Design And Synthesis Of Potent And Multifunctional Aldose Reductase Inhibitors Based On Quinoxalinones

Diabetes mellitus is a commonly chronic disease caused by insulin deficiency or by insulin resistance in bodies. In this disease the abnormally high levels of blood glucose trigger the abnormally enhanced polyol pathway and mostly then cause so-called long-term complications such as neuropathy, nephropathy, retinopathy, cataracts, and stroke by damaging blood vessels and peripheral nerves. Therefore, how to develop effective treatment for diabetic complications has become one of the main challenges in the international medical community today. A great many of studies show that the polyol pathway-linked accumulation of sorbitol and series of oxidative stress are leading causes of diabetic complications. ALR2 inhibitors(ARIs) restrain the abnormal accumulation of sorbitol and may indirectly inhibit oxidative stress, so they have potential for the therapeutic drugs of diabetic complications. It is not enough to prevent and treat pathological changes in different tissues only by inhibiting the accumulation of sorbitol with ARIs, and it will be a feasible strategy to suppress directly oxidative stress and simultaneously inhibit the accumulation of sorbitol, and also the key to research and development of drugs for treating diabetic complications. Therefore, in this study, both the inhibition of aldose reductase and directly antioxidation are planned to be combined into an organic whole, and the resulting multifunctionality will be greatly potential to make it developed into the effective drug for diabetic complications.Quinoxaline and quinoxaline derivatives have attracted considerable attention because they are born with a wide range of properties from dyes to reagents in organic synthesis, electrochemical materials, and pharmaceuticals, especially as ARIs. Based on the review of the development of quinoxaline compounds as therapeutic drugs for diabetes complications and quinoxalin-2(1H)-one as core structure, design and synthesis by the modifications of the C3 side chain and substitutions on the phenyl ring of the quinoxaline core structure produced several series of compounds during the course of development of more efficient ALIs. In particular, phenolic structure was introduced to the designed compounds for the combination of antioxidant activity with the aldose reductase(ALR2) inhibition and in turn for enhancing the ability of the inhibitors for treating diabetes complications. The synthetized compounds were evaluated by the inhibitory effect on ALR2 as well as aldehyde reductase(ALR1) having primary and secondary structures homological to that of ALR2, and also by antioxidant activity by tests of DPPH radical scavenging and suppressing lipid peroxidation. Most of the synthetic series 39a-g containing the C3 side chain of 2,4-dihydroxyphenyl showed potent and selective effect on the ALR2 inhibition with IC50 values in the range of 0.032- 0.468 μM, and 2-(3-(2,4-dihydroxyphenyl)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid(39b) was the most active, but they had low antioxidant activity although two phenolic hydroxyl groups were involved in the compounds. However, most of the series 41 containing the C3 side chain of para-hydroxystyryl revealed not only good activity in the ALR2 inhibition but also potent antioxidant activity in the tests of the DPPH radical scavenging and suppressing lipid peroxidation, and 2-(3-(3-methoxy-4-hydroxystyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid 41 d was even as strong as the well-known antioxidant Trolox at the concentration of 100 μM in the tests of antioxidant potency. This verifies the significant efficiency of cleaning up oxidative stress with the series, and then suggests success in the development of multifunctional ARIs having potencies of the ALR2 inhibition and antioxidant. Further SAR analysis concludes that the introduction of ortho-hydroxyl to the para-hydroxyphenyl C3 side chain in 37 f greatly prompted the inhibitory activity(39a) against ALR2, and particularly the insertion of the vinyl spacer into the C3 side chain of 37 f more greatly enhanced the inhibitory activity but also achieved the installation of strong antioxidant function(41a). As a result, the C3 para-hydroxystyryl side chain was specified as the key structure to the quinoxaline compounds 41a-b and 41 d, which could represent significant leads for the discovery of multifunctional ALR2 inhibitors. Molecular docking was used to analyse and demonstrate the design of ARIs. Docking results revealed the binding mode between compounds and ALR2, which is helpful for explaining the excellent activity and selectivity of target compouds.