Synthesis and Biological Evaluation of 5-benzyl-3-pyridyl-1H-1,2,4-triazole Derivatives as Xanthine Oxidase Inhibitors

2020 ◽  
Vol 16 (1) ◽  
pp. 119-127
Author(s):  
Song-Ye Li ◽  
Ting-Jian Zhang ◽  
Qing-Xia Wu ◽  
Kamara M. Olounfeh ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Xanthine Oxidase ◽  
Inhibitory Activity ◽  
Binding Pocket ◽  
Biological Evaluation ◽  
Triazole Derivatives ◽  
Xanthine Oxidase Inhibitors ◽  
Ic50 Value ◽  
Molecular Modelling Studies ◽  
Modelling Studies

Background: Topiroxostat is an excellent xanthine oxidase (XO) inhibitor, possessing a specific 3,5-diaryl-1,2,4-triazole framework. Objective: The present work was aimed to investigate the preliminary structure-activity relationship (SAR) of 2-cyanopyridine-4-yl-like fragments of topiroxostat analogues. Methods: A series of 5-benzyl-3-pyridyl-1H-1,2,4-triazole derivatives (1a-j and 2a-j) were designed and synthesized by replacement of the 2-cyanopyridine-4-yl moiety with substituted benzyl groups. XO inhibitory activity in vitro was evaluated. Furthermore, molecular modeling simulations were performed to predict the possible interactions between the synthesized compounds and XO binding pocket. Results: The SARs analysis demonstrated that 3,5-diaryl-1,2,4-triazole framework is not essential; in spite of its lower potency, 5-benzyl-3-pyridyl-1H-1,2,4-triazole is an acceptable scaffold for XO inhibitory activity to some extent. A 3′-nitro and a 4′-sec-butoxy group link to the benzyl moiety will be welcome. Furthermore, the most promising compound, 1h, was identified with an IC50 value of 0.16 μM, and the basis of XO inhibition by 1h was rationalized through the aid of molecular modelling studies. Conclusion: Compound 1h could be a lead compound for further investigation and the present work may provide some insight into the search for more structurally diverse XO inhibitors with topiroxostat as a prototype.

scholarly journals UFLC-MS-IT-TOF and Bioassay Guided Isolation of Flavonoids as Xanthine Oxidase Inhibitors from Diospyros dumetorum

2017 ◽  
Vol 12 (11) ◽  
pp. 1934578X1701201
Author(s):  
Zhen-Tao Deng ◽  
Tong-Hua Yang ◽  
Xiao-Yan Huang ◽  
Xing-Long Chen ◽  
Jian-Gang Zhang ◽  
...  
Keyword(s):  
Xanthine Oxidase ◽  
Inhibitory Activity ◽  
Folk Medicine ◽  
Hydroxyl Groups ◽  
Active Constituents ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Pulmonary Abscess ◽  
Xanthine Oxidase Inhibitors

Diospyros dumetorum is an important folk medicine for treating pulmonary abscess and inflammation. The leaves of D. dumetorum revealed xanthine oxidase (XOD) inhibitory activity. With the guidance of UFLC-MS-IT-TOF analyses combined with bioassay in vitro, 15 flavonoids were isolated from the active parts of D. dumetorum. Except for 11 (IC50 > 200μM), all compounds showed obvious XOD inhibitory activity with IC50 values of 32.5 ± 0.7 ~ 145.0 ± 3.3 μM. The preliminary structure-activity relationships study suggested that glycosylation on C-3 was unfavorable for XOD inhibitory activity; hydroxyl groups on ring B were essential for maintaining activity; the activity was closely related with the position of galloylation. This is the first recognition of the XOD inhibitory activity and active constituents of D. dumetorum, and will provide valuable information for this plant as a new resource for treating hyperuricemia and gout.

Synthesis and bioevaluation of 2-phenyl-5-methyl-2H-1,2,3-triazole-4-carboxylic acid/carbohydrazide derivatives as potent xanthine oxidase inhibitors

RSC Advances ◽  
2016 ◽  
Vol 6 (115) ◽  
pp. 114879-114888 ◽  
Author(s):  
Ailong Shi ◽  
Defa Wang ◽  
He Wang ◽  
Yue Wu ◽  
Haiqiu Tian ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Xanthine Oxidase ◽  
Carboxylic Acids ◽  
Inhibitory Activity ◽  
Xanthine Oxidase Inhibitors

A series of 2-phenyl-5-methyl-2H-1,2,3-triazole-4-carboxylic acids/carbohydrazides as analogues of febuxostat were synthesized and evaluated for their in vitro xanthine oxidase (XO) inhibitory activity.

scholarly journals Comparative Study of Xanthine Oxidase Inhibitory Activity Of Methanolic Leaf Extracts Of CalophyllumBlancoi (Bitaog), Diospyrospilosanthera (Bolongeta) and SyzygiumCumini (Duhat)

2020 ◽  
Vol 11 (SPL4) ◽  
pp. 531-537
Author(s):  
Jan Asuncion ◽  
Mariane May Domingo ◽  
Rave Harvey Sienna ◽  
ZhaineMarille Villa ◽  
Jennifer Anne Loyola
Keyword(s):  
Xanthine Oxidase ◽  
Inhibitory Activity ◽  
Leaf Extract ◽  
Leaf Extracts ◽  
Standard Drug ◽  
Ic50 Value ◽  
Vitro Analysis ◽  
In Vitro Analysis

Gout is characterized as an inflammation and warmth in the joints. It is associated with hyperuricemia wherein an upregulation of xanthine oxidase in purine degradation leads to increased levels of uric acid in the blood. Gout is not fatal. However, it affects one’s quality of life. Thus, this research primarily focuses in determining the inhibitory activity of xanthine oxidase in the methanolic leaf extract of bitaog (Calophyllumblancoi), bolongeta (Diospyrospilosanthera), and duhat (Syzygiumcumini) in gout. A quantitative-experimental research method was used in the study and the data were obtained by measuring the percent inhibition of the samples using UV-Vis spectrophotometer at 290 nm. The results showed that the methanolic leaf extract of above stated plants exhibited exemplary inhibition in comparison with the standard drug, allopurinol. The IC50  value determines the ability of the inhibitor to decrease the biotransformation of a substrate. The principle behind IC50 is, the lower the value the higher the inhibition. The bitaog (Calophyllumblancoi) trials have the lowest IC50 value with an average of 124.3 after the standard drug, followed by bolongeta (Diospyrospilosanthera) have an average of 155.3 IC50 value. Then duhat (Syzygiumcumini) showed the highest IC50 an average of 208.8. The bitaog (Calophyllumblancoi), next to allopurinol, showed the highest inhibition among all the extracts followed by the bolongeta (Diospyrospilosanthera). The least inhibitory activity was observed in duhat (Syzygiumcumini). Hence, it can be concluded that bitaog (Calophyllumblancoi), bolongeta (Diospyrospilosanthera), and duhat (Syzygiumcumini) can inhibit xanthine oxidase using in vitro analysis.

Efficient synthesis and characterization of novel indolizines: exploration of in vitro COX-2 inhibitory activity and molecular modelling studies

2018 ◽  
Vol 42 (7) ◽  
pp. 4893-4901 ◽  
Author(s):  
Sandeep Chandrashekharappa ◽  
Katharigatta N. Venugopala ◽  
Christophe Tratrat ◽  
Fawzi M. Mahomoodally ◽  
Bandar E. Aldhubiab ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Inhibitory Activity ◽  
Synthesis And Characterization ◽  
Efficient Synthesis ◽  
Molecular Modelling Studies ◽  
Modelling Studies ◽  
Cox 2

Novel indolizine scaffolds as COX-2 inhibiting agents.

Anticholinesterase and Antioxidant Activities of Natural Abietane Diterpenoids with Molecular Docking Studies

2020 ◽  
Vol 17 (3) ◽  
pp. 269-284 ◽  
Author(s):  
Gülaçtı Topçu ◽  
Atilla Akdemir ◽  
Ufuk Kolak ◽  
Mehmet Öztürk ◽  
Mehmet Boğa ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Antioxidant Activities ◽  
Cholinergic Neurons ◽  
Docking Studies ◽  
Mammalian Brain ◽  
Abietane Diterpenoids ◽  
Selective Ligand ◽  
Molecular Modelling Studies ◽  
Modelling Studies

Background: Alzheimer’s Disease (AD) is one of the most prevalent causes of dementia in the world, and no drugs available that can provide a complete cure. Cholinergic neurons of the cerebral cortex of AD patients are lost due to increased activity of cholinesterase enzymes. Objectives: Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) are the two major classes of cholinesterases in the mammalian brain. The involvement of oxidative stress in the progression of AD is known. Thus, the objective of this study is to determine strong ChE inhibitors with anti-oxidant activity. Methods: In this study, 41 abietane diterpenoids have been assayed for antioxidant and anticholinesterase (both for AChE and BuChE) properties in vitro, which were previously isolated from Salvia species, and structurally determined by spectroscopic methods, particularly intensive 1D- and 2DNMR and mass experiments. Molecular modeling studies were performed to rationalize the in vitro ChE inhibitory activity of several abietane diterpenoids compared with galantamine. Results: Thirteen out of the tested 41 abietane diterpenoids exhibited at least 50% inhibition on either AChE or BuChE. The strongest inhibitory activity was obtained for Bractealine against BuChE (3.43 μM) and AChE (33.21 μM) while the most selective ligand was found to be Hypargenin E against BuChE enzyme (6.93 μM). A full correlation was not found between anticholinesterase and antioxidant activities. The results obtained from molecular modelling studies of Hypargenin E and Bractealine on AChE and BuChE were found to be in accordance with the in vitro anti-cholinesterase activity tests. Conclusion: Abietane diterpenoids are promising molecules for the treatment of mild-moderate AD.

scholarly journals Phloroglucinol Derivatives from Dryopteris crassirhizoma as Potent Xanthine Oxidase Inhibitors

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 122
Author(s):  
Heung Joo Yuk ◽  
Ji-Yul Kim ◽  
Yoon-Young Sung ◽  
Dong-Seon Kim
Keyword(s):  
Xanthine Oxidase ◽  
Inhibitory Activity ◽  
Etoac Extract ◽  
Xanthine Oxidase Inhibitors ◽  
Ic50 Value ◽  
Phloroglucinol Derivatives ◽  
Acetyl Group ◽  
Potent Inhibitory Activity ◽  
Better Than ◽  
Comparative Activity

Dryopteris crassirhizoma rhizomes are used as a traditional medicine in Asia. The EtOAc extract of these roots has shown potent xanthine oxidase (XO) inhibitory activity. However, the main phloroglucinols in D. crassirhizoma rhizomes have not been analyzed. Thus, we investigated the major constituents responsible for this effect. Bioassay-guided purification isolated four compounds: flavaspidic acid AP (1), flavaspidic acid AB (2), flavaspidic acid PB (3), and flavaspidic acid BB (4). Among these, 1 showed the most potent inhibitory activity with a half-maximal inhibitory concentration (IC50) value of 6.3 µM, similar to that of allopurinol (IC50 = 5.7 µM) and better than that of oxypurinol (IC50 = 43.1 µM), which are XO inhibitors. A comparative activity screen indicated that the acetyl group at C3 and C3′ is crucial for XO inhibition. For example, 1 showed nearly 4-fold higher efficacy than 4 (IC50 = 20.9 µM). Representative inhibitors (1–4) in the rhizomes of D. crassirhizoma showed reversible and noncompetitive inhibition toward XO. Furthermore, the potent inhibitors were shown to be present in high quantities in the rhizomes by a UPLC-QTOF-MS analysis. Therefore, the rhizomes of D. crassirhizoma could be used to develop nutraceuticals and medicines for the treatment of gout.

scholarly journals Bis-thiobarbiturates as Promising Xanthine Oxidase Inhibitors: Synthesis and Biological Evaluation

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1443
Author(s):  
João L. Serrano ◽  
Diana Lopes ◽  
Melani J. A. Reis ◽  
Renato E. F. Boto ◽  
Samuel Silvestre ◽  
...  
Keyword(s):  
Xanthine Oxidase ◽  
Biological Activities ◽  
Chemical Change ◽  
Biological Evaluation ◽  
Reference Drug ◽  
Xanthine Oxidase Inhibitors ◽  
Low Cytotoxicity ◽  
Synthesis And Biological Evaluation ◽  
Better Than

Xanthine oxidase (XO) is the enzyme responsible for the conversion of endogenous purines into uric acid. Therefore, this enzyme has been associated with pathological conditions caused by hyperuricemia, such as the disease commonly known as gout. Barbiturates and their congeners thiobarbiturates represent a class of heterocyclic drugs capable of influencing neurotransmission. However, in recent years a very large group of potential pharmaceutical and medicinal applications have been related to their structure. This great diversity of biological activities is directly linked to the enormous opportunities found for chemical change off the back of these findings. With this in mind, sixteen bis-thiobarbiturates were synthesized in moderate to excellent reactional yields, and their antioxidant, anti-proliferative, and XO inhibitory activity were evaluated. In general, all bis-thiobarbiturates present a good antioxidant performance and an excellent ability to inhibit XO at a concentration of 30 µM, eight of them are superior to those observed with the reference drug allopurinol (Allo), nevertheless they were not as effective as febuxostat. The most powerful bis-thiobarbiturate within this set showed in vitro IC50 of 1.79 μM, which was about ten-fold better than Allo inhibition, together with suitable low cytotoxicity. In silico molecular properties such as drug-likeness, pharmacokinetics, and toxicity of this promising barbiturate were also analyzed and herein discussed.

Design, Synthesis, Molecular Docking and Biological Evaluation of 1-(benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol Derivatives as Antiproliferative Agents

2019 ◽  
Vol 16 (10) ◽  
pp. 837-845
Author(s):  
Sandhya Jonnala ◽  
Bhaskar Nameta ◽  
Murthy Chavali ◽  
Rajashaker Bantu ◽  
Pallavi Choudante ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Mouse Skin ◽  
Coupling Reaction ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Design Synthesis

A class of 1-((benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol derivatives (4a-t) has been synthesized in good yields through a three component coupling reaction. The newly synthesized compounds were evaluated for their in vitro antiproliferative activity against five cell lines such as DU145 (human prostate cancer), MDA-MB-B231 (human breast cancer), SKOV3 (human ovarian cancer), B16-F10 (mouse skin melanoma) and CHO-K1 (Chinese hamster ovary cells), a noncancerous cell line. In vitro inhibitory activity indicates that compounds 4a, 4b, 4c, 4d, 4g, 4j, and 4o exhibited potent anti-proliferative behavior. Among them, compounds 4g, 4j and 4o found to be the most active members exhibiting remarkable growth inhibitory activity. Molecular docking facilitates to investigate the probable binding mode and key active site interactions in tubulins α and β proteins. The docking results are complementary to experimental results.

Phenanthridine Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Design, Synthesis and Biological Evaluation

2020 ◽  
Vol 16 ◽  
Author(s):  
Reema Abu Khalaf ◽  
Shorooq Alqazaqi ◽  
Maram Aburezeq ◽  
Dima Sabbah ◽  
Ghadeer Albadawi ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Biological Evaluation ◽  
Ligand Docking ◽  
Biological Assessment ◽  
Hypoglycemic Agents ◽  
Binding Affinities ◽  
Oral Hypoglycemic Agents ◽  
Design Synthesis ◽  
Dpp Iv

Background: Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduces the deterioration of gut-derived endogenous incretin hormones that are secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of pancreas. Objective: In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors was carried out. The target compounds were docked to study the molecular interactions and binding affinities against DPP-IV enzyme. Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed. Results: In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 µM concentration, where compound 3d harboring ortho-fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669 and Y752 backbones. Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.

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