Chemoselective Synthesis, DFT Analysis, Molecular Docking, and ADMET Profiling of Ethyl 2-(2-Phenylhydrazinyl) cyclopent-1-ene-1-carboxylate

Abstract

The integration of experimental synthesis with computational approaches provides a valuable strategy for investigating the structural, electronic, and biological interaction properties of organic compounds. In the present study, ethyl 2-(2-phenylhydrazinyl) cyclopent-1-ene-1-carboxylate (1) was synthesized through the chemoselective condensation of ethyl 2-oxocyclopentane-1-carboxylate with phenylhydrazine in ethanol. The reaction afforded the target compound as an off-white solid in 19% isolated yield, with preferential reaction at the ketone functionality while preserving the ester group.
Density functional theory (DFT) calculations were performed at the B3LYP/6-31G level to investigate molecular geometry, electronic structure, and global reactivity descriptors. The optimized structure exhibited no imaginary vibrational frequencies, with a calculated HOMO–LUMO energy gap of 4.5135 eV and a dipole moment of 2.8675 Debye. Molecular electrostatic potential mapping further identified electron-rich and electron-deficient regions potentially involved in intermolecular interactions.
Molecular docking simulations using MOE 2024 were conducted against three bacterial proteins: Escherichia coli DNA gyrase B (6KZV), Staphylococcus aureus penicillin-binding protein 4 (5TW8), and Bacillus subtilis CotA laccase (1OF0). Compound 1 exhibited docking scores of −6.955, −5.839, and −5.081 kcal/mol, respectively, indicating predicted binding interactions within the investigated protein pockets. In silico ADMET assessment revealed favorable physicochemical properties and compliance with established drug-likeness criteria. However, predicted cytochrome P450 inhibition and potential organ-specific toxicity highlighted important pharmacokinetic and safety concerns.
Overall, the findings provide a preliminary characterization of the synthesized compound and identify its potential for further structure-based investigation. Experimental biological evaluation, mechanistic studies, and toxicity assessment are required before any therapeutic relevance can be established.