Lead optimization of isocytosine-derived xanthine oxidase inhibitors

Bajaj, Komal; Burudkar, Sandeep; Shah, Pranay; Keche, Ashish P.; Ghosh, Usha; Tannu, Prashant; Khanna, Smriti; Srivastava, Ankita; Deshmukh, Nitin; Dixit, Amol; Ahire, Yogesh S.; Damre, Anagha; Nemmani, Kumar V.S.; Kulkarni-Almeida, Asha; B-Rao, Chandrika; Sharma, Rajiv; Sivaramakrishnan, H.

doi:10.1016/j.bmcl.2012.11.057

Cited by 33 publications

(20 citation statements)

References 9 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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“…These new analoguesi ncreased the in vitro inhibitory activity to the nanomolar range, but were found to be only similar to the reference compounds allopurinol and febuxostat at reducing uric acid levels in ar at model if administeredi ntraperitoneally,a nd with very low efficacy if administered orally.S ubsequent work was conducted to increase the oral bioavailability of the isocytosine-derived lead compound 181. [129] The loss of the hydroxy group with ac oncomitantd ecrease in in vitro activity was necessary to increase the pharmacokinetic properties of the lead compound,w hich resulted in amore orally bioavailablem olecule 184,w hich was demonstrated to be as effective as allopurinol in reducing serum uric acid levels at the 3htime point.…”

Section: Other Miscellaneous Compoundsmentioning

confidence: 99%

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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“…Hyperuricemia, a pathological condition, arises due to persistent excessive level of serum uric acid (sUA) which is correlated with overproduction or under-excretion of uric acid (UA). Chronic hyperuricemia is associated with many disorders including cardiovascular, inflammation, ischaemia-reperfusion, cancer, aging, meta-bolic and oxidative stress [4]. In mammals, sUA level is modulated by the enzyme xanthine oxidase (XO; a molybdoflavoprotein) which is involved in purine metabolism pathways.…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking Studies on Isocytosine Analogues as Xanthine Oxidase Inhibitors

Roy

Narang

Gupta³

et al. 2018

Drug Res (Stuttg)

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Flexible docking simulations were carried out on a series of isocytosine analogs as xanthine oxidase (XO) inhibitors. This was done by analysing the interaction of these compounds at the active site of XO. The binding free energies of the analogs were calculated using GoldScore. The binding modes of the best-fit conformation were studied, providing some handy important interactions. The results obtained henceforth provided an insight into the pharmacophoric structural requirements for XO inhibition for this class of molecules.

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Lead optimization of isocytosine-derived xanthine oxidase inhibitors

Cited by 33 publications

References 9 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

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

Molecular Docking Studies on Isocytosine Analogues as Xanthine Oxidase Inhibitors

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