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A novel series of (1,2-benzothiazin-4-yl)acetic acid enantiomers was prepared by chiral resolution, and their absolute configurations were determined using the PGME method. The biological evaluation of the racemate and single enantiomers has shown a remarkable difference for the aldose reductase inhibitory activity and selectivity. The (R)-(−)-enantiomer exhibited the strongest aldose reductase activity with an IC50value of 0.120 μM, which was 35 times more active than the S-(+)-enantiomer. Thus, the stereocenter at the C4 position of this scaffold was shown to have a major impact on the activity and selectivity. [ABSTRACT FROM AUTHOR]

Abstract: Novel quinoxalinone derivatives were synthesized and tested for their inhibitory activity against aldose reductase. Among them, N1-acetate derivatives had significant activity in a range of IC50 values from low micromolar to submicromolar, and compound 15a bearing a C3-phenethyl side chain was identified as the most potent inhibitor with an IC50 value of 0.143 μM. The structure–activity studies suggested that both C3-phenethyl and C6-NO2 groups play an important role in enhancing the activity and selectivity of the quinoxalinone based inhibitors. [Copyright &y& Elsevier]

A copper catalyst system for the asymmetric 1,4-hydrosilylation of the α,β-unsaturated carboxylate class was developed by which synthesis of (+)- and (-)-enantiomers of 1,2-benzothiazine-1,1-dioxide acetates has been achieved with a good yield and an excellent level of enantioselectivity. A comparative structure-activity relationship study yielded the following order of aldose reductase inhibition activity: (-)-enantiomers > racemic > (+)-enantiomers. Further, a molecular docking study suggested that the (-)-enantiomer had significant binding affinity and thus increased inhibition activity. [ABSTRACT FROM AUTHOR]

Abstract: A novel, non-acid series of nitroquinoxalinone derivatives was synthesized and tested for their inhibitory activity against aldose reductase as targeting enzyme. All active compounds displayed an 8-nitro group, and showed significant activity in IC50 values ranging from 1.54 to 18.17μM. Among them 6,7-dichloro-5,8-dinitro-3-phenoxyquinoxalin-2(1H)-one (7e), exhibited the strongest aldose reductase activity with an IC50 value of 1.54μM and a good SAR (structure–activity relationship) profile. [Copyright &y& Elsevier]

Quinoxalin-2(1H)-one based design and synthesisproduced several series of aldose reductase (ALR2) inhibitor candidates.In particular, phenolic structure was installed in the compounds forthe combination of antioxidant activity and strengthening the abilityto fight against diabetic complications. Most of the series 6showed potent and selective effects on ALR2 inhibition withIC50values in the range of 0.032–0.468 μM,and 2-(3-(2,4-dihydroxyphenyl)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (6e) was the most active.More significantly, most of the series 8revealed notonly good activity in the ALR2 inhibition but also potent antioxidantactivity, and 2-(3-(3-methoxy-4-hydroxystyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid (8d) was even as strong asthe well-known antioxidant Trolox at a concentration of 100 μM,verifying the C3 p-hydroxystyryl side chain as thekey structure for alleviating oxidative stress. These results thereforesuggest an achievement of multifunctional ALR2 inhibitors having bothpotency for ALR2 inhibition and as antioxidants. [ABSTRACT FROM AUTHOR]

Abstract: Due to the importance of aldose reductase (ALR2) as a potential drug target in the treatment of diabetic complications, there are increasing interests in design and synthesis of ALR2 inhibitors. Here, we prepared 1,2-benzothiazine 1,1-dioxide acetic acid derivatives and investigated their inhibition activity. Most of these derivatives were found to be active with IC50 values ranging from 0.11μM to 10.42μM, and compound 8d, 2-[2-(4-bromo-2-fluorobenzyl)-1,1-dioxido-2H-1,2-benzothiazin-4(3H)-ylidene]acetic acid, showed the most potent inhibition activity. Further, SAR and docking studies suggest that in comparison with the α,β-unsaturated derivatives, the saturated carboxylic acid derivatives had a greater binding affinity with the enzyme and thus an enhanced inhibition activity. Therefore, development of more powerful ARIs based on benzothiazine 1,1-dioxide by stereo-controlled synthesis could be expected. [Copyright &y& Elsevier]

Abstract: A series of pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide acetic acid derivatives were synthesized and tested for their inhibitory activity against aldose reductase (ALR2). These derivatives were found to be potent aldose reductase inhibitors with IC50 values ranging from 0.038μM to 11.29μM. Most but not all of them showed a strong ALR2 inhibition activity and significant selectivity, which were further supported by docking studies. Of these inhibitors, compound 7d exhibited highest inhibition activity. Structure–activity relationship studies indicate the requirement of N2-benzyl group with electron-withdrawing substituents and N4-acetic acid group in the pyridothiadiazine scaffold. [Copyright &y& Elsevier]