2, respectively. Furthermore, computational evaluations of drug-likeness indicated that all synthesized compounds possess favourable pharmacokinetic profiles.