“…The lenses were quickly dissected and rinsed with saline. ALR2 from rat lens was partially purified according to the reported procedure as follows [ 41 ]: lenses were quickly removed from rats following euthanasia and stored at −80 °C until used. The lenses were homogenized in a glass homogenizer with a teflon pestle in 5 vol of cold distilled water.…”
Section: Methodsmentioning
confidence: 99%
“…The study was approved by the Ethics Committee of the Institute and performed in accordance with the Principles of Laboratory Animal Care (NIH publication 83–25, revised 1985) and the Slovak law regulating animal experiments (Decree 289, Part 139, July 9, 2003). ALR1 from rat kidney was partially purified according to the reported procedure as follows [ 41 ]: kidneys were homogenized in a knife homogenizer followed by processing in a glass homogenizer with a teflon pestle in 3 vol of 10 mM sodium phosphate buffer, pH 7.2, containing 0.25 M sucrose, 2.0 mM EDTA dipotassium salt, and 2.5 mM 2-mercaptoethanol. The homogenate was centrifuged at 10.000 g at 0–4 °C for 30 min and the supernatant was subjected to ammonium sulfate fractional precipitation at 40%, 50%, and 75% salt saturation.…”
Section: Methodsmentioning
confidence: 99%
“…ALR2 and ALR1 activities were assayed spectrophotometrically by determining NADPH consumption at 340 nm with a UV/Vis Perkin-Elmer Spectrometer Lamda 20 [ 41 ]. In order to determine ALR2 inhibitory activity D,L-glyceraldehyde was used as substrate and the measurements took place in 0.067 M phosphate buffer pH 6.2 at 30 °C, whereas ALR1 inhibitory activity was determined with D-glucuronate as a substrate and the measurements took place in 0.1 M phosphate buffer, pH 7.2 at 37 °C.…”
Section: Methodsmentioning
confidence: 99%
“…Since it is significant for ARIs to be highly permeable through biological barriers and, in general, orally active, we performed a screening of our compounds through Lipinski’s “rule of five” and Veber’s criteria. The values of MW, hydrogen bond donors (HBD), HBA, TPSA, and the number of rotatable bonds (NRB) [ 41 ] were calculated by ADME Boxes 3.0 and are shown in Table 2 .…”
Sepsis is a life-threatening disease that affects millions of people worldwide. Microbial infections that lead to sepsis syndrome are associated with an increased production of inflammatory molecules. Aldose reductase has recently emerged as a molecular target that is involved in various inflammatory diseases, including sepsis. Herein, a series of previously synthesized benzothiazole-based thiazolidinones that exhibited strong antibacterial and antifungal activities has been evaluated for inhibition efficacy against aldose reductase and selectivity toward aldehyde reductase under in vitro conditions. The most promising inhibitor 5 was characterized with IC
50
value of 3.99 μM and a moderate selectivity. Molecular docking simulations revealed the binding mode of compounds at the active site of human aldose reductase. Moreover, owning to the absence of an acidic pharmacophore, good membrane permeation of the novel aldose reductase inhibitors was predicted. Excellent “drug-likeness” was assessed for most of the compounds by applying the criteria of Lipinski’s “rule of five”.
“…The lenses were quickly dissected and rinsed with saline. ALR2 from rat lens was partially purified according to the reported procedure as follows [ 41 ]: lenses were quickly removed from rats following euthanasia and stored at −80 °C until used. The lenses were homogenized in a glass homogenizer with a teflon pestle in 5 vol of cold distilled water.…”
Section: Methodsmentioning
confidence: 99%
“…The study was approved by the Ethics Committee of the Institute and performed in accordance with the Principles of Laboratory Animal Care (NIH publication 83–25, revised 1985) and the Slovak law regulating animal experiments (Decree 289, Part 139, July 9, 2003). ALR1 from rat kidney was partially purified according to the reported procedure as follows [ 41 ]: kidneys were homogenized in a knife homogenizer followed by processing in a glass homogenizer with a teflon pestle in 3 vol of 10 mM sodium phosphate buffer, pH 7.2, containing 0.25 M sucrose, 2.0 mM EDTA dipotassium salt, and 2.5 mM 2-mercaptoethanol. The homogenate was centrifuged at 10.000 g at 0–4 °C for 30 min and the supernatant was subjected to ammonium sulfate fractional precipitation at 40%, 50%, and 75% salt saturation.…”
Section: Methodsmentioning
confidence: 99%
“…ALR2 and ALR1 activities were assayed spectrophotometrically by determining NADPH consumption at 340 nm with a UV/Vis Perkin-Elmer Spectrometer Lamda 20 [ 41 ]. In order to determine ALR2 inhibitory activity D,L-glyceraldehyde was used as substrate and the measurements took place in 0.067 M phosphate buffer pH 6.2 at 30 °C, whereas ALR1 inhibitory activity was determined with D-glucuronate as a substrate and the measurements took place in 0.1 M phosphate buffer, pH 7.2 at 37 °C.…”
Section: Methodsmentioning
confidence: 99%
“…Since it is significant for ARIs to be highly permeable through biological barriers and, in general, orally active, we performed a screening of our compounds through Lipinski’s “rule of five” and Veber’s criteria. The values of MW, hydrogen bond donors (HBD), HBA, TPSA, and the number of rotatable bonds (NRB) [ 41 ] were calculated by ADME Boxes 3.0 and are shown in Table 2 .…”
Sepsis is a life-threatening disease that affects millions of people worldwide. Microbial infections that lead to sepsis syndrome are associated with an increased production of inflammatory molecules. Aldose reductase has recently emerged as a molecular target that is involved in various inflammatory diseases, including sepsis. Herein, a series of previously synthesized benzothiazole-based thiazolidinones that exhibited strong antibacterial and antifungal activities has been evaluated for inhibition efficacy against aldose reductase and selectivity toward aldehyde reductase under in vitro conditions. The most promising inhibitor 5 was characterized with IC
50
value of 3.99 μM and a moderate selectivity. Molecular docking simulations revealed the binding mode of compounds at the active site of human aldose reductase. Moreover, owning to the absence of an acidic pharmacophore, good membrane permeation of the novel aldose reductase inhibitors was predicted. Excellent “drug-likeness” was assessed for most of the compounds by applying the criteria of Lipinski’s “rule of five”.
“…Compound a4 (IC 50 = 67.08 µM) was evaluated for its inhibition of sorbitol accumulation by ex‐vivo study in rat lenses and was as active as Sorbinil (IC 50 = 72.79 µM). [ 66 ] Molecules having pyrazine ring exert numerous pharmacological actions like antidiabetic, antioxidant, antianginal, antidepressant, antihistamine, and so on. By considering this Han et al in 2016 have synthesized pyrazine‐pyridine hybrid compound B with congeners.…”
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.
Inhibition of aldose reductase (AKR1B1) is a promising option for the treatment of diabetic complications. However, most of the developed small molecule inhibitors lack selectivity or suffer from low bioactivity. To address this limitation, a novel series of quinazolin-4(1H)-one derivatives as potent and selective inhibitors of AKR1B1 were designed and synthesized. Aldose reductase inhibitory activities of the novel compounds were characterized by IC 50 values ranging from 0.015 to 31.497 μM. Markedly enhanced selectivity of these derivatives was also recorded, which was further supported by docking studies. Of these inhibitors, compound 5g exhibited the highest inhibition activity with selectivity indices reaching 1190.8. The structure-activity relationship highlighted the importance of N1-acetic acid and N3benzyl groups with electron-withdrawing substituents on the quinazolin-4(1H)-one scaffold for the construction of efficient and selective AKR1B1 inhibitors.
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