Novel zerumbone-secondary amide hybrids: ultrasonic synthesis, cytotoxic evaluation, molecular docking and <i>in silico</i> ADMET studies

Zerumbone, along with its various derivatives and structurally related compounds, has attracted significant scientific interest due to its broad-spectrum pharmacological properties, particularly its anticancer potential. In this study, novel zerumbone-secondary amide hybrids were successfully designed and synthesized with high yields using both conventional and ultrasonic methods. Reactions performed under ultrasonic conditions required significantly shorter reaction times than those conducted without ultrasound while maintaining comparable product yields. The cytotoxicity of the synthesized derivatives was evaluated against four human cancer cell lines: hepatocellular carcinoma (HepG2), lung carcinoma (A549), acute leukemia (HL-60), and gastric carcinoma (AGS). Most derivatives exhibited significant cytotoxic activity, with those derived from azazerumbone 2 demonstrating greater potency than those derived from azazerumbone 1. The incorporation of secondary amide groups has been confirmed to enhance the cytotoxic activity of the newly synthesized derivatives against cancer cells. Notably, compounds 4c, 4g, and 4i displayed the strongest cytotoxicity across all tested cell lines, with IC₅₀ values ranging from 0.81 ± 0.04 to 4.14 ± 0.44 μg mL^-1, comparable to those of zerumbone and ellipticine. Docking studies revealed a strong correlation between the biological activity of zerumbone-secondary amide hybrids and their binding affinity to EGFR tyrosine kinase, further highlighting the crucial role of secondary amide groups in enhancing their anticancer potential. Furthermore, pharmacokinetic predictions indicate that compounds 4c, 4g, and 4i possess favorable drug-like properties, reinforcing their potential as lead candidates for anticancer drug development.