Acetic acid derivatives of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide as a novel class of potent aldose reductase inhibitors.
A series of novel benzothiadiazine 1,1-dioxide derivatives were synthesized and tested for their inhibitory activity against aldose reductase. Of these derivatives, 17 compounds, having a substituted N2-benzyl group and a N4-acetic acid group on the benzothiadiazine, were found to be potent and selective aldose reductase inhibitors in vitro with IC50 values ranging from 0.032 to 0.975 μM. 9m proved to be the most active in vitro. The eight top-scoring compounds coming from the in vitro test for ALR2 inhibition activity were then tested in vivo, whereby three derivatives, 9i, 9j, and 9m, demonstrated a significantly preventive effect on sorbitol accumulation in the sciatic nerve in the 5-day streptozotocin-induced diabetic rats in vivo. Structure-activity relationship and molecular docking studies highlighted the importance of substitution features of N4-acetic acid group and halogen-substituted N2-benzyl group in the benzothiadiazine scaffold and indicated that substitution with hallogen at C-7 had a remarkably strong effect on ALR2 inhibition potency.
Department of Applied Chemistry, School of Chemical Engineering and Environment, Beijing Institute of Technology, Zhongguancun South Street, 100081 Beijing, China.
Xin
X
Chen
Changjin
C
Zhu
Fan
F
Guo
Xiaowei
X
Qiu
Yanchun
Y
Yang
Shuzhen
S
Zhang
Minlan
M
He
Shagufta
S
Parveen
Chaojun
C
Jing
Yan
Y
Li
Bing
B
Ma
D019342:Acetic Acid / Q000737:chemistry*; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001581:Benzothiadiazines / Q000737:chemistry / Q000494:pharmacology*; D003499:Cyclic S-Oxides / Q000737:chemistry / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship
C587795:(2-(2,4,5-trifluorobenzyl)-7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide-4-yl)acetic acid; C587793:(2-(2,4,5-trifluorobenzyl)-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide-4-yl)acetic acid; C587794:(2-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide-4-yl)acetic acid; D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; D000449:Aldehyde Reductase; D019342:Acetic Acid