Design, Synthesis, and In Silico Assessment of Phthalazine Derivatives using DFT, Molecular Docking, and ADMET Analysis

Abstract

A series of phthalazine derivatives was synthesized, starting from 2-(1-oxo-4-phenylphthalazin-2(1H)-yl)acetohydrazide (1), which was efficiently converted into the oxadiazole phthalazine derivative (2) in excellent yield through a reaction with carbon disulfide under reflux. Subsequently, compound (2) served as a key intermediate to prepare a diverse range of new phthalazine derivatives (3–6) by reacting it with various alkyl halides and ethyl chloroacetate. All synthesized compounds were characterized using IR, NMR, and mass spectrometry. In addition, the molecular geometries of compounds (3–6) were optimized using density functional theory (DFT). For the in-silico evaluation, molecular docking studies were conducted against two bacterial target proteins (PDB IDs: 6TLS and 4OD9) for the synthesized derivatives. All ligands exhibited significant binding affinity values, ranging from -6.24 to -7.92 kcal/mol. Finally, drug-likeness and ADME properties were predicted using SwissADME. These findings highlight the newly synthesized phthalazine derivatives as promising antibacterial candidates for further biological investigation.