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      In silico design and synthesis of targeted rutin derivatives as xanthine oxidase inhibitors

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          Abstract

          Background

          Xanthine oxidase is an important enzyme of purine catabolism pathway and has been associated directly in pathogenesis of gout and indirectly in many pathological conditions like cancer, diabetes and metabolic syndrome. In this research rutin, a bioactive flavonoid was explored to determine the capability of itself and its derivatives to inhibit xanthine oxidase.

          Objective

          To develop new xanthine oxidase inhibitors from natural constituents along with antioxidant potential.

          Method

          In this report, we designed and synthesized rutin derivatives hybridized with hydrazines to form hydrazides and natural acids to form ester linkage with the help of molecular docking. The synthesized compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential.

          Results

          The enzyme kinetic studies performed on rutin derivatives showed a potential inhibitory effect on XO ability in competitive manner with IC 50 value ranging from 04.708 to 19.377 µM and RU3a 3 was revealed as most active derivative. Molecular simulation revealed that new rutin derivatives interacted with the amino acid residues PHE798, GLN1194, ARG912, GLN 767, ALA1078 and MET1038 positioned inside the binding site of XO. Results of antioxidant activity revealed that all the derivatives showed very good antioxidant potential.

          Conclusion

          Taking advantage of molecular docking, this hybridization of two natural constituent could lead to desirable xanthine oxidase inhibitors with improved activity.

          Electronic supplementary material

          The online version of this article (10.1186/s13065-019-0585-8) contains supplementary material, which is available to authorized users.

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          Most cited references32

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          Xanthine oxidase is involved in free radical production in type 1 diabetes: protection by allopurinol.

          José Valls, Jose Viña, Rafael Márquez … (2002)
          The aim of this work was to study the mechanism of free radical formation in type 1 diabetes and its possible prevention. We have found oxidation of blood glutathione and an increase in plasma lipoperoxide levels in both human type 1 diabetes and experimental diabetes. Peroxide production by mitochondria does not increase in diabetes. On the contrary, the activity of xanthine oxidase, a superoxide-generating enzyme, increases in liver and plasma of diabetic animals. The increase in plasma xanthine oxidase activity may be explained by the increase in the hepatic release of this enzyme, which is not due to nonspecific membrane damage: release of other hepatic enzymes, such as the amino transferases, does not increase in diabetes. Superoxide formation by aortic rings of rabbits increases significantly in diabetes. This is completely inhibited by allopurinol, an inhibitor of xanthine oxidase. Heparin, which releases xanthine oxidase from the vessel wall, also decreases superoxide formation by aortic rings of diabetic animals. Treatment with allopurinol decreases oxidative stress in type 1 diabetic patients: hemoglobin glycation, glutathione oxidation, and the increase in lipid peroxidation are prevented. These results may have clinical significance in the prevention of late-onset vascular complications of diabetes.
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            Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase.

            Y Takano, K. Becker, Shiro Kondo … (2005)
            The purine analogue, allopurinol, has been in clinical use for more than 30 years as an inhibitor of xanthine oxidase (XO) in the treatment of hyperuricemia and gout. As consequences of structural similarities to purine compounds, however, allopurinol, its major active product, oxypurinol, and their respective metabolites inhibit other enzymes involved in purine and pyrimidine metabolism. Febuxostat (TEI-6720, TMX-67) is a potent, non-purine inhibitor of XO, currently under clinical evaluation for the treatment of hyperuricemia and gout. In this study, we investigated the effects of febuxostat on several enzymes in purine and pyrimidine metabolism and characterized the mechanism of febuxostat inhibition of XO activity. Febuxostat displayed potent mixed-type inhibition of the activity of purified bovine milk XO, with Ki and Ki' values of 0.6 and 3.1 nM respectively, indicating inhibition of both the oxidized and reduced forms of XO. In contrast, at concentrations up to 100 muM, febuxostat had no significant effects on the activities of the following enzymes of purine and pyrimidine metabolism: guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, purine nucleoside phosphorylase, orotate phosphoribosyltransferase and orotidine-5'-monophosphate decarboxylase. These results demonstrate that febuxostat is a potent non-purine, selective inhibitor of XO, and could be useful for the treatment of hyperuricemia and gout.
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              Xanthine oxidase as a source of free radical damage in myocardial ischemia.

              D. Chambers, D. Parks, G. Patterson … (1985)
              Experiments were performed to determine if xanthine oxidase is a source of free radicals during myocardial ischemia. Open chest dogs were subjected to 1 h of total occlusion of the left anterior descending coronary artery followed by 4 h of reperfusion. Directly after coronary artery occlusion, Ce141 microspheres were injected into the left atrium to mark the ischemic bed. At the end of reperfusion, the hearts were removed and sectioned. Autoradiography determined the ischemic myocardium at risk, and the necrotic zone was determined by triphenyl-tetrazolium staining. Animals were divided into three groups: control, allopurinol (24-h oral pretreatment 400 mg, then 50 mg/kg IV bolus on occlusion); and superoxide dismutase starting with occlusion (15 000 U/kg). The size of the infarct as a percentage of the tissue at risk was: 23.1 +/- 4.1 for the control; 8.7 +/- 1.2 for the allopurinol group; and 5.4 +/- 1.2 for the superoxide dismutase group. The infarcts in the allopurinol and superoxide dismutase groups were significantly smaller than those in the control groups. In a second series of experiments we determined the xanthine oxidase/xanthine dehydrogenase content of dog myocardium. The left anterior descending branch was ligated for 30 min and then biopsies were removed from both the normal and the ischemic regions. Total enzyme content did not differ between the two regions averaging 0.259 U/g protein for the ischemic tissue and 0.225 U/g protein for the normal region. Only 9.8% of the enzyme was in the oxidase form in the normal region while 32.8% was in the oxidase form in the ischemic zone.(ABSTRACT TRUNCATED AT 250 WORDS)
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                Author and article information

                Contributors
                Neelam Malik: neelammdurtk@gmail.com
                Priyanka Dhiman: priyankamdurtk@gmail.com
                Anurag Khatkar:
                ORCID: http://orcid.org/0000-0002-0856-3620
                dranuragkhatkarmdurtk@gmail.com , anuragpharmacy@gmail.com
                Journal
                Journal ID (nlm-ta): BMC Chem
                Journal ID (iso-abbrev): BMC Chem
                Title: BMC Chemistry
                Publisher: Springer International Publishing (Cham )
                ISSN (Electronic): 2661-801X
                Publication date (Electronic): 23 May 2019
                Publication date PMC-release: 23 May 2019
                Publication date Collection: December 2019
                Volume: 13
                Issue: 1
                Electronic Location Identifier: 71
                Affiliations
                [1 ]ISNI 0000 0004 1790 2262, GRID grid.411524.7, Faculty, Department of Pharmaceutical Sciences, , M.D. University, ; Rohtak, 124001 India
                [2 ]ISNI 0000 0004 1790 2262, GRID grid.411524.7, Laboratory for Preservation Technology and Enzyme Inhibition Studies, Department of Pharmaceutical Sciences, , M.D. University, ; Rohtak, Haryana India
                Author information
                http://orcid.org/0000-0002-0856-3620
                Article
                Publisher ID: 585
                DOI: 10.1186/s13065-019-0585-8
                PMC ID: 6661775
                SO-VID: 6f8dcca8-ee88-4324-83ba-737ac8499275
                Copyright © © The Author(s) 2019
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 21 January 2019
                Date accepted : 2 May 2019
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                Keywords: rutin,xanthine oxidase,molecular docking,antioxidant
                Data availability:
                Keywords: rutin, xanthine oxidase, molecular docking, antioxidant

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