Synergistic integration of trifluoromethyl and phenolic moieties into novel hydrazone scaffolds: Synthesis, spectroscopic elucidation, and multidimensional antioxidant evaluation
Journal of Molecular Structure, cilt.1373, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 1373
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.molstruc.2026.146754
- 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)
- Anahtar Kelimeler: Antioxidant activity, Computational drug discovery, Phenolic compounds, Quantum chemical calculations, Trifluoromethylated hydrazones
- Isparta Uygulamalı Bilimler Üniversitesi Adresli: Evet
Özet
Oxy-radical damage is a central mechanism in various diseases, prompting the search for novel scaffolds with enhanced stability and radical-scavenging efficiency. In this study, we report the design and synthesis of eight novel hydrazone derivatives (3a–h) featuring a synergistic integration of a metabolic-stabilizing trifluoromethyl (-CF3) group and radical-scavenging phenolic hydroxyl moieties. The compounds were synthesized in high yields (80–92%), and FTIR, NMR, and mass spectrometry rigorously elucidated their structures. Crucially, comprehensive 2D COSY and NOESY NMR analyses in DMSO-d6 using 3a as a representative model confirmed that the synthesized hydrazones exist exclusively in the thermodynamically favored, conformationally rigid E-configuration across the azomethine core. To decode the electronic environment, quantum chemical calculations were conducted using Density Functional Theory (DFT/B3LYP/6-311++G(d,p)), where theoretical NMR and vibrational data showed high correlation with experimental findings. The antioxidant capacity was experimentally determined using CUPRAC and DPPH assays. Among the tested derivatives, compound 3d (3,4-dihydroxy) emerged as the most potent scavenger. It exhibited a TEAC value of 3.33 ± 0.11 and an EC50 of 6.95 ± 0.24 µM in the CUPRAC assay, and a TEAC value of 0.71 ± 0.02 with an IC50 of 41.87 ± 1.42 µM in the DPPH assay, significantly outperforming the standard Trolox. SAR analysis revealed that the "catechol effect" in dihydroxylated derivatives facilitates superior electron donation compared to monohydroxylated analogs. Computational investigations through FMO, MEP, ELF, NCI-RDG, and LOL analyses identified the azomethine bridge and phenolic oxygens as key reactive sites. Furthermore, 100 ns MD simulations and MM-PBSA calculations confirmed the structural resilience and high binding stability of the lead compounds within the Human Serum Albumin (HSA, PDB ID: 1N45) cavity, with 3d exhibiting a binding energy of -253.872 kJ/mol. These results position these novel fluorinated hydrazones as promising multi-functional templates for preliminary antioxidant lead development.