Pyrazole-chalcone derivatives as selective COX-2 inhibitors: design, virtual screening, and in vitro analysis

Macarini Anelise F.; Sobrinho Thales U. C.; Rizzi Gerusa W.; Correa Rogerio

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Pyrazole-chalcone derivatives as selective COX-2 inhibitors: design, virtual screening, and in vitro analysis

机译：吡唑 - 硫酮衍生物作为选择性Cox-2抑制剂：设计，虚拟筛选和体外分析

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In the process of research and development of new drugs, in silico analyzes are widely used. They address the pharmacokinetics of the molecules in study and can predict the binding mode and affinity, using a docking software. This approach can optimize the development of new drugs, reducing costs, time, and resources. In this study, a library of 300 pyrazole-chalcone derivatives were designed, the in silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties were evaluated, and a structure-based virtual screening was performed using AutoDock Vina. The docking results exhibited that the derivatives binding mode at the COX-2 active site is similar to celecoxib, the reference drug, and presented similar binding energy. Six compounds were synthetized and tested for in vitro inhibition of the COX-1 and COX-2 isoenzymes and the selectivity index (SI) was calculated. The compound 2a11 showed the best activity for COX-2 (IC50COX-2=0.73M) whereas the control, celecoxib, resulted IC50COX-2=0.88M. All the other compounds synthetized presented better potency for COX-2 inhibition than the control. Compound 2a23 exhibited the higher SI, of 280.17 (IC50COX-1=210.13M/ IC50COX-2=0.75M), while celecoxib was 246.88 (IC50COX-1=217.26M/ IC50COX-2=0.88M). These results corroborate with a possible anti-inflammatory activity and COX-2 selectivity of the new compounds synthetized.

机译：在新药物的研究和开发过程中，在硅分析中被广泛使用。它们使用对接软件来解决研究中分子的药代动力学，可以预测结合模式和亲和力。这种方法可以优化新药的发展，降低成本，时间和资源。在该研究中，设计了300种吡唑 - 硫酮衍生物的文库，评估了Silico拍摄室（吸收，分布，代谢，排泄和毒性）性质，使用Autodock Vina进行基于结构的虚拟筛选。对接结果表明COX-2活性位点处的衍生物结合模式类似于Celecoxib，参考药物，并呈现出类似的结合能量。合成六种化合物并测试过体体外抑制COX-1和COX-2同工酶，并计算选择性指数（Si）。化合物2A11显示了COX-2（IC50cox-2 = 0.73m）的最佳活性，而控制，Celecoxib导致IC50cox-2 = 0.88m。所有其他化合物合成的所有化合物都呈现了COX-2抑制的效力比对照。化合物2a23表现出较高的Si，280.17（IC 50cox-1 = 210.13m / ic 50cox-2 = 0.75m），而Celecoxib为246.88（IC50cox-1 = 217.26m / ic50cox-2 = 0.88M）。这些结果通过合成的新化合物的可能的抗炎活性和COX-2选择性进行了腐蚀。

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来源
《Medicinal chemistry research: an international journal for rapid communications on design and mechanisms of action of biologically active agents》 |2019年第8期|共11页
作者
Macarini Anelise F.; Sobrinho Thales U. C.; Rizzi Gerusa W.; Correa Rogerio;
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作者单位

Univ Vale Itajai Nucleo Invest Quim Farmaceut NIQFAR Rua Uruguai 458 BR-88302901 Itajai SC;

Univ Vale Itajai Curso Engn Quim Escola Mar Ciencia &

Tecnol Rua Uruguai 458 BR-88302901 Itajai;

Univ Vale Itajai Nucleo Invest Quim Farmaceut NIQFAR Rua Uruguai 458 BR-88302901 Itajai SC;

Univ Vale Itajai Nucleo Invest Quim Farmaceut NIQFAR Rua Uruguai 458 BR-88302901 Itajai SC;

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原文格式 PDF
正文语种 eng
中图分类药学;
关键词
Pyrazole-Chalcones; Molecular docking; Medicinal Chemistry; COX-2 inhibition; ADMET; Anti-inflammatory;

机译：吡唑 - 丘酮;分子对接;药用化学;COX-2抑制;允许抗炎;

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专利

1. Pyrazole-chalcone derivatives as selective COX-2 inhibitors: design, virtual screening, and in vitro analysis [J] . Macarini Anelise F., Sobrinho Thales U. C., Rizzi Gerusa W., Medicinal chemistry research: an international journal for rapid communications on design and mechanisms of action of biologically active agents . 2019,第8期

机译：吡唑 - 硫酮衍生物作为选择性Cox-2抑制剂：设计，虚拟筛选和体外分析
2. Design, Synthesis and Biological Evaluation of4-(Imidazolylmethyl)-2-(4-methylsulfonyl phenyl)-Quinoline Derivatives as Selective COX-2 Inhibitors and In-vitro Anti-breast Cancer Agents [J] . Azizi Ebrahim, Ghodsi Razieh, Zarghi Afshin Iranian Journal of Pharmaceutical Research . 2016,第1期

机译：4-（咪唑基甲基）-2-（4-甲基磺酰基苯基）-喹啉衍生物作为选择性COX-2抑制剂和体外抗乳腺癌药物的设计，合成和生物学评价
3. Design ,synthesis and In-vitro antitumor evaluation of new 2, 3-diaryl-indenopyrazole and 2,3-diaryl-benzofuropyrazole derivatives as selective cyclooxygenase (COX-2) inhibitors [J] . T. Zebardast, A. Zarghi, F. H.Shirazi Research in Pharmaceutical Sciences . 2012,第5期

机译：新的2,3-二芳基茚并吡唑和2,3-二芳基苯并呋喃吡唑衍生物作为选择性环加氧酶（COX-2）抑制剂的设计，合成和体外抗肿瘤评估
4. Pharmacoinformatics Approach to the Discovery of Novel Selective COX-2 Inhibitors by in silico Virtual Screening [C] . Omix Yu-Chian Chen IEEE International Joint Conference on Neural Networks . 2008

机译：在硅虚拟筛选中，PharmacoInocatics方法发现新型选择性Cox-2抑制剂的发现
5. Design of Novel Inhibitors for Infectious Diseases using Structure-based Drug Design: Virtual Screening, Homology Modeling and Molecular Dynamics. [D] . Ramamoorthy, Divya. 2012

机译：使用基于结构的药物设计设计新型传染病抑制剂：虚拟筛选，同源性建模和分子动力学。
6. Design Synthesis and Biological Evaluation of4-(Imidazolylmethyl)-2-(4-methylsulfonyl phenyl)-Quinoline Derivatives as Selective COX-2 Inhibitors and In-vitro Anti-breast Cancer Agents [O] . Razieh Ghodsi, Ebrahim Azizi, Afshin Zarghi 2016

机译：作为选择性COX-2抑制剂和体外抗乳腺癌药物的4-（咪唑基甲基）-2-（4-甲基磺酰基苯基）-喹啉衍生物的设计合成和生物学评价
7. Design and Synthesis of Some 5-Substituted-2-(4-(azido or methylsulfonyl) phenyl)-1H-indole Derivatives as Selective Cyclooxygenase (COX-2) Inhibitors [O] . Afshin Zarghi 2008

机译：设计和合成一些5取代的-2-（4-（甲基磺酰基）苯基）-1H-吲哚衍生物作为选择性环氧酶（COX-2）抑制剂
8. To Investigate the Therapeutic Efforts of the COX-2 Inhibitor NS-398 as a Single Agent, and in Combination with Vitamin D, in Vitro and in Vivo [R] . Lee, Y. 2008

机译：研究COX-2抑制剂Ns-398作为单一药物和与维生素D联合应用的体外和体内治疗方法

Pyrazole-chalcone derivatives as selective COX-2 inhibitors: design, virtual screening, and in vitro analysis

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