“…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.…”
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.
“…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.…”
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.
“…Molecules that is; s1 (R 1 = propyl, R 2 = CH 3 ) and s2 (R 1 = isobutyl, R 2 = CH 3 ) are the most potent compounds of the series with IC 50 = 41 and 73 nM. When H is substituted at R 1 and R 2 positions, as in the case of compound s3 ALR 2 activity decreases IC 50 = 490 nM [ 84 ] (Figure 1). …”
Heterocyclic scaffolds of natural as well as synthetic origin provide almost all categories of drugs exhibiting a wide range of pharmacological activities, such as antibiotics, antidiabetic and anticancer agents, and so on. Under normal homeostasis, aldose reductase 2 (ALR2) regulates vital metabolic functions; however, in pathological conditions like diabetes, ALR2 is unable to function and leads to secondary diabetic complications. ALR2 inhibitors are a novel target for the treatment of retinopathy (cataract) influenced by diabetes. Epalrestat (stat), an ALR2 inhibitor, is the only drug candidate that was approved in the last four decades; the other drugs from the stat class were retracted after clinical trial studies due to untoward iatrogenic effects. The present study summarizes the recent development (2014 and onwards) of this pharmacologically active ALR2 heterocyclic scaffold and illustrates the rationale behind the design, structure-activity relationships, and biological studies performed on these molecules. The aim of the current review is to pave a straight path for medicinal chemists and chemical biologists, and, in general, to the drug discovery scientists to facilitate the synthesis and development of novel ALR2 inhibitors that may serve as lead molecules for the treatment of diseases related to the ALR2 enzyme.diabetic-related complications (cataract), novel heterocyclic scaffolds, structure-activity relationship studies, synthetic aldose reductase 2 inhibitors
| INTRODUCTIONDiabetes mellitus (DM) is an autoimmune metabolic disorder mainly characterized by hyperglycemia which occurs due to impairment in normal blood glucose homeostasis. In DM, there is either no secretion of insulin by the islet of pancreatic β cells or diminished response to glucose by secreted insulin in the body. [1] Diabetes is of two types that is, insulin-dependent diabetes mellitus and insulin-independent diabetes mellitus also termed type 1 and type 2 DM, respectively. Pathophysiological conditions that induce DM include autoimmune imbalance, hormonal as well as the sedentary lifestyle of an individual, additionally urbanization, and exposure to harmful chemicals are other causes of disease. [2] Blood glucose homeostasis is regulated by several hormones. However, insulin and glucagon predominantly performed aforesaid functions. [3] Insulin reduces excess blood sugar levels either by inhibiting glucose synthesis by the liver or by increasing peripheral glucose utilization through the liver, skeletal muscles, and adipose tissues.
“…The alcoholic raw material ethanol from CWP and the Orleans acetic fermented production process were efficient to produce vinegar, meeting the requirements of FAO ( 2016), which requires a minimum composition of 4% of AA (40 g L -1 ) so that the vinegar is adequate to human consumption. Besides, AA may be employed at large scale commercial applications such as in the areas of cosmetic, medicines, beverages, and food preservation, due to its nutritive, antioxidant, and astringent properties, among other applications (Kucerova-Chlupacova et al, 2020;Pal & Nayak, 2017), being those future applications for the AA obtained from the CWP.…”
Sooro Renner Nutrição S.A. company is found in the Western Region of Paraná/Brazil, which is highlighted nationally and in Latin America concerning the production of whey protein concentrate (WPC). During the production of WPC, performed in ultrafiltration membranes, the subproduct cheese whey permeate (CWP) is generated, which is rich in nutrients, such as lactose, minerals, and vitamins. This subproduct is reported as a potential culture medium to grow microorganisms. Thus, this research, performed in partnership with the Sooro company, aimed to develop biotechnological products employing sequential fermentations to fully use this subproduct bioconverting the ethanol obtained from CWP into vinegar employing the acetic bacterium Acetobacter aceti and different methods - Orleans, aerated, and stirred. The biotransformation into ethanol was performed by Kluyveromyces marxianus (alcoholic fermentation step) using a 2³ factorial experimental design to investigate the influence of lactose concentration, temperature, and pH. The maximum ethanol production was 47.18±0.05 g L-1, employing the conditions 88 g L-1 of lactose, 29 °C, and pH 4.5 in 45 h. Besides ethanol, probiotic cellular biomass, prebiotic galacto-oligosaccharides, and organic acids were also produced. In the oxidation stage, the Orleans method presented the best production: 42.30±0.08 g L-1 of acetic acid in 21 days. After this production, reductions of chemical oxygen demand and biochemical oxygen demand of the CWP were 60 and 65%, respectively. The results showed the great potential of CWP as a fermentation medium to obtain biotechnological products as a rentable and viable alternative to fully use CWP.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
