Novel green synthesis of polyfunctionally substituted phthalazines promoted by visible light, DFT studies and...

Visible-Light-Mediated synthesis is a green and efficient technique that has garnered interest from organic chemists. A new series of polyfunctionally substituted phthalazine derivatives 3a-j were synthesized via a metal-free reaction of pyridazines 1a-d with arylidenes 2a-d in the presence of a catalytic amount of piperidine, in absolute ethanol as a solvent, under white LED lamp irradiation at room temperature using open air as oxidant, in 90-93% yields. A radical mechanism via single-electron transfer (SET) was confirmed using a radical scavenger. All synthesized products 3a-j were screened as potential antimicrobial and antibiofilm agents. Both compounds 3g and 3j are the most promising derivatives. Compound 3g displayed outstanding activity against Pseudomonas aeruginosa and Klebsiella pneumoniae with a MIC value of 3.12 and 12.5 µg/mL, respectively. Compound 3j gave a Minimum Inhibitory Concentration (MIC) value of 6.25 µg/mL for P. aeruginosa. As prospective antibiofilm agents against P. aeruginosa, compounds 3g and 3j exhibited inhibition with 81% and 75%, respectively. The geometrical structures were optimized using Density Functional Theory (DFT), frontier molecular orbitals (HOMO-LUMO), along with global reactivity descriptors, such as chemical potential, electronegativity and electrophilicity, were computed to assess the compounds' chemical reactivity and stability. Spectral characteristics were interpreted to support the theoretical findings, while Molecular Electrostatic Potential (MEP) mapping was employed to visualize charge distribution and potential reactive sites. Furthermore, topological analyses, including Electron Localization Function (ELF) and Reduced Density Gradient/Non-Covalent Interaction (RDG/NCI) analysis, offered insights into intra- and intermolecular interactions and the nature of non-covalent bonding. Molecular docking simulations were performed and revealed favorable binding affinities and key interactions within the active sites, indicating potential antimicrobial and enzyme-inhibitory properties, especially with 3j-3LD6 with binding energy of - 9.5 kcal/mol.