1,2-Benzothiazine 1,1-dioxide carboxylate derivatives as novel potent inhibitors of aldose reductase.
Due to the importance of aldose reductase (ALR2) as a potential drug target in the treatment of diabetic complications, there are increasing interests in design and synthesis of ALR2 inhibitors. Here, we prepared 1,2-benzothiazine 1,1-dioxide acetic acid derivatives and investigated their inhibition activity. Most of these derivatives were found to be active with IC(50) values ranging from 0.11 μM to 10.42 μM, and compound 8d, 2-[2-(4-bromo-2-fluorobenzyl)-1,1-dioxido-2H-1,2-benzothiazin-4(3H)-ylidene]acetic acid, showed the most potent inhibition activity. Further, SAR and docking studies suggest that in comparison with the α,β-unsaturated derivatives, the saturated carboxylic acid derivatives had a greater binding affinity with the enzyme and thus an enhanced inhibition activity. Therefore, development of more powerful ARIs based on benzothiazine 1,1-dioxide by stereo-controlled synthesis could be expected.
Department of Applied Chemistry, Beijing Institute of Technology, No. 5, Zhongguancun South Street, 100081 Beijing, China.
Xin
X
Chen
Shuzhen
S
Zhang
Yanchun
Y
Yang
Saghir
S
Hussain
Minlan
M
He
Dequan
D
Gui
Bing
B
Ma
Chaojun
C
Jing
Zhixin
Z
Qiao
Changjin
C
Zhu
Qun
Q
Yu
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D013843:Thiazines; D000449:Aldehyde Reductase