9-Benzoyl 9-deazaguanines as potent xanthine oxidase inhibitors

Rodrigues, Marili Villa Nova; Barbosa, Alexandre Ferraz; Silva, Júlia F. da; Santos, Deborah A. dos; Vanzolini, Kenia L.; Moraes, Marcela Cristina de; Corrêa, Arlene G.; Cass, Quézia B.

doi:10.1016/j.bmc.2015.12.006

Cited by 29 publications

(18 citation statements)

References 35 publications

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“…Inhibitory activity in the nanomolar range was also reported for al ibrary of 9-benzoyl-9-deazaguanines by Rodrigues et al in 2016. [76] The most active compound had an itro group at the meta positiono ft he phenyl ring 70.T he othera nalogues in the library had either none or one, two, or three halogen substituents on the phenyl ring, and they all showedl ower activity than the nitro-substituted compound. It was also reported that the lead compound 2-amino-3,5-dihydro-7-(3-nitrobenzoyl)pyrrolo[3,2-d]pyrimidin-4-one (70, K i = 55.1 nm compared to K i = 1.55 mm for allopurinol) exhibitedg ood selectivity toward XO, with very weak activity toward purine nucleoside phosphorylase (PNP).…”

Section: Pyrrolo[23-d]pyrimidines and Pyrazolo[34-b]pyridinesmentioning

confidence: 99%

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

2019

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Xanthine oxidase (XO) is the enzyme responsible for the catabolism of purines and their conversion into uric acid. XO is thus the target for the treatment of hyperuricemia and gout. For more than 50 years the only XO inhibitor drug available on the market was the purine analogue allopurinol. In the last decade there has been a resurgence in the search for new inhibitors of XO, as the activity of XO and hyperuricemia have also been associated with a variety of conditions such as diabetes, hypertension, and other cardiovascular diseases. In recent years the non‐purine inhibitor febuxostat was approved in Europe and the USA for the treatment of hyperuricemia. This drug was followed by another XO inhibitor called topiroxostat. This review discusses the molecular structures and activities of the multiple classes of inhibitors that have been developed since the discovery of allopurinol, with a brief review of the molecular interactions between inhibitors and XO active site residues for the most important molecules. The challenges ahead for the discovery of new inhibitors of XO with novel chemical structures are discussed.

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Section: Pyrrolo[23-d]pyrimidines and Pyrazolo[34-b]pyridinesmentioning

confidence: 99%

“…Inhibitory activity in the nanomolar range was also reported for a library of 9‐benzoyl‐9‐deazaguanines by Rodrigues et al. in 2016 . The most active compound had a nitro group at the meta position of the phenyl ring 70 .…”

Section: Purine‐based and Purine‐like Inhibitors Of Xomentioning

confidence: 99%

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

2019

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“…2‐Amino‐3 H ,5 H ‐7‐(3‐nitrobenzoyl)pyrrolo[3,2‐ d ] pyrimidin‐4‐one ( 70 ) was observed to be effective and more potent XO inhibitor than allopurinol. It was found to be a noncompetitive inhibitor having more affinity for enzyme–substrate complex than the free enzyme . Lesinurad ( 71 ) got US‐FDA approval in the United States as the first combination therapy with a XO inhibitor mainly with allopurinol or febuxostat for the treatment of hyperuricemia associated with gout .…”

Section: Xanthine Oxidasementioning

confidence: 99%

Toward an Understanding of Structural Insights of Xanthine and Aldehyde Oxidases: An Overview of their Inhibitors and Role in Various Diseases

Kumar

Joshi

Kler

et al. 2017

Medicinal Research Reviews

101

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Almost all drug molecules become the substrates for oxidoreductase enzymes, get metabolized into more hydrophilic products and eliminated from the body. These metabolites sometime may be more potent, active, inactive, or toxic in nature compared to parent molecule. Xanthine oxidoreductase and aldehyde oxidase belong to molybdenum containing family and are well characterized for their structures and functions, in particular to their ability to oxidize/hydroxylate the xenobiotics. Their upregulated clinical levels causing oxidative stress are associated with pathways either directly involved in the progression of diseases, gout, or indirectly with the succession of other diseases such as diabetes, cancer, etc. Herein, we have put forth a comprehensive review on the xanthine and aldehyde oxidases pertaining to their structures, functions, pathophysiological role, and a comparative analysis of structural insights of xanthine and aldehyde oxidases' binding domains with endogenous ligands or inhibitors. Though both the enzymes are molybdenum containing and are likely to share some common pathways and interact with inhibitors in a similar manner but we have focused on structural prerequisites for inhibitor specificity to both the enzymes keeping in view of the existing X-ray structures. This review also provides futuristic implications in the design of inhibitors derived from inorganic complexes or small organic molecules considering the spatial features and structural insights of both the enzymes.

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“…For this reason, inhibition of XO has been an obvious target to control uric acid level in blood. It has been shown that XO inhibitors may be useful for the treatment of hepatic disease, cancer, inflammation, and gout which is caused by the generation of uric acid and superoxide anion radical [35].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of S-Substituted Perhalo-2-nitrobuta-1,3-dienes as Novel Xanthine Oxidase, Tyrosinase, Elastase, and Neuraminidase Inhibitors

Onul

Ertik

Mermer

et al. 2018

Journal of Chemistry

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S-substituted perhalo-2-nitrobuta-1,3-dienes 3a, b were synthesized by the reaction of polyhalo-2-nitrobuta-1,3-dienes 1a, b with allyl mercaptan. 1-(2,3-Dibromopropanethio)-4-bromo-1,3,4-trichloro-2-nitrobuta-1,3-diene 4 was obtained from the addition of bromine to S-substituted polyhalo-2-nitrobuta-1,3-diene 3b in carbon tetrachloride. Sulfoxides 5a, b, and 6 were obtained from the reaction of thiosubstituted polyhalonitrobutadienes 3a, b, and 4 with m-CPBA in CHCl 3 . The structures of the new compounds were determined by spectroscopic data (FTIR, 1 H NMR, 13 C NMR, MS). These compounds exhibited antixanthine oxidase, antityrosinase, antielastase, and antineuraminidase activities.

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9-Benzoyl 9-deazaguanines as potent xanthine oxidase inhibitors

Cited by 29 publications

References 35 publications

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

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

Toward an Understanding of Structural Insights of Xanthine and Aldehyde Oxidases: An Overview of their Inhibitors and Role in Various Diseases

Synthesis and Biological Evaluation of S-Substituted Perhalo-2-nitrobuta-1,3-dienes as Novel Xanthine Oxidase, Tyrosinase, Elastase, and Neuraminidase Inhibitors

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