Picolinic acid derived hydrazone-Schiff bases as potent thymidine phosphorylase inhibitors

Abstract

Hydrazone-Schiff base derivatives are promising thymidine phosphorylase (TP) inhibitors because of their multipurpose structural framework that enables robust interactions with the active site of enzyme and effective modulation of its activity. The present study reports the synthesis, characterization and in vitro thymidine phosphorylase inhibitory activity, where the compounds showed excellent to moderate inhibitory activity. Compound 9 (IC ₅₀  = 5.4 ± 0.1 µM) was found as the most potent inhibitor better than the standard 7-deazaxanthine. Structure activity relationship (SAR) investigation exposed that the position as well as nature of the attached groups significantly altered the inhibitory potential. Molecular docking against TP (PDB: 1UOU) yielded binding energies (BE) ranging from −6.478 to −11.961 kcal/mol, with compound 9 showing the most favorable BE (−11.961 kcal/mol). DFT calculations provided global reactivity indices, compound 11 displayed the highest electrophilicity (5.921 eV) and charge transfer capacity (Δ N  = 2.476), while 9 exhibited an optimal balance of hardness (2.435 eV) and electrophilicity (3.788 eV). Reduced density gradient (RDG) analysis visualized the non-covalent interaction landscapes, where the depth of the attractive spike (sign( λ ₂ )ρ) directly correlated with BE and IC ₅₀ . The integrated computational–experimental approach establishes a clear electronic and topological basis for TP inhibition. These findings position the picolinic acid hydrazone-Schiff base scaffold as a promising template for developing next-generation anti-angiogenic agents, with compound 9 as a lead for further optimization.