Efficient Synthesis using One-Pot Method and In Silico Analysis of Pyridazinone Derivatives as Inhibitor for Aldose Reductase Enzymes

This research aims to synthesize a series of pyridazinone derivatives (4a-4d, 5, 6a-6d), investigate their activities against the aldose reductase enzyme, and analyze their pharmacology profiles. Substituted-acetophenone were reacted with glyoxylic acid and hydrazine through a one-pot process using a heating reactor to obtain compounds 4a - 4d. Meanwhile, compounds 5 and 6a - 6d using a stirring technique, were synthesized combining compound 4d with p-chloro benzene sulphonic acid for compound 5 and combining compounds 4a - 4d with ethyl chloro acetate to produce compounds 6a - 6d. The MOE 2021.010 software package was taken to perform the molecular docking analysis. The ADMET profiles were performed using online pre-ADME and ProTox II. In this research, 9 pyridazinone derivatives (4a-4d, 5, and 6a-6d) were synthesized. Three of them are new compounds, namely 6a, 6b, and 5. The docking results predicted that compound 5 exhibits the best inhibition against the aldose reductase with a binding free energy value of 12.61 kcal/mol. The tolrestat as positive control has binding free energy values of 14.13 kcal/mol. Compound 5 binds with essential residues at the active site, which builds 5 hydrogen bonds with His110, Tyr48, Cys298, and Asn160 and 3 hydrophobic interactions with His110, Trp111, and Tyr209. The ADMET result provides information about the pharmacotherapy potential of all molecules. But for compound 5, structure modification is needed to improve its safety, especially to remove its hepatoxicity. This information could support that compound 5 can be considered as a reference for further drug design development to be a potential agent for aldose reductase enzymes inhibitor. HIGHLIGHTS The research demonstrates an efficient synthesis of Pyridazinone Derivatives using a one-pot reactor method. The compound structures were confirmed by IR, H-NMR, and MS spectrophotometers. The molecular docking results confirm that new compound 5 exhibits the best inhibition against the aldose reductase with a binding free energy value of −12.61 kcal/mol. Based on Lipinski’s rule of five and ADMET profiles, pyridazinone derivatives (5 and 6a-6d) have exhibited safe properties as drug candidates. GRAPHICAL ABSTRACT