|
In vitro inhibitory concentration against Xanthine oxidase
|
Bos taurus
|
260.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of 1-phenylpyrazoles as xanthine oxidase inhibitors.
Year : 2001
Volume : 11
Issue : 7
First Page : 879
Last Page : 882
Authors : Ishibuchi S, Morimoto H, Oe T, Ikebe T, Inoue H, Fukunari A, Kamezawa M, Yamada I, Naka Y.
Abstract : A series of 1-phenylpyrazoles was evaluated for inhibitory activity against xanthine oxidase in vitro. Of the compounds prepared, 1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid (Y-700) had the most potent enzyme inhibition and displayed longer-lasting hypouricemic action than did allopurinol in a rat model of hyperuricemia induced by the uricase inhibitor potassium oxonate.
|
Inhibition of human xanthine oxidase at 30 uM
|
Homo sapiens
|
93.8
%
|
|
Journal : Bioorg. Med. Chem.
Title : The screening and characterization of 6-aminopurine-based xanthine oxidase inhibitors.
Year : 2007
Volume : 15
Issue : 10
First Page : 3450
Last Page : 3456
Authors : Hsieh JF, Wu SH, Yang YL, Choong KF, Chen ST.
Abstract : Xanthine oxidase (XO) is a key enzyme which can catalyze xanthine to uric acid causing hyperuricemia in humans. By using the fractionation technique and inhibitory activity assay, an active compound that prevents XO from reacting with xanthine was isolated from wheat leaf. It was identified by the Mass and NMR as 6-aminopurine (adenine). A structure-activity study based on 6-aminopurine was conducted. The inhibition of XO activity by 6-aminopurine (IC(50)=10.89+/-0.13 microM) and its analogues was compared with that by allopurinol (IC(50)=7.82+/-0.12 microM). Among these analogues, 2-chloro-6(methylamino)purine (IC(50)=10.19+/-0.10 microM) and 4-aminopyrazolo[3,4-d] pyrimidine (IC(50)=30.26+/-0.23 microM) were found to be potent inhibitors of XO. Kinetics study showed that 2-chloro-6(methylamino)purine is non-competitive, while 4-aminopyrazolo[3,4-d]pyrimidine is competitive against XO.
|
Antioxidant activity assessed as inhibition of xanthine-xanthine oxidase generated superoxide anion radical production at 0.5 mM
|
None
|
42.3
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and free radical scavenging activity of some new spiropyranocoumarins.
Year : 2008
Volume : 18
Issue : 21
First Page : 5781
Last Page : 5781
Authors : Panteleon V, Kostakis IK, Marakos P, Pouli N, Andreadou I.
Abstract : A series of novel spiro-substituted 4-hydroxypyranocoumarins and their corresponding dihydropyrano cis-diols has been synthesized. Among them the spiroadamantylpyranocoumarin and the diols can interact with the stable free radical 1,1-diphenyl-2-picrylhydrazyl and scavenge superoxide anions generated in the xanthine-xanthine oxidase system.
|
Inhibition of xanthine oxidase at 100 uM
|
None
|
96.3
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of N-aryl-5-amino-4-cyanopyrazole derivatives as potent xanthine oxidase inhibitors.
Year : 2008
Volume : 43
Issue : 4
First Page : 771
Last Page : 780
Authors : Gupta S, Rodrigues LM, Esteves AP, Oliveira-Campos AM, Nascimento MS, Nazareth N, Cidade H, Neves MP, Fernandes E, Pinto M, Cerqueira NM, Brás N.
Abstract : Some pyrazolo[3,4-d]pyrimidines, structurally related with allopurinol, a well known xanthine oxidase inhibitor, clinically used in the therapy of gout, have also been reported as potent inhibitors of xanthine oxidase and the growth of several human tumour cell lines. Considering the potential interest of this family of compounds, the aim of the present study was to synthesise and provide a full chemical characterization of new N-aryl-5-amino-4-cyanopyrazole derivatives and their corresponding pyrazolo[3,4-d]pyrimidines. Their biological activity pertaining to the xanthine oxidase inhibition and effect on the growth of three tumour cell lines (MCF-7, NCI-H460, and SF-268) are also provided. With only one exception, the synthesised compounds showed no effect on the growth of the three tumour cell lines. However, a strong xanthine oxidase inhibitory activity was observed for almost all pyrazolo[3,4-d]pyrimidines tested, revealing some of them IC(50) values below 1 microM. The results of the molecular docking studies of these compounds, against xanthine oxidoreductase are also described, providing an atomistic explanation of the differences in the inhibitory efficiency. MEP calculations were used to explain different inhibitory efficiency of similar inhibitors.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
7.7
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Antioxidant activity assessed as inhibition of superoxide at 20 ug/mL
|
None
|
90.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Novel keto-enamine Schiffs bases from 7-hydroxy-4-methyl-2-oxo-2H-benzo[h] chromene-8,10-dicarbaldehyde as potential antidyslipidemic and antioxidant agents.
Year : 2008
Volume : 43
Issue : 11
First Page : 2592
Last Page : 2596
Authors : Sashidhara KV, Rosaiah JN, Bhatia G, Saxena JK.
Abstract : A series of Schiff bases have been synthesized from dicarbaldehyde of benzocoumarin, in which the reactions were regioselective and the products existed in the keto-enamine form, in which the aromaticity of the relevant ring was disrupted. The compounds were evaluated in vitro for their antioxidant and in vivo for their antidyslipidemic activity for the first time. Compounds 3 and 7 possess significant lipid lowering and antioxidant activity.
|
Inhibition of xanthine oxidase assessed as decrease in uric acid production by spectrophotometry
|
None
|
240.0
nM
|
|
Journal : J. Nat. Prod.
Title : Structure-activity relationship and classification of flavonoids as inhibitors of xanthine oxidase and superoxide scavengers.
Year : 1998
Volume : 61
Issue : 1
First Page : 71
Last Page : 76
Authors : Cos P, Ying L, Calomme M, Hu JP, Cimanga K, Van Poel B, Pieters L, Vlietinck AJ, Vanden Berghe D.
Abstract : The structure-activity relationship of flavonoids as inhibitors of xanthine oxidase and as scavengers of the superoxide radical, produced by the action of the enzyme xanthine oxidase, was investigated. The hydroxyl groups at C-5 and C-7 and the double bond between C-2 and C-3 were essential for a high inhibitory activity on xanthine oxidase. Flavones showed slightly higher inhibitory activity than flavonols. All flavonoid derivatives except isorhamnetin (30) were less active than the original compounds. For a high superoxide scavenging activity on the other hand, a hydroxyl group at C-3' in ring B and at C-3 were essential. According to their effect on xanthine oxidase and as superoxide scavengers, the flavonoids could be classified into six groups: superoxide scavengers without inhibitory activity on xanthine oxidase (category A), xanthine oxidase inhibitors without any additional superoxide scavenging activity (category B), xanthine oxidase inhibitors with an additional superoxide scavenging activity (category C), xanthine oxidase inhibitors with an additional pro-oxidant effect on the production of superoxide (category D), flavonoids with a marginal effect on xanthine oxidase but with a prooxidant effect on the production of superoxide (category E), and finally, flavonoids with no effect on xanthine oxidase or superoxide (category F).
|
Antioxidant activity assessed as superoxide-scavenging activity by nitrite method
|
None
|
230.0
nM
|
|
Journal : J. Nat. Prod.
Title : Structure-activity relationship and classification of flavonoids as inhibitors of xanthine oxidase and superoxide scavengers.
Year : 1998
Volume : 61
Issue : 1
First Page : 71
Last Page : 76
Authors : Cos P, Ying L, Calomme M, Hu JP, Cimanga K, Van Poel B, Pieters L, Vlietinck AJ, Vanden Berghe D.
Abstract : The structure-activity relationship of flavonoids as inhibitors of xanthine oxidase and as scavengers of the superoxide radical, produced by the action of the enzyme xanthine oxidase, was investigated. The hydroxyl groups at C-5 and C-7 and the double bond between C-2 and C-3 were essential for a high inhibitory activity on xanthine oxidase. Flavones showed slightly higher inhibitory activity than flavonols. All flavonoid derivatives except isorhamnetin (30) were less active than the original compounds. For a high superoxide scavenging activity on the other hand, a hydroxyl group at C-3' in ring B and at C-3 were essential. According to their effect on xanthine oxidase and as superoxide scavengers, the flavonoids could be classified into six groups: superoxide scavengers without inhibitory activity on xanthine oxidase (category A), xanthine oxidase inhibitors without any additional superoxide scavenging activity (category B), xanthine oxidase inhibitors with an additional superoxide scavenging activity (category C), xanthine oxidase inhibitors with an additional pro-oxidant effect on the production of superoxide (category D), flavonoids with a marginal effect on xanthine oxidase but with a prooxidant effect on the production of superoxide (category E), and finally, flavonoids with no effect on xanthine oxidase or superoxide (category F).
|
Inhibition of XOD
|
None
|
180.0
nM
|
|
Journal : J. Nat. Prod.
Title : Chemical constituents from the aerial parts of Artemisia minor.
Year : 2009
Volume : 72
Issue : 6
First Page : 1198
Last Page : 1201
Authors : He ZZ, Yan JF, Song ZJ, Ye F, Liao X, Peng SL, Ding LS.
Abstract : Four new compounds including three bicoumarins, arteminorins A-C (1-3), and one neolignan, arteminorin D (4), together with 31 known ones were isolated from the aerial parts of Artemisia minor. Their structures were established on the basis of spectroscopic data and comparison with those of the related known compounds. Ethyl caffeate (27) showed in vitro cytotoxicity against the HepG2 cancer cell line. Arteminorin C (3) and luteolin (19) showed inhibitory activity on xanthine oxidase (XOD), and caffeic acid (28) exhibited inhibitory activity on protein tyrosine phosphatase 1B (PTP1B).
|
Antioxidant activity assessed as inhibition non-enzymatic reactants generated superoxide anion at 20 ug/ml by spectrophotometry
|
None
|
80.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel coumarin derivatives as potential antidyslipidemic agents.
Year : 2010
Volume : 20
Issue : 14
First Page : 4248
Last Page : 4251
Authors : Sashidhara KV, Kumar A, Kumar M, Sonkar R, Bhatia G, Khanna AK.
Abstract : A series of novel benzocoumarin derivatives were synthesized and evaluated for their in vivo antidyslipidemic and in vitro antioxidant activities. Among 11 compounds tested, 2 compounds showed potent antidyslipidemic activity and 3 compounds showed potent antioxidant activity.
|
Inhibition of rat liver xanthine oxidase by spectrophotometry
|
Rattus norvegicus
|
753.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and xanthine oxidase inhibitory activity of 7-methyl-2-(phenoxymethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives.
Year : 2011
Volume : 19
Issue : 1
First Page : 211
Last Page : 220
Authors : Sathisha KR, Khanum SA, Chandra JN, Ayisha F, Balaji S, Marathe GK, Gopal S, Rangappa KS.
Abstract : An elevated level of blood uric acid (hyperuricemia) is the underlying cause of gout. Xanthine oxidase is the key enzyme that catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid. Allopurinol, a widely used xanthine oxidase inhibitor is the most commonly used drug to treat gout. However, a small but significant portion of the population suffers from adverse effects of allopurinol that includes gastrointestinal upset, skin rashes and hypersensitivity reactions. Moreover, an elevated level of uric acid is considered as an independent risk factor for cardiovascular diseases. Therefore use of allopurinol-like drugs with minimum side effects is the ideal drug of choice against gout. In this study, we report the synthesis of a series of pyrimidin-5-one analogues as effective and a new class of xanthine oxidase inhibitors. All the synthesized pyrimidin-5-one analogues are characterized by spectroscopic techniques and elemental analysis. Four (6a, 6b, 6d and 6f) out of 20 synthesized molecules in this class showed good inhibition against three different sources of xanthine oxidase, which were more potent than allopurinol based on their respective IC(50) values. Molecular modeling and docking studies revealed that the molecule 6a has very good interactions with the Molybdenum-Oxygen-Sulfur (MOS) complex a key component in xanthine oxidase. These results highlight the identification of a new class of xanthine oxidase inhibitors that have potential to be more efficacious, than allopurinol, to treat gout and possibly against cardiovascular diseases.
|
Inhibition of bovine milk xanthine oxidase by spectrophotometry
|
Bos taurus
|
730.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and xanthine oxidase inhibitory activity of 7-methyl-2-(phenoxymethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives.
Year : 2011
Volume : 19
Issue : 1
First Page : 211
Last Page : 220
Authors : Sathisha KR, Khanum SA, Chandra JN, Ayisha F, Balaji S, Marathe GK, Gopal S, Rangappa KS.
Abstract : An elevated level of blood uric acid (hyperuricemia) is the underlying cause of gout. Xanthine oxidase is the key enzyme that catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid. Allopurinol, a widely used xanthine oxidase inhibitor is the most commonly used drug to treat gout. However, a small but significant portion of the population suffers from adverse effects of allopurinol that includes gastrointestinal upset, skin rashes and hypersensitivity reactions. Moreover, an elevated level of uric acid is considered as an independent risk factor for cardiovascular diseases. Therefore use of allopurinol-like drugs with minimum side effects is the ideal drug of choice against gout. In this study, we report the synthesis of a series of pyrimidin-5-one analogues as effective and a new class of xanthine oxidase inhibitors. All the synthesized pyrimidin-5-one analogues are characterized by spectroscopic techniques and elemental analysis. Four (6a, 6b, 6d and 6f) out of 20 synthesized molecules in this class showed good inhibition against three different sources of xanthine oxidase, which were more potent than allopurinol based on their respective IC(50) values. Molecular modeling and docking studies revealed that the molecule 6a has very good interactions with the Molybdenum-Oxygen-Sulfur (MOS) complex a key component in xanthine oxidase. These results highlight the identification of a new class of xanthine oxidase inhibitors that have potential to be more efficacious, than allopurinol, to treat gout and possibly against cardiovascular diseases.
|
Inhibition of microbial xanthine oxidase by spectrophotometry
|
None
|
730.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and xanthine oxidase inhibitory activity of 7-methyl-2-(phenoxymethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives.
Year : 2011
Volume : 19
Issue : 1
First Page : 211
Last Page : 220
Authors : Sathisha KR, Khanum SA, Chandra JN, Ayisha F, Balaji S, Marathe GK, Gopal S, Rangappa KS.
Abstract : An elevated level of blood uric acid (hyperuricemia) is the underlying cause of gout. Xanthine oxidase is the key enzyme that catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid. Allopurinol, a widely used xanthine oxidase inhibitor is the most commonly used drug to treat gout. However, a small but significant portion of the population suffers from adverse effects of allopurinol that includes gastrointestinal upset, skin rashes and hypersensitivity reactions. Moreover, an elevated level of uric acid is considered as an independent risk factor for cardiovascular diseases. Therefore use of allopurinol-like drugs with minimum side effects is the ideal drug of choice against gout. In this study, we report the synthesis of a series of pyrimidin-5-one analogues as effective and a new class of xanthine oxidase inhibitors. All the synthesized pyrimidin-5-one analogues are characterized by spectroscopic techniques and elemental analysis. Four (6a, 6b, 6d and 6f) out of 20 synthesized molecules in this class showed good inhibition against three different sources of xanthine oxidase, which were more potent than allopurinol based on their respective IC(50) values. Molecular modeling and docking studies revealed that the molecule 6a has very good interactions with the Molybdenum-Oxygen-Sulfur (MOS) complex a key component in xanthine oxidase. These results highlight the identification of a new class of xanthine oxidase inhibitors that have potential to be more efficacious, than allopurinol, to treat gout and possibly against cardiovascular diseases.
|
Antioxidant activity assessed as inhibition of xanthine-xanthine oxidase generated superoxide anion radical production assessed as formazone formation at 20 ug/ml after 30 mins by spectrophotometric analysis
|
None
|
42.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and anti-inflammatory activity of novel biscoumarin-chalcone hybrids.
Year : 2011
Volume : 21
Issue : 15
First Page : 4480
Last Page : 4484
Authors : Sashidhara KV, Kumar M, Modukuri RK, Sonkar R, Bhatia G, Khanna AK, Rai S, Shukla R.
Abstract : A series of synthesized novel biscoumarin-chalcone hybrids were evaluated for their anti-inflammatory and antioxidant activity. The tested compounds significantly inhibit the carrageenin induced paw oedema in albino rats and also exhibit important scavenging activities. These compounds thus constitute an interesting template for the design of new therapeutic tools against inflammation.
|
Inhibition of bovine xanthine oxidase assessed as uric acid formation using xanthine as substrate at 10 uM after 30 mins by spectrophotometric analysis
|
Bos taurus
|
100.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Identification of novel isocytosine derivatives as xanthine oxidase inhibitors from a set of virtual screening hits.
Year : 2012
Volume : 20
Issue : 9
First Page : 2930
Last Page : 2939
Authors : B-Rao C, Kulkarni-Almeida A, Katkar KV, Khanna S, Ghosh U, Keche A, Shah P, Srivastava A, Korde V, Nemmani KV, Deshmukh NJ, Dixit A, Brahma MK, Bahirat U, Doshi L, Sharma R, Sivaramakrishnan H.
Abstract : In recent years, xanthine oxidase has emerged as an important target not only for gout but also for cardiovascular and metabolic disorders involving hyperuricemia. Contrary to popular belief, recent clinical trials with uricosurics have demonstrated that enhanced excretion of uric acid is, by itself, not adequate to treat hyperuricemia; simultaneous inhibition of production of uric acid by inhibition of xanthine oxidase is also important. Virtual screening of in-house synthetic library followed by in vitro and in vivo testing led to the identification of a novel scaffold for xanthine oxidase inhibition. In vitro activity results corroborated the results from molecular docking studies of the virtual screening hits. The isocytosine scaffold maintains key hydrogen bonding and pi-stacking interactions in the deep end of the xanthine-binding pocket, which anchors it in an appropriate pose to inhibit binding of xanthine and shows promise for further lead optimization using structure-based drug design approach.
|
Inhibition of xanthine oxidase- mediated uric acid formation after 5 mins by spectrophotometry
|
None
|
0.53
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Xanthine oxidase inhibitory activity of constituents of Cinnamomum cassia twigs.
Year : 2012
Volume : 22
Issue : 14
First Page : 4625
Last Page : 4628
Authors : Ngoc TM, Khoi NM, Ha do T, Nhiem NX, Tai BH, Don DV, Luong HV, Son DC, Bae K.
Abstract : A methanol extract of the twigs of Cinnamomum cassia was found to inhibit xanthine oxidase. Purification of the methanol extract afforded three new phenolic glycosides, cinnacasolide A-C (11-13), together with 10 known compounds (1-10). The structures of the three new compounds were determined by interpretation of spectroscopic data. Cinnamaldehyde derivatives 1-5 and 7 were significant inhibitors of xanthine oxidase, with IC(50) values ranging from 7.8 to 36.3 μg/mL. The results indicate that the acyl group of these cinnamaldehyde derivatives plays an important role in the inhibition of xanthine oxidase.
|
Antioxidant activity assessed as inhibition of superoxide anion radical generation at 200 ug/ml by spectrophotometry
|
None
|
41.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of amide based fibrates as possible antidyslipidemic and antioxidant agents.
Year : 2012
Volume : 57
First Page : 302
Last Page : 310
Authors : Sashidhara KV, Palnati GR, Dodda RP, Sonkar R, Khanna AK, Bhatia G.
Abstract : A novel series of amide based fibrates were synthesized and evaluated for antidyslipidemic activity in triton induced hyperlipidemic rats. Interestingly, the compound 13 produced striking reduction in serum levels of total cholesterol (TC), phospholipids (PL) and triglycerides (TG). In addition, it exhibited improved lipoprotein lipase activity and found to possess moderate radical scavenging potential. The results of the above studies shows that the compounds synthesized on fibrate based pharmacophores might result in identification of new lead for dyslipidemia.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
-35.6
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
10.8
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
8.4
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of Oryctolagus cuniculus (rabbit) AOX in liver cytosol at IC50 concentration
|
Oryctolagus cuniculus
|
18.0
%
|
|
Journal : J Agric Food Chem
Title : Neonicotinoid insecticides: oxidative stress in planta and metallo-oxidase inhibition.
Year : 2011
Volume : 59
Issue : 9
First Page : 4860
Last Page : 4867
Authors : Ford KA, Gulevich AG, Swenson TL, Casida JE.
Abstract : Neonicotinoids not only control insect pests but also sometimes independently alter plant growth and response to stress. We find that imidacloprid, thiacloprid, acetamiprid, thiamethoxam, and clothianidin but not nitenpyram and dinotefuran induce foliar lesions and peroxidative damage in soybean ( Glycine max ) seedlings assayed with the 3,3'-diaminobenzidine stain. The chloropyridinyl-carboxylic acid (COOH) but not the -carboxaldehyde (CHO) metabolites induce peroxidative damage but in a different pattern. Surprisingly, the chlorothiazolyl -CHO and -COOH metabolites induce chlorosis but no clear superimposable peroxidative damage or cell death. Four metallo-oxidases known to modulate reactive oxygen species were not sensitive in vitro to the parent neonicotinoid itself but were to several CHO and COOH metabolites and related compounds, with a sensitivity order of CHO > COOH and tyrosinase > xanthine oxidase and aldehyde oxidase > catalase. Although metallo-oxidase inhibition does not correlate overall with lesion formation, it may play an as yet unknown role in plant response to neonicotinoids.
|
Inhibition of Agaricus bisporus (mushroom) tyrosinase at IC50 concentration
|
Agaricus bisporus
|
4.0
%
|
|
Journal : J Agric Food Chem
Title : Neonicotinoid insecticides: oxidative stress in planta and metallo-oxidase inhibition.
Year : 2011
Volume : 59
Issue : 9
First Page : 4860
Last Page : 4867
Authors : Ford KA, Gulevich AG, Swenson TL, Casida JE.
Abstract : Neonicotinoids not only control insect pests but also sometimes independently alter plant growth and response to stress. We find that imidacloprid, thiacloprid, acetamiprid, thiamethoxam, and clothianidin but not nitenpyram and dinotefuran induce foliar lesions and peroxidative damage in soybean ( Glycine max ) seedlings assayed with the 3,3'-diaminobenzidine stain. The chloropyridinyl-carboxylic acid (COOH) but not the -carboxaldehyde (CHO) metabolites induce peroxidative damage but in a different pattern. Surprisingly, the chlorothiazolyl -CHO and -COOH metabolites induce chlorosis but no clear superimposable peroxidative damage or cell death. Four metallo-oxidases known to modulate reactive oxygen species were not sensitive in vitro to the parent neonicotinoid itself but were to several CHO and COOH metabolites and related compounds, with a sensitivity order of CHO > COOH and tyrosinase > xanthine oxidase and aldehyde oxidase > catalase. Although metallo-oxidase inhibition does not correlate overall with lesion formation, it may play an as yet unknown role in plant response to neonicotinoids.
|
Antioxidant activity assessed as inhibition of xanthine-xanthine oxidase generated superoxide anion radical production at 200 ug/ml after 30 min by NBT reduction assay
|
None
|
-77.0
%
|
|
Journal : Med Chem Res
Title : Lipid lowering and antioxidant activity of flavones in triton treated hyperlipidemic rats
Year : 2011
Volume : 20
Issue : 9
First Page : 1622
Last Page : 1626
Authors : Bhatia G, Khanna AK, Sonkar R, Mishra SK, Srivastava S, Lakshmi V
|
Antioxidant activity assessed as inhibition of xanthine oxidase-mediated superoxide anion release at 20 ug/ml after 30 min relative to control
|
None
|
-83.0
%
|
|
Journal : Med Chem Res
Title : Expedient synthesis of some novel pregnane derivatives and their evaluation as anti-oxidant and anti-dyslipidemic agents
Year : 2011
Volume : 20
Issue : 1
First Page : 36
Last Page : 46
Authors : Sethi A, Bhatia G, Khanna AK, Khan MM, Bishnoi A, Pandey AK, Maurya A
|
Inhibition of xanthine oxidase (unknown origin) using xanthine as substrate assessed as uric acid formation preincubated for 5 mins followed by substrate addition measured every minute up to 8 mins by spectrophotometric analysis
|
Homo sapiens
|
1.6
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of pyrazolo[4,3-d]pyrimidine analogues.
Year : 2013
Volume : 67
First Page : 152
Last Page : 157
Authors : Yuan L, Song C, Li C, Li Y, Dong L, Yin S.
Abstract : A series of pyrazolo[3,4-d]pyrimidine analogues 3, 4, 5a-f, 6a-f with various amines and ester groups at C-4 and N-1 were synthesized and evaluated for antitumour activity. They were also evaluated for xanthine oxidase inhibitory activity, with most compounds having no significant impact. Compound 5e had the strongest activity against human hepatoma carcinoma cells 7402 and 7221, with half-maximal inhibitory concentration values of 4.55 and 6.28, respectively. Structure-activity relationship studies indicate that chlorine atoms in the structure of 4-((4-(substituted amides)phenyl)amino pyrazolo[4,3-d]pyrimidine analogues is crucial for antitumour activity.
|
Antioxidant activity assessed as inhibition of superoxide anion generation at 200 ug/mL after 30 mins by NBT reduction assay relative to control
|
None
|
51.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Hybrid benzofuran-bisindole derivatives: new prototypes with promising anti-hyperlipidemic activities.
Year : 2013
Volume : 68
First Page : 38
Last Page : 46
Authors : Sashidhara KV, Modukuri RK, Sonkar R, Rao KB, Bhatia G.
Abstract : A series of different benzofuran-bisindole hybrids were synthesized and evaluated in vitro for their antioxidant and in vivo for antidyslipidemic activity in triton WR-1339 induced hyperlipidemic rats. Among the series, compounds 4a, 4c, 4h and 4j showed significant decrease in plasma levels of total cholesterol (TC), phospholipids (PL) and triglycerides (TG) followed by increase in post heparin lipolytic activity (PHLA). In addition, the active hybrids possessed moderate antioxidant properties and increased the plasma lecithin cholesterol acyltransferase (LCAT) activity, which plays a key role in lipoprotein metabolism contributing to an increased level of HDL-C in serum. These results indicate that these hybrids constitute novel prototypes for the management of dyslipidemia.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
68.8
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
84.36
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of bovine milk xanthine oxidase using xanthine as substrate at 10 times I50 preincubated for 1 hr at 4 degC measured after 10 fold dilution relative to control
|
Bos taurus
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and enzymic activity of some novel xanthine oxidase inhibitors. 3-Substituted 5,7-dihydroxypyrazolo(1,5-alpha)pyrimidines.
Year : 1976
Volume : 19
Issue : 2
First Page : 291
Last Page : 296
Authors : Springer RH, Dimmitt MK, Novinson T, O'Brien DE, Robins RK, Simon LN, Miller JP.
Abstract : A series of 3-substituted 5,7-dihydroxypyrazolo[1,5-alpha]pyrimidines containing various aromatic [phenyl- (3e), 3-pyridyl- (3f), p-bromophenyl- (3g), p-chlorophenyl- (3h), p-acetamidophenyl- (3i), p-tolyl- (3j), m-tolyl- (3k), 3,4-methylenedioxyphenyl- (3m), or naphthyl- (3n)] or nonaromatic [hydrogen- (3a), nitro- (3b), bromo- (3c), or chloro- (3d)] substituents in the 3 position was synthesized and tested as inhibitors of xanthine oxidase. The compounds (3a-m) were synthesized by condensation of the appropriate 3-amino-4-substituted pyrazole with diethyl malonate in alcoholic sodium methoxide and neutralization of the resulting enol sodium salts. As inhibitors of xanthine oxidase, 3e-n greater than 3a,c,d congruent to allopurinol greater than 3b. The 3-aryl-substituted compounds 3e-n were 30-160 times better xanthine oxidase inhibitors than allopurinol using hypoxanthine as substrate and 10-80 times better using xanthine as substrate, as evidenced by a comparison of Ki values. The inhibition by all compounds (3a-n) was totally reversible and of the noncompetitive or mixed type. A study of the pH dependence of xanthine oxidase inhibition by 3a,e,g and allopurinol indicated that the 3-aryl substituents facilitated binding to the enzyme. These and the above results show that the compounds reported here inhibit xanthine oxidase by a mechanism which is significantly different from that of allopurinol.
|
Inhibition of bovine milk xanthine oxidase using xanthine as substrate at 10 times I50 preincubated for 20 mins at 25 degC measured after 10 fold dilution relative to control
|
Bos taurus
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and enzymic activity of some novel xanthine oxidase inhibitors. 3-Substituted 5,7-dihydroxypyrazolo(1,5-alpha)pyrimidines.
Year : 1976
Volume : 19
Issue : 2
First Page : 291
Last Page : 296
Authors : Springer RH, Dimmitt MK, Novinson T, O'Brien DE, Robins RK, Simon LN, Miller JP.
Abstract : A series of 3-substituted 5,7-dihydroxypyrazolo[1,5-alpha]pyrimidines containing various aromatic [phenyl- (3e), 3-pyridyl- (3f), p-bromophenyl- (3g), p-chlorophenyl- (3h), p-acetamidophenyl- (3i), p-tolyl- (3j), m-tolyl- (3k), 3,4-methylenedioxyphenyl- (3m), or naphthyl- (3n)] or nonaromatic [hydrogen- (3a), nitro- (3b), bromo- (3c), or chloro- (3d)] substituents in the 3 position was synthesized and tested as inhibitors of xanthine oxidase. The compounds (3a-m) were synthesized by condensation of the appropriate 3-amino-4-substituted pyrazole with diethyl malonate in alcoholic sodium methoxide and neutralization of the resulting enol sodium salts. As inhibitors of xanthine oxidase, 3e-n greater than 3a,c,d congruent to allopurinol greater than 3b. The 3-aryl-substituted compounds 3e-n were 30-160 times better xanthine oxidase inhibitors than allopurinol using hypoxanthine as substrate and 10-80 times better using xanthine as substrate, as evidenced by a comparison of Ki values. The inhibition by all compounds (3a-n) was totally reversible and of the noncompetitive or mixed type. A study of the pH dependence of xanthine oxidase inhibition by 3a,e,g and allopurinol indicated that the 3-aryl substituents facilitated binding to the enzyme. These and the above results show that the compounds reported here inhibit xanthine oxidase by a mechanism which is significantly different from that of allopurinol.
|
Inhibition of human xanthine oxidase
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Nat. Prod.
Title : X-ray crystal structure of a xanthine oxidase complex with the flavonoid inhibitor quercetin.
Year : 2014
Volume : 77
Issue : 7
First Page : 1693
Last Page : 1699
Authors : Cao H, Pauff JM, Hille R.
Abstract : Xanthine oxidase catalyzes the sequential hydroxylation of hypoxanthine to uric acid via xanthine as intermediate. Deposition of crystals of the catalytic product uric acid or its monosodium salt in human joints with accompanying joint inflammation is the major cause of gout. Natural flavonoids are attractive leads for rational design of preventive and therapeutic xanthine oxidase inhibitors due to their beneficial antioxidant, anti-inflammatory, and antiproliferative activities in addition to their micromolar inhibitory activities toward xanthine oxidase. We determined the first complex X-ray structure of mammalian xanthine oxidase with the natural flavonoid inhibitor quercetin at 2.0 Å resolution. The inhibitor adopts a single orientation with its benzopyran moiety sandwiched between Phe 914 and Phe 1009 and ring B pointing toward the solvent channel leading to the molybdenum active center. The favorable steric complementarity of the conjugated three-ring structure of quercetin with the active site and specific hydrogen-bonding interactions of exocyclic hydroxy groups with catalytically relevant residues Arg 880 and Glu 802 correlate well with a previously reported structure-activity relationship of flavonoid inhibitors of xanthine oxidase. The current complex provides a structural basis for the rational design of flavonoid-type inhibitors against xanthine oxidase useful for the treatment of hyperuricemia, gout, and inflammatory disease states.
|
Inhibition of xanthine oxidase (unknown origin)
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Hydroxylated chalcones with dual properties: Xanthine oxidase inhibitors and radical scavengers.
Year : 2016
Volume : 24
Issue : 4
First Page : 578
Last Page : 587
Authors : Hofmann E, Webster J, Do T, Kline R, Snider L, Hauser Q, Higginbottom G, Campbell A, Ma L, Paula S.
Abstract : In this study, we evaluated the abilities of a series of chalcones to inhibit the activity of the enzyme xanthine oxidase (XO) and to scavenge radicals. 20 mono- and polyhydroxylated chalcone derivatives were synthesized by Claisen-Schmidt condensation reactions and then tested for inhibitory potency against XO, a known generator of reactive oxygen species (ROS). In parallel, the ability of the synthesized chalcones to scavenge a stable radical was determined. Structure-activity relationship analysis in conjunction with molecular docking indicated that the most active XO inhibitors carried a minimum of three hydroxyl groups. Moreover, the most effective radical scavengers had two neighboring hydroxyl groups on at least one of the two phenyl rings. Since it has been proposed previously that XO inhibition and radical scavenging could be useful properties for reduction of ROS-levels in tissue, we determined the chalcones' effects to rescue neurons subjected to ROS-induced stress created by the addition of β-amyloid peptide. Best protection was provided by chalcones that combined good inhibitory potency with high radical scavenging ability in a single molecule, an observation that points to a potential therapeutic value of this compound class.
|
Inhibition of xanthine oxidase (unknown origin) using xanthine as substrate assessed as inhibition of uric acid formation after 30 mins by spectrophotometric method
|
Homo sapiens
|
950.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : On the vasoprotective mechanisms underlying novel β-phosphorylated nitrones: Focus on free radical characterization, scavenging and NO-donation in a biological model of oxidative stress.
Year : 2016
Volume : 119
First Page : 197
Last Page : 217
Authors : Cassien M, Petrocchi C, Thétiot-Laurent S, Robin M, Ricquebourg E, Kandouli C, Asteian A, Rockenbauer A, Mercier A, Culcasi M, Pietri S.
Abstract : A series of new hybrid 2-(diethoxyphosphoryl)-N-(benzylidene)propan-2-amine oxide derivatives with different aromatic substitution (PPNs) were synthesized. These molecules were evaluated for their EPR spin trapping potential on eleven different radicals and NO-donation properties in vitro, cytotoxicity and vasoprotective effect on precontracted rat aortic rings. A subfamily of the new PPNs featured an antioxidant moiety occurring in natural phenolic acids. From the experimental screening of these hydroxyphenyl- and methoxyphenyl-substituted PPNs, biocompatible nitrones 4d, and 4g-4i deriving from caffeic, gallic, ferulic and sinapic acids, which combined improved EPR probing of ROS formation, vasorelaxant action and antioxidant potency, might be potential drug candidate alternatives to PBN and its analogues.
|
Inhibition of Shigella dysenteriae type 1 Shiga toxin A subunit in African green monkey Vero cells assessed as inhibition of Stx-induced cytotoxicity pre-treated with compound for 1 hr followed by Stx exposure for 24 hrs by neutral red uptake assay relative to untreated control
|
Shigella dysenteriae
|
76.0
%
|
|
Journal : J Med Chem
Title : In Silico Discovery and Validation of Amide Based Small Molecule Targeting the Enzymatic Site of Shiga Toxin.
Year : 2016
Volume : 59
Issue : 23
First Page : 10763
Last Page : 10773
Authors : Chauhan V, Chaudhary D, Pathak U, Saxena N, Dhaked RK.
Abstract : Shiga toxin (Stx), a category B biothreat agent, is a ribosome inactivating protein and toxic to human and animals. Here, we designed and synthesized small molecules that block the active site of the Stx A subunit. On the basis of binding energy, 20 molecules were selected for synthesis and evaluation. These molecules were primarily screened using fluorescence-based thermal shift assay and in vitro in Vero cells. Among 32 molecules (including 12 reported), six molecules offered protection with IC50 of 2.60-23.90 μM. 4-Nitro-N-[2-(2-phenylsulfanylethylamino)ethyl]benzamide hydrochloride is the most potent inhibitor with IC50 at 7.96 μM and selectivity index of 22.23 and is better than any known small molecule inhibitor of Stx. Preincubation with Stx offered full protection against Shiga toxin in mice. Surface plasmon resonance assay further confirmed that these molecules bind specifically to Stx A subunit. Further optimization is continued to identify a potential candidate which will be in vivo effective.
|
Antihyperuricemic activity in fasted Kun Ming mouse assessed as inhibition of potassium oxonate-induced uric acid level in serum at 10 mg/kg qd administered 1 hr post potassium oxonate-challenge for 7 days via oral gavage measured 1 hr post last dose by phosphotungstic acid method relative to vehicle-treated control
|
Mus musculus
|
118.32
%
|
|
Journal : Bioorg Med Chem
Title : Discovery of novel curcumin derivatives targeting xanthine oxidase and urate transporter 1 as anti-hyperuricemic agents.
Year : 2017
Volume : 25
Issue : 1
First Page : 166
Last Page : 174
Authors : Ao GZ, Zhou MZ, Li YY, Li SN, Wang HN, Wan QW, Li HQ, Hu QH.
Abstract : A series of curcumin derivatives as potent dual inhibitors of xanthine oxidase (XOD) and urate transporter 1 (URAT1) was discovered as anti-hyperuricemic agents. These compounds proved efficient effects on anti-hyperuricemic activity and uricosuric activity in vivo. More importantly, some of them exhibited proved efficient effects on inhibiting XOD activity and suppressing uptake of uric acid via URAT1 in vitro. Especially, the treatment of 4d was demonstrated to improve uric acid over-production and under-excretion in oxonate-induced hyperuricemic mice through regulating XOD activity and URAT1 expression. Docking study was performed to elucidate the potent XOD inhibition of 4d. Compound 4d may serve as a tool compound for further design of anti-hyperuricemic drugs targeting both XOD and URAT1.
|
Inhibition of xanthine oxidase (unknown origin) assessed as reduction in uric acid formation preincubated for 5 mins followed by addition of xanthine substrate measured every minute up to 8 mins
|
Homo sapiens
|
3.6
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of novel curcumin derivatives targeting xanthine oxidase and urate transporter 1 as anti-hyperuricemic agents.
Year : 2017
Volume : 25
Issue : 1
First Page : 166
Last Page : 174
Authors : Ao GZ, Zhou MZ, Li YY, Li SN, Wang HN, Wan QW, Li HQ, Hu QH.
Abstract : A series of curcumin derivatives as potent dual inhibitors of xanthine oxidase (XOD) and urate transporter 1 (URAT1) was discovered as anti-hyperuricemic agents. These compounds proved efficient effects on anti-hyperuricemic activity and uricosuric activity in vivo. More importantly, some of them exhibited proved efficient effects on inhibiting XOD activity and suppressing uptake of uric acid via URAT1 in vitro. Especially, the treatment of 4d was demonstrated to improve uric acid over-production and under-excretion in oxonate-induced hyperuricemic mice through regulating XOD activity and URAT1 expression. Docking study was performed to elucidate the potent XOD inhibition of 4d. Compound 4d may serve as a tool compound for further design of anti-hyperuricemic drugs targeting both XOD and URAT1.
|
Inhibition of bovine xanthine oxidase assessed as reduction in uric acid levels at 50 uM using xanthine as substrate after 120 mins by spectrophotometry
|
Bos taurus
|
95.1
%
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery and biological evaluation of some (1H-1,2,3-triazol-4-yl)methoxybenzaldehyde derivatives containing an anthraquinone moiety as potent xanthine oxidase inhibitors.
Year : 2017
Volume : 27
Issue : 4
First Page : 729
Last Page : 732
Authors : Zhang TJ, Li SY, Yuan WY, Wu QX, Wang L, Yang S, Sun Q, Meng FH.
Abstract : A series of (1H-1,2,3-triazol-4-yl)methoxybenzaldehyde derivatives containing an anthraquinone moiety were synthesized and identified as novel xanthine oxidase inhibitors. Among them, the most promising compounds 1h and 1k were obtained with IC50 values of 0.6μM and 0.8μM, respectively, which were more than 10-fold potent compared with allopurinol. The Lineweaver-Burk plot revealed that compound 1h acted as a mixed-type xanthine oxidase inhibitor. SAR analysis showed that the benzaldehyde moiety played a more important role than the anthraquinone moiety for inhibition potency. The basis of significant inhibition of xanthine oxidase by 1h was rationalized by molecular modeling studies.
|
Invivo inhibition of xanthine oxidase in Wistar rat at 50 mg/kg, ip using 6-mercaptopurine as substrate after 6 hrs by UPLC method relative to control
|
Rattus norvegicus
|
100.0
%
|
|
Journal : Bioorg Med Chem
Title : Xanthine oxidase inhibitory activity of nicotino/isonicotinohydrazides: A systematic approach from in vitro, in silico to in vivo studies.
Year : 2017
Volume : 25
Issue : 8
First Page : 2351
Last Page : 2371
Authors : Zafar H, Hayat M, Saied S, Khan M, Salar U, Malik R, Choudhary MI, Khan KM.
Abstract : Change in life style and eating habits has led to an increased prevalence of hyperuricemia worldwide. The role of hyperuricemia is no more restricted to gout, but it has a central role in progression of CVD, hypertension, metabolic syndrome, and arthritis. Among the different factors involved in regulation of serum uric acid, xanthine oxidase (XO) is the best pharmacological target to control the levels of serum uric acid as it catalyzes the final steps in uric acid production. In the current study, a systemic search for the inhibitors of xanthine oxidase, starting from synthesis to in vitro screening and leading to in vivo studies is presented. Benzylidene nicotino/isonicotinohydrazides (1-54) were synthesized by treating nicotinic/isonicotinic hydrazides with substituted aromatic aldehyde, and characterized by EI-MS and 1H NMR. Elemental analysis was also performed. All synthetic compounds were screened for xanthine oxidase inhibitory activity initially using an in vitro spectroscopic XO inhibition assay. Among them twenty-two derivatives were found to be active with IC50 values between 0.96 and 330.4μM, as compared to standard drug allopurinol IC50=2.00±0.01μM. Kinetic studies of five most active compounds (8, 35, 36, 39, and 45) with low IC50 values between 0.96 and 54.8μM showed a competitive mode of inhibition. Further in silico molecular docking was carried out to study the interactions of these inhibitors with catalytically important amino acid residues in XO. Three compounds 8, 35, and 36 with IC50 values of 10, 12.4, and 0.96μM, respectively, were also found to be non-cytotoxic, and thus selected for in vivo studies. A simple and physiologically relevant animal model was used to analyze the in vivo XO inhibitory activity of these compounds. Among these, two compounds 35, and 36 showed a significant inhibition in male Wistar rats, and identified as potential lead molecules for anti-hyperuricemic drug development.
|
Antioxidant activity assessed as DPPH free radical scavenging activity incubated for 30 mins at 2000 uM
|
None
|
20.5
%
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and evaluation of hydroxychalcones as multifunctional non-purine xanthine oxidase inhibitors for the treatment of hyperuricemia.
Year : 2017
Volume : 27
Issue : 15
First Page : 3602
Last Page : 3606
Authors : Xie Z, Luo X, Zou Z, Zhang X, Huang F, Li R, Liao S, Liu Y.
Abstract : A series of hydroxychalcone derivatives have been designed, synthesized and evaluated for human xanthine oxidase (XO) inhibitory activity. Most of the tested compounds acted moderate XO inhibition with IC50 values in the micromolar rang. Molecular docking and kinetic studies have been performed to explain the binding modes of XO with the selected compounds. In addition, in vitro antioxidant screening results indicated that some of the hydroxychalcones possessed good anti-free radical activities. Furthermore, the preferred compounds 16 and 18 were able to significantly inhibit hepatic xanthine oxidase activity and reduced serum uric acid level of hyperuricemic mice in vivo. In summary, compounds 16 and 18 with balanced activities of antioxidant, XO inhibition and serum uric acid reduction, which are promising candidates for the treatment of hyperuricemia and gout.
|
Binding affinity to bovine milk xanthine oxidase assessed as reduction in conversion of 4-HPP to 4,6-diHPP by measuring cytochrome c reduction by spectrophotometric assay
|
Bos taurus
|
0.54
nM
|
|
Journal : Eur J Med Chem
Title : Xanthine oxidase inhibitors beyond allopurinol and febuxostat; an overview and selection of potential leads based on in silico calculated physico-chemical properties, predicted pharmacokinetics and toxicity.
Year : 2017
Volume : 135
First Page : 491
Last Page : 516
Authors : Šmelcerović A, Tomović K, Šmelcerović Ž, Petronijević Ž, Kocić G, Tomašič T, Jakopin Ž, Anderluh M.
Abstract : Xanthine oxidase (XO), a versatile metalloflavoprotein enzyme, catalyzes the oxidative hydroxylation of hypoxanthine and xanthine to uric acid in purine catabolism while simultaneously producing reactive oxygen species. Both lead to the gout-causing hyperuricemia and oxidative damage of the tissues where overactivity of XO is present. Over the past years, significant progress and efforts towards the discovery and development of new XO inhibitors have been made and we believe that not only experts in the field, but also general readership would benefit from a review that addresses this topic. Accordingly, the aim of this article was to overview and select the most potent recently reported XO inhibitors and to compare their structures, mechanisms of action, potency and effectiveness of their inhibitory activity, in silico calculated physico-chemical properties as well as predicted pharmacokinetics and toxicity. Derivatives of imidazole, 1,3-thiazole and pyrimidine proved to be more potent than febuxostat while also displaying/possessing favorable predicted physico-chemical, pharmacokinetic and toxicological properties. Although being structurally similar to febuxostat, these optimized inhibitors bear some structural freshness and could be adopted as hits for hit-to-lead development and further evaluation by in vivo studies towards novel drug candidates, and represent valuable model structures for design of novel XO inhibitors.
|
Inhibition of bovine milk xanthine-oxygen reductase using xanthine as substrate by spectrophotometric assay
|
Bos taurus
|
260.0
nM
|
|
Journal : Eur J Med Chem
Title : Xanthine oxidase inhibitors beyond allopurinol and febuxostat; an overview and selection of potential leads based on in silico calculated physico-chemical properties, predicted pharmacokinetics and toxicity.
Year : 2017
Volume : 135
First Page : 491
Last Page : 516
Authors : Šmelcerović A, Tomović K, Šmelcerović Ž, Petronijević Ž, Kocić G, Tomašič T, Jakopin Ž, Anderluh M.
Abstract : Xanthine oxidase (XO), a versatile metalloflavoprotein enzyme, catalyzes the oxidative hydroxylation of hypoxanthine and xanthine to uric acid in purine catabolism while simultaneously producing reactive oxygen species. Both lead to the gout-causing hyperuricemia and oxidative damage of the tissues where overactivity of XO is present. Over the past years, significant progress and efforts towards the discovery and development of new XO inhibitors have been made and we believe that not only experts in the field, but also general readership would benefit from a review that addresses this topic. Accordingly, the aim of this article was to overview and select the most potent recently reported XO inhibitors and to compare their structures, mechanisms of action, potency and effectiveness of their inhibitory activity, in silico calculated physico-chemical properties as well as predicted pharmacokinetics and toxicity. Derivatives of imidazole, 1,3-thiazole and pyrimidine proved to be more potent than febuxostat while also displaying/possessing favorable predicted physico-chemical, pharmacokinetic and toxicological properties. Although being structurally similar to febuxostat, these optimized inhibitors bear some structural freshness and could be adopted as hits for hit-to-lead development and further evaluation by in vivo studies towards novel drug candidates, and represent valuable model structures for design of novel XO inhibitors.
|
Inhibition of xanthine oxidase (unknown origin) assessed as reduction in uric acid formation using xanthine as substrate after 10 mins
|
Homo sapiens
|
100.0
nM
|
|
Journal : Eur J Med Chem
Title : Xanthine oxidase inhibitors beyond allopurinol and febuxostat; an overview and selection of potential leads based on in silico calculated physico-chemical properties, predicted pharmacokinetics and toxicity.
Year : 2017
Volume : 135
First Page : 491
Last Page : 516
Authors : Šmelcerović A, Tomović K, Šmelcerović Ž, Petronijević Ž, Kocić G, Tomašič T, Jakopin Ž, Anderluh M.
Abstract : Xanthine oxidase (XO), a versatile metalloflavoprotein enzyme, catalyzes the oxidative hydroxylation of hypoxanthine and xanthine to uric acid in purine catabolism while simultaneously producing reactive oxygen species. Both lead to the gout-causing hyperuricemia and oxidative damage of the tissues where overactivity of XO is present. Over the past years, significant progress and efforts towards the discovery and development of new XO inhibitors have been made and we believe that not only experts in the field, but also general readership would benefit from a review that addresses this topic. Accordingly, the aim of this article was to overview and select the most potent recently reported XO inhibitors and to compare their structures, mechanisms of action, potency and effectiveness of their inhibitory activity, in silico calculated physico-chemical properties as well as predicted pharmacokinetics and toxicity. Derivatives of imidazole, 1,3-thiazole and pyrimidine proved to be more potent than febuxostat while also displaying/possessing favorable predicted physico-chemical, pharmacokinetic and toxicological properties. Although being structurally similar to febuxostat, these optimized inhibitors bear some structural freshness and could be adopted as hits for hit-to-lead development and further evaluation by in vivo studies towards novel drug candidates, and represent valuable model structures for design of novel XO inhibitors.
|
Inhibition of butter milk XOD (unknown origin) at 1 uM using xanthine as substrate after 8 mins relative to control
|
Not specified
|
10.0
%
|
|
Journal : Eur J Med Chem
Title : Structure-activity relations of rosmarinic acid derivatives for the amyloid β aggregation inhibition and antioxidant properties.
Year : 2017
Volume : 138
First Page : 1066
Last Page : 1075
Authors : Taguchi R, Hatayama K, Takahashi T, Hayashi T, Sato Y, Sato D, Ohta K, Nakano H, Seki C, Endo Y, Tokuraku K, Uwai K.
Abstract : Amyloid-β aggregation inhibitors are expected to be therapeutic or prophylactic agents for Alzheimer's disease. Rosmarinic acid, which is one of the main aggregation inhibitors derived from Lamiaceae, was employed as a lead compound and its 25 derivatives were synthesized. In this study, the structure-activity relations of rosmarinic acid derivatives for the amyloid-β aggregation inhibitory effect (MSHTS assay), antioxidant properties, and xanthine oxidase inhibition were evaluated. Among the tested compounds, compounds 16d and 19 were found to the most potent amyloid aggregation inhibitors. The SAR revealed that the necessity of the presence of the phenolic hydroxyl on one side of the molecule as well as the lipophilicity of the entire molecule. The importance of these structural properties was also supported by docking simulations.
|
Inhibition of butter milk XOD (unknown origin) at 10 uM using xanthine as substrate after 8 mins relative to control
|
Not specified
|
90.0
%
|
|
Journal : Eur J Med Chem
Title : Structure-activity relations of rosmarinic acid derivatives for the amyloid β aggregation inhibition and antioxidant properties.
Year : 2017
Volume : 138
First Page : 1066
Last Page : 1075
Authors : Taguchi R, Hatayama K, Takahashi T, Hayashi T, Sato Y, Sato D, Ohta K, Nakano H, Seki C, Endo Y, Tokuraku K, Uwai K.
Abstract : Amyloid-β aggregation inhibitors are expected to be therapeutic or prophylactic agents for Alzheimer's disease. Rosmarinic acid, which is one of the main aggregation inhibitors derived from Lamiaceae, was employed as a lead compound and its 25 derivatives were synthesized. In this study, the structure-activity relations of rosmarinic acid derivatives for the amyloid-β aggregation inhibitory effect (MSHTS assay), antioxidant properties, and xanthine oxidase inhibition were evaluated. Among the tested compounds, compounds 16d and 19 were found to the most potent amyloid aggregation inhibitors. The SAR revealed that the necessity of the presence of the phenolic hydroxyl on one side of the molecule as well as the lipophilicity of the entire molecule. The importance of these structural properties was also supported by docking simulations.
|
Inhibition of xanthine oxidase (unknown origin) using xanthine as substrate preincubated for 5 mins followed by substrate addition measured every min for 10 mins by spectrophotometric method
|
Homo sapiens
|
80.41
%
|
|
Journal : Eur J Med Chem
Title : Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents.
Year : 2018
Volume : 143
First Page : 829
Last Page : 842
Authors : Figueiredo J, Serrano JL, Cavalheiro E, Keurulainen L, Yli-Kauhaluoma J, Moreira VM, Ferreira S, Domingues FC, Silvestre S, Almeida P.
Abstract : Barbituric and thiobarbituric acid derivatives have become progressively attractive to medicinal chemists due to their wide range of biological activities. Herein, different series of 1,3,5-trisubstituted barbiturates and thiobarbiturates were prepared in moderate to excellent yields and their activity as xanthine oxidase inhibitors, antioxidants, antibacterial agents and as anti-proliferative compounds was evaluated in vitro. Interesting bioactive barbiturates were found namely, 1,3-dimethyl-5-[1-(2-phenylhydrazinyl)ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6c) and 1,3-dimethyl-5-[1-[2-(4-nitrophenyl)hydrazinyl]ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6e), which showed concomitant xanthine oxidase inhibitory effect (IC50 values of 24.3 and 27.9 μM, respectively), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (IC50 values of 18.8 and 23.8 μM, respectively). In addition, 5-[1-(2-phenylhydrazinyl)ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6d) also revealed DPPH radical scavenger effect, with an IC50 value of 20.4 μM. Moreover, relevant cytotoxicity against MCF-7 cells (IC50 = 13.3 μM) was observed with 5-[[(2-chloro-4-nitrophenyl)amino]methylene]-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (7d). Finally, different 5-hydrazinylethylidenepyrimidines revealed antibacterial activity against Acinetobacter baumannii (MIC values between 12.5 and 25.0 μM) which paves the way for developing new treatments for infections caused by this Gram-negative coccobacillus bacterium, known to be an opportunistic pathogen in humans with high relevance in multidrug-resistant nosocomial infections. The most promising bioactive barbiturates were studied in silico with emphasis on compliance with the Lipinski's rule of five as well as several pharmacokinetics and toxicity parameters.
|
In vivo inhibition of XOD activity in liver of Kunming mouse model of potassium oxonate-induced hyperuricemia at 10 mg/kg, po treated 1 hr post potassium oxonate addition measured after 1 hr relative to control
|
Mus musculus
|
47.1
%
|
|
Journal : Bioorg Med Chem
Title : Development of benzoxazole deoxybenzoin oxime and acyloxylamine derivatives targeting innate immune sensors and xanthine oxidase for treatment of gout.
Year : 2018
Volume : 26
Issue : 8
First Page : 1653
Last Page : 1664
Authors : Huang J, Zhou Z, Zhou M, Miao M, Li H, Hu Q.
Abstract : Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and anti-acute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD.
|
Hypouricemic effect in Kunming mouse assessed as inhibition of hepatic XOD activity at 10 mg/kg, po measured after 1 hr relative to control
|
Mus musculus
|
27.9
%
|
|
Journal : Bioorg Med Chem
Title : Development of benzoxazole deoxybenzoin oxime and acyloxylamine derivatives targeting innate immune sensors and xanthine oxidase for treatment of gout.
Year : 2018
Volume : 26
Issue : 8
First Page : 1653
Last Page : 1664
Authors : Huang J, Zhou Z, Zhou M, Miao M, Li H, Hu Q.
Abstract : Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and anti-acute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD.
|
Inhibition of bovine milk xanthine oxidase using xanthine as substrate preincubated for 15 mins followed by substrate addition measured after 30 mins by UV-VIS spectrophotometric analysis
|
Bos taurus
|
250.0
nM
|
|
Journal : Eur J Med Chem
Title : Xanthine oxidase inhibitory activity of natural and hemisynthetic flavonoids from Gardenia oudiepe (Rubiaceae) in vitro and molecular docking studies.
Year : 2018
Volume : 143
First Page : 577
Last Page : 582
Authors : Santi MD, Paulino Zunini M, Vera B, Bouzidi C, Dumontet V, Abin-Carriquiry A, Grougnet R, Ortega MG.
Abstract : Xanthine oxidase (XO), an enzyme widely distributed among mammalian tissues, is associated with the oxidation of xanthine and hypoxanthine to form uric acid. Reactive oxygen species are also released during this process, leading to oxidative damages and to the pathology called gout. Available treatments mainly based on allopurinol cause serious side effects. Natural products such as flavonoids may represent an alternative. Thus, a series of polymethoxyflavones isolated and hemisynthesized from the bud exudates of Gardenia oudiepe has been evaluated for in vitro XO inhibitory activity. Compounds 1, 2 and 3 were more active than the reference inhibitor, Allopurinol (IC50 = 0.25 ± 0.004 μM) with IC50 values of (0.004 ± 0.001) μM, (0.05 ± 0.01) μM and (0.09 ± 0.003) μM, respectively. Structure-activity relationships were established. Additionally, a molecular docking study using MOE™ tool was carried out to establish the binding mode of the most active flavones with the enzyme, showing important interactions with its catalytic residues. These promising results, suggest the use of these compounds as potential leads for the design and development of novel XO inhibitors.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
15.53
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
6.23
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
15.5
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
24.59
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
22.61
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
2.36
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-1.92
%
|
|
|
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
|
-27.22
%
|
|
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.
|
Anti-hyperuricemic activity in potassium oxonate-induced acute hyperuricemia Sprague-Dawley rat model assessed as reduction in AUC of uric acid in serum at 10 mg/kg, ig pretreated for 1 hr followed by potassium oxonate challenge and measured at 2 hrs post drug administration (Rvb = 23%)
|
Rattus norvegicus
|
38.7
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of 2-(4-alkoxy-3-cyano)phenyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives as novel xanthine oxidase inhibitors.
Year : 2019
Volume : 181
First Page : 111558
Last Page : 111558
Authors : Mao Q, Dai X, Xu G, Su Y, Zhang B, Liu D, Wang S.
Abstract : In our previous study, we reported a series of 1-hydroxy-2-phenyl-1H-imidazole-5-carboxylic acid derivatives that presented excellent in vitro xanthine oxidase (XO) inhibitory potency. To further investigate the structure-activity relationships of these compounds, the imidazole ring was transformed to a pyrimidine ring to design 2-(4-alkoxy-3-cyano)phenyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (8a-8j), 2-(4-alkoxy-3-cyano)phenyl-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (9c, 9e, 9j, 9l) and 2-(4-alkoxy-3-cyano)phenyl-6-imino-1,6-dihydropyrimidine-5-carboxylic acids (10c, 10e, 10j, 10l). These compounds exhibited remarkable in vitro XO inhibitory potency with IC<sub>50</sub> values ranging from 0.0181 μM to 0.5677 μM. Specifically, compounds 10c and 10e, with IC<sub>50</sub> values of 0.0240 μM and 0.0181 μM, respectively, emerged as the most potent XO inhibitors, and their potencies were comparable to that of febuxostat. Structure-activity relationship analysis revealed that the methyl group at 4-position of pyrimidine ring could damage the potency, and the XO inhibitory potency was maintained when carbonyl group was changed to an imino group. Lineweaver-Burk plot analysis revealed that the representative compound 10c acted as a mixed-type inhibitor. A potassium oxonate induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 10c, and the results showed that compound 10c (5 mg/kg) was able to significantly lower the serum uric acid level. Furthermore, in acute oral toxicity study, no sign of toxicity was observed when the mice were administered with a single 2000 mg/kg oral dose of compound 10c. These results suggested that compound 10c was a potent and promising uric acid-lowing agent for the treatment of hyperuricemia.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
15.51
%
|
|
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
|
0.35
%
|
|
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
|
0.35
%
|
|
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 xanthine oxidase (unknown origin)
|
Homo sapiens
|
700.0
nM
|
|
Journal : Eur J Med Chem
Title : Pharmacological urate-lowering approaches in chronic kidney disease.
Year : 2019
Volume : 166
First Page : 186
Last Page : 196
Authors : Li X, Liu J, Ma L, Fu P.
Abstract : Chronic kidney disease (CKD) has become a global public health issue and uric acid (UA) remains a major risk factor of CKD. As the main organ for the elimination of UA, kidney owned a group of urate transporters in tubular epithelium. Kidney disease hampered the UA excretion, and the accumulation of serum UA in return harmed the renal function. Commercially, there are three kinds of agents targeting at urate-lowering, xanthine oxidoreductase inhibitor which prevents the production of UA, uricosuric which increases the concentration of UA in urine thus decreasing serum UA level, and uricase which converts UA to allantoin resulting in the dramatic decrement of serum UA. Of note, in patients with CKD, administration of above-mentioned agents, alone or combined, needs special attention. New evidence is emerging for the efficacy of several urate-lowering drugs for the treatment of hyperuricemia in patients with CKD. Besides, loads of novel and promising drug candidates and phytochemicals are in the different phases of research and development. As of today, there is insufficient evidence to recommend the widespread use of UA-lowering therapy to prevent or slow down the progression of CKD. The review summarized the evidence and perspectives about the treatment of hyperuricemia with CKD for medicinal chemist and nephrologist.
|
In vivo inhibition of xanthine oxidase in potassium oxonate-induced hyperuricemia mouse model assessed as reduction enzyme activity in liver at 10 mg/kg relative to control
|
Mus musculus
|
47.9
%
|
|
Journal : Bioorg Med Chem Lett
Title : Development of novel NLRP3-XOD dual inhibitors for the treatment of gout.
Year : 2020
Volume : 30
Issue : 4
First Page : 126944
Last Page : 126944
Authors : Wang W, Pang J, Ha EH, Zhou M, Li Z, Tian S, Li H, Hu Q.
Abstract : Gout is a crystalline-related arthropathy caused by the deposition of monosodium urate (MSU). Acute gouty arthritis is the most common first symptom of gout. Studies have shown that NOD-like receptor protein 3 (NLRP3) inflammasome as pattern recognition receptors can be activated by uric acid crystallization, triggering immune inflammation and causing acute gouty arthritis symptoms. Currently, the treatment of gout mainly includes two basic methods: reducing uric acid and alleviating inflammation. In this paper, 22 novel benzoxazole and benzimidazole derivatives were synthesized from deoxybenzoin oxime derivatives. These compounds have good inhibitory effects on NLRP3 and XOD screened by our research group in the early stage. The inhibitory activities of XOD and NLRP3 and their derivatives were also screened. Notably, compound 9b is a multi-targeting inhibitor of NLRP3 and XOD with excellent potency in treating hyperuricemia and acute gouty arthritis.
|
In vivo inhibition of xanthine oxidase in mouse assessed as reduction in enzyme activity in liver at 10 mg/kg relative to control
|
Mus musculus
|
25.3
%
|
|
Journal : Bioorg Med Chem Lett
Title : Development of novel NLRP3-XOD dual inhibitors for the treatment of gout.
Year : 2020
Volume : 30
Issue : 4
First Page : 126944
Last Page : 126944
Authors : Wang W, Pang J, Ha EH, Zhou M, Li Z, Tian S, Li H, Hu Q.
Abstract : Gout is a crystalline-related arthropathy caused by the deposition of monosodium urate (MSU). Acute gouty arthritis is the most common first symptom of gout. Studies have shown that NOD-like receptor protein 3 (NLRP3) inflammasome as pattern recognition receptors can be activated by uric acid crystallization, triggering immune inflammation and causing acute gouty arthritis symptoms. Currently, the treatment of gout mainly includes two basic methods: reducing uric acid and alleviating inflammation. In this paper, 22 novel benzoxazole and benzimidazole derivatives were synthesized from deoxybenzoin oxime derivatives. These compounds have good inhibitory effects on NLRP3 and XOD screened by our research group in the early stage. The inhibitory activities of XOD and NLRP3 and their derivatives were also screened. Notably, compound 9b is a multi-targeting inhibitor of NLRP3 and XOD with excellent potency in treating hyperuricemia and acute gouty arthritis.
