Inhibitors of Xanthine Oxidase: Scaffold Diversity and Structure‐Based Drug Design

Luna, Giuseppe Antonio Di; Dolzhenko, Anton V.; Mancera, Ricardo L.

doi:10.1002/cmdc.201900034

Cited by 67 publications

(35 citation statements)

References 170 publications

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“…In addition to these clinically used drugs, over the years, several other molecules with XO inhibitory activity have been described [6][7][8][9]. Despite the existence of some reviews in this topic [6,7,[9][10][11], it is necessary to complement these works with a study focusing on the hit to lead evolution in the development of new XO inhibitors with improved potency and safety when compared with the clinically used drugs. Interestingly, as can be seen in this review, natural molecules and semisynthetic analogues and derivatives constitute a large group of compounds being explored at the moment in this context.…”

Section: Introductionmentioning

confidence: 99%

From Xanthine Oxidase Inhibition to In Vivo Hypouricemic Effect: An Integrated Overview of In Vitro and In Vivo Studies with Focus on Natural Molecules and Analogues

Serrano

Figueiredo

Almeida

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Hyperuricemia is characterized by elevated uric acid (UA) levels on blood, which can lead to gout, a common pathology. These high UA levels are associated with increased purine ingestion and metabolization and/or its decreased excretion. In this field, xanthine oxidase (XO), by converting hypoxanthine and xanthine to UA, plays an important role in hyperuricemia control. Based on limitations and adverse effects associated with the use of allopurinol and febuxostat, the most known approved drugs with XO inhibitory effect, the search for new molecules with XO activity is growing. However, despite the high number of studies, it was found that the majority of tested products with relevant XO inhibition were left out, and no further pharmacological evaluation was performed. Thus, in the present review, available information published in the past six years concerning isolated molecules with in vitro XO inhibition complemented with cytotoxicity evaluation as well as other relevant studies, including in vivo hypouricemic effect, and pharmacokinetic/pharmacodynamic profile was compiled. Interestingly, the analysis of data collected demonstrated that molecules from natural sources or their mimetics and semisynthetic derivatives constitute the majority of compounds being explored at the moment by means of in vitro and in vivo animal studies. Therefore, several of these molecules can be useful as lead compounds and some of them can even have the potential to be considered in the future clinical candidates for the treatment of hyperuricemia.

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Section: Introductionmentioning

confidence: 99%

From Xanthine Oxidase Inhibition to In Vivo Hypouricemic Effect: An Integrated Overview of In Vitro and In Vivo Studies with Focus on Natural Molecules and Analogues

Serrano

Figueiredo

Almeida

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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“…With the availability of a handful of XO inhibitors in clinical use for treating hyperuricemia, the novel drugs addressing cardiac complications are demanding [70]. Recently, non-purine-like XO inhibitors have drawn significant attention, so they do not interfere with other facets of purine metabolism [48]. XO inhibitors could be equally useful for diabetic patients [71].…”

Section: Discussionmentioning

confidence: 99%

“…Amino acid residues participating in forming Pi-Pi and Pi-cation interactions were also investigated. Amentoflavone (1) and 6-paradol (3) was surrounded by several amino acid residues (Glu 802, Asn 768, Phe 914, ser 876, and Arg 880), which were described as active site residues [48]. It has been reported that Arg 880 and Glu 802 residues play a key role in the hydroxylation of substrate xanthine [49].…”

Section: Xo Molecular Docking Analysismentioning

confidence: 99%

In-SilicoAnalysis of Secondary Metabolites that Modulates Enzymes of Cholesterol Target

Marahatha

Basnet

Bhattarai

et al. 2020

Preprint

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Hypercholesterolemia has posed a serious threat of heart diseases and stroke worldwide. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid biosynthesis, is regarded as the root of reactive oxygen species (ROS) that generates atherosclerosis and cholesterol crystals. β-Hydroxy β-methylglutaryl-coenzyme A reductase (HMGR) is a rate-limiting enzyme in cholesterol biosynthesis. Although some commercially available enzyme inhibiting drugs have effectively reduced the cholesterol level, most of them have failed to meet the requirements of being apt drug candidates. Here, we have carried out an in-silico analysis of secondary metabolites that have already shown good inhibitory activity against XO and HMGR. Out of 118 secondary metabolites reviewed, sixteen molecules inhibiting XO and HMGR were taken based on IC50 values reported in vitro assays. Further, receptor-based virtual screening was carried out against secondary metabolites using GOLD Protein-Ligand Docking Software, combined with subsequent post-docking, to study the binding affinities of ligands to the enzymes. In-Silico ADMET analysis was carried out to study their pharmacokinetic properties, followed by toxicity prediction through ProTox-II. The molecular docking of amentoflavone (1) (GOLD score 70.54), and ganomycin I (9) (GOLD score 59.61) evinced that the drug has effectively bind at the competitive site of XO and HMGR, respectively. Besides, 6-paradol (3) and selgin (4) could be potential drug candidates to inhibit XO. Likewise, n-octadecanyl-O-α-D-glucopyranosyl(6’→1”)-O-α-D-glucopyranoside (10) could be potential drug candidates to maintain serum cholesterol. In-silico ADMET analysis showed that the sixteen metabolites were optimal within the categorical range in comparison to commercially available XO and HMGR inhibitors, respectively. Toxicity analysis through Protox-II revealed that 6-gingerol (2), ganoleucoin K (11), and ganoleucoin Z (12) are toxic for human use. This computational analysis supports earlier experimental evidence towards the inhibition of XO and HMGR by natural products. Further study is necessary to explore the clinical efficacy of these secondary molecules, which might be alternatives for the treatment of hypercholesterolemia.Graphical abstract

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“…The 1,3,5‐triazine ( I ) (Figure ) is a simple, but privileged heterocycle, which has been incorporated as the central core ring in a number of drugs showing, to cite someone, antitumoral, antimicrobial, antiviral, or antimalarial therapeutic potential, among the diverse array of biological activities that this functional motif is able to afford to the molecules that bear it. The fusion of 1,3,5‐triazines with other rings usually results in even more versatile structures . The 1,3,5‐triazine heterocyclic motif is also endowed with electronic properties that have been used with in designing new molecular structures or platforms …”

Section: Figurementioning

confidence: 99%

Synthesis, Monoamine Oxidase Inhibition and Computational Analysis of Diversely Substituted N‐Propargylated‐1,3,5‐triazines

et al. 2019

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In this work six diversely substituted N-propargylated-1,3,5triazines have been designed, synthesized, and evaluated as monoamine oxidase (MAO) inhibitors. Very surprisingly, only 4,6-dichloro-N-(prop-2-yn-1-yl)-1,3,5-triazin-2-amine (1) showed modest, but selective MAOÀ B inhibition (IC 50 = 14.2 � 0.7 μM), whose binding affinity has been investigated by computational analysis The 1,3,5-triazine (I) ( Figure 1) is a simple, but privileged heterocycle, [1a] which has been incorporated as the central core ring in a number of drugs showing, to cite someone, antitumoral, [2] antimicrobial, [3] antiviral, [4] or antimalarial [5] therapeutic potential, among the diverse array of biological activities that this functional motif is able to afford to the molecules that bear it. The fusion of 1,3,5-triazines with other rings usually results in even more versatile structures. [1b] The 1,3,5-triazine heterocyclic motif is also endowed with electronic properties that have been used with in designing new molecular structures or platforms. [6] From the synthetic point of view, the easy, and simple protocol to prepare diversely substituted 1,3,5-triazines is the key point that clearly explains the large literature available on the chemistry and reactivity of this type of compounds. The obvious starting material for the synthesis of all of them is the readily available 2,4,6-trichloro-1,3,5-triazine ("cyanuric chloride") (1) (Figure 1), bearing three chlorine atoms that can be totally or stepwise substituted by different type of O-, ad N-attacking nucleophiles leading to large and diverse families of molecules suitably functionalized at will for pharmacological analysis. [7] In particular, in the context of the therapeutic strategy based on multitarget small molecules (MTSM) [8,9] for designing novel ligands for complex diseases, such as Alzheimer's disease (AD), [10] cancer or stroke, the special features integrated in the 1,3,5-triazine (I) allow for instance the incorporation of a diverse and selected number of functional and structural motifs. In other words, the subtle and targeted incorporation of a number of pharmacophoric groups. Doing that it is expected that in only one "triazine" derivative, each pharmacophore be able to modulate its own receptor or enzymatic system, giving in all the desired combined pharmacological activity to deal with a precise pathology. The recent literature is rich and shows nice examples on how this protocol is carried out and how it works in the practice. For instance, Hoda and co-workers have reported MTSM for AD that combine the inhibition of cholinesterase (ChEs) enzymes with the inhibition of betaamyloid aggregation based on the careful selection of triazolopyrimidine-triazine scaffolds. [11] Our recent developments of novel MTSM for AD based on indolepropargylamines able to inhibit inter alia the monoamine oxidase (MAO) enzymes, and whose most advanced hitcompound is Contilisant, [12] prompted us to explore the rich [a] Dr. Figure 1. General structure of 1,3,5-triazne (I), and structur...

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Inhibitors of Xanthine Oxidase: Scaffold Diversity and Structure‐Based Drug Design

Cited by 67 publications

References 170 publications

From Xanthine Oxidase Inhibition to In Vivo Hypouricemic Effect: An Integrated Overview of In Vitro and In Vivo Studies with Focus on Natural Molecules and Analogues

From Xanthine Oxidase Inhibition to In Vivo Hypouricemic Effect: An Integrated Overview of In Vitro and In Vivo Studies with Focus on Natural Molecules and Analogues

In-SilicoAnalysis of Secondary Metabolites that Modulates Enzymes of Cholesterol Target

Synthesis, Monoamine Oxidase Inhibition and Computational Analysis of Diversely Substituted N‐Propargylated‐1,3,5‐triazines

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