Synthesis, Structural Elucidation and in Silico Evaluation of Two Novel Pyridine Derivatives - DFT, ADMET and Docking Studies

Abstract

Pyridine and its derivatives are pervasive and present in a comprehensive range of natural organic compounds, serving as fundamental structural motifs in biological active entities such as vitamins, alkaloids, nucleotides, and coenzymes essential for metabolism. Owing to the relevance, two novel pyridine derivatives are synthesized through condensation reactions. Their structures are elucidated using (NMR) (¹H and C¹³) and (FTIR) spectroscopy, and validated through single crystal X-ray diffraction. Assessment of the intermolecular interaction revealed that presence of N–H⋯N and C–H⋯O type of hydrogen bonds. DFT calculations showed HOMO–LUMO energy gap for compound A and B respectively to be 3.772 eV and 4.051 eV. The higher energy gap of compound B is due to the presence of amide linkage in contrast with the compound A wherein ester linkage. Time-dependent DFT calculations showed electronic transitions with absorptions at 297.07 nm and 329.26 nm respectively in compound A and B that are in excellent agreement with experimental UV-Visible spectra that peaks at 293.60 nm and 312.79 nm respectively. Further, NBO analysis revealed that major hyperconjugation across the pyridine rings and heteroatom linkages aligns with the hydrogen bonding contacts confirming that electronic delocalization’s reinforces intra and intermolecular bonding and stabilizes the framework. Molecular docking and ADMET analysis are carried out to provide preliminary theoretical insights into binding feasibility and pharmacokinetics tendencies toward vascular endothelial growth factor recptor-2 PDB ID:3WZE with docking scores of –8.1 kcal/mol and –7.7 kcal/mol. Collectively, the integration of experimental and computational approaches demonstrates their structural stability, electronic features, and biological relevance, rendering them as rational foundation for future derivative optimization and experimental validation.