Design, Synthesis and Biopharmacological Evaluation of Heterocyclic Compounds as Aldose Reductase Inhibitors

The aim of my PhD work was to design, synthesize and test novel heterocyclic compounds able to inhibit the enzyme aldose reductase. Experimental and clinical evidence demonstrate that the pathogenic mechanism leading to diabetic complications is causally linked to an increased activity of the enzyme Aldose Reductase (alditol:NADP+ oxidoreductase, EC1.1.1.21, ALR2). ALR2 catalyzes the reduction of glucose to sorbitol in the so called polyol pathway, a metabolic pathway that becomes activated during diabetic conditions. Sorbitol is formed more rapidly than it is converted to fructose, so it accumulates increasing cellular osmolarity. Moreover, the activation of the polyol pathway causes an imbalance in cytosolic cofactor ratios contributing to the onset of hyperglycemic oxidative stress. Osmotic stress, together with oxidative stress, triggers the activation of downstream mechanisms leading to the development of long-term diabetic complications, represented by a progressive impairment of nervous, renal, vascular and visual systems. Inhibition of ALR2 is therefore a useful therapeutic strategy to prevent the onset, or at least delay, the progression and the severity of diabetic complications. I focused my research interest in the ALR2 inhibitors field with the aim to disclose novel drug candidate for the topical treatment of diabetic visual impairments, which are the leading cause of blindness in people aged from 20 to 75.