Synthesis, DFT, in silico, antimicrobial and anticancer studies of triazole-hydrazone sulfonate derivatives targeting brain tumors via DNA damage, cytotoxicity and migration suppression
JOURNAL OF MOLECULAR STRUCTURE, cilt.1381, 2027 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 1381
- Basım Tarihi: 2027
- Doi Numarası: 10.1016/j.molstruc.2026.147731
- Dergi Adı: JOURNAL OF MOLECULAR STRUCTURE
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Chimica, Compendex, INSPEC, Academic Search Ultimate (EBSCO), Engineering Source (EBSCO)
- Karadeniz Teknik Üniversitesi Adresli: Evet
Özet
A new series of (E)-4-((2-(2-(4-amino-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetyl)hydrazono)methyl)phenyl benzene/4-substituted benzenesulfonates (5a-5c) was successfully synthesized via a straightforward synthetic route. The structures of the obtained compounds were fully characterized and confirmed by spectroscopic techniques, including FT-IR, & sup1;H NMR, and & sup1;& sup3;C NMR, and by LC-MS/MS analysis. Density functional theory was used to investigate the spectral, electronic, and NLO properties of the 1,2,4-triazole-based hydrazone derivatives (5a-5c). IR and NMR spectroscopic values were found to be consistent with the theoretical results. Molecular reactivities were compared using calculated quantum-chemical parameters. The reactive sites of the molecules were determined through MEP and FMO analysis. Furthermore, NLO analysis demonstrated that the molecules could have significant potential for NLO applications. The anticancer potential of the synthesized compounds 5a, 5b, and 5c was evaluated against brain tumor cell lines (A172, C6, SH-SY5Y, B35, U87MG, and IDHmut-U87), various solid tumor cell lines (HT29, HeLa, and MCF7), and normal fibroblast cells (FL). The study investigated their antiproliferative activity using the MTT assay, cytotoxic effects through LDH release analysis, DNA damage induction, cell migration inhibition, DNA-binding properties, and treatment-induced morphological alterations. A series of novel triazole-based derivatives (5a-5c) were synthesized and evaluated for their anticancer potential against human cancer cell lines. Among the tested compounds, 5c exhibited the most potent antiproliferative activity and was therefore selected for detailed computational investigation targeting phosphatidylinositol-3-kinase alpha (PI3K alpha), a key regulator of cancer cell growth and survival. In addition, the antimicrobial activities of compounds 5a-5c were evaluated against a panel of Gram-positive and Gram-negative bacteria as well as Candida species. The tested compounds exhibited moderate antimicrobial activity, with MIC values ranging from 156 to 625 & micro;g/mL. The highest antibacterial activity was observed for compound 5c against Bacillus subtilis and for compound 5a against Staphylococcus aureus (MIC = 156 & micro;g/mL), while compounds 5b and 5c showed enhanced antifungal activity against Candida tropicalis (MIC = 156 & micro;g/mL). Molecular docking analysis revealed that compound 5c displayed the most favorable binding affinity toward the ATP-binding pocket of PI3K alpha, with a binding energy of -10.05 kcal/mol and extensive interactions with catalytically important residues. The predicted binding mode was further validated through a 100 ns molecular dynamics simulation, which demonstrated stable protein-ligand interactions, low structural fluctuations, preserved protein compactness, and persistent hydrogen-bond formation throughout the simulation. MM/GBSA calculations yielded a favorable binding free energy of -20.44 +/- 4.05 kcal/mol, indicating strong binding stability. Per-residue energy decomposition analysis identified Ile932, Val850, Ile800, Ile848, Met922, and Val851 as the major contributors to ligand stabilization. Overall, the combined experimental and computational findings suggest that compound 5c may represent a promising PI3K alpha-targeting anticancer candidate and warrants further biological investigation.