title: Synthesis, characterization, hypoglycemic and aldose reductase inhibition activity of arylsulfonylspiro[fluorene-9,5'-imidazolidine]-2',4'-diones.
abstract: A series of 3-arylsulfonylspiroimidazolidine-2,4-diones (2a-g) and their corresponding rearranged products, 1-arylsulfonylspiroimidazolidine-2,4-diones (3a-g) were synthesized and evaluated for antidiabetic and aldose reductase inhibition activity. Three of the compounds (2b, 2c and 3c) were found more potent in-vivo hypoglycemic agents than the commercial drug glibenclamide. The free energy of binding (ΔG) values showed that the compounds are active against aldose reductase and aldehyde reductase enzymes, which was also estimated using molecular mechanics Poisson-Boltzmann surface area method. Of the tested compounds, 2b was found to be the most potent in-vitro selective inhibitor of ALR2 possessing an IC50 value of 0.89 μm. Structure activity relationship and molecular docking revealed the importance of substitution features of aryl group of aryllsulfonylimidazolidine-2,4-dione scaffold. It was observed that the substitution with a halogen at para position of the aryl group had a remarkable effect on ALR2 inhibition potency.
authors.affiliation: Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Zafar
authors.initials: Z
authors.lastname: Iqbal
authors.affiliation: Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan. Electronic address: shameed@qau.edu.pk.
authors.forename: Shahid
authors.initials: S
authors.lastname: Hameed
authors.affiliation: Department of Pharmaceutical Sciences, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
authors.forename: Sher
authors.initials: S
authors.lastname: Ali
authors.affiliation: Department of Pharmaceutical Sciences, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan.
authors.forename: Yildiz
authors.initials: Y
authors.lastname: Tehseen
authors.affiliation: Fraunhofer Institute SCAI, Department of Bioinformatics, Sankt Augustin, Germany.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahid
authors.affiliation: Department of Pharmaceutical Sciences, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan. Electronic address: drjamshed@ciit.edu.pk.
authors.forename: Jamshed
authors.initials: J
authors.lastname: Iqbal
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D048289:Imidazolidines; D000449:Aldehyde Reductase
keywords: Aldose reductase inhibition; Anti-diabetic; Imidazolidine-2,4-dione; Sulfonylurea