Novel Green Synthesis of Polyfunctionally Substituted Phthalazines Promoted by Visible Light, DFT Studies and Molecular Docking with Antimicrobial and Antibiofilm Potency

Visible-Light-Mediated synthesis is a green and efficient technique which garnered interest from organic chemists. A series of new polyfunctionally substituted phthalazine derivatives 3a-j have synthesized via the reaction of pyridazines 1a-d with arylidenes 2a-d in the presence of a catalytic amount of piperidine in abs. ethanol as a solvent and under white LED lamb irradiation in open air. All synthesized products 3a-j have screened as potential antimicrobial and antibiofilm agents. Both compounds 3g and 3j are the most promising derivatives. Compound 3g displayed outstanding activity against P. aeruginosa and K. pneumoniae with a MIC value of 3.12 and 12.5 µg/mL, respectively. Compound 3j gave a 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.