Identification of novel isocytosine derivatives as xanthine oxidase inhibitors from a set of virtual screening hits

B-Rao, Chandrika; Kulkarni-Almeida, Asha; Katkar, Kamlesh V.; Khanna, Smriti; Ghosh, Usha; Keche, Ashish P.; Shah, Pranay; Srivastava, Ankita; Korde, Vaidehi; Nemmani, Kumar V.S.; Deshmukh, Nitin; Dixit, Amol; Brahma, Manoja K.; Bahirat, Umakant Ashok; Doshi, Lalit; Sharma, Rajiv; Sivaramakrishnan, H.

doi:10.1016/j.bmc.2012.03.019

Cited by 53 publications

(15 citation statements)

References 34 publications

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“…Febuxostat and topiroxostat (Figure ) are both non‐purine XO inhibitors which possess excellent XO inhibitory activities and have been introduced into market in 2009 and 2013, respectively. Their approval greatly promoted the research of non‐purine XO inhibitors, and a number of compounds based on the scaffolds of febuxostat and topiroxostat have been recently reported such as Y‐700, isoxazoles, imidazoles, 1,2,3‐triazoles, selenazoles, 2‐(indol‐5‐yl)thiazoles, isocytosines, phenyl‐1,2,4‐triazoles, 4‐(pyridin‐4‐yl)‐1,2,3‐triazoles, and isonicotinamides…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and molecular docking studies of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives as xanthine oxidase inhibitors

Zhang

Wei

et al. 2018

Chem Biol Drug Des

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A series of N-(9,10-anthraquinone-2-carbonyl)amino acid derivatives (1a-j) was designed and synthesized as novel xanthine oxidase inhibitors. Among them, the L/D-phenylalanine derivatives (1d and 1i) and the L/D-tryptophan derivatives (1e and 1j) were effective with micromolar level potency. In particular, the L-phenylalanine derivative 1d (IC = 3.0 μm) and the D-phenylalanine derivative 1i (IC = 2.9 μm) presented the highest potency and were both more potent than the positive control allopurinol (IC = 8.1 μm). Preliminary SAR analysis pointed that an aromatic amino acid fragment, for example, phenylalanine or tryptophan, was essential for the inhibition; the D-amino acid derivative presented equal or greater potency compared to its L-enantiomer; and the 9,10-anthraquinone moiety was welcome for the inhibition. Molecular simulations provided rational binding models for compounds 1d and 1i in the xanthine oxidase active pocket. As a result, compounds 1d and 1i could be promising lead compounds for further investigation.

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Section: Introductionmentioning

confidence: 99%

Design, synthesis, and molecular docking studies of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives as xanthine oxidase inhibitors

Zhang

Wei

et al. 2018

Chem Biol Drug Des

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“…Out of all the docked compounds, three scored better than allopurinol. At 100 μM, the highest inhibition was obtained for 24 (98%), followed by 23 (79%) and 22 (76%) …”

Section: Xanthine Oxidasementioning

confidence: 98%

“…The molecular modeling study (Fig. C) for compound 28 showed the electrostatic interactions with Asn786 and Lys771 …”

Section: Xanthine Oxidasementioning

confidence: 99%

“…8A) for XO inhibition by virtual screening of an in-house synthetic library followed by in vitro and in vivo testing. Out of all the docked compounds, three scored better than allopurinol.At 100 M, the highest inhibition was obtained for 24 (98%), followed by 23 (79%) and 22 (76%) 131. In continuation to above, Khanna et al carried out the SAR study for lead generation by structure-guided design approach(Fig.…”

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confidence: 96%

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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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“…In general, topiroxostat analogues were not as abundant as febuxostat analogues, a typical representative is the pyridyl-1,2,4triazoles reported by Takahiro Sato et al [19] which possess excellent potency ( Figure 1). Furthermore, other XO inhibitors with various structural classes have also been recently published, including isocytosines, [5,[20][21][22] N-(1,3-diaryl-3oxo-propyl)amides, [23] N-acetyl pyrazolines, [24] hydroxylated chalcones, [25] 9-deazaguanines, [26] benzimidazoles, [27] flavonoids, [28,29] fraxamosides, [30] pyrano [3,2-d]pyrimidines, [31] 2-arylbenzo[b]furans [32] , and benzaldehydes. [33] We have focused on the structural modifications of fivemembered ring and the structure activity relationship (SAR) investigations of classical XO inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives as xanthine oxidase inhibitors

Zhang

et al. 2017

Chem Biol Drug Des

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A series of 5-(4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)benzonitrile derivatives (1a-p) was designed, synthesized, and identified as xanthine oxidase inhibitors with micromolar level potencies. Among them, the most promising compounds 1j and 1k were obtained with IC values of 8.1 and 6.7 μm, respectively. The Lineweaver-Burk plot revealed that compound 1k acted as a mixed-type xanthine oxidase inhibitor. SAR analysis revealed that a carbon atom occupying the X position is not as effective as a nitrogen atom, and an iso-pentyloxy or a cyclopentyloxy at the 2-position of benzonitrile moiety will benefit the inhibitory potency. The basis of xanthine oxidase inhibition by 1k was rationalized by molecular modeling studies.

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Identification of novel isocytosine derivatives as xanthine oxidase inhibitors from a set of virtual screening hits

Cited by 53 publications

References 34 publications

Design, synthesis, and molecular docking studies of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives as xanthine oxidase inhibitors

Design, synthesis, and molecular docking studies of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives as xanthine oxidase inhibitors

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

Design, synthesis, and biological evaluation of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives as xanthine oxidase inhibitors

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