In Silico Design and Synthesis of Targeted Curcumin Derivatives as Xanthine Oxidase Inhibitors

Author(s): Neelam Malik, Priyanka Dhiman, Anurag Khatkar*.

Journal Name: Current Drug Targets

Volume 20 , Issue 5 , 2019

  Journal Home
Translate in Chinese
Submit Manuscript
Submit Proposal

Graphical Abstract:


Background: Curcumin is a well-known pharmacophore and some of its derivatives are shown to target xanthine oxidase (XO) to alleviate disorders caused by the excess production of uric acid.

Objective: Curcumin based derivatives were designed, synthesized and evaluated for their antioxidant and xanthine oxidase inhibitory potential.

Method: In this report, we designed and synthesized two series of curcumin derivatives modified by inserting pyrazole and pyrimidine ring to central keto group. The synthesized compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential.

Results: Results showed that pyrazole analogues of curcumin produced excellent XO inhibitory potency with the IC50 values varying from 06.255 µM to 10.503 µM. Among pyrimidine derivatives compound CU3a1 having ortho nitro substitution exhibited more potent xanthine oxidase inhibitory activity than any other curcumin derivative of this series.

Conclusion: Curcumin derivatives CU5b1, CU5b2, CU5b3, and CU3a1 showed a potent inhibitory activity against xanthine oxidase along with good antioxidant potential.

Keywords: Xanthine oxidase, in-silico design, antioxidant, curcumin.

Romão MJ, Huber R. Structure and function of the xanthine-oxidase family of molybdenum enzymes InMetal Sites in Proteins and Models Redox Centres. Springer: Berlin, Heidelberg 1998; pp. 69-9.
Brondino CD, Romão MJ, Moura I, Moura JJ. Molybdenum and tungsten enzymes: the xanthine oxidase family. Curr Opin Chem Biol 2006; 10(2): 109-14.
Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol 2004; 555(3): 589-606.
Harrison R. Structure and function of xanthine oxidoreductase: where are we now? Free Radic Biol Med 2002; 33(6): 774-97.
Chen C, Lü JM, Yao Q. Hyperuricemia-related diseases and xanthine oxidoreductase (XOR) inhibitors: an overview. Med Sci Monit 2016; 22: 2501.
Gliozzi M, Malara N, Muscoli S, Mollace V. The treatment of hyperuricemia. Int J Cardiol 2016; 213: 23-7.
Nishino T, Okamoto K. Mechanistic insights into xanthine oxidoreductase from development studies of candidate drugs to treat hyperuricemia and gout. J Biol Inorg Chem 2015; 20(2): 195-207.
Haidari F, Keshavarz SA, Shahi MM, Mahboob SA, Rashidi MR. Effects of parsley (Petroselinum crispum) and its flavonol constituents, kaempferol and quercetin, on serum uric acid levels, biomarkers of oxidative stress and liver xanthine oxidoreductase aactivityinoxonate-induced hyperuricemic rats. Iran J Pharm Res 2011; 10(4): 811.
Klinenberg JR, Goldfinger SE, Seegmiller JE. The effectiveness of the xanthine oxidase inhibitor allopurinol in the treatment of gout. Ann Intern Med 1965; 62(4): 639-47.
Pacher P, Nivorozhkin A, Szabó C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 2006; 58(1): 87-114.
McInnes GT, Lawson DH, Jick H. Acute adverse reactions attributed to allopurinol in hospitalised patients. Ann Rheum Dis 1981; 40(3): 245.
Takano Y, Hase-Aoki K, Horiuchi H, et al. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci 2005; 76(16): 1835-47.
Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: A twenty‐eight–day, multicenter, phase II, randomized, double‐blind, placebo‐controlled, dose‐response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum 2005; 52(3): 916-23.
Iwanaga T, Kobayashi D, Hirayama M, Maeda T, Tamai I. Involvement of uric acid transporter in increased renal clearance of the xanthine oxidase inhibitor oxypurinol induced by a uricosuric agent, benzbromarone. Drug Metab Dispos 2005; 12(6): 824-30.
Das DK, Engelman RM, Clement R, et al. Role of xanthine oxidase inhibitor as free radical scavenger: a novel mechanism of action of allopurinol and oxypurinol in myocardial salvage. ‎. Biochem Biophys Res Commun 1987; 148(1): 314-9.
Hall J, Gillen M, Yang X, et al. THU0432 Pharmacokinetics, pharmacodynamics, and tolerability of concomitant multiple dose administration of verinurad (RDEA3170) and allopurinol in adult male subjects with gout. Ann Rheum Dis 2017; 370-1.
Okamoto K, Kawaguchi Y, Eger BT, Pai EF, Nishino T. Crystal structures of urate bound form of xanthine oxidoreductase: substrate orientation and structure of the key reaction intermediate. ‎. J Am Chem Soc 2010; 132(48): 17080-3.
Okamoto K, Eger BT, Nishino T, Pai EF, Nishino T. Mechanism of inhibition of xanthine oxidoreductase by allopurinol: crystal structure of reduced bovine milk xanthine oxidoreductase bound with oxipurinol. Nucleosides Nucleotides Nucleic Acids 2008; 27(6-7): 888-93.
Fernandez ML, Stupar D, Croll T, Leavesley D, Upton Z. Xanthine oxidoreductase: a novel therapeutic target for the treatment of chronic wounds? Adv Wound Care 2018; 7(3): 95-104.
Jordan A, Gresser U. Side effects and interactions of the xanthine oxidase inhibitor febuxostat. Pharmaceuticals 2018; 11(2): 51.
Bordoloi D, Kunnumakkara AB. The potential of curcumin: A multitargeting agent in cancer cell chemosensitization InRole of nutraceuticals in cancer chemosensitization. Elsevier 2018; pp. 31-60.
Prasad S, Gupta SC, Tyagi AK, Aggarwal BB. Curcumin, a component of golden spice: from bedside to bench and back. Biotechnol Adv 2014; 32(6): 1053-64.
Kant V, Gopal A, Pathak NN, et al. Antioxidant and anti-inflammatory potential of curcumin accelerated the cutaneous wound healing in streptozotocin-induced diabetic rats. Int Immunopharmacol 2014; 20(2): 322-30.
Wang J, Wang H, Zhu R, et al. Anti-inflammatory activity of curcumin-loaded solid lipid nanoparticles in IL-1β transgenic mice subjected to the lipopolysaccharide-induced sepsis. Biomat 2015; 53: 475-83.
Zhang Y, Liang D, Dong L, et al. Anti-inflammatory effects of novel curcumin analogs in experimental acute lung injury. Respir Res 2015; 16(1): 43.
Cianciulli A, Calvello R, Porro C, et al. PI3k/Aktsignalling pathway plays a crucial role in the anti-inflammatory effects of curcumin in LPS-activated microglia. Int Immunopharmacol 2016; 36: 282-90.
Edwards RL, Luis PB, Varuzza PV, et al. The anti-inflammatory activity of curcumin is mediated by its oxidative metabolites. J Biol Chem 2017.
Menon VP, Sudheer AR. Antioxidant and anti-inflammatory properties of curcumin. The molecular targets and therapeutic uses of curcumin in health and disease In: Springer: Boston MA 2007; pp. 105-25.
Ao GZ, Zhou MZ, Li YY, et al. Discovery of novel curcumin derivatives targeting xanthine oxidase and urate transporter 1 as anti-hyperuricemic agents. Bioorg Med Chem 2017; 25(1): 166-74.
Malik N, Dhiman P, Khatkar A. In-silico design and admet studies of natural compounds as inhibitors of xanthine oxidase (xo) enzyme. Curr Drug Metab 2017; 18(6): 577-93.
Dhiman P, Malik N, Verma PK, Khatkar A. Synthesis and biological evaluation of thiazolo and imidazo N-(4-nitrophenyl)-7-methyl-5-aryl-pyrimidine-6 carboxamide derivatives. Res Chem Intermed 2015; 41(11): 8699-711.
Patel A, Patel NM. Determination of polyphenols and free radical scavenging activity of Tephrosia purpurea linn leaves (Leguminosae). Pharmacogn Rev 2010; 2(3): 152.
Chou KC, Jiang SP, Liu WM, Fee CH. Graph theory of enzyme kinetics: 1. Steady-state reaction system. Sci Sin 1979; 22: 341-58.
Chou KC, Forsen S. Graphical rules for enzyme-catalyzed rate laws. Biochem J 1980; 187: 829-35.
Zhou GP, Deng MH. An extension of Chou’s graphic rules for deriving enzyme kinetic equations to systems involving parallel reaction pathways. Biochem J 1984; 222: 169-76.
Chou KC. Graphic rules in steady and non-steady enzyme kinetics. J Biol Chem 1989; 264: 12074-9.
Althaus IW, Chou JJ, Gonzales AJ, et al. Steady-state kinetic studies with the non-nucleoside HIV-1 reverse transcriptase inhibitor U-87201E. J Biol Chem 1993; 268: 6119-24.
Chou KC. Review: Applications of graph theory to enzyme kinetics and protein folding kinetics. Steady and non-steady state systems. Biophys Chem 1990; 35: 1-24.
Althaus IW, Gonzales AJ, Chou JJ, et al. The quinoline U-78036 is a potent inhibitor of HIV-1 reverse transcriptase. J Biol Chem 1993; 268: 14875-80.
Chou KC. Graphic rule for drug metabolism systems. Curr Drug Metab 2010; 11: 369-78.
Zhou GP. The disposition of the LZCC protein residues in wenxiang diagram provides new insights into the protein-protein interaction mechanism. J Theor Biol 2011; 284: 142-8.
Althaus IW, Chou JJ, Gonzales AJ, et al. Kinetic studies with the nonnucleoside HIV-1 reverse transcriptase inhibitor U-88204E. Biochem 1993; 32: 6548-54.
Chou KC. Review: Structural bioinformatics and its impact to biomedical science. Curr Med Chem 2004; 11: 2105-34.
Chou KC, Watenpaugh KD, Heinrikson RL. A Model of the complex between cyclindependent kinase 5 (Cdk5) and the activation domain of neuronal Cdk5 activator. BBRC 1999; 259: 420-8.
Zhang J, Luan CH, Johnson GVW. Identification of the N-terminal functional domains of Cdk5 by molecular truncation and computer modeling Proteins. Struct Funct Genet 2002; 48: 447-53.
Chou KC, Jones D, Heinrikson RL. Prediction of the tertiary structure and substrate binding site of caspase-8. FEBS Lett 1997; 419: 49-54.
Chou KC, Tomasselli AG, Heinrikson RL. Prediction of the tertiary structure of a caspase-9/inhibitor complex. FEBS Lett 2000; 470: 249-56.
Chou KC, Wei DQ, Zhong WZ. Binding mechanism of coronavirus main proteinase with ligands and its implication to drug design against SARS. (Erratum: ibid. 2003, Vol.310, 675). BBRC 2003; 308: 148-51.
Huang RB, Du QS, Wang CH. An in-depth analysis of the biological functional studies based on the NMR M2 channel structure of influenza A virus. BBRC 2008; 377: 1243-7.
Chou KC. Molecular therapeutic target for type-2 diabetes. J Proteome Res 2004; 3: 1284-8.
Pielak RM, Jason R, Schnell JR, Chou JJ. Mechanism of drug inhibition and drug resistance of influenza A M2 channel. Proceedings of National Academy of Science USA 2009; 106: 7379-84.
Chou KC, Chen NY. The biological functions of low-frequency phonons. Sci Sin 1977; 20: 447-57.
Wang JF, Chou KC. Insight into the molecular switch mechanism of human Rab5a from molecular dynamics simulations. BBRC 2009; 390: 608-12.
Chou KC. Low-frequency resonance and cooperativity of hemoglobin. Trends Biochem Sci 1989; 14: 212-3.
Wang JF, Chou KC. Insights from studying the mutation-induced allostery in the M2 proton channel by molecular dynamics. PEDS 2010; 23: 663-6.
Chou KC, Mao B. Collective motion in DNA and its role in drug intercalation. Biopolymers 1988; 27: 1795-815.
Chou KC, Zhang CT, Maggiora GM. Solitary wave dynamics as a mechanism for explaining the internal motion during microtubule growth. Biopolymers 1994; 34: 143-53.
Chou KC. Review: Low-frequency collective motion in biomacromolecules and its biological functions. Biophys Chem 1988; 30: 3-48.
Chen W, Feng PM, Lin H. iSS-PseDNC: identifying splicing sites using pseudo dinucleotide composition. BMRI 2014; 2014: 623149.
Feng PM, Chen W, Lin H, Chou KC. iHSP-PseRAAAC: Identifying the heat shock protein families using pseudo reduced amino acid alphabet composition. Anal Biochem 2013; 442: 118-25.
Chen W, Ding H, Feng P, Lin H. iACP: a sequence-based tool for identifying anticancer peptides. Oncotarget 2016; 7: 16895-909.
Cheng X, Xiao X, Chou KC. pLoc-mPlant: predict subcellular localization of multi-location plant proteins via incorporating the optimal GO information into general PseAAC. Mol Bio Sys 2017; 13: 1722-7.
Cheng X, Xiao X, Chou KC. pLoc-mVirus: predict subcellular localization of multi-location virus proteins via incorporating the optimal GO information into general PseAAC Gene (Erratum: ibid,2018, Vol.644, 156-156) 2017; 628: 315-21.
Cheng X, Zhao SG, Lin WZ, Xiao X, Chou KC. pLoc-mAnimal: predict subcellular localization of animal proteins with both single and multiple sites. Bioinformatics 2017; 33: 3524-31.
Xiao X, Cheng X, Su S, Nao Q, Chou KC. pLoc-mGpos: Incorporate key gene ontology information into general PseAAC for predicting subcellular localization of Gram-positive bacterial proteins. Nat Sci 2017; 9: 331-49.
Cheng X, Xiao X. pLoc-mEuk: Predict subcellular localization of multi-label eukaryotic proteins by extracting the key GO information into general PseAAC. Genomics 2018; 110: 50-8.
Cheng X, Xiao X, Chou KC. pLoc-mGneg: Predict subcellular localization of Gram-negative bacterial proteins by deep gene ontology learning via general PseAAC. Genomics 2018; 110: 231-9.
Cheng X, Xiao X, Chou KC. pLoc-mHum: predict subcellular localization of multi-location human proteins via general PseAAC to winnow out the crucial GO information. Bioinformatics 2018; 34: 1448-56.
Cheng X, Lin WZ, Xiao X. pLoc_bal-mAnimal: predict subcellular localization of animal proteins by balancing training dataset and PseAAC. Bioinformatics 2018.
Chou KC. Impacts of bioinformatics to medicinal chemistry. Med Chem 2015; 11: 218-34.
Chou KC. An unprecedented revolution in medicinal chemistry driven by the progress of biological science. Curr Top Med Chem 2017; 17: 2337-58.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [593 - 603]
Pages: 11
DOI: 10.2174/1389450120666181122100511
Price: $58

Article Metrics

PDF: 15