Novel A New Benzenesulfonylurea-Substituted Pyridazinone Derivative with Antidiabetic Effect as the Peroxisome Proliferator-activated Receptor (PPAR-γ-) Agonismple Abstract Yuni Fatisa, Elvi Yenti, Ihsan Ikhtiaruddin, Neni Frimayanti, Jasril, Arif Yasthophi mple Abstract
Department of Chemistry Education, Faculty of Tarbiyah and Keguruan, Universitas Islam Negeri Sultan Syarif Kasim Riau, Pekanbaru, Indonesia
Department of Chemistry, Faculty Mathematic and Natural Sciences, Universitas Riau
, Pekanbaru, Indonesia
Department of Pharmacy, Sekolah Tinggi Ilmu Farmasi (STIFAR) Riau, Pekanbaru,
Indonesia
Abstract
Peroxisome Proliferator-activated Receptor (PPAR-γ-) protein is one of the target proteins for insulin sensitivity therapy in Type 2 DM patients. PPAR-γ- has a key role as a nuclear receptor that regulates the expression of several genes related to metabolism. This research aims to synthesize a new benzenesulfonylurea-substituted pyridazinone derivative yaitu (E)-N^-(1-(4-(3-(4-methoxyphenyl)-6-oxopyridazin-1(6H)-yl)phenyl)ethylidene)-4-methylbenzenesulfonohydrazide (8) and predicted it activity as the PPAR-γ- agonist using a molecular docking approach and ADMET profile. The new compound 8 was obtained through a Schiff base condensation reaction between compound 6 with p-tosyl hydrazine and a glacial acetic acid catalyst using monowave. The purity of this compound was determined by TLC test, melting point measurement and HPLC. The structure of synthesized compound was confirmed through UV spectroscopy, FTIR, 1H-NMR and HRMS analysis. Molecular docking studies were carried out on the crystal structure of the human PPAR-γ- Ligand Binding Domain target protein in complex with the α--aryloxyphenyl acetic acid agonist (PDB ID 1ZEO). The results of the molecular docking study show that compound 8 has a lower binding free energy than rosiglitazone (positive control) with a free energy value (S score) = -13.513 kcal/mol and -8.3089 kcal/mol, respectively. Compound 8 can form hydrogen bonds with residues His323 and Ser289, π--π- interactions with Phe363 and π--H interactions with Cys285. The interaction of compound 8 is also similar to the interaction between the native ligand agonists α--aryloxyphenyl acetic acid and rosiglitazone with the target protein. Furthermore, compound 8 is predicted to have a moderate ADME profile. The results of this study support that compound 8 can be developed as a PPAR-γ- agonist candidate for antidiabetic therapeutic agent.
