• Novel multifunctional agents targeting long-term d

My thesis work focuses on design, synthesis and biological evaluation of 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 (EC1.1.1.21, ALR2). ALR2 catalyzes the reduction of glucose to sorbitol in the presence of NADPH as cofactor 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 and oxidative stress trigger 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.
As a part of a long lasting program dedicated to the development of novel heterocyclic compounds endowed with ALR2 inhibitory activity, a number of derivatives with a benzofurazan nucleus were developed as potential active compounds, on the basis of preliminary data obtained from a virtual screening study.
The target inhibitors were synthesized from commercially available derivatives and two series were developed. Within the two series, different substituents were introduced in various positions around the central core, in order to verify the influence of electron-withdrawal, electron-release and orientation on the inhibitory potency of these molecules.
The effectiveness of all the synthesized compounds were extensively evaluated through in vitro tests, performed to assess both their inhibitory activity toward ALR2 and their selectivity with respect to aldehyde reductase (EC1.1.1.2, ALR1), an enzyme closely related to ALR2. Moreover, additional assays were performed to point out possible anti-oxidant and NO-donor properties of the novel compounds.