Acetic Acid Derivatives of 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide as a Novel Class of Potent Aldose Reductase Inhibitors

Abstract

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.

Copper‐Catalyzed Trifluoromethylation and Cyclization of Aromatic‐Sulfonyl‐Group‐Tethered Alkenes for the Construction of 1,2‐Benzothiazinane Dioxide Type Compounds

“…(Figure 1). [2] Nowadays, in order to satisfy the need of a daily expanding global market, synthesis of new 1,2-benzothiazinane compounds is in high demanded. [2] Nowadays, in order to satisfy the need of a daily expanding global market, synthesis of new 1,2-benzothiazinane compounds is in high demanded.…”

Antidiabetic potential: In vitro inhibition effects of bromophenol and diarylmethanones derivatives on metabolic enzymes

“…In literature, there are many studies on the inhibition of AR. For example, Chen et al studied acetic acid derivatives of 3,4‐dihydro‐2 H ‐1,2,4‐benzothiadiazine‐1,1‐dioxide inhibiting AR and they determined that their compound 8a showed most selective and potent inhibition. In another study, novel benzofuroxane derivatives showed AR inhibitory and compounds 46a , b in that study displayed promising profiles as ARI among them …”

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

“…Ponalrestat was withdrawn from clinical trials due to lack of efficacy. Besides, a number of potent ARIs were recently designed and synthesized based on various chemical core structures including (benzothiazol-2-yl)methylindole (lidorestat) [36], naphtho [1,2-d]isothiazole [55], oxadiazole [56], aromatic thiadiazine-1,1-dioxide [57,58], and quinoxalinone [59]. All of them bear a chemical group of acetic acid on the core.…”