Design, synthesis, molecular docking, and crystal structure of benzohydrazide derivative as anti-cancer agents

Prostate cancer (PCa) is a predominant malignancy in males, primarily influenced by androgen receptor (AR) activation, and presents limited treatment options in advanced stages. This research presents the design, synthesis, and thorough assessment of new benzohydrazide derivatives as effective androgen receptor antagonists, aiming to fulfill the demand for efficient, low-toxicity agents in prostate cancer treatment. Compounds (6 a-h) were designed using structure-based molecular docking against AR (PDB ID: 3V49 ), which indicated significant van der Waals interactions with hydrophobic residues (TRP741, LEU873) and hydrogen bonds with LEU704/HIE876 that maintain the inactive conformation and inhibit helix-12 closure. These compounds were synthesized via Schiff base condensation, characterized using spectral methods and single-crystal XRD (6d, 6 g, 6 h), and evaluated for ADME compliance, molecular dynamics stability, in vitro cytotoxicity (PC-3, LNCaP), apoptosis induction, and DNMT1 inhibition. Compounds 6d (LNCaP IC50: 7.17 ± 1.87 μM; PC-3 IC50: 32.09 ± 0.86 μM) and 6 g (LNCaP IC50: 10.45 ± 0.7 μM; PC-3 IC50: 44.65 ± 0.32 μM) demonstrated greater potency than bicalutamide, exhibiting dose-dependent effects, inducing apoptosis in LNCaP cells (AO/EtBr staining), showing non-toxicity to 3 T3 cells, and moderate inhibition of DNMT1 by 6d (23.9% at 100 μM). The presence of methoxy/hydroxy para-substituents enhanced activity by improving binding affinity, as indicated by Glide scores of −11.776 kcal/mol. The findings indicate that benzohydrazide derivatives featuring electron-donating substitutions are promising candidates for androgen receptor-specific therapy in prostate cancer.