Development of 2‐(Substituted Benzylamino)‐4‐Methyl‐1, 3‐Thiazole‐5‐Carboxylic Acid Derivatives as Xanthine Oxidase Inhibitors and Free Radical Scavengers

Ali, Rahmat; Kumar, Suresh; Afzal, Obaid; Shalmali, Nishtha; Sharma, Manju; Bawa, Sandhya

doi:10.1111/cbdd.12686

Cited by 30 publications

(21 citation statements)

References 39 publications

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“…Xanthine oxidase (XO) is a key rate‐limited enzyme in uric acid production in humans which oxidizes hypoxanthine from nucleic acid metabolites into xanthine and xanthine into uric acid . The overproduction of uric acid can lead to hyperuricemia, which is a major cause of gout.…”

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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“…The progress of the reaction was monitored by TLC using toluene:ethyl acetate:formic acid (5:4:1) as a solvent system. The solid precipitate obtained was filtered, washed with water, dried, and recrystallized from ethanol 28. Spectral characterization of compounds 5b – 5u is covered in Supplementary materials.…”

Section: Methodsmentioning

confidence: 99%

Synthesis, anti-inflammatory, analgesic, COX1/2-inhibitory activity, and molecular docking studies of hybrid pyrazole analogues

Alam¹,

Alam²,

Khan³

et al. 2016

DDDT

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This article reports on the design, synthesis, and pharmacological activity of a new series of hybrid pyrazole analogues: 5a–5u. Among the series 5a–5u, the compounds 5u and 5s exhibited potent anti-inflammatory activity of 80.63% and 78.09% and inhibition of 80.87% and 76.56% compared with the standard drug ibuprofen, which showed 81.32% and 79.23% inhibition after 3 and 4 hours, respectively. On the basis of in vivo studies, 12 compounds were selected for assessment of their in vitro inhibitory action against COX1/2 and TNFα. The compounds 5u and 5s showed high COX2-inhibitory activity, with half-maximal inhibitory concentrations of 1.79 and 2.51 μM and selectivity index values of 72.73 and 65.75, respectively, comparable to celecoxib (selectivity index =78.06). These selected compounds were also tested for TNFα, cytotoxicity, and ulcerogenicity. Docking studies were also carried out to determine possible interactions of the potent compounds (5u and 5s), which also showed high docking scores of −12.907 and −12.24 compared to celecoxib, with a −9.924 docking score. These selective COX2 inhibitors were docked into the active site of COX2, and showed the same orientation and binding mode to that of celecoxib (selective COX2 inhibitor). Docking studies also showed that the SO2NH2 of 5u and 5s is inserted deep inside the selective pocket of the COX2-active site and formed a hydrogen-bond interaction with His90, Arg513, Phe518, Ser353, Gln192, and Ile517, which was further validated by superimposed docked pose with celecoxib.

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“…An additional linker between the phenyl ring and the thiazole ring of febuxostat capable of producing more hydrogen bonding between inhibitor and enzyme was explored by Ali et al . in their work on 2‐(benzylamino)‐4‐methyl‐1,3‐thiazole‐5‐carboxylic acid derivatives 131 .…”

Section: Non‐purine‐like Inhibitors Of Xomentioning

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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Development of 2‐(Substituted Benzylamino)‐4‐Methyl‐1, 3‐Thiazole‐5‐Carboxylic Acid Derivatives as Xanthine Oxidase Inhibitors and Free Radical Scavengers

Cited by 30 publications

References 39 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

Synthesis, anti-inflammatory, analgesic, COX1/2-inhibitory activity, and molecular docking studies of hybrid pyrazole analogues

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

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