Phthalazine ring incorporated 3-methyl-2,6-diarylpiperidin-4-one based hybrids: Synthesis, Spectral characterization, DFT studies, Molecular docking, In silico ADME predictions and Antibacterial activity

Abstract

Phthalazine ring bearing piperidin-4-one based hydrazone derivatives 2(a-e) were synthesized by incorporating a biologically active phthalazine ring into the piperidin-4-one moeity through hydrazone formation. The structure of the compounds 2(a-e) were identified by FT-IR, ¹H NMR, ¹³C NMR, HSQC and HRMS-ESI spectral studies which furnished the clear evidence of the expected structures. From the NMR analysis, it was evident that the piperidin-4-one ring possesses a chair conformation, and all the compounds display an (E)-configuration around the C=N bond. DFT calculations for compound 2b, using a 6-311++G(d,p) basis set, provided insights into the electronic properties of the compounds. Hydrazone ligands were docked with the bacterial protein (PDB ID: 4HLC) through Autodock 4.0. All the ligands demonstrate significant binding energy values between -6.15 and -7.79 kcal/mol. ADME studies reveals the favorable pharmacokinetic profiles of the compounds. The antibacterial activity of the synthesized compounds 2(a-e) was evaluated using the agar well diffusion method, where the inhibitory zone was measured to assess their antibacterial properties. Compounds with bromo and methyl substitutions (2c and 2d) show outstanding inhibition against the pathogens used.