Synthesis, Hypoglycemic, Anti-inflammatory Activity Screening of Novel Substituted 5-[morpholino(phenyl)methyl]-thiazolidine-2,4-diones and Their Molecular Docking Studies

INTRODUCTION: Synthesis of novel substituted 5-[morpholino(phenyl)methyl]-thiazolidine-2,4-diones and screening for their in vivo hypoglycaemic activity and in vitro anti-inflammatory activity. Molecular docking studies to find out active potential lead molecules.
METHODS: Substituted aromatic aldehydes, thiazolidine-2,4-dione and morpholine on mannich reaction gives title compounds. Characterized by physical and spectral methods. In vivo hypoglycemic activity was carried out on Alloxan induced Wister albino rats by tail tipping method. In vitro anti-inflammatory activity was performed by Human Red Blood Cell (HRBC) membrane stabilization and protein denaturation methods. Using AutoDock, molecular docking studies were carried out to find out best fit ligands.
RESULTS: Series of substituted 5-[morpholino(phenyl)methyl]-thiazolidine-2,4-diones were synthesized and chemically they were confirmed by spectral techniques. Acute toxic studies of in vivo hypoglycemic activity results revealed that compounds 4c, 4h, and 4n exhibited good activity at 35 mg/kg body weight. Chronic toxic study results indicate that compound 4h and 4n exhibited good activity at 70 mg/kg body weight. Anti-inflammatory activity results indicate highest inhibition was shown by the compounds 4k and 4f at 500 µg/ml in HRBC membrane stabilization method. In protein denaturation, highest inhibition was shown by compound 4k at 500 µg/ml. In molecular docking studies, compounds 4h and 4n exhibited higher binding affinity at PPARγ receptor protein and compound 4k exhibited higher binding affinity at COX-1 and COX-2 actives sites.
DISCUSSION AND CONCLUSION: Microwave irradiation technique produced high yield at low reaction times. Presence of electron releasing group at para position of the phenyl ring may have ability to produce hypoglycaemic activity and presence of electron withdrawing groups at para position of phenyl ring possess anti-inflammatory activity. The results showed that some compounds exhibited good hypoglycaemic and anti-inflammatory activities. Compounds 4h and 4n exhibited higher binding affinity at PPARγ receptor protein and compound 4k exhibited higher binding affinity at COX isoenzymes active sites in molecular docking studies.