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A series of pyrido[2,3- b ]pyrazin-3(4 H )-one based derivatives were designed as inhibitors of aldose reductase (ALR2), the enzyme which plays a key role in the development of diabetes complications as well as in the oxidative stress processes associated with diabetes and other pathologies. Most of the derivatives, having a substituted C2 aromatic group and a N4 acetic acid group on the core structure, were found to be potent and selective aldose reductase inhibitors with submicromolar IC 50 values, and 9c was the most active with IC 50 value 0.009 μM. Particularly, a number of the designed compounds bearing phenolic hydroxyl substituted C2-styryl side chain showed excellent not only in ALR2 inhibition but also in antioxidant, and among these 11i was proved to be the top one with an antioxidant ability even comparable to that of the well-known antioxidant Trolox. Structure-activity relationship and molecular docking studies highlighted the importance of phenolic hydroxyl substituents and vinyl spacer in C2 side chain of the scaffold for the construction of efficient and multifunctional ALR2 inhibitors. [ABSTRACT FROM AUTHOR]

In this study, a series of phenyl β-aldehyde ketones were designed and synthesized as novel dual inhibitors of aldose reductase (ALR2) and α-glucosidase. The results showed substantial inhibition of ALR2 and α-glucosidase by the synthetic compounds and also demonstrated the antioxidant activity of these inhibitors. Among them, compound 5l had the most potent inhibitory effect on both enzymes, with non-competitive inhibition patterns, and was the most effective antioxidant in tests for 2,2-diphenyl-1-picrylhydrazyl radical scavenging and lipid peroxidation suppression. High lipophilicity and negligible cytotoxicity were also observed for this compound. Analysis indicated that the β-aldehyde ketone moiety might play a vital role in the inhibitory effect on the enzymes and that the phenolic hydroxy group was the key structure for intensifying the inhibitory and antioxidant activities. Overall, the results confirmed the successful synthesis of potent ALR2 and α-glucosidase inhibitors with antioxidant activity. [ABSTRACT FROM AUTHOR]

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]

Aldose Reductase (AR, ALR2) is a member of the aldo‐keto reductase superfamily that plays a critical role in diabetic complications. In this work, benzothiazolone was employed as the scaffold, and the C6 position was modified with aryl and heterocyclic groups to design potent inhibitor against ALR2. 2‐(6‐(4‐hydroxystyryl)‐2‐oxobenzothiazol‐3(2H)‐yl)acetic acid (6 c) was identified the most active with IC50 value of 18.8 nM. 2‐(6‐(3,4‐dihydroxyphenyl)‐2‐oxobenzothiazol‐3(2H)‐yl)acetic acid (4 c) and 2‐(6‐(4‐hydroxy‐3‐methoxystyryl)‐2‐oxobenzothiazol‐3(2H)‐yl)acetic acid (6 b) were also strong in the ALR2 inhibition, and even exhibited good antioxidant activity by tests of DPPH radical scavenging and lipid peroxidation suppression. 6 b having C6‐hydroxymethoxystyryl sidechain is suggested as a promising candidate for further structure optimizations. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract A series of quinoxalinone scaffold-based acyl sulfonamides were designed as aldose reductase inhibitors and evaluated for aldose reductase (ALR2)/aldehyde reductase (ALR1) inhibition and antioxidation. Compounds 9b-g containing styryl side chains at C3-side exhibited good ALR2 inhibitory activity and selectivity. Of them, 9g demonstrated the most potent inhibitory activity with an IC 50 value of 0.100 μM, and also exhibited excellent antioxidant activity, even comparable to the typical antioxidant Trolox. Compounds 9 had higher lipid-water partition coefficients relative to the carboxylic acid compounds 8 , indicating that they may have better lipophilicity and membrane permeability. Structure-activity relationship (SAR) studies found that acyl trifluoromethanesulfonamide group at N1 and the C3-dihydroxystyryl side chain were the key structure for improving the aldose reductase inhibitory activity and antioxidant activity. [ABSTRACT FROM AUTHOR]

To enhance aldose reductase (ALR2) inhibition and add antioxidant ability, phenolic hydroxyl was introduced both to the quinoxalinone core and C3 side chain, resulting in a series of derivatives as ALR2 inhibitors. Biological activity tests suggested that most of the derivatives were potent and selective inhibitors with IC 50 values ranging from 0.059 to 6.825 μM, and 2-(3-(4-hydroxystyryl)-7-methoxy-2-oxoquinoxalin-1(2 H )-yl)acetic acid ( 6b ) was the most active. Particularly, it was encouraging to find that some derivatives endowed with obvious antioxidant activity, and among them the phenolic 3,4-dihydroxyl compound 6f with 7-hydroxyl in the quinoxalinone core showed the most potent activity, even comparable with the well-known antioxidant Trolox. Structure-activity relationship and docking studies highlighted the importance of phenolic hydroxyl both in C3 side chain and the core structure for constructing potent ALR2 inhibitors with antioxidant activity. [ABSTRACT FROM AUTHOR]

A series of aldose reductase (ALR2) inhibitors based on pyridothiadiazine were prepared and evaluated for their activities in ALR2 inhibition, DPPH scavenging, and MDA inhibition. Comparison studies were carried out between analogs having either hydroxyl or methoxy groups substituted on the N2-benzyl side chains of the compounds. Most of the hydroxy-substituted compounds were found to be more potent compared to their methoxy-substituted analogs with respect to DPPH inhibition (>93%) and MDA inhibition (>73%). However, ALR2 inhibitory activity was found to be affected by the electron-withdrawing substituent at the C7 position in addition to the effect of the N2-substituted benzyl group. These results provide an array of multifunctional ALR2 inhibitors possessing capacities both for ALR2 inhibition and as antioxidants. [ABSTRACT FROM AUTHOR]

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]

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: 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]

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]

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]

Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant. [Display omitted] • A novel class of benzoxazolone derivatives had significant activities in antioxidant and inhibition of aldose reductase. • Most potent one of them showed the activities in diabetic mice and also in blood glucose normalization. • An alleviation in diabetic nephropathy was confirmed by urinary proteins reduction and kidney hematoxylin-eosin staining. [ABSTRACT FROM AUTHOR]

As rate-limited enzyme of polyol pathway, aldose reductase (ALR2) is one of the key inhibitory targets for alleviating diabetic complications. To reduce the toxic side effects of the inhibitors and to decrease the level of oxidative stress, the inhibitory selectivity towards ALR2 against detoxicating aldehyde reductase (ALR1) and antioxidant activity are included in the design of multifunctional ALR2 inhibitors. Hydroxypyridinone derivatives were designed, synthesized and evaluated their inhibitory behavior and antioxidant activity. Notably, {2-[2-(3,4-dihydroxy-phenyl)-vinyl]-5-hydroxy-4-oxo-4H-pyridin-1-yl}-acetic acid (7l) was the most potent, with IC50 values of 0.789 μM. Moreover, 7l showed excellent selectivity towards ALR2 with selectivity index 25.23, which was much higher than that of eparlestat (17.37), the positive control. More significantly, 7l performed powerful antioxidative action. At a concentration of 1 μM, phenolic compounds 7l scavenged DPPH radical with an inhibitory rate of 41.48%, which was much higher than that of the well-known antioxidant Trolox, at 11.89%. Besides, 7l remarkably suppressed lipid peroxidation with a rate of 88.76% at a concentration of 100 μM. The binding mode derived from molecular docking proved that the derivatives were tightly bound to the activate site, suggesting strongly inhibitory action of derivatives against ALR2. Therefore, these results provided an achievement of multifunctional ALR2 inhibitors capable with potency for both selective ALR2 inhibition and as antioxidants. [ABSTRACT FROM AUTHOR]

Dihydrobenzoxazinone derivatives revealed potent activities of aldose reductase inhibition and antioxidant against diabetic complications. Dihydrobenzoxazinone based design and synthesis produced two series of compounds as aldose reductase (ALR2) inhibitor candidates. In particular, phenolic residues were embodied into the compounds for the combination of strengthening the inhibitory acitvity and antioxidant ability to retard the progression of diabetic complications. Most of the derivatives with styryl side chains exhibited excellent activities on selective ALR2 inhibition with IC 50 values ranging from 0.082 to 0.308 μM, and {8-[2-(4-hydroxy-phenyl)-vinyl]-2-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl}-acetic acid (3a) was the most potent. More significantly, most of dihydrobenzoxazinone compounds revealed not only good inhibitory effect on ALR2, but also showed powerful antioxidant activity. Notably, phenolic compound 3a was even comparable to the well-known antioxidant Trolox, confirming that the C8 p-hydroxystyryl substitution was key structure of lowering oxidative stress. Therefore, these results provided an achievement of multifunctional ALR2 inhibitors possessing capacities for both ALR2 inhibition and as antioxidants. [ABSTRACT FROM AUTHOR]