Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur/Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity

Hlaváč, Matúš; Kovacikova, Lucia; Prnová, Marta Šoltésová; Šramel, Peter; Addová, Gabriela; Májeková, Magdaléna; Hanquet, Gilles; Boháč, Andrej; Štefek, Milan

doi:10.1021/acs.jmedchem.9b01747

Cited by 20 publications

(12 citation statements)

References 42 publications

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“…Thus, it is suggested that these carboxylic pyridinones might readily and totally blockade the activate site catalyzing the reduction of aldose. Notably, an additional hydrogen bond was formed vigorously between the hydroxyl group in C2-styryl side chain of 7l and residue Thr 103 which located in specificity pocket, letting the specificity pocket be closed, which is in line with the recently published docking result of potent inhibitors, cemtirestat O-analog [23]. Thus, it was proved that 7l was much more active than the others.…”

Section: Molecular Dockingsupporting

confidence: 77%

“…Therefore, selective inhibition of ALR2 is desirable in the design of new ARIs. Although ARL2 differential inhibitors were promising to selectively inhibit the reduction of hemiacetal aldose rather than that of toxic aldehyde [19], regarding its significant role in the detoxification of ALR1, selective ALR2 inhibition was still the major topic focused on ARI research [20][21][22][23]. Endowed with potent ALR2 inhibitory activity, compounds with carboxylic acid moiety were mostly developed among synthetic ARIs.…”

Section: Introductionmentioning

confidence: 99%

“…Notably, novel 2-styryl-1H-pyridin-4-ones showed Endowed with potent ALR2 inhibitory activity, compounds with carboxylic acid moiety were mostly developed among synthetic ARIs. (4-Oxo-2-thioxothiazolidin-3-yl) acetic acid [20], rhodanine-3-hippuric acid derivatives [21], 2-phenoxypyrido[3,2-b]pyrazin-3(4H)-one [22] and 2-(3-oxo-2H- [1,2,4]triazino [5,6-b]indol-5(3H)-yl) acetic acid [23] showed high inhibitory efficacy with attractive IC 50 values (23~42 nM), suggesting that the carboxylic group is the key moiety preforming outstanding activity. However, the antioxidant properties of these inhibitors need to be improved.…”

Section: Introductionmentioning

confidence: 99%

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(5-Hydroxy-4-oxo-2-styryl-4H-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase Inhibitors

Chen

Zhang

et al. 2020

Molecules

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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.

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Section: Molecular Dockingsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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(5-Hydroxy-4-oxo-2-styryl-4H-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase Inhibitors

Chen

Zhang

et al. 2020

Molecules

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“…Isatin possess antimicrobial, anti-inflammatory, antitumor, anticonvulsant, anthelmintic, analgesic, antiviral, anti-HIV, and antioxidative actions. Cemtirestat—2-(3-thioxo-2 H -[1,2,4]triazino[5,6-b]indole-5(3 H )-yl)acetic acid [( 2 ) in Figure 1 ]—which can be prepared by a three-step synthesis from isatin [ 6 ] is classified as a highly selective and efficient aldose reductase inhibitor with antioxidant properties [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Oxidative Degradation of High-Molar-Mass Hyaluronan: Effects of Some Indole Derivatives to Hyaluronan Decay

Valachová

Mach

Šoltés

2020

IJMS

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Indole derivatives such as isatin (a natural compound), cemtirestat, stobadine, and its derivatives (synthetic compounds) are known to have numerous positive effects on human health due to regulation of oxidative status. The aim of the study was to assess radical scavenging capacities of these compounds and explore their potential protective effects against reactive oxygen species formed during Cu(II) ions and ascorbate-induced degradation of high-molar-mass hyaluronan. Based on the IC50 values determined by the ABTS assay, the most effective compound was SM1M3EC2·HCl reaching the value ≈ 11 µmol/L. The lowest IC50 value reached in the DPPH assay was reported for cemtirestat ≈ 3 µmol/L. Great potency of inhibition of hyaluronan degradation was shown by cemtirestat, followed by isatin even at low concentration 10 µmol/L. On the other hand, stobadine·2HCl had also a protective effect on hyaluronan degradation, however at greater concentrations compared to cemtirestat or isatin. SME1i-ProC2·HCl reported to be a less effective compound and SM1M3EC2·HCl can be considered almost ineffective compared to stobadine·2HCl. In conclusion, our results showed that both isatin and cemtirestat were capable of attenuating the degradation of high-molar-mass hyaluronan due to their ability to complex/sequester cupric ions.

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“…Considering excellent “lead-likeness” of cemtirestat ( 5a ) [ 76 ], we proceeded with optimization of its thioxotriazinoindole scaffold by replacing sulfur with oxygen, with the aim to improve the inhibitory efficacy and selectivity. Based on preliminary molecular modeling and docking calculations, a series of 2-(3-oxo-2 H -[ 1 , 2 , 4 ]triazino[5,6- b ]indol-5(3 H )-yl)acetic acid derivatives 7a – d was proposed, synthesized and their AR inhibitory efficacy and selectivity determined [ 79 ].…”

Section: Studies At the Level Of Isolated Enzymes And Free Radical Models In Vitro And In Silico: Sarmentioning

confidence: 99%

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

et al. 2021

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Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure–activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of ‘drug-likeness”. Novel promising structures of putative multifunctional ARIs/AOs are designed.

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Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur/Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity

Cited by 20 publications

References 42 publications

(5-Hydroxy-4-oxo-2-styryl-4H-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase Inhibitors

(5-Hydroxy-4-oxo-2-styryl-4H-pyridin-1-yl)-acetic Acid Derivatives as Multifunctional Aldose Reductase Inhibitors

Oxidative Degradation of High-Molar-Mass Hyaluronan: Effects of Some Indole Derivatives to Hyaluronan Decay

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

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