Anticancer efficacy of thiazole-naphthyl derivatives targeting DNA: Synthesis, crystal structure, density functional theory, molecular docking, and molecular dynamics studies.

Two newly synthesized ligands, 1-((2-(4-(4-methoxyphenyl)thiazol-2-yl)hydrazono)methyl)naphthalen-2-ol (HL1) and 1-((2-(4-(naphthalen-1-yl)thiazol-2-yl)hydrazono)methyl)naphthalen-2-ol (HL2) were characterized using spectroscopy and single X-ray crystallography. Both belong to triclinic systems with space groups P21/c (HL1) and P-1 (HL2), exhibiting planar structures. Biological assays revealed significant antitumor activity, with HL2 showing significant antitumor activity against HepG2 cells (IC: 3.2 ± 0.1 μM) compared to HL1 (IC: 7.3 ± 0.3 μM). Mechanistic studies revealed HL2 induces apoptosis, while HL1 triggers necroptosis, and both were non-toxic to peripheral blood mononuclear cells (PBMC). UV-Vis titration showed that HL2 binds more strongly to DNA (K: 1.08 ± 0.215 × 10 M) than HL1 (K: 1.02 ± 0.155 × 10 M), attributed to stronger naphthyl chromophore stacking with DNA base pairs. Supporting this, hypochromic effects, circular dichroism spectra, and increased DNA viscosity suggest HL2 is a moderate intercalator, while HL1 functions as a groover binder. Docking studies revealed that in HL2, an additional naphthyl group enhances DNA binding affinity, explaining its superior efficacy. Molecular dynamics simulations further confirmed the stable binding of both ligands to DNA in the biological environment. These experimental and theoretical findings highlight the superior binding affinity of HL2 and its potential as a promising candidate for cancer therapy.