Pyridine-pyrimidine-based azo-aroylhydrazones with enhanced antioxidant potential: Experimental and computational evaluation
Journal of Molecular Structure, vol.1364, 2026 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 1364
- Publication Date: 2026
- Doi Number: 10.1016/j.molstruc.2026.145897
- Journal Name: Journal of Molecular Structure
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Chimica, Compendex, INSPEC, Academic Search Ultimate (EBSCO), Engineering Source (EBSCO)
- Keywords: Antioxidant candidates, Azo-aroylhydrazone derivatives, CUPRAC assay, MD simulation, Pyridine-pyrimidine hybrids, Structure-activity relationship
- Isparta University of Applied Sciences Affiliated: Yes
Abstract
Nine novel azo-aroylhydrazone derivatives were synthesized from a carboxylic acid precursor structurally related to nilotinib, integrating pyridine and pyrimidine heterocycles within their frameworks. The compounds were characterized by FT-IR, NMR, and mass spectrometry. The configuration of compound 4b was elucidated using 2D NMR techniques, confirming an E-geometry in DMSO‑d6 solution. The antioxidant potential of the synthesized compounds was evaluated through in vitro CUPRAC and DPPH assays, complemented by in silico molecular docking simulations. In the CUPRAC assay, seven derivatives exhibited superior antioxidant capacity compared to the reference Trolox, with compound 4i demonstrating the highest activity (TEAC = 1.24). Conversely, none of the compounds showed significant radical scavenging activity in the DPPH assay, suggesting a mechanism-specific antioxidant profile for this series. Molecular docking and MM/PBSA analyses indicated that 4i forms the most stable complex with the 2C9V protein, further supported by 100 ns MD simulations. DFT calculations at the B3LYP/6–311++G(d,p) level revealed that 4i has the lowest HOMO-LUMO gap (ΔE = 3.313 eV) and highest softness, consistent with its strong electron-transfer ability and enhanced radical scavenging. Taken together, these findings reveal that compound 4i, with its optimal electronic structure and strong radical-scavenging efficiency, represents a promising lead molecule for the development of bioactive antioxidant agents.