title: Effect of C7 modifications on benzothiadiazine-1,1-dioxide derivatives on their inhibitory activity and selectivity toward aldose reductase.
abstract: The development and progression of chronic complications in diabetic patients, such as retinopathy, nephropathy, neuropathy, cataracts, and stroke, are related to the activation and/or overexpression of aldose reductase (ALR2), which is a member of the aldo-keto reductase superfamily. A structure-activity relationship study focused on the C7 position of 1,2,4-benzothiadiazine-1,1-dioxide derivatives was pursued in an attempt to discover ALR2 inhibitors with enhanced potency and selectivity. These studies led to a series of new C7-substituted compounds, which were evaluated for their inhibitory activity against ALR2; they exhibited IC(50) values in the range of 2.80-45.13 nM. Two compounds with a C7-dimethylcarbamoyl and a C7-diethylcarbamoyl substituent, respectively, were found to be the most active and presented excellent selectivity for ALR2 over aldehyde reductase (ALR1). The structure-activity relationship analyses and molecular modeling studies presented herein highlight the importance of hydrophobic and bulky groups at the C7 position for inhibitory activity and selectivity toward ALR2.
authors.affiliation: Department of Applied Chemistry, Beijing Institute of Technology, Zhongguancun South Street, 100081 Beijing, China.
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Shagufta
authors.initials: S
authors.lastname: Parveen
authors.forename: Saghir
authors.initials: S
authors.lastname: Hussain
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Yang
authors.forename: Chaojun
authors.initials: C
authors.lastname: Jing
authors.forename: Changjin
authors.initials: C
authors.lastname: Zhu
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001581:Benzothiadiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; C576693:Akr1b1 protein, rat; D000449:Aldehyde Reductase