Abstract

SYNTHESIS, AND COMPUTATIONAL INVESTIGATION OF A 3,4- DIHYDROPYRIMIDINE-2(1H)-ONE DERIVATIVE: DFT, ADME, AND MOLECULAR DOCKING STUDIES

*Rajendra K. Pawar

Abstract

A 3,4-dihydropyrimidine-2(1H)-one derivative was synthesized via a one-pot condensation reaction involving 4-nitrobenzaldehyde, urea, and ethyl acetoacetate, with sulfamic acid serving as a mild and ecofriendly catalyst in ethanol. The structure was confirmed by FT-IR, 1H and 13C NMR spectroscopy. Density Functional Theory (DFT) calculations at the B3LYP/6-311++G(d,p) level provided optimized geometries, bond lengths, bond angles, revealing a partially planar, conjugated framework stabilized by resonance across the pyrimidine, ester, and nitrophenyl moieties. Frontier molecular orbital analysis showed a HOMO–LUMO gap of 4.09 eV, suggesting moderate chemical reactivity. Molecular electrostatic potential (MEP) mapping identified regions of high electron density around electronegative atoms and electron-deficient zones over hydrogen atoms, providing insight into possible reactive sites and non-covalent interactions. In silico ADME evaluation predicted favorable pharmacokinetic and drug-likeness properties, including good solubility, high gastrointestinal absorption, and compliance with Lipinski’s rule of five. Molecular docking revealed stable interactions with sterol 14-α demethylase (CYP51) and E. coli DNA gyrase B. Key interactions with CYP51 included a conventional hydrogen bond with TYR132, a carbon–hydrogen bond with ILE304, a π–donor hydrogen bond with TYR118, hydrophobic and π–alkyl interactions with PHE228 and HIS310, and a π–alkyl interaction with the heme group (HEM601). Docking with DNA gyrase B showed π–cation interactions with ARG76, π–anion interactions with GLU50, and hydrophobic contacts with ILE78 and ILE94. These interactions suggest the compound’s potential antifungal and antibacterial activity, highlighting it as a promising scaffold for further medicinal chemistry exploration.

Keywords: 3,4-Dihydropyrimidine-2(1H)-one, DFT, FMO’s, Molecular Docking, ADME.