Novel Cinnamaldehyde Hydrazones: Design, In Silico Evaluation, Synthesis, and Cytotoxic Activity

(1) Background: Cinnamaldehyde exhibits a broad spectrum of biological activities, and its α,β-unsaturated aldehyde scaffold serves as a versatile platform for the design of hydrazone derivatives with improved pharmacological properties. (2) Methods: In this study, eight cinnamaldehyde-based hydrazones were synthesized via a one-step condensation reaction between cinnamaldehyde and para-substituted acylhydrazides. Prior to synthesis, an in silico assessment of physicochemical, pharmacokinetic, ADME (absorption, distribution, metabolism, elimination), lead-likeness, and drug-likeness properties was conducted using SwissADME, ACD/Labs v. 9.10, and MDL QSAR v2.2.0.0.446 software. Structural characterization by IR, 1H NMR, 13C NMR, and HR ESI–MS confirmed successful formation of the hydrazone linkage. Cytotoxic activity was evaluated using the MTT assay against selected cancer cell lines. (3) Results: All compounds exhibited favorable lead-like characteristics, including suitable molecular weight, moderate lipophilicity, and acceptable predicted ADME profiles. Biological evaluation revealed moderate, structure-dependent antiproliferative activity with clear cell line selectivity. Among the series, compound CA8 showed the most promising profile, displaying the highest cytotoxic activity against T-cell leukemia KE-37 cells (IC50 = 20.3 ± 2.8 μM), comparable to reference drug melphalan (IC50 = 21.40 ± 3.9 μM), and the highest selectivity index (≥19.7). Structure–activity analysis suggests that an amino substituent enhances both potency and selectivity. (4) Conclusions: Overall, these findings identify cinnamaldehyde hydrazones as a promising scaffold for anticancer drug development and provide a strong basis for further structural optimization.