Novel Non-carboxylic Acid Benzothiadiazine1,1-dioxide Derivatives As Aldose Reductase Inhibitors

Diabetes mellitus is a chronic disease that requires long-term medical attention both tolimit the development of its devastating complications and to manage them when they dooccur. Most diabetic patients suffer from so-called long-term complications such asneuropathy, nephropathy, retinopathy and cataracts. Numbers evidence reveals a linkbetween glucose metabolism via the polyol pathway and long-term diabetic complications.As the first enzyme of the polyol metabolic pathway, Aldose reductase (ALR2) catalyzesthe NADPH-dependent reduction of glucose to sorbitol, which was found to be implicatedin the etiology of the long-term diabetic complications. If we can synthesize somecompounds which inhibit ALR2activity, we will have the chance to prevent theaccumulation of sorbitol in vivo. Thus, we can make some drugs for the treatment ofdiabetic complications.As one number of sulfonyl group-containing compounds, benzothiadiazine1,1-dioxidederivatives have been widely studied because of their significant roles in developingtherapeutics for a number of diseases. Most of the carboxylic acids benzothiadiazinederivatives as aldose reductase inhibitors, which have been reported by our previousresearch group, exhibited high inhibitory activity and selectivity in the activity tests.However, most of the typical carboxylic acid ARIs showed potent in vitro activity but theireffectiveness decreased in vivo. Based on the review of the development ofbenzothiadiazine1,1-dioxide derivatives act as therapeutic drugs for diabetes and itscomplications, we synthesized a compound bearing substituent groups at the N4-Phosphateand N2-benzyl substituents in the benzothiadiazine1,1-dioxide structure(58). But the targetcompound can not be obtained, because of its weak stability even under weakly acidic oralkaline conditions.Continue investigations have done in the discovery of a series ofbenzothiadiazine-based nitro derivatives as novel, highly potent and selective ARIs. Amongthem,7-bromo-5-nitro-4H-benzo[e][1,2,4]thiadiazine1,1-dioxide (63a) was the most activecompound with an IC50value of4.6μM. It is noteworthy that the attachment of nitrogroup to the compound7-bromo-4H-benzo[e][1,2,4]thiadiazine1,1-dioxide (55) leading tocompounds63a-b showed significant effect on the inhibitory activity of the ALR2inhibition, and even compound63a was more active than the carboxylic acid compound 2-(7-bromo-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-4-yl)acetic acid (62). However, nitroderivatives of65a-b and67a-b all showed low activity. Compound7a, the most active asdescribed above, was docked into the binding pocket of the humanALR2/NADP+/lidorestat complex (PDB entry code1Z3N). Docking results explained theabove conclusions. Paper for the development of novel aldose reductase inhibitors has laida valuable foundation.