Synthesis & biological evaluation of novel sulfonyl hydrazone derivatives.
Sulfonyl hydrazone derivatives represent promising scaffolds in cancer progression, immune evasion, and treatment resistance. However, it remains underexploited due to the challenge of achieving selective inhibition without harming normal cellular functions. This study reports the design, synthesis, and comprehensive evaluation of novel sulfonyl hydrazone derivatives (2a-o) that strategically combine two privileged scaffolds with complementary anticancer mechanisms. Following complete structural characterization by FT-IR and NMR spectroscopy, an integrated experimental-computational workflow enabled the identification and mechanistic evaluation of compound 2 h as a promising hit candidate. Compound 2 h was selected for its favorable balance of anticancer potency, selectivity, and drug-likeness. In vitro evaluation against the human glioblastoma cell line (U87) and the human pancreatic cancer cell line (T3M4) demonstrated that sulfonyl hydrazone derivatives exhibit moderate anticancer activity. The compound 2 h demonstrates moderate antiproliferative activity with an IC50 of 67.60 ± 4.02 µM, whereas it affects normal human umbilical vein endothelial cells (HUVECs) with an IC50 of 194.91 ± 7,00 µM. Furthermore, in silico assessments indicated favorable physicochemical and absorption properties, alongside predicted liabilities to be addressed in future optimization. To elucidate the molecular mechanism underlying the observed anticancer activity, an integrated computational workflow including target prediction, molecular docking, and deep-learning-based structural modeling was employed. These analyses nominated cathepsin B (CTSB) as the most plausible candidate target, pending experimental confirmation, supported by its cancer-selective expression and favorable binding interactions with compound 2 h within the catalytic active site. The results highlight sulfonyl hydrazone derivatives as promising scaffolds for anticancer drug development and identify compound 2 h as a potential hit candidate for further structural optimization targeting cathepsin B.