Bencilideno-isofalohidrazidas Citostáticas con Neurotoxicidad Disminuida

Benzylidene-isophthaloylhydrazides possess functional groups capable of thiol alkylation, hydrogen bonding, and van der Waals interactions, making them promising scaffolds for anticancer drug design. This study involved the synthesis of such derivatives (1a-o) and evaluation of their cytotoxicity, tumor selectivity, neurotoxicity, structure-activity relationships, and drug-like properties to identify candidates with high anticancer potency and diminished neuronal toxicity.

Compounds 1a-l were synthesized by condensation of isophthalohydrazide with substituted aryl aldehydes, while 1m-o were formed from benzoylhydrazide analogs. Cytotoxicity was measured using oral squamous cell carcinoma cells (Ca9-22, HSC-2), normal oral cells (HGF, HPC), and NGF-differentiated PC-12 neuronal cells using MTT assays. Selectivity index (SI) and anticancer/neurotoxicity ratio (RAN) were calculated. Cell-cycle progression and apoptosis induction were examined using flow cytometry and western blotting. Torsion angles (θ_A, θ_B) and other physicochemical parameters were determined using computational analysis, and QSAR correlations were assessed.

Most of the compounds showed greater cytotoxicity towards neoplastic cells than non-malignant ones. Compound 1h displayed the highest tumor specificity (SI >59.5) and minimal neurotoxicity, outperforming doxorubicin, melphalan, and cisplatin. Compounds 1d, 1f, and 1h exhibited high RAN values, indicating reduced neuronal toxicity. Cell-cycle analysis revealed that 1h induced S-phase accumulation with a modest increase in apoptotic subG₁ populations, accompanied by caspase-3 activation. The dimeric analogs were significantly more potent than their monomeric counterparts, and higher torsion angles generally correlated with enhanced activity. ADME (Absorption, Distribution, Metabolism, and Excretion) properties evaluation showed favorable drug-like characteristics across the series.

Benzylidene-isophthaloylhydrazides - particularly compound 1h - are promising antineoplastic agents with noteworthy tumor selectivity and low neurotoxicity accompanied by favorable ADME properties. Their robust activity, favorable ADME properties, and clear structural trends support further optimization and preclinical development.