Isocytosine-based inhibitors of xanthine oxidase: Design, synthesis, SAR, PK and in vivo efficacy in rat model of hyperuricemia

Khanna, Smriti; Burudkar, Sandeep; Bajaj, Komal; Shah, Pranay; Keche, Ashish P.; Ghosh, Usha; Desai, Avani V.; Srivastava, Ankita; Kulkarni-Almeida, Asha; Deshmukh, Nitin; Dixit, Amol; Brahma, Manoja K.; Bahirat, Umakant Ashok; Doshi, Lalit; Nemmani, Kumar V.S.; Tannu, Prashant; Damre, Anagha; B-Rao, Chandrika; Sharma, Rajiv; Sivaramakrishnan, H.

doi:10.1016/j.bmcl.2012.10.029

Cited by 48 publications

(15 citation statements)

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“…However, these drugs are associated with adverse effects such as gastrointestinal, hepatic, renal, and allergic reactions. [ 16 ] In this study, 11 selected constituents of C. nutans were evaluated on the docking behavior of XO. The docking studies and binding free energy calculations as in Table 5 show isoorientin to be having the highest interaction energy (−49.80 kcal/mol) with that of XO.…”

Section: Resultsmentioning

confidence: 99%

Molecular docking analysis of selected Clinacanthus nutans constituents as xanthine oxidase, nitric oxide synthase, human neutrophil elastase, matrix metalloproteinase 2, matrix metalloproteinase 9 and squalene synthase inhibitors

et al. 2016

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Background:Clinacanthus nutans (Burm. f.) Lindau has gained popularity among Malaysians as a traditional plant for anti-inflammatory activity.Objective:This prompted us to carry out the present study on a selected 11 constituents of C. nutans which are clinacoside A–C, cycloclinacoside A1, shaftoside, vitexin, orientin, isovitexin, isoorientin, lupeol and β-sitosterol.Materials and Methods:Selected 11 constituents of C. nutans were evaluated on the docking behavior of xanthine oxidase (XO), nitric oxide synthase (NOS), human neutrophil elastase (HNE), matrix metalloproteinase (MMP 2 and 9), and squalene synthase (SQS) using Discovery Studio Version 3.1. Also, molecular physicochemical, bioactivity, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and toxicity prediction by computer assisted technology analyzes were also carried out.Results:The molecular physicochemical analysis revealed that four ligands, namely clinacoside A–C and cycloclinacoside A1 showed nil violations and complied with Lipinski's rule of five. As for the analysis of bioactivity, all the 11 selected constituents of C. nutans exhibited active score (>0) toward enzyme inhibitors descriptor. ADMET analysis showed that the ligands except orientin and isoorientin were predicted to have Cytochrome P4502D6 inhibition effect. Docking studies and binding free energy calculations revealed that clinacoside B exhibited the least binding energy for the target enzymes except for XO and SQS. Isovitexin and isoorientin showed the potentials in the docking and binding with all of the six targeted enzymes, whereas vitexin and orientin docked and bound with only NOS and HNE.Conclusion:This present study has paved a new insight in understanding these 11 C. nutans ligands as potential inhibitors against XO, NOS, HNE, MMP 2, MMP 9, and SQS.SUMMARY Isovitexin and isoorientin (Clinacanthus nutans constituent) showed potentials in the docking and binding with all of the six targeted enzymes (xanthine oxidase [XO], nitric oxide synthase [NOS], human neutrophil elastase [HNE], matrix metalloproteinase [MMP 2 and 9], and squalene synthase [SQS])Moreover, clinacoside B (C. nutans constituent) exhibited the least binding energy for the target enzymes except for XO and SQSInterestingly, all of the selected ligands from C. nutans showed the potential to dock and bind with HNE. Abbreviations used: C. nutans: Clinacanthus nutans, XO: Xanthine oxidase, NOS: Nitric oxide synthase, HNE: Human neutrophil elastase, MMP: Matrix metalloproteinase, SQS: Squalene synthase, ADMET: Absorption, Distribution, Metabolism, Excretion, and Toxicity, TOPKAT: Toxicity prediction by the computer assisted technology

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Section: Resultsmentioning

confidence: 99%

Molecular docking analysis of selected Clinacanthus nutans constituents as xanthine oxidase, nitric oxide synthase, human neutrophil elastase, matrix metalloproteinase 2, matrix metalloproteinase 9 and squalene synthase inhibitors

et al. 2016

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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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“…The in vitro activity of 178 was improved when the methoxy group was substituted with either an isobutoxy group 181 (a 16-fold increase in activity), or with ap henyl ring 182 (a 30fold increase in activity). [128] Compound 181 wasu sed as al ead molecule to furthere xplore the effecto fs ubstituents in the ortho positiont ot he isobutoxy group. The IC 50 values ranged from more than 20 mm for the trifluoromethoxyg roup to 20 nm for the cyano group 183.…”

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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Isocytosine-based inhibitors of xanthine oxidase: Design, synthesis, SAR, PK and in vivo efficacy in rat model of hyperuricemia

Cited by 48 publications

References 7 publications

Molecular docking analysis of selected Clinacanthus nutans constituents as xanthine oxidase, nitric oxide synthase, human neutrophil elastase, matrix metalloproteinase 2, matrix metalloproteinase 9 and squalene synthase inhibitors

Molecular docking analysis of selected Clinacanthus nutans constituents as xanthine oxidase, nitric oxide synthase, human neutrophil elastase, matrix metalloproteinase 2, matrix metalloproteinase 9 and squalene synthase 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

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