Design, synthesis, and evaluation of 1,4-benzodioxane-hydrazone derivatives as potential therapeutics for skin cancer: In silico, in vitro, and in vivo studies

In the pursuit of novel chemotherapeutic agents for skin Cancer, we synthesized a series of 1,4-benzodioxane-hydrazone derivatives (7a-l) using the Wolff-Kishner reaction. These compounds were initially screened against the NCI-60 oncological cell lines in a one-dose assay at 10 μM. Among them, compound 7e emerged as a potent inhibitor of Cancer cell growth across 56 cell lines, with an average GI₅₀ of 6.92 μM. Notably, it exhibited enhanced efficacy in melanoma cell lines, including MDA-MB-435, M14, SK-MEL-2, and UACC-62, with GI₅₀ values of 0.20, 0.46, 0.57, and 0.27 μM, respectively. Apoptosis assay and cell cycle analysis studies revealed that compound 7e induced Apoptosis and caused S-phase arrest in MDA-MB-435 cells. Furthermore, an in vitro enzyme inhibition assay against mTOR kinase yielded an IC₅₀ of 5.47 μM, while molecular docking studies of compound 7e (docking score: -8.105 kcal/mol) supported its binding affinity. Compound 7e adhered to Lipinski's rule of five and displayed favourable ADMET properties. In vivo studies demonstrated its safety and efficacy in ameliorating skin Cancer in a mice model when administered intraperitoneally at 20 mg/kg. Structure-activity relationships were established through in vitro, in vivo, molecular docking, and molecular dynamics analysis. Collectively, these findings highlight 1,4-benzodioxane-hydrazone derivatives as promising scaffold for the development of novel chemotherapeutic agents for skin Cancer.