Design, synthesis and biological evaluation of 1-hydroxy-2-phenyl-4-pyridyl-1H-imidazole derivatives as xanthine oxidase inhibitors

Zhang, Tingjian; Lv, Yunying; Lei, Yu; Liu, Dan; Yao, Feng; Zhao, Jiaxing; Chen, Shaolei; Meng, Fan‐hao; Wang, Shao-Jie

doi:10.1016/j.ejmech.2018.01.060

Cited by 39 publications

(16 citation statements)

References 35 publications

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“…High production of uric acid can lead to gout; therefore, inhibition of this enzyme has been targeted as a therapeutic approach, with imidazole having been employed for a long time as a scaffold for XO inhibitors [14]. As the activity of XO produces both uric acid and reactive oxygen species, a XO inhibitor with antioxidant properties could show a good therapeutic profile, inhibiting the enzyme and controlling the oxidative damage to tissues near it [14,15].…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Silico Screening of 2,4,5-Trisubstituted Imidazole Derivatives as Potential Xanthine Oxidase and Acetylcholinesterase Inhibitors, Antioxidant, and Antiproliferative Agents

et al. 2020

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The employment of privileged scaffolds in medicinal chemistry supplies scientists with a solid start in the search for new and improved therapeutic molecules. One of these scaffolds is the imidazole ring, from which several derivatives have shown a wide array of biological activities. A series of 2,4,5-triphenyl imidazole derivatives were synthesized, characterized, and evaluated in vitro as antioxidant molecules using 1,1-diphenyl-2-picrylhydrazyl (DPPH.) and 2-2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS.+) assays, acetylcholinesterase (AChE) and xanthine oxidase (XO) inhibitors as well as antiproliferative agents. Additional in silico studies such as docking and determination of their absorption, distribution, metabolism, and excretion (ADME) properties were calculated. Compounds 3 and 10 were the most active antioxidants in both the DPPH and ABTS assays (EC50 of 0.141 and 0.174 mg/mL, and 0.168 and 0.162 mg/mL, respectively). In the enzymatic inhibition, compound 1 showed the best activity, inhibiting 25.8% of AChE at a concentration of 150 μg/mL, and compound 3 was the most active XO inhibitor with an IC50 of 85.8 μg/mL. Overall, against the six different evaluated cancerous cell lines, molecules 2, 10, and 11 were the most antiproliferative compounds. In silico predictions through docking point out 11, and ADME analysis to 11 and 12, as good candidates for being lead compounds for further derivations.

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Section: Introductionmentioning

confidence: 99%

In Vitro and In Silico Screening of 2,4,5-Trisubstituted Imidazole Derivatives as Potential Xanthine Oxidase and Acetylcholinesterase Inhibitors, Antioxidant, and Antiproliferative Agents

et al. 2020

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“…Xanthine oxidase (XOD) is a key enzyme in purine metabolism that facilities the hydroxylation of both hypoxanthine and xanthine in the last two steps of urate biosynthesis in humans causing hyperuricemia [8]. Hyperuricemia refers to abnormally high levels of uric acid caused by overproduction or decreased excretion of uric acid, and is a key inducer of gout, in addition to the excessive formation of superoxide radicals resulting in many pathological conditions including inflammation, hypertension, and atherosclerosis [9].…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory and Anti-Hyperuricemic Functions of Two Synthetic Hybrid Drugs with Dual Biological Active Sites

Almeer

Hammad

Leheta

et al. 2019

IJMS

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The present study aimed to test the anti-inflammatory and xanthine oxidase inhibitory activities of two synthesized molecules and compare them to routinely prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac and the serum urate-lowering drug, allopurinol. The anti-inflammatory effects of the designed compounds (A and B) were evaluated in carrageenan (CAR)-induced paw edema in mice. The levels of nitric oxide and myeloperoxidase activity were measured in paw skin using biochemical methods. Additionally, prostaglandin E2 (PGE2), C-reactive protein (CRP), cyclooxygenase-2 (Cox-2), tumor necrosis factor-α (TNFα), interleukin (IL)-1β, IL-2 and IL-10, and monocyte chemoattractant protein-1 (MCP1) were assessed by enzyme-linked immunosorbent assay (ELISA). The expression of inflammation-related genes was confirmed by real-time qPCR. The expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were estimated using immunohistochemistry, and xanthine oxidase inhibitory activity was evaluated using an in vitro assay. The results revealed that compounds A and B decreased inflammation, as was observed by a reduction in the elevation of all the tested markers. In addition, the tested compounds markedly decreased paw swelling, mobilization of inflammatory cells, iNOS-, and NF-κB-immunoreactive cells in a mouse model of paw edema. Interestingly, both compounds were potent xanthine oxidase inhibitors as well as Cox inhibitors with higher activity in favor of compound B providing potential dual acting series of anti-hyperuricemic and anti-inflammatory therapeutic agents.

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“…In 2018 the same group [95] published work that continued the investigationo ni midazole derivatives. They synthesized and tested al ibrary of both 1-hydroxy-2-phenyl-4-pyridyl-1Himidazole derivatives 113 and1 -hydroxy-2-phenyl-3-pyridyl-1Himidazole derivatives 114.T hey aimed to retain the favorable interactions of the enzyme with the 1-hydroxy-2-(4-alkoxy-3-cyanophenyl) moiety of compound 110 and the pyridine moiety from topiroxostat (109).…”

Section: Febuxostat and Topiroxostat Analoguesmentioning

confidence: 99%

“…In 2018 the same group published work that continued the investigation on imidazole derivatives. They synthesized and tested a library of both 1‐hydroxy‐2‐phenyl‐4‐pyridyl‐1 H ‐imidazole derivatives 113 and 1‐hydroxy‐2‐phenyl‐3‐pyridyl‐1 H ‐imidazole derivatives 114 .…”

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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Design, synthesis and biological evaluation of 1-hydroxy-2-phenyl-4-pyridyl-1H-imidazole derivatives as xanthine oxidase inhibitors

Cited by 39 publications

References 35 publications

In Vitro and In Silico Screening of 2,4,5-Trisubstituted Imidazole Derivatives as Potential Xanthine Oxidase and Acetylcholinesterase Inhibitors, Antioxidant, and Antiproliferative Agents

In Vitro and In Silico Screening of 2,4,5-Trisubstituted Imidazole Derivatives as Potential Xanthine Oxidase and Acetylcholinesterase Inhibitors, Antioxidant, and Antiproliferative Agents

Anti-Inflammatory and Anti-Hyperuricemic Functions of Two Synthetic Hybrid Drugs with Dual Biological Active Sites

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

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