|
Inhibition of crude aldose reductase of rat lens
|
Rattus norvegicus
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and aldose reductase inhibitory activity of substituted 2-oxoquinoline-1-acetic acid derivatives.
Year : 1986
Volume : 29
Issue : 10
First Page : 2024
Last Page : 2028
Authors : DeRuiter J, Brubaker AN, Whitmer WL, Stein JL.
Abstract : A number of 2-oxoquinoline-1-alkanoic acids that contain the N-acylglycine fragment found in several known inhibitors of aldose reductase were synthesized and tested in the rat lens assay. All of the target compounds were prepared by alkylation of the appropriate 2-oxoquinoline intermediates with a halo ester, followed by hydrolysis of the intermediate esters. In the rat lens assay, the 1-acetic acid derivatives 9a-e display the highest level of aldose reductase inhibitor activity with IC50 values of 0.45-6.0 microM. Modification of the 1-acetic acid moiety by esterification, substitution of an alpha-methyl group, or insertion of an additional methylene unit results in reduced inhibitory potency. Structure-activity data also suggests that both the benzene and 2-oxopyridine rings of 9a-e contribute substantially toward activity and that inhibitory potency is influenced by aromatic ring substituents.
|
In vitro inhibitory activity against partially purified rat lens Aldose reductase at a dose of 5e-7M
|
None
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Highly selective aldose reductase inhibitors. 1. 3-(Arylalkyl)-2,4,5-trioxoimidazolidine-1-acetic acids.
Year : 1996
Volume : 39
Issue : 9
First Page : 1924
Last Page : 1927
Authors : Ishii A, Kotani T, Nagaki Y, Shibayama Y, Toyomaki Y, Okukado N, Ienaga K, Okamoto K.
Abstract : A series of 3-(arylalkyl)-2,4,5-trioxoimidazolidine-1-acetic acids (1) was prepared and tested for aldose reductase (AR) and aldehyde reductase (ALR) inhibitory activities. These compounds showed strong inhibitory activity against AR without significant inhibitory activity for ALR. The ratio of IC50(ALR)/IC50(AR) was > 1000 in some compounds. On the basis of pharmacological tests such as the recovery of reduced motor nerve conduction velocity and toxicological profile, 3-(3-nitrobenzyl)-2,4,5-trioxoimidazolidine-1-acetic acid (NZ-314) was selected as the candidate for clinical development.
|
Inhibitory activity against purified rat lens aldose reductase (RLAR)
|
None
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Molecular modeling studies of aldose reductase inhibitors.
Year : 1994
Volume : 37
Issue : 6
First Page : 787
Last Page : 792
Authors : Lee YS, Pearlstein R, Kador PF.
Abstract : Molecular modeling studies using the AM1 quantum chemical method and a torsional fitting method have been conducted on a series of aldose reductase inhibitors (ARIs) possessing an ionizable group and/or functional group susceptible to nucleophilic attack with the aim of defining the spatial position of ARI pharmacophores. AM1 quantum chemical calculations were conducted on ARIs possessing only an ionizable group to obtain their optimized geometries. These optimized structures were then superimposed on the model compound spirofluorene-9,5'-imidazolidine-2',4'-dione (17). This superposition study suggests that a negative charge center residing in the vicinity of the 2'-oxygen of the imidazolidine-2',4'-dione ring participates in the binding interactions. In addition, the optimized geometries of ARIs possessing both an ionizable group and an electronegative functional group were superimposed on spirofluorene-9,5'-imidazolidine-2',4'-dione (17). The latter results also suggest the presence of a region where nucleophilic substitution can occur.
|
Inhibitory activity against rat lens aldose reductase(AR).
|
Rattus norvegicus
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Highly selective aldose reductase inhibitors. 3. Structural diversity of 3-(arylmethyl)-2,4,5-trioxoimidazolidine-1-acetic acids.
Year : 1997
Volume : 40
Issue : 5
First Page : 684
Last Page : 694
Authors : Kotani T, Nagaki Y, Ishii A, Konishi Y, Yago H, Suehiro S, Okukado N, Okamoto K.
Abstract : Accumulation of intracellular sorbitol, the reduced product of glucose, catalyzed by aldose reductase (AR) (EC 1.1.1.21), is thought to be the cause of the development of diabetic complications. Our attention is focused on finding compounds which inhibit AR without significantly inhibiting aldehyde reductase (ALR) (EC 1.1.1.2). The uracil or 2,4-dioxoimidazolidine skeleton having the benzothiazolyl or 4-chloro-3-nitrophenyl group as an aryl part indicated not only extremely high AR inhibitory activity but also AR selectivity. The ratio of IC50(ALR)/IC50(AR) of 3-[(5-chlorobenzothiazol-2-yl)methyl]-1,2,3,4-tetrahydro-2,4- dioxopyrimidine-1-acetic acid (47d) was more than 17 500. The uracil skeleton with the benzothiazolyl moiety seemed to be the best combination for selective AR inhibition.
|
Inhibitory activity measured against rat lens aldose reductase using 3-pyridinecarboxaldehyde as substrate
|
None
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : A highly specific aldose reductase inhibitor, ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate, and its congeners.
Year : 1991
Volume : 34
Issue : 3
First Page : 1011
Last Page : 1018
Authors : Mylari BL, Beyer TA, Siegel TW.
Abstract : Ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate (1, EBPC) is a potent and specific inhibitor of aldose reductase. It was greater than 4000X more potent in its inhibition of rat lens aldose reductase than the closely related rat or pig kidney aldehyde reductase, thus making it the most selective inhibitor of a NADPH-dependent carbonyl reductase identified to date. In agreement with this observation, it was found to be a highly potent inhibitor of aldose reductase from rat sciatic nerve with greater than 98% inhibition at 1 microM, but it was practically devoid of activity against aldehyde reductases from rat liver and brain. Inhibition of aldose reductase was mixed type for glyceraldehyde (Ki = 8.0 x 10(-8) M) and noncompetitive for NADPH (Ki = 1.70 x 10(-8) M). Its potential as an in vitro tool to quantitate monomeric aldo/keto reductase activities in crude tissue extracts is presented. Structure-activity relationships emerging from synthetic modifications of EBPC are discussed. Several modifications were found to be active in vitro against aldose reductase from human placenta and in vivo in a rat model of diabetic complications, but none was more potent than EBPC.
|
Inhibitory activity against aldose reductase enzyme
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Substituted pyrrol-1-ylacetic acids that combine aldose reductase enzyme inhibitory activity and ability to prevent the nonenzymatic irreversible modification of proteins from monosaccharides.
Year : 2003
Volume : 46
Issue : 3
First Page : 417
Last Page : 426
Authors : Nicolaou I, Demopoulos VJ.
Abstract : Starting from the known inhibitory activity of (3-benzoylpyrrol-1-yl)acetic acid (I) and (2-benzoylpyrrol-1-yl)acetic acid (II), a series of 3-aroyl and 2,4-bis-aroyl derivatives (54-75) were synthesized and tested for inhibition of aldose reductase, an enzyme involved in the appearance of diabetic complications. It was found that a number of the tested compounds exhibited considerable activity in the micromolar range. Important structural features for the potent compounds is the presence of substituents with relatively low Hammett sigma values and/or moieties which increase their overall aromatic area. The most active derivative was the [2,4-bis(4-methoxybenzoyl)pyrrol-1-yl]acetic acid (75), with potency favorably compared to known ARIs such as tolrestat, epalrestat, zopolrestat, and fidarestat. Four selected derivatives were also evaluated for their ability to interfere with the oxidative modification of serum albumin in an in vitro experimental glycation model of diabetes mellitus. All of them showed considerable activity, comparable to the known inhibitor trolox. Our results, taken together, indicate that compound 75 combines favorably two biological activities directly connected to a number of pathological conditions related to the chronic diabetes mellitus.
|
Inhibition of aldose reductase in rat lens homogenates by fluorophotometer
|
Rattus norvegicus
|
72.0
nM
|
|
Journal : J. Nat. Prod.
Title : New flavonol oligoglycosides and polyacylated sucroses with inhibitory effects on aldose reductase and platelet aggregation from the flowers of Prunus mume.
Year : 2002
Volume : 65
Issue : 8
First Page : 1151
Last Page : 1155
Authors : Yoshikawa M, Murakami T, Ishiwada T, Morikawa T, Kagawa M, Higashi Y, Matsuda H.
Abstract : The methanolic extract from the fresh flowers of Prunus mume exhibited inhibitory effects against aldose reductase and platelet aggregation. From the methanolic extract, two new flavonol oligoglycosides, 2' '-O-acetylrutin and 2' '-O-acetyl-3'-O-methylrutin, and two new polyacylated sucroses, prunoses I and II, were isolated together with 11 known constituents. The structures of 2' '-O-acetylrutin, 2' '-O-acetyl-3'-O-methylrutin, and prunoses I and II were determined on the basis of chemical and physicochemical evidence as quercetin 3-O-alpha-L-rhamnopyranosyl(1-->6)-2' '-O-acetyl-beta-D-glucopyranoside, 3'-O-methylquercetin 3-O-alpha-L-rhamnopyranosyl(1-->6)-2' '-O-acetyl-beta-D-glucopyranoside, 1,4,3',4',6'-penta-O-acetyl-6-O-p-coumaroylsucrose, and 1,3',4',6'-tetra-O-acetyl-6-O-p-coumaroylsucrose, respectively. The flavonol glycosides and prunose I were found to inhibit aldose reductase, while prunoses I and II inhibited platelet aggregation induced by thrombin.
|
Inhibition of rat lens aldose reductase
|
Rattus norvegicus
|
70.0
nM
|
|
Journal : J. Nat. Prod.
Title : Erigeroflavanone, a flavanone derivative from the flowers of Erigeron annuus with protein glycation and aldose reductase inhibitory activity.
Year : 2008
Volume : 71
Issue : 4
First Page : 713
Last Page : 715
Authors : Yoo NH, Jang DS, Yoo JL, Lee YM, Kim YS, Cho JH, Kim JS.
Abstract : A novel 2,3-dioxygenated flavanone, erigeroflavanone ( 1), as well as eight known flavonoids and two known gamma-pyranone derivatives, were isolated from an ethyl acetate-soluble extract of the flowers of Erigeron annuus. The structure of compound 1 was elucidated by interpretation of spectroscopic data. All of the isolates were subjected to in vitro bioassays to evaluate their inhibitory activity against advanced glycation end products formation and rat lens aldose reductase.
|
Inhibition of human muscle recombinant aldose reductase by spectrophotometry
|
Homo sapiens
|
0.03
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Structures and aldose reductase inhibitory effects of bromophenols from the red alga Symphyocladia latiuscula.
Year : 2005
Volume : 68
Issue : 4
First Page : 620
Last Page : 622
Authors : Wang W, Okada Y, Shi H, Wang Y, Okuyama T.
Abstract : Three new bromophenols, 2,2',3,6,6'-pentabromo-3',4,4',5-tetrahydroxydibenzyl ether (1), bis(2,3,6-tribromo-4,5-dihydroxyphenyl)methane (2), and 2,2',3,5',6-pentabromo-3',4,4',5-tetrahydroxydiphenylmethane (3), were isolated from the red alga Symphyocladia latiuscula. Two bromophenols, 2,3,6-tribromo-4,5-dihydroxymethylbenzene (4) and 2,3,6-tribromo-4,5-dihydroxybenzaldehyde (5), were also reported for the first time as natural products. Their structures were elucidated on the basis of chemical and spectroscopic methods including HREIMS, HRFABMS, and 1D and 2D NMR spectral techniques. Compounds 1-5 exhibited significant aldose reductase inhibitory activity.
|
Inhibition of reductase activity of N-terminal 6His-tagged AKR1B10 expressed in Escherichia coli BL21(DE3) assessed as inhibition of NADPH linked pyridine-3-aldehyde reduction
|
None
|
330.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Chromene-3-carboxamide derivatives discovered from virtual screening as potent inhibitors of the tumour maker, AKR1B10.
Year : 2010
Volume : 18
Issue : 7
First Page : 2485
Last Page : 2490
Authors : Endo S, Matsunaga T, Kuwata K, Zhao HT, El-Kabbani O, Kitade Y, Hara A.
Abstract : A human aldose reductase-like protein, AKR1B10 in the aldo-keto reductase (AKR) superfamily, was recently identified as a therapeutic target in the treatment of several types of cancer. In order to identify potential leads for new inhibitors of AKR1B10, we adopted the virtual screening approach using the automated program icm, which resulted in the discovery of several chromene-3-carboxamide derivatives as potent competitive inhibitors. The most potent (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide inhibited the reductase activity of AKR1B10 with a K(i) value of 2.7nM, and the metabolism of farnesal and 4-hydroxynonenal in the AKR1B10-overexpressed cells from 0.1microM with an IC(50) value equal to 0.8microM.
|
Inhibition of N-terminal 6His-tagged human aldose reductase expressed in Escherichia coli BL21(DE3) mediated NADPH linked pyridine-3-aldehyde reduction
|
Homo sapiens
|
21.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Chromene-3-carboxamide derivatives discovered from virtual screening as potent inhibitors of the tumour maker, AKR1B10.
Year : 2010
Volume : 18
Issue : 7
First Page : 2485
Last Page : 2490
Authors : Endo S, Matsunaga T, Kuwata K, Zhao HT, El-Kabbani O, Kitade Y, Hara A.
Abstract : A human aldose reductase-like protein, AKR1B10 in the aldo-keto reductase (AKR) superfamily, was recently identified as a therapeutic target in the treatment of several types of cancer. In order to identify potential leads for new inhibitors of AKR1B10, we adopted the virtual screening approach using the automated program icm, which resulted in the discovery of several chromene-3-carboxamide derivatives as potent competitive inhibitors. The most potent (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide inhibited the reductase activity of AKR1B10 with a K(i) value of 2.7nM, and the metabolism of farnesal and 4-hydroxynonenal in the AKR1B10-overexpressed cells from 0.1microM with an IC(50) value equal to 0.8microM.
|
Inhibition of bovine lens aldose reductase assessed as inhibition of NDAPH oxidation by non-linear regression analysis
|
Bos taurus
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In vitro evaluation of 5-arylidene-2-thioxo-4-thiazolidinones active as aldose reductase inhibitors.
Year : 2011
Volume : 21
Issue : 1
First Page : 200
Last Page : 203
Authors : Maccari R, Del Corso A, Giglio M, Moschini R, Mura U, Ottanà R.
Abstract : 2-Thioxo-4-thiazolidinone derivatives were evaluated as aldose reductase inhibitors (ARIs) and most of them exhibited good or excellent in vitro efficacy. Out of the tested compounds, most N-unsubstituted analogues were found to possess inhibitory effects at low micromolar doses and two of them exhibited higher potency than sorbinil, used as a reference drug. The insertion of an acetic chain on N-3 of the thiazolidinone scaffold led to analogues with submicromolar affinity for ALR2 and IC(50) values very similar to that of epalrestat, the only ARI currently used in therapy.
|
Inhibition of bovine lens ALR2
|
Bos taurus
|
170.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Identification of 5-arylidene-4-thiazolidinone derivatives endowed with dual activity as aldose reductase inhibitors and antioxidant agents for the treatment of diabetic complications.
Year : 2011
Volume : 46
Issue : 7
First Page : 2797
Last Page : 2806
Authors : Ottanà R, Maccari R, Giglio M, Del Corso A, Cappiello M, Mura U, Cosconati S, Marinelli L, Novellino E, Sartini S, La Motta C, Da Settimo F.
Abstract : In continuing the search for more effective 5-arylidene-4-thiazolidinones as aldose reductase inhibitors, a new set of suitably substituted compounds (4, 5 and 8) was explored. Acetic acids 5, particularly 5a and 5h, proved to be interesting inhibitors of the enzyme as well as excellent antioxidant agents that are potentially able to counteract the oxidative stress associated with both diabetic complications as well as other pathologies. Molecular docking experiments supported SAR studies.
|
DRUGMATRIX: Aldose Reductase enzyme inhibition (substrate: DL-Glyceraldehyde)
|
Rattus norvegicus
|
32.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Inhibition of Wistar rat lens ALR2 using D,L-glyceraldehyde as substrate after 10 mins by UV/VIS double spectrophotometric analysis
|
Rattus norvegicus
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 1,2-Benzothiazine 1,1-dioxide carboxylate derivatives as novel potent inhibitors of aldose reductase.
Year : 2011
Volume : 19
Issue : 23
First Page : 7262
Last Page : 7269
Authors : Chen X, Zhang S, Yang Y, Hussain S, He M, Gui D, Ma B, Jing C, Qiao Z, Zhu C, Yu Q.
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 IC(50) values ranging from 0.11 μM to 10.42 μM, 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.
|
Inhibition of rat lens aldose reductase using DL-glyceraldehyde as substrate after 30 mins by fluorescence microplate reader analysis
|
Rattus norvegicus
|
72.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Antidiabetogenic oligostilbenoids and 3-ethyl-4-phenyl-3,4-dihydroisocoumarins from the bark of Shorea roxburghii.
Year : 2012
Volume : 20
Issue : 2
First Page : 832
Last Page : 840
Authors : Morikawa T, Chaipech S, Matsuda H, Hamao M, Umeda Y, Sato H, Tamura H, Kon'i H, Ninomiya K, Yoshikawa M, Pongpiriyadacha Y, Hayakawa T, Muraoka O.
Abstract : A methanol extract of the bark of Shorea roxburghii (Dipterocarpaceae) was found to inhibit plasma glucose elevation in sucrose-loaded mice. From the extract, three new 3-ethyl-4-phenyl-3,4-dihydroisocoumarins, 1'S-dihydrophayomphenol A(2) (1) and phayomphenols B(1) (2) and B(2) (3), were isolated together with 24 known compounds including 20 stilbenoids and oligostilbenoids. The structures of 1-3 were determined on the basis of their spectroscopic properties as well as of chemical evidences. Among the isolates, (-)-hopeaphenol (6), hemsleyanol D (8), (+)-α-viniferin (15), and (-)-balanocarpol (18) showed inhibitory activity against plasma glucose elevation in sucrose-loaded rats at doses of 100-200mg/kg, p.o. To clarify the mode of action of the antihyperglycemic property, effects of these oligostilbenoids on gastric emptying in mice, those on glucose uptake in isolated intestinal tissues as well as inhibitory activities against rat intestinal α-glucosidase and rat lens aldose reductase were examined.
|
Inhibition of human recombinant AKR1B1 expressed in Escherichia coli BL21 cells using pyridine-3-aldehyde as substrate by spectrophotometry
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of novel (1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acids as selective inhibitors for AKR1B1.
Year : 2012
Volume : 20
Issue : 1
First Page : 356
Last Page : 367
Authors : Minehira D, Takeda D, Urata H, Kato A, Adachi I, Wang X, Matsuya Y, Sugimoto K, Takemura M, Endo S, Matsunaga T, Hara A, Koseki J, Narukawa K, Hirono S, Toyooka N.
Abstract : New substituted (1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acids were designed as the inhibitor of AKR1B1 based upon the structure of rhetsinine, a minor alkaloidal component of Evodia rutaecarpa, and twenty derivatives were synthesized and evaluated. The most active compound of the series was (2-benzyl-6-methoxy-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acid (7m), which showed comparable inhibitory activity for AKR1B1 (IC(50)=0.15μM) with clinically used epalrestat (IC(50)=0.1μM). In the view of activity and selectivity, the most potent compound was (2-benzyl-6-carboxy-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acid (7t), which showed strong inhibitory effect (IC(50)=0.17μM) and very high selectivity for AKR1B1 against AKR1A1 (311:1) and AKR1B10 (253:1) compared with epalrestat.
|
Inhibition of recombinant N-His6-tagged AKR1B10 expressed in Escherichia coli BL21 cells using pyridine-3-aldehyde as substrate by spectrophotometry
|
None
|
330.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of novel (1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acids as selective inhibitors for AKR1B1.
Year : 2012
Volume : 20
Issue : 1
First Page : 356
Last Page : 367
Authors : Minehira D, Takeda D, Urata H, Kato A, Adachi I, Wang X, Matsuya Y, Sugimoto K, Takemura M, Endo S, Matsunaga T, Hara A, Koseki J, Narukawa K, Hirono S, Toyooka N.
Abstract : New substituted (1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acids were designed as the inhibitor of AKR1B1 based upon the structure of rhetsinine, a minor alkaloidal component of Evodia rutaecarpa, and twenty derivatives were synthesized and evaluated. The most active compound of the series was (2-benzyl-6-methoxy-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acid (7m), which showed comparable inhibitory activity for AKR1B1 (IC(50)=0.15μM) with clinically used epalrestat (IC(50)=0.1μM). In the view of activity and selectivity, the most potent compound was (2-benzyl-6-carboxy-1-thioxo-1,2,3,4-tetrahydro-β-carbolin-9-yl)acetic acid (7t), which showed strong inhibitory effect (IC(50)=0.17μM) and very high selectivity for AKR1B1 against AKR1A1 (311:1) and AKR1B10 (253:1) compared with epalrestat.
|
Inhibition of Sprague-Dawley rat lens aldose reductase
|
Rattus norvegicus
|
67.0
nM
|
|
Journal : J. Nat. Prod.
Title : Chemical constituents from the aerial parts of Aster koraiensis with protein glycation and aldose reductase inhibitory activities.
Year : 2012
Volume : 75
Issue : 2
First Page : 267
Last Page : 270
Authors : Lee J, Lee YM, Lee BW, Kim JH, Kim JS.
Abstract : Two new eudesmane-type sesquiterpene glucosides, 9β-O-(E-p-hydroxycinnamoyl)-1β,6β-dihydroxy-trans-eudesm-3-en-6-O-β-D-glucopyranoside (1) and 9α-O-(E-p-hydroxycinnamoyl)-1α,6α-11-trihydroxy-trans-eudesm-3-en-6-O-β-D-glucopyranoside (2), were isolated by the activity-guidedfractionation of an EtOAc-soluble fraction from the aerial parts of Aster koraiensis. A new dihydrobenzofuran glucoside, (2R,3S)-6-acetyl-2-[1-O-(β-D-glucopyranosyl)-2-propenyl]-5-hydroxy-3-methoxy-2,3-dihydrobenzofuran (3), was also isolated, in addition to 15 known compounds. The structures of 1-3 were determined by spectroscopic data interpretation. All of the isolates were evaluated for in vitro inhibitory activity against the formation of advanced glycation end-products and rat lens aldose reductase.
|
Inhibition of Sprague-Dawley albino rat ALR2 assessed as enzyme-mediated oxidation of NADPH using D,L-glyceraldehyde as substrate by spectrophotometric analysis
|
Rattus norvegicus
|
170.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Progresses in the pursuit of aldose reductase inhibitors: the structure-based lead optimization step.
Year : 2012
Volume : 51
First Page : 216
Last Page : 226
Authors : Ramunno A, Cosconati S, Sartini S, Maglio V, Angiuoli S, La Pietra V, Di Maro S, Giustiniano M, La Motta C, Da Settimo F, Marinelli L, Novellino E.
Abstract : Aldose reductase (ALR2) is a crucial enzyme in the development of the major complications of diabetes mellitus. Very recently it has been demonstrated that the ARL2 inhibitor, fidarestat, significantly prevents inflammatory signals (TNF-α, LPS) that cause cancer (colon, breast, prostate and lung), metastasis, asthma, and other inflammatory diseases. Currently, fidarestat is in phase III clinical trial for diabetic neuropathy and was found to be safe. Thus the finding of novel, potent ARL2 inhibitors is today more than in the past in great demand as they can pave the way for a novel therapeutic approach for a number of diseases besides the diabetes. Herein, starting from the virtual screening-derived ALR2 inhibitor S12728 (1), a rational receptor-based lead optimization has been undertaken. The design and synthetic efforts here reported led to the discovery of several new compounds endowed with low micromolar/submicromolar activities.
|
Inhibition of Sprague-Dawley albino rat ALR1 assessed as enzyme-mediated oxidation of NADPH using D,L-glyceraldehyde as substrate by spectrophotometric analysis
|
Rattus norvegicus
|
940.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Progresses in the pursuit of aldose reductase inhibitors: the structure-based lead optimization step.
Year : 2012
Volume : 51
First Page : 216
Last Page : 226
Authors : Ramunno A, Cosconati S, Sartini S, Maglio V, Angiuoli S, La Pietra V, Di Maro S, Giustiniano M, La Motta C, Da Settimo F, Marinelli L, Novellino E.
Abstract : Aldose reductase (ALR2) is a crucial enzyme in the development of the major complications of diabetes mellitus. Very recently it has been demonstrated that the ARL2 inhibitor, fidarestat, significantly prevents inflammatory signals (TNF-α, LPS) that cause cancer (colon, breast, prostate and lung), metastasis, asthma, and other inflammatory diseases. Currently, fidarestat is in phase III clinical trial for diabetic neuropathy and was found to be safe. Thus the finding of novel, potent ARL2 inhibitors is today more than in the past in great demand as they can pave the way for a novel therapeutic approach for a number of diseases besides the diabetes. Herein, starting from the virtual screening-derived ALR2 inhibitor S12728 (1), a rational receptor-based lead optimization has been undertaken. The design and synthetic efforts here reported led to the discovery of several new compounds endowed with low micromolar/submicromolar activities.
|
Inhibition of Sprague-Dawley albino rat kidney Aldehyde reductase by spectrophotometry
|
Rattus norvegicus
|
940.0
nM
|
|
Journal : J. Med. Chem.
Title : Benzofuroxane derivatives as multi-effective agents for the treatment of cardiovascular diabetic complications. Synthesis, functional evaluation, and molecular modeling studies.
Year : 2012
Volume : 55
Issue : 23
First Page : 10523
Last Page : 10531
Authors : Sartini S, Cosconati S, Marinelli L, Barresi E, Di Maro S, Simorini F, Taliani S, Salerno S, Marini AM, Da Settimo F, Novellino E, La Motta C.
Abstract : Diabetes mellitus is the major risk factor for cardiovascular disorders. Aldose reductase, the rate-limiting enzyme of the polyol pathway, plays a key role in the pathogenesis of diabetic complications. Accordingly, inhibition of this enzyme is emerging as a major therapeutic strategy for the treatment of hyperglycemia-induced cardiovascular pathologies. In this study, we describe a series of 5(6)-substituted benzofuroxane derivatives, 5a-k,m, synthesized as aldose reductase inhibitors. Besides inhibiting efficiently the target enzyme, 5a-k,m showed additional NO donor and antioxidant properties, thus emerging as novel multi-effective compounds. The benzyloxy derivative 5a, the most promising of the whole series, showed a well-balanced, multifunctional profile consisting of submicromolar ALR2 inhibitory efficacy (IC50=0.99±0.02 μM), significant and spontaneous NO generation properties, and excellent hydroxyl radical scavenging activity. Computational studies of the novel compounds clarified the aldose reductase inhibitory profile observed, thus rationalizing structure-activity relationships of the whole series.
|
Inhibition of Sprague-Dawley albino rat lens ALR2 by spectrophotometry
|
Rattus norvegicus
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : Benzofuroxane derivatives as multi-effective agents for the treatment of cardiovascular diabetic complications. Synthesis, functional evaluation, and molecular modeling studies.
Year : 2012
Volume : 55
Issue : 23
First Page : 10523
Last Page : 10531
Authors : Sartini S, Cosconati S, Marinelli L, Barresi E, Di Maro S, Simorini F, Taliani S, Salerno S, Marini AM, Da Settimo F, Novellino E, La Motta C.
Abstract : Diabetes mellitus is the major risk factor for cardiovascular disorders. Aldose reductase, the rate-limiting enzyme of the polyol pathway, plays a key role in the pathogenesis of diabetic complications. Accordingly, inhibition of this enzyme is emerging as a major therapeutic strategy for the treatment of hyperglycemia-induced cardiovascular pathologies. In this study, we describe a series of 5(6)-substituted benzofuroxane derivatives, 5a-k,m, synthesized as aldose reductase inhibitors. Besides inhibiting efficiently the target enzyme, 5a-k,m showed additional NO donor and antioxidant properties, thus emerging as novel multi-effective compounds. The benzyloxy derivative 5a, the most promising of the whole series, showed a well-balanced, multifunctional profile consisting of submicromolar ALR2 inhibitory efficacy (IC50=0.99±0.02 μM), significant and spontaneous NO generation properties, and excellent hydroxyl radical scavenging activity. Computational studies of the novel compounds clarified the aldose reductase inhibitory profile observed, thus rationalizing structure-activity relationships of the whole series.
|
Inhibition of rat kidney NADPH-dependent aldose reductase assessed as DL-glyceraldehyde conversion to glycerol preincubated for 20 mins followed by NADPH addition measured after 5 mins by UV-Visible spectrophotometric analysis
|
Rattus norvegicus
|
100.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of new epalrestat analogues as aldose reductase inhibitors (ARIs).
Year : 2014
Volume : 71
First Page : 53
Last Page : 66
Authors : Reddy TN, Ravinder M, Bagul P, Ravikanti K, Bagul C, Nanubolu JB, Srinivas K, Banerjee SK, Rao VJ.
Abstract : Baylis-Hillman chemistry derived four series of new epalrestat analogues were synthesized. Three structural changes are introduced in these 39 new epalrestat analogues synthesized. All compounds were evaluated for their in vitro aldose reductase inhibitory (ALR) activity. Biological activity data indicates that compounds 6, 16, 19, 28 and 29 are potent and the activity is in the range of reference drug, epalrestat. Molecular modelling studies were performed to understand the binding interactions of these active molecules with the ALR protein. Molecular docking data indicates the key interactions of epalrestat were retained in some of the active compounds whereas some new interactions were noticed for other molecules. The modifications introduced on epalrestat have impact for developing a new-type of ALR inhibitor.
|
Inhibition of bovine aldose reductase assessed as oxidation of NADPH
|
Bos taurus
|
170.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Structure-activity relationships and molecular modelling of new 5-arylidene-4-thiazolidinone derivatives as aldose reductase inhibitors and potential anti-inflammatory agents.
Year : 2014
Volume : 81
First Page : 1
Last Page : 14
Authors : Maccari R, Vitale RM, Ottanà R, Rocchiccioli M, Marrazzo A, Cardile V, Graziano AC, Amodeo P, Mura U, Del Corso A.
Abstract : A series of 5-(carbamoylmethoxy)benzylidene-2-oxo/thioxo-4-thiazolidinone derivatives (6-9) were synthesized as inhibitors of aldose reductase (AR), enzyme which plays a crucial role in the development of diabetes complications as well as in the inflammatory processes associated both to diabetes mellitus and to other pathologies. In vitro inhibitory activity indicated that compounds 6-9a-d were generally good AR inhibitors. Acetic acid derivatives 8a-d and 9a-d were shown to be the best enzyme inhibitors among the tested compounds endowed with significant inhibitory ability levels reaching submicromolar IC50 values. Moreover, some representative AR inhibitors (7a, 7c, 9a, 9c, 9d) were assayed in cultures of human keratinocytes in order to evaluate their capability to reduce NF-kB activation and iNOS expression. Compound 9c proved to be the best derivative endowed with both interesting AR inhibitory effectiveness and ability to reduce NF-kB activation and iNOS expression. Molecular docking and molecular dynamics simulations were undertaken to investigate the binding modes of selected compounds into the active site of AR in order to rationalize the inhibitory effectiveness of these derivatives.
|
Inhibition of Wistar rat eye lens aldose reductase-2 using D-L glyceraldehyde as substrate assessed as oxidation of NADPH preincubated for 10 mins followed by substrate addition measured for 4 mins by spectrophotometric analysis
|
Rattus norvegicus
|
120.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Structure-activity relationships studies of quinoxalinone derivatives as aldose reductase inhibitors.
Year : 2014
Volume : 80
First Page : 383
Last Page : 392
Authors : Hussain S, Parveen S, Hao X, Zhang S, Wang W, Qin X, Yang Y, Chen X, Zhu S, Zhu C, Ma B.
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.
|
Inhibition of aldose reductase (unknown origin) at 10 ug/ml
|
Homo sapiens
|
55.56
%
|
|
Journal : Eur. J. Med. Chem.
Title : Chalcones and their therapeutic targets for the management of diabetes: structural and pharmacological perspectives.
Year : 2015
Volume : 92
First Page : 839
Last Page : 865
Authors : Mahapatra DK, Asati V, Bharti SK.
Abstract : Diabetes Mellitus (DM) is the fastest growing metabolic disorder affecting about 387 million people across the globe and is estimated to affect 592 million people by year 2030. The search for newer anti-diabetic agents is the foremost need to control the accelerating diabetic population. Several natural and (semi) synthetic chalcones deserve the credit of being potential candidates that act by modulating the therapeutic targets PPAR-γ, DPP-4, α-glucosidase, PTP1B, aldose reductase, and stimulate insulin secretion and tissue sensitivity. In this review, a comprehensive study (from January 1977 to October 2014) of anti-diabetic chalcones, their molecular targets, structure activity relationships (SARs), mechanism of actions (MOAs) and patents have been described. The compounds which showed promising activity and have a well-defined MOAs, SARs must be considered as prototype for the design and development of potential anti-diabetic agents. They should be evaluated critically at all clinical stages to ensure their therapeutic and toxicological profile to meet the demand of diabetics.
|
Inhibition of Wistar rat lenses ALR2 using D,L-glyceraldehyde as substrate preincubated for 10 mins before substrate addition measured after 5 mins by spectrophotometry
|
Rattus norvegicus
|
84.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of potent and multifunctional aldose reductase inhibitors based on quinoxalinones.
Year : 2015
Volume : 58
Issue : 3
First Page : 1254
Last Page : 1267
Authors : Qin X, Hao X, Han H, Zhu S, Yang Y, Wu B, Hussain S, Parveen S, Jing C, Ma B, Zhu C.
Abstract : Quinoxalin-2(1H)-one based design and synthesis produced several series of aldose reductase (ALR2) inhibitor candidates. In particular, phenolic structure was installed in the compounds for the combination of antioxidant activity and strengthening the ability to fight against diabetic complications. Most of the series 6 showed potent and selective effects on ALR2 inhibition with IC50 values 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 8 revealed not only good activity in the ALR2 inhibition but also potent antioxidant activity, and 2-(3-(3-methoxy-4-hydroxystyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid (8d) was even as strong as the well-known antioxidant Trolox at a concentration of 100 μM, verifying the C3 p-hydroxystyryl side chain as the key structure for alleviating oxidative stress. These results therefore suggest an achievement of multifunctional ALR2 inhibitors having both potency for ALR2 inhibition and as antioxidants.
|
Inhibition of Wistar rat kidney ALR1 using D,L-glyceraldehyde as substrate preincubated at 10 uM for 10 mins before substrate addition measured after 5 mins by spectrophotometry
|
Rattus norvegicus
|
73.6
%
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of potent and multifunctional aldose reductase inhibitors based on quinoxalinones.
Year : 2015
Volume : 58
Issue : 3
First Page : 1254
Last Page : 1267
Authors : Qin X, Hao X, Han H, Zhu S, Yang Y, Wu B, Hussain S, Parveen S, Jing C, Ma B, Zhu C.
Abstract : Quinoxalin-2(1H)-one based design and synthesis produced several series of aldose reductase (ALR2) inhibitor candidates. In particular, phenolic structure was installed in the compounds for the combination of antioxidant activity and strengthening the ability to fight against diabetic complications. Most of the series 6 showed potent and selective effects on ALR2 inhibition with IC50 values 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 8 revealed not only good activity in the ALR2 inhibition but also potent antioxidant activity, and 2-(3-(3-methoxy-4-hydroxystyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid (8d) was even as strong as the well-known antioxidant Trolox at a concentration of 100 μM, verifying the C3 p-hydroxystyryl side chain as the key structure for alleviating oxidative stress. These results therefore suggest an achievement of multifunctional ALR2 inhibitors having both potency for ALR2 inhibition and as antioxidants.
|
Inhibition of Wistar rat lens aldose reductase using D,L-glyceraldehyde as substrate incubated for 1 min measured for 4 mins by spectrophotometry
|
Rattus norvegicus
|
250.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of novel aldose reductase inhibitors based on carboxymethylated mercaptotriazinoindole scaffold.
Year : 2015
Volume : 58
Issue : 6
First Page : 2649
Last Page : 2657
Authors : Stefek M, Soltesova Prnova M, Majekova M, Rechlin C, Heine A, Klebe G.
Abstract : Fifteen compounds, sharing an indole-1-acetic acid moiety as a common fragment, were selected from commercial databases for testing aldose reductase inhibition. 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (13) was the most promising inhibitor, with an IC50 in the submicromolar range and high selectivity, relative to aldehyde reductase. The crystal structure of aldose reductase complexed with 13 revealed an interaction pattern explaining its high affinity. Physicochemical parameters underline the excellent "leadlikeness" of 13 as a promising candidate for further structure optimizations.
|
Inhibition of Wistar rat ALR2 using D,L-glyceraldehyde as substrate assessed as oxidation of NADPH preincubated for 10 mins followed by substrate addition measured for 4 mins by spectrophotometric analysis
|
Rattus norvegicus
|
85.68
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phenolic 4-hydroxy and 3,5-dihydroxy derivatives of 3-phenoxyquinoxalin-2(1H)-one as potent aldose reductase inhibitors with antioxidant activity.
Year : 2015
Volume : 25
Issue : 18
First Page : 3924
Last Page : 3927
Authors : Zou Y, Qin X, Hao X, Zhang W, Yang S, Yang Y, Han Z, Ma B, Zhu C.
Abstract : A group of novel quinoxalinone derivatives (4a-h) were prepared and investigated for their inhibitory activity against ALR2 and antioxidant activity. Most of them were found to be potent aldose reductase inhibitors with IC50 values ranging from 0.019 to 0.982 μM. The most active compound 2-(3-(4-hydroxyphenoxy)-6-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (4c) also had an excellent selectivity. In addition, a number of compounds showed strong antioxidant activity and the phenolic 3,5-dihydroxyl compound 4f with 7-chloro in the quinoxalinone core was most active in scavenging the DPPH radical and suppressing lipid peroxidation.
|
Inhibition of Wistar rat ALR1 using sodium D-glucuronate as substrate assessed as oxidation of NADPH at 10 uM preincubated for 10 mins followed by substrate addition measured for 4 mins by spectrophotometric analysis relative to control
|
Rattus norvegicus
|
73.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phenolic 4-hydroxy and 3,5-dihydroxy derivatives of 3-phenoxyquinoxalin-2(1H)-one as potent aldose reductase inhibitors with antioxidant activity.
Year : 2015
Volume : 25
Issue : 18
First Page : 3924
Last Page : 3927
Authors : Zou Y, Qin X, Hao X, Zhang W, Yang S, Yang Y, Han Z, Ma B, Zhu C.
Abstract : A group of novel quinoxalinone derivatives (4a-h) were prepared and investigated for their inhibitory activity against ALR2 and antioxidant activity. Most of them were found to be potent aldose reductase inhibitors with IC50 values ranging from 0.019 to 0.982 μM. The most active compound 2-(3-(4-hydroxyphenoxy)-6-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (4c) also had an excellent selectivity. In addition, a number of compounds showed strong antioxidant activity and the phenolic 3,5-dihydroxyl compound 4f with 7-chloro in the quinoxalinone core was most active in scavenging the DPPH radical and suppressing lipid peroxidation.
|
Inhibition of ALR2 from rat lens using D,L-glyceraldehyde as substrate measured as absorption of NADPH for 4 mins by UV/vis spectrophotmetry
|
Rattus norvegicus
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of benzothiadiazine derivatives exhibiting dual activity as aldose reductase inhibitors and antioxidant agents.
Year : 2016
Volume : 26
Issue : 12
First Page : 2880
Last Page : 2885
Authors : Zhu S, Hao X, Zhang S, Qin X, Chen X, Zhu C.
Abstract : Several multifunctional benzothiadiazine derivatives were synthesized and examined for their inhibition to the enzyme aldose reductase and in vitro antioxidant activity to identify novel drugs for diabetes and its complications. Most of them exhibited good inhibitory activity. Importantly, a number of compounds demonstrated strong antioxidant activity and one compound in particular was extremely active in the DPPH radical scavenging and MDA inhibition analysis. The DPPH radical scavenging rate with this compound was 98.0%, 92.3% and 42.1% at concentrations of 100μM, 10μM, and 1μM, respectively, and the initial reaction rate was faster than Trolox at a concentration of 10μM.
|
Antioxidant activity assessed as DPPH free radical scavenging activity at 100 uM after 40 mins by UV-Vis spectrophotometry
|
None
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of benzothiadiazine derivatives exhibiting dual activity as aldose reductase inhibitors and antioxidant agents.
Year : 2016
Volume : 26
Issue : 12
First Page : 2880
Last Page : 2885
Authors : Zhu S, Hao X, Zhang S, Qin X, Chen X, Zhu C.
Abstract : Several multifunctional benzothiadiazine derivatives were synthesized and examined for their inhibition to the enzyme aldose reductase and in vitro antioxidant activity to identify novel drugs for diabetes and its complications. Most of them exhibited good inhibitory activity. Importantly, a number of compounds demonstrated strong antioxidant activity and one compound in particular was extremely active in the DPPH radical scavenging and MDA inhibition analysis. The DPPH radical scavenging rate with this compound was 98.0%, 92.3% and 42.1% at concentrations of 100μM, 10μM, and 1μM, respectively, and the initial reaction rate was faster than Trolox at a concentration of 10μM.
|
Reduction of MDA level in Wistar rat brain at 100 uM after 30 mins in presence of ascorbic acid by UV-vis spectrophotmetry relative to control
|
Rattus norvegicus
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of benzothiadiazine derivatives exhibiting dual activity as aldose reductase inhibitors and antioxidant agents.
Year : 2016
Volume : 26
Issue : 12
First Page : 2880
Last Page : 2885
Authors : Zhu S, Hao X, Zhang S, Qin X, Chen X, Zhu C.
Abstract : Several multifunctional benzothiadiazine derivatives were synthesized and examined for their inhibition to the enzyme aldose reductase and in vitro antioxidant activity to identify novel drugs for diabetes and its complications. Most of them exhibited good inhibitory activity. Importantly, a number of compounds demonstrated strong antioxidant activity and one compound in particular was extremely active in the DPPH radical scavenging and MDA inhibition analysis. The DPPH radical scavenging rate with this compound was 98.0%, 92.3% and 42.1% at concentrations of 100μM, 10μM, and 1μM, respectively, and the initial reaction rate was faster than Trolox at a concentration of 10μM.
|
Inhibition of recombinant human ALR2 assessed as reduction in NADPH oxidation measured for 5 mins in presence of D,L-glyceraldehyde by spectrophotometric method
|
Homo sapiens
|
85.0
nM
|
|
Journal : Eur J Med Chem
Title : Green fluorescent protein chromophore derivatives as a new class of aldose reductase inhibitors.
Year : 2017
Volume : 125
First Page : 965
Last Page : 974
Authors : Saito R, Hoshi M, Kato A, Ishikawa C, Komatsu T.
Abstract : A number of (Z)-4-arylmethylene-1H-imidazol-5(4H)-ones, which are related to the fluorescent chromophore of the Aequorea green fluorescent protein (GFP), have been synthesized and evaluated their in vitro inhibitory activity against recombinant human aldose reductase for the first time. The GFP chromophore model 1a, with a p-hydroxy group on the 4-benzylidene and a carboxymethyl group on the N1 position, exhibited strong bioactivity with an IC50 value of 0.36 μM. This efficacy is higher than that of sorbinil, a known highly potent aldose reductase inhibitor. Compound 1h, the 2-naphtylmethylidene analogue of 1a, exhibited the best inhibitory effect among the tested copounds with an IC50 value of 0.10 μM. Structure-activity relationship studies combined with docking simulations revealed the interaction mode of the newly synthesized inhibitors toward the target protein as well as the structural features required to gain a high inhibitory activity. In conclusion, the GFP chromophore model compounds synthesized in this study have proved to be potential drugs for diabetic complications.
|
Inhibition of rat kidney ALR1 using sodium D-glucuronate as substrate assessed as decrease in NADPH oxidation at 10 uM preincubated for 10 mins followed by substrate addition measured for 5 mins by spectrophotometer
|
Rattus norvegicus
|
70.8
%
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and structure-activity relationship studies of phenolic hydroxyl derivatives based on quinoxalinone as aldose reductase inhibitors with antioxidant activity.
Year : 2017
Volume : 27
Issue : 4
First Page : 887
Last Page : 892
Authors : Hao X, Han Z, Li Y, Li C, Wang X, Zhang X, Yang Q, Ma B, Zhu C.
Abstract : 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 IC50 values ranging from 0.059 to 6.825μM, and 2-(3-(4-hydroxystyryl)-7-methoxy-2-oxoquinoxalin-1(2H)-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.
|
Inhibition of rat lens ALR2 using D,L-glyceraldehyde as substrate assessed as decrease in NADPH oxidation preincubated for 10 mins followed by substrate addition measured for 4 mins by spectrophotometer
|
Rattus norvegicus
|
86.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and structure-activity relationship studies of phenolic hydroxyl derivatives based on quinoxalinone as aldose reductase inhibitors with antioxidant activity.
Year : 2017
Volume : 27
Issue : 4
First Page : 887
Last Page : 892
Authors : Hao X, Han Z, Li Y, Li C, Wang X, Zhang X, Yang Q, Ma B, Zhu C.
Abstract : 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 IC50 values ranging from 0.059 to 6.825μM, and 2-(3-(4-hydroxystyryl)-7-methoxy-2-oxoquinoxalin-1(2H)-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.
|
Inhibition of goat lenses ALR2 using glyceraldehyde as substrate measured for 5 mins by UV-spectrophotometric method
|
Capra hircus
|
90.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of low micromolar dual inhibitors for aldose reductase (ALR2) and poly (ADP-ribose) polymerase (PARP-1) using structure based design approach.
Year : 2017
Volume : 27
Issue : 11
First Page : 2324
Last Page : 2330
Authors : Chadha N, Silakari O.
Abstract : Clinical studies have revealed that diabetic retinopathy is a multifactorial disorder. Moreover, studies also suggest that ALR2 and PARP-1 co-occur in retinal cells, making them appropriate targets for the treatment of diabetic retinopathy. To find the dual inhibitors of ALR2 and PARP-1, the structure based design was carried out in parallel for both the target proteins. A series of novel thiazolidine-2,4-dione (TZD) derivatives were therefore rationally designed, synthesized and their in vitro inhibitory activities against ALR2 and PARP-1 were evaluated. The experimental results showed that compounds 5b and 5f, with 2-chloro and 4-fluoro substitutions, showed biochemical activities in micromolar and submicromolar range (IC50 1.34-5.03μM) against both the targeted enzymes. The structure-activity relationship elucidated for these novel inhibitors against both the enzymes provide new insight into the binding mode of the inhibitors to the active sites of enzymes. The positive results of the biochemical assay suggest that these compounds may be further optimized and utilized for the treatment of diabetic retinopathy.
|
Inhibition of aldose reductase (unknown origin)
|
Homo sapiens
|
93.9
nM
|
|
Journal : Bioorg Med Chem Lett
Title : 1-Acetyl-5-phenyl-1H-pyrrol-3-ylacetate: An aldose reductase inhibitor for the treatment of diabetic nephropathy.
Year : 2017
Volume : 27
Issue : 18
First Page : 4482
Last Page : 4487
Authors : Xiu ZM, Wang LP, Fu J, Xu J, Liu L.
Abstract : Diabetic nephropathy (DN) is the most common and serious complication in diabetes mellitus, but the efficacy of available strategies for preventing this disorder remains poor. The aim of this study was to investigate the possible beneficial effects of 1-acetyl-5-phenyl-1H-pyrrol-3-ylacetate (APPA), an aldose reductase inhibitor, on DN. In the present study, a model of rat glomerular mesangial cells (HBZY-1) damaged by high glucose was used to confirm the protective effects of APPA in vitro. Then, a rat model of streptozotocin-induced diabetes was used to assess the effects of APPA in vivo. APPA increased viability and reduced apoptosis in HBZY-1 cells. In vivo, APPA improved the signs of DN as determined by measurements of blood glucose, urinary microalbumin, serum total antioxidant capacity, serum catalase activity, serum glutathione levels, and serum total superoxide dismutase activity. Hematoxylin and eosin staining of kidney tissue confirmed the protective effect. Moreover, APPA reduced the levels of transforming growth factor-β1, collagen IV, and laminin in HBZY-1cells incubated in high glucose, and in serum in DN rats. In summary, APPA can effectively prevent apoptosis and the symptoms of streptozotocin-induced diabetes by inhibiting the polyol pathway in rats. This suggests that APPA could be a potential drug in treating DN.
|
Inhibition of Sprague-Dawley rat lenses ALR2 using DL-glyceraldehyde as substrate pretreated for 10 mins followed by substrate addition measured for 5 mins by spectrophotometric analysis
|
Rattus norvegicus
|
170.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Quinazolinone-based rhodanine-3-acetic acids as potent aldose reductase inhibitors: Synthesis, functional evaluation and molecular modeling study.
Year : 2017
Volume : 27
Issue : 20
First Page : 4760
Last Page : 4764
Authors : El-Sayed S, Metwally K, El-Shanawani AA, Abdel-Aziz LM, El-Rashedy AA, Soliman MES, Quattrini L, Coviello V, la Motta C.
Abstract : A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat. Structure-activity relationship studies indicated that bulky substituents at the 3-phenyl ring of the quinazolinone moiety are generally not tolerated in the active site of the enzyme. Insertion of a methoxy group on the central benzylidene ring was found to have a variable effect on ALR-2 activity depending on the nature of peripheral quinazolinone ring substituents. Removal of the acetic acid moiety led to inactive or weakly active target compounds. Docking and molecular dynamic simulations of the most active rhodanine-3-acetic acid derivatives were also carried out, to provide the basis for further structure-guided design of novel inhibitors.
|
Inhibition of ALR2 in Wistar rat eye lens assessed as reduction in NADPH consumption preincubated for 1 min followed by D,L-glyceraldehyde addition measured after 4 mins by spectrophotometric analysis
|
Rattus norvegicus
|
227.0
nM
|
|
Journal : Bioorg Med Chem
Title : Structure optimization of tetrahydropyridoindole-based aldose reductase inhibitors improved their efficacy and selectivity.
Year : 2017
Volume : 25
Issue : 24
First Page : 6353
Last Page : 6360
Authors : Majekova M, Ballekova J, Prnova M, Stefek M.
Abstract : In our previous study, tetrahydropyridoindoles carboxymethylated in position 8 were identified as aldose reductase (ALR2) inhibitors with mild efficacy and selectivity yet with significant antioxidant activity. In the present study we proceeded with optimization of the tetrahydropyridoindole scaffold by shifting the carboxymethyl pharmacophore from position 8 to position 5, with the aim to improve the biological activity. Commercial databases were screened for the presence of tetrahydropyridoindoles carboxymethylated in position 5 and an experimental set of eight compounds was created. Mild inhibition characterized by IC50 in micromolar range was recorded for compound 8 with the isopropyl substituent at the piperidine nitrogen (position 2). This alkylated tertiary nitrogen is characterized by a rather high basicity (pKa ∼ 10.4) with complete protonization at physiological pH. On the other hand, ALR2 inhibition activity of the low basicity derivatives 3-7 with an acyl substituted nitrogen in position 2 (pKa ∼ -1 to -3) was characterized with IC50 values in low and medium nanomolar region. Docking into the binding site of human recombinant enzyme AKR1B1 performed for 3 revealed an interaction network responsible for the high affinity and selectivity. In ex vivo experiment, sorbitol accumulation in isolated rat eye lenses was significantly inhibited by 3 in the presence of high glucose, starting at a concentration as low as 0.1 μM. Moreover, in streptozotocin-induced diabetic rats, compound 3 administered intragastrically (i.g., 50 mg/kg/day) for five consecutive days significantly inhibited sorbitol accumulation in red blood cells and the sciatic nerve. Molecular obesity indices predicted along with water solubility point an excellent "lead-likeness" of compound 3, with prospects of further structure optimizations.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
1.25
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of human recombinant aldose reductase expressed in Escherichia coli BL21 (DE3) pLysS assessed as reduction in NADPH oxidation using L-idose as substrate
|
Homo sapiens
|
102.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : An investigation on 4-thiazolidinone derivatives as dual inhibitors of aldose reductase and protein tyrosine phosphatase 1B, in the search for potential agents for the treatment of type 2 diabetes mellitus and its complications.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3712
Last Page : 3720
Authors : Maccari R, Del Corso A, Paoli P, Adornato I, Lori G, Balestri F, Cappiello M, Naß A, Wolber G, Ottanà R.
Abstract : Designed multiple ligands (DMLs), developed to modulate simultaneously a number of selected targets involved in etiopathogenetic mechanisms of a multifactorial disease, such as diabetes mellitus (DM), are considered a promising alternative to combinations of drugs, when monotherapy results to be unsatisfactory. In this work, compounds 1-17 were synthesized and in vitro evaluated as DMLs directed to aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two key enzymes involved in different events which are critical for the onset and progression of type 2 DM and related pathologies. Out of the tested 4-thiazolidinone derivatives, compounds 12 and 16, which exhibited potent AR inhibitory effects along with interesting inhibition of PTP1B, can be assumed as lead compounds to further optimize and balance the dual inhibitory profile. Moreover, several structural portions were identified as features that could be useful to achieve simultaneous inhibition of both human AR and PTP1B through binding to non-catalytic regions of both target enzymes.
|
Inhibition of ALR2 in rat lens assessed as reduction in sorbitol accumulation at 50 uM preincubated for 30 mins followed by D-glucose addition and measured after 3 hrs by resazurin based fluorescence analysis relative to control
|
Rattus norvegicus
|
25.0
%
|
|
Journal : J Med Chem
Title : Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur/Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity.
Year : 2020
Volume : 63
Issue : 1
First Page : 369
Last Page : 381
Authors : Hlaváč M, Kováčiková L, Prnová MŠ, Šramel P, Addová G, Májeková M, Hanquet G, Boháč A, Štefek M.
Abstract : Inhibition of aldose reductase (AR), the first enzyme of the polyol pathway, is a promising approach in treatment of diabetic complications. We proceeded with optimization of the thioxotriazinoindole scaffold of the novel AR inhibitor cemtirestat by replacement of sulfur with oxygen. A series of 2-(3-oxo-2H-[1,2,4]triazino[5,6-b]indol-5(3H)-yl)acetic acid derivatives (OTIs), designed by molecular modeling and docking, were synthesized. More electronegative and less bulky oxygen of OTIs compared to the sulfur of the original thioxotriazinoindole congeners was found to form a stronger H-bond with Leu300 of AR and to render larger rotational flexibility of the carboxymethyl pharmacophore. AR inhibitory activities of the novel compounds were characterized by the IC50 values in a submicromolar range. Markedly enhanced inhibition selectivity relative to the structurally related aldehyde reductase was recorded. To conclude, structure modification of the original carboxymethylated thioxotriazinoindole cemtirestat by isosteric replacement of sulfur with oxygen in combination with variable N(2) simple substituents provided novel analogues with increased AR inhibition efficacy and markedly improved selectivity.
|
Inhibition of human recombinant ALR2 expressed in Escherichia coli using DL-glyceraldehyde as substrate and NADPH at 50 uM preincubated for 5 mins followed by substrate addition and measured after 30 mins at 2 mins interval by spectrophotometry relative to control
|
Homo sapiens
|
90.17
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of human recombinant ALR2 expressed in Escherichia coli using DL-glyceraldehyde as substrate and NADPH preincubated for 5 mins followed by substrate addition and measured after 30 mins at 2 mins interval by spectrophotometry relative to control
|
Homo sapiens
|
620.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of rat kidney ALR1 using DL-glyceraldehyde as substrate and NADPH at 50 uM preincubated for 5 mins followed by substrate addition and measured for 30 mins at 2 mins interval by spectrophotometry relative to control
|
Rattus norvegicus
|
88.24
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat erythrocytes assessed as reduction in sorbitol accumulation at 0.1 uM incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
33.25
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat erythrocytes assessed as reduction in sorbitol accumulation at 1 uM incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
58.46
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat erythrocytes assessed as reduction in sorbitol accumulation at 10 uM incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
77.64
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat erythrocytes assessed as reduction in sorbitol accumulation at 50 uM incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
94.55
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat erythrocytes assessed as reduction in sorbitol accumulation incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
510.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat sciatic nerve assessed as reduction in sorbitol accumulation at 0.1 uM incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
31.27
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat sciatic nerve assessed as reduction in sorbitol accumulation at 1 uM incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
51.39
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat sciatic nerve assessed as reduction in sorbitol accumulation at 10 uM incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
68.45
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat sciatic nerve assessed as reduction in sorbitol accumulation at 50 uM incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
90.43
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat sciatic nerve assessed as reduction in sorbitol accumulation incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis
|
Rattus norvegicus
|
860.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat lens assessed as reduction in sorbitol accumulation at 0.1 uM incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
35.14
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat lens assessed as reduction in sorbitol accumulation at 1 uM incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
56.84
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat lens assessed as reduction in sorbitol accumulation at 10 uM incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
73.14
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat lens assessed as reduction in sorbitol accumulation at 50 uM incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
88.84
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of ALR2 in rat lens assessed as reduction in sorbitol accumulation incubated for 3 hrs in presence of 28 mM glucose by gas chromatographic analysis relative to control
|
Rattus norvegicus
|
530.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Cytotoxicity against HEK293 cells assessed as reduction in cell viability at 25 uM incubated for 48 hrs by MTT assay relative to control
|
Homo sapiens
|
10.32
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Cytotoxicity against HEK293 cells assessed as reduction in cell viability at 50 uM incubated for 48 hrs by MTT assay relative to control
|
Homo sapiens
|
12.03
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Cytotoxicity against HEK293 cells assessed as reduction in cell viability at 100 uM incubated for 48 hrs by MTT assay relative to control
|
Homo sapiens
|
13.73
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Cytotoxicity against HEK293 cells assessed as reduction in cell viability at 200 uM incubated for 48 hrs by MTT assay relative to control
|
Homo sapiens
|
18.28
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of new arylsulfonylspiroimidazolidine-2',4'-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress.
Year : 2019
Volume : 168
First Page : 154
Last Page : 175
Authors : Iqbal Z, Morahan G, Arooj M, Sobolev AN, Hameed S.
Abstract : A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).
|
Inhibition of Wistar rat lens ALR2 using L-glyceraldehyde as substrate preincubated for 10 mins followed by substrate addition and measured for 4 mins by spectrophotometric method
|
Rattus norvegicus
|
31.0
nM
|
|
Journal : Bioorg Med Chem
Title : Designing of acyl sulphonamide based quinoxalinones as multifunctional aldose reductase inhibitors.
Year : 2019
Volume : 27
Issue : 8
First Page : 1658
Last Page : 1669
Authors : Ji Y, Chen X, Chen H, Zhang X, Fan Z, Xie L, Ma B, Zhu C.
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<sub>50</sub> 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.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
17.17
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
11.66
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.75
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.1
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.15
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.25
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.15
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.1
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.25
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of human recombinant AKR1B1 assessed as D,L-glyceraldehyde reduction incubated in sodium phosphate buffer at pH 6.2 in presence of NADPH
|
Homo sapiens
|
110.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Early identification of promiscuous attributes of aldose reductase inhibitors using a DMSO-perturbation assay.
Year : 2020
Volume : 30
Issue : 2
First Page : 126815
Last Page : 126815
Authors : Tomohara K, Hasegawa N, Adachi I, Horino Y, Nose T.
Abstract : Aldose reductase (AR) inhibitors are used clinically to treat long-term diabetic complications. Previous studies reported a series of AR inhibitory candidates, but unfortunately the mode of inhibition was poorly described due mainly to the lack of readily available methods for evaluating the specificity. The present study examined the AR inhibitory effects of novel synthetic hydantoins and their structural relatives, some of which were obtained from chemically engineered extracts of natural plants, and discovered several novel AR inhibitors with moderate inhibitory activity. The identified inhibitors were then subjected to a two-step mechanistic characterization using a detergent-addition assay and our novel dimethyl sulfoxide (DMSO)-perturbation assay. The detergent-addition assay revealed aggregation-based inhibitors, and the subsequent DMSO-perturbation assay identified nonspecific binding inhibitors. Thus, the present study demonstrates the usefulness of the DMSO-perturbation screen for identifying nonspecific binding characteristics of AR inhibitors.
|
Inhibition of human recombinant AKR1B1 assessed as D,L-glyceraldehyde reduction pretreated with 0.3M DMSO followed by compound addition by DMSO-perturbation assay
|
Homo sapiens
|
110.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Early identification of promiscuous attributes of aldose reductase inhibitors using a DMSO-perturbation assay.
Year : 2020
Volume : 30
Issue : 2
First Page : 126815
Last Page : 126815
Authors : Tomohara K, Hasegawa N, Adachi I, Horino Y, Nose T.
Abstract : Aldose reductase (AR) inhibitors are used clinically to treat long-term diabetic complications. Previous studies reported a series of AR inhibitory candidates, but unfortunately the mode of inhibition was poorly described due mainly to the lack of readily available methods for evaluating the specificity. The present study examined the AR inhibitory effects of novel synthetic hydantoins and their structural relatives, some of which were obtained from chemically engineered extracts of natural plants, and discovered several novel AR inhibitors with moderate inhibitory activity. The identified inhibitors were then subjected to a two-step mechanistic characterization using a detergent-addition assay and our novel dimethyl sulfoxide (DMSO)-perturbation assay. The detergent-addition assay revealed aggregation-based inhibitors, and the subsequent DMSO-perturbation assay identified nonspecific binding inhibitors. Thus, the present study demonstrates the usefulness of the DMSO-perturbation screen for identifying nonspecific binding characteristics of AR inhibitors.
|
Inhibition of human recombinant AKR1B1 assessed as D,L-glyceraldehyde reduction pretreated with 0.7M DMSO followed by compound addition by DMSO-perturbation assay
|
Homo sapiens
|
150.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Early identification of promiscuous attributes of aldose reductase inhibitors using a DMSO-perturbation assay.
Year : 2020
Volume : 30
Issue : 2
First Page : 126815
Last Page : 126815
Authors : Tomohara K, Hasegawa N, Adachi I, Horino Y, Nose T.
Abstract : Aldose reductase (AR) inhibitors are used clinically to treat long-term diabetic complications. Previous studies reported a series of AR inhibitory candidates, but unfortunately the mode of inhibition was poorly described due mainly to the lack of readily available methods for evaluating the specificity. The present study examined the AR inhibitory effects of novel synthetic hydantoins and their structural relatives, some of which were obtained from chemically engineered extracts of natural plants, and discovered several novel AR inhibitors with moderate inhibitory activity. The identified inhibitors were then subjected to a two-step mechanistic characterization using a detergent-addition assay and our novel dimethyl sulfoxide (DMSO)-perturbation assay. The detergent-addition assay revealed aggregation-based inhibitors, and the subsequent DMSO-perturbation assay identified nonspecific binding inhibitors. Thus, the present study demonstrates the usefulness of the DMSO-perturbation screen for identifying nonspecific binding characteristics of AR inhibitors.
|
Inhibition of AKR1B10 (unknown origin) pretreated with 0.25M DMSO followed by compound treatment by DMSO-perturbation assay
|
Homo sapiens
|
35.2
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Early identification of promiscuous attributes of aldose reductase inhibitors using a DMSO-perturbation assay.
Year : 2020
Volume : 30
Issue : 2
First Page : 126815
Last Page : 126815
Authors : Tomohara K, Hasegawa N, Adachi I, Horino Y, Nose T.
Abstract : Aldose reductase (AR) inhibitors are used clinically to treat long-term diabetic complications. Previous studies reported a series of AR inhibitory candidates, but unfortunately the mode of inhibition was poorly described due mainly to the lack of readily available methods for evaluating the specificity. The present study examined the AR inhibitory effects of novel synthetic hydantoins and their structural relatives, some of which were obtained from chemically engineered extracts of natural plants, and discovered several novel AR inhibitors with moderate inhibitory activity. The identified inhibitors were then subjected to a two-step mechanistic characterization using a detergent-addition assay and our novel dimethyl sulfoxide (DMSO)-perturbation assay. The detergent-addition assay revealed aggregation-based inhibitors, and the subsequent DMSO-perturbation assay identified nonspecific binding inhibitors. Thus, the present study demonstrates the usefulness of the DMSO-perturbation screen for identifying nonspecific binding characteristics of AR inhibitors.
|
Inhibition of AKR1B10 (unknown origin) pretreated with 0.42M DMSO followed by compound treatment by DMSO-perturbation assay
|
Homo sapiens
|
39.3
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Early identification of promiscuous attributes of aldose reductase inhibitors using a DMSO-perturbation assay.
Year : 2020
Volume : 30
Issue : 2
First Page : 126815
Last Page : 126815
Authors : Tomohara K, Hasegawa N, Adachi I, Horino Y, Nose T.
Abstract : Aldose reductase (AR) inhibitors are used clinically to treat long-term diabetic complications. Previous studies reported a series of AR inhibitory candidates, but unfortunately the mode of inhibition was poorly described due mainly to the lack of readily available methods for evaluating the specificity. The present study examined the AR inhibitory effects of novel synthetic hydantoins and their structural relatives, some of which were obtained from chemically engineered extracts of natural plants, and discovered several novel AR inhibitors with moderate inhibitory activity. The identified inhibitors were then subjected to a two-step mechanistic characterization using a detergent-addition assay and our novel dimethyl sulfoxide (DMSO)-perturbation assay. The detergent-addition assay revealed aggregation-based inhibitors, and the subsequent DMSO-perturbation assay identified nonspecific binding inhibitors. Thus, the present study demonstrates the usefulness of the DMSO-perturbation screen for identifying nonspecific binding characteristics of AR inhibitors.
|
Inhibition of AKR1B1 in rat lenses
|
Rattus norvegicus
|
81.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Novel quinolin-4(1H)-one derivatives as multi-effective aldose reductase inhibitors for treatment of diabetic complications: Synthesis, biological evaluation, and molecular modeling studies.
Year : 2020
Volume : 30
Issue : 9
First Page : 127101
Last Page : 127101
Authors : Han Z, Zhu J, Zhang Y, Zhang Y, Zhang H, Qi G, Zhu C, Hao X.
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Inhibition of AKR1A1 in rat kidney at 10 uM relative to control
|
Rattus norvegicus
|
43.1
%
|
|
Journal : Bioorg Med Chem Lett
Title : Novel quinolin-4(1H)-one derivatives as multi-effective aldose reductase inhibitors for treatment of diabetic complications: Synthesis, biological evaluation, and molecular modeling studies.
Year : 2020
Volume : 30
Issue : 9
First Page : 127101
Last Page : 127101
Authors : Han Z, Zhu J, Zhang Y, Zhang Y, Zhang H, Qi G, Zhu C, Hao X.
|
Inhibition of rat lens ALR2 using D,L-glyceraldehyde as substrate preincubated for 5 mins at 30 degC followed by substrate addition and measured after 4 mins in presence of NADPH
|
Rattus norvegicus
|
45.0
nM
|
|
Journal : Bioorg Med Chem
Title : Dihydrobenzoxazinone derivatives as aldose reductase inhibitors with antioxidant activity.
Year : 2020
Volume : 28
Issue : 20.0
First Page : 115699
Last Page : 115699
Authors : Chen H,Zhang X,Zhang X,Fan Z,Liu W,Lei Y,Zhu C,Ma B
Abstract : 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 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.
|
Inhibition of recombinant human ALR2 using D,L-glyceraldehyde and NADPH as substrate preincubated for 3 mins followed by substrate addition and measured for 3 mins by spectrophotometric analysis
|
Homo sapiens
|
66.5
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Pterin-7-carboxamides as a new class of aldose reductase inhibitors.
Year : 2016
Volume : 26
Issue : 20.0
First Page : 4870
Last Page : 4874
Authors : Saito R,Suzuki S,Sasaki K
Abstract : Aldose reductase is related to the onset and progression of diabetic complications, such as neuropathy, retinopathy, angiopathy, and so on: therefore molecules that are capable of inhibiting the enzyme are potential drugs for treatment of diabetic complications. Epalrestat is the sole aldose reductase inhibitor that is clinically used, but still has some drawbacks. Thus, the development of new aldose reductase inhibitors is still desired. We have synthesized a series of new pterin-7-carboxamides, and evaluated their in vitro inhibitory activities against human aldose reductase. All newly synthesized compounds exhibited the inhibitory activity. Among them, 1a having a glycine side chain exhibits the highest activity comparable to that of sorbinil, a highly active aldose reductase inhibitor. Molecular docking of 1a on the active site of the enzyme indicated this compound interacts with amino acid residues that are specific to the enzyme and related to suppressing side effects. Based on these results, we proved perin-7-carboxamides to be a new class of aldose reductase inhibitors, and particularly compound 1a was found to be a good candidate for further biological investigations as a drug for treatment of diabetic complications with fewer side effects.
|
Inhibition of Wistar rat lens ALR2 assessed as reduction in NADPH oxidation using D,L-glyceraldehyde and NADPH as substrate preincubated for 10 mins followed by substrate addition and measured for 4 mins by spectrophotometric analysis
|
Rattus norvegicus
|
108.1
nM
|
|
Journal : Eur J Med Chem
Title : Multifunctional agents based on benzoxazolone as promising therapeutic drugs for diabetic nephropathy.
Year : 2021
Volume : 215
First Page : 113269
Last Page : 113269
Authors : Zhang X,Chen H,Lei Y,Zhang X,Xu L,Liu W,Fan Z,Ma Z,Yin Z,Li L,Zhu C,Ma B
Abstract : 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.
|
Antioxidant activity in STZ-induced diabetic Kunming mouse assessed as reduction in liver MDA level at 80 mg/kg, po administered daily via gavage for 8 weeks and measured at 6 hrs post-final drug dose relative to STZ-treated group
|
Mus musculus
|
65.0
%
|
|
Journal : Eur J Med Chem
Title : Multifunctional agents based on benzoxazolone as promising therapeutic drugs for diabetic nephropathy.
Year : 2021
Volume : 215
First Page : 113269
Last Page : 113269
Authors : Zhang X,Chen H,Lei Y,Zhang X,Xu L,Liu W,Fan Z,Ma Z,Yin Z,Li L,Zhu C,Ma B
Abstract : 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.
|
Inhibition of ALR2 in Wistar rat lens assessed as reduction in NADPH consumption using D,L-glyceraldehyde and NADPH as substrate preincubated for 1 mins followed by substrate addition and measured upto 4 mins by spectrophotometric analysis
|
Rattus norvegicus
|
227.0
nM
|
|
