Synthesis of Some New Arylsufony(spiroimidazolidine)diones as potential drug candidates for treatment of diabetes and diabetic complications

Abstract

Diabetes mellitus, more simply called diabetes, is a chronic disorder that occurs when there are raised levels of glucose in the blood stream. With diabetes, a body either does not make enough insulin or can not effectively use the insulin it does make. If hyperglycemia is left untreated over the long period, it can lead to life threatening health complications such as cardiovascular disease, neuropathy, nephropathy and eye disease leading to retinopathy and blindness. Excessive level of glucose may also disrupt the electron transport chain, leading to over production of superoxide anion radicals, known as principle source of oxidative stress. In present study, some novel arylsulfonyl[spiroimidazolidine]diones were synthesized that can be effective in the management of diabetes and diabetes complications as a single medicent. Cyclic ketones of varying structures were transformed to spiroimidazoidine-2ʹ,4ʹdiones using modified Bucherer-Burg reaction, followed by condensation with different aylsulfonyl chlorides leading to 3ʹ-arylsulfonylspiroimidazoidine-2ʹ,4ʹ-diones. Finally, these 3ʹ-arylsulfonylspiroimidazoidine-2ʹ,4ʹ-diones were rearranged to their corresponding 1ʹ-arylsulfonylspiroimidazoidine-2ʹ,4ʹ-diones derivatives. Spiroimidazolidine-2ʹ,4ʹ-diones substituted with arylsulfonyl group at different positions are the molecules having all the minimum requirements for enhanced hypoglycemic activity and aldose reductase inhibition. After successful synthesis, target compounds were evaluated for their potential to release insulin directly from beta cells (MIN6 cell) at non-toxic concentration as determined by microculture tetrazolium (MTT) assay on mouse insulinoma 6 (MIN6) and human embryonic kidney 293 (HEK293) cell lines. Some of the compounds exhibited high potency when compared with standard drug, tolbutamide or gliclazide. Some compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications. The results were further validated by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy