一种邻硝基砜基苯甲酸的制备方法
申请/专利权人:
华中师范大学
申请/专利号:
CN201310085891.0
申请时间:
2013-3-18
公开号:
CN104059001A
公开时间:
2014-09-24
主申请人地址:
430079 湖北省武汉市洪山区珞瑜路152号
摘要:
本发明提供了一种邻硝基砜基苯甲酸的制备方法,该方法包括在催化剂的存在下,将具有式(1)所示结构的邻硝基砜基甲苯与氧化剂在溶剂中进行反应,得到具有式(2)所示结构的邻硝基砜基苯甲酸,R1为H或C1-C5的烷基,其中,所述催化剂选自钒化合物、钴化合物、铜化合物、铁化合物、锰化合物、钨化合物和银化合物中的至少两种。采用本发明提供的方法能够提高邻硝基砜基甲苯的转化率以及邻硝基砜基苯甲酸的收率。<img file="DDA00002930476700011.TIF" wi="1664" he="343" />
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一种制备6-位被取代的水杨酸甲酯的方法
申请/专利权人:
华中师范大学
申请/专利号:
CN201310229631.6
申请时间:
2013-6-8
公开号:
CN104230715A
公开时间:
2014-12-24
主申请人地址:
430079 湖北省武汉市洪山区珞瑜路152号
摘要:
一种制备6-位被取代的水杨酸甲酯的方法,该方法包括在取代反应条件下,将式1所示化合物与式2所示化合物接触,得到含有式3所示化合物的反应产物,然后在开环反应条件下,使式3所示化合物进行开环反应,得到式4所示6-位被取代的水杨酸甲酯,其中,R为碳原子数为4-20的取代或未取代的芳基或者碳原子数为2-14的烯基。本发明具有反应路线短、产率高等优点。<img file="DDA00003322684600011.TIF" wi="496" he="344" />R-B(OH)<sub>2</sub>式2<img file="DDA00003322684600012.TIF" wi="530" he="352" /><img file="DDA00003322684600013.TIF" wi="434" he="296" />。
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Understanding resistance mechanism of protoporphyrinogen oxidase-inhibiting herbicides: Insights from computational mutation scanning and site-directed mutagenesis
作者:
Hao, Ge-Fei;Tan, Ying;Xu, Wei-Fang;Cao, Run-Jie;Xi, Zhen* ;...
期刊:
Journal of Agricultural and Food Chemistry ,2014年62(29):7209-7215 ISSN:0021-8561
通讯作者:
Xi, Zhen
作者机构:
[Yang, Guang-Fu; Xu, Wei-Fang; Tan, Ying; Cao, Run-Fie; Hao, Ge-Fei] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Hubei, Peoples R China.;[Xi, Zhen] Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.;[Yang, Guang-Fu] Collaborat Innovat Ctr Chem Sci & Engn, Tianjin 300072, Peoples R China.
通讯机构:
[Xi, Zhen] N;Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.
关键词:
PPO;resistance mechanism;computational mutation scanning;herbicide;mutagenesis
摘要:
The potential of protoporphyrinogen oxidase (PPO) to develop resistance against five PPO-inhibiting herbicides has been studied using computational mutation scanning (CMS) protocol, leading to valuable insights into the resistance mechanisms and structure-resistance relationship of the PPO inhibitors. The calculated shifts in the binding free energies caused by the mutations correlated very well with those derived from the corresponding experimental data obtained from site-directed mutagenesis of PPO, leading to valuable insights into the resistance mechanisms of PPO inhibitors. The calculated entropy change was related to the conformational flexibility of the inhibitor, which demonstrated that inhibitors with appropriate conformational flexibility may inhibit both the wild type and mutants simultaneously. The reasonable correlation between the computational and experimental data further validate that CMS protocol is valuable for predicting resistance associated with amino acid mutations on target proteins. ©2014 American Chemical Society.
语种:
英文
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新型吡唑-喹唑啉酮衍生物的合成及除草活性测试
作者机构:
[杨光富; 徐玉玲; 李俊; 陈琼] 农药与化学生物学教育部重点实验室,华中师范大学化学学院
会议名称:
中国化学会第29届学术年会
会议时间:
2014-08-04
会议地点:
北京
会议论文集名称:
中国化学会第29届学术年会摘要集——第40分会:化学与农业
关键词:
除草剂;喹唑啉酮;吡唑
摘要:
对羟苯基丙酮酸双氧化酶(HPPD)属于非血红素铁-酪氨酸蛋白酶,在植物体内可催化4-羟基苯丙酮酸(HPPA)转化为尿黑酸(HGA)。[1]HPPD是上世纪90年代确定的除草剂靶标,它是一类需光型除草剂靶标,在光的作用下可使植物产生白化症状而死亡。[2-3]该酶抑制剂用于除草具有高效、低毒、广谱、残留低、环境相容性好、使用安全等特点。[1,3]在已商品化的HPPD抑制剂中,苯甲酰基吡唑类衍生物因其结
语种:
中文
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Pyrazolone–quinazolone hybrids: A novel class of human 4-hydroxyphenylpyruvate dioxygenase inhibitors
作者:
Xu, Yu-Ling;Lin, Hong-Yan;Cao, Run-Jie;Ming, Ze-Zhong;Yang, Wen-Chao* ;...
期刊:
Bioorganic & Medicinal Chemistry ,2014年22(19):5194-5211 ISSN:0968-0896
通讯作者:
Yang, Wen-Chao
作者机构:
[Yang, Guang-Fu; Xu, Yu-Ling; Yang, Wen-Chao; Ming, Ze-Zhong; Lin, Hong-Yan; Cao, Run-Jie] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan 430079, Peoples R China.;[Yang, Guang-Fu] Collaborat Innovat Ctr Chem Sci & Engn, Tianjin 30071, Peoples R China.
通讯机构:
[Yang, Wen-Chao] C;Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan 430079, Peoples R China.
关键词:
Human HPPD inhibitors;Type I tyrosinemia;Pyrazolone;Quinazolones
摘要:
4-Hydroxyphenylpyruvate dioxygenase (HPPD), converting 4-hydroxyphenylpyruvate acid to homogentisate, is an important target for treating type I tyrosinemia and alkaptonuria due to its significant role in tyrosine catabolism. However, only one commercial drug, NTBC, also known as nitisinone, has been available for clinical use so far. Herein, we have elucidated the structure-based design of a series of pyrazolone-quinazolone hybrids that are novel potent human HPPD inhibitors through the successful integration of various techniques including computational simulations, organic synthesis, and biochemical characterization. Most of the new compounds displayed potent inhibitory activity against the recombinant human HPPD in nanomolar range. Compounds 3h and 3u were identified as the most potent candidates with Kivalues of around 10 nM against human HPPD, about three-fold more potent than NTBC. Molecular modeling indicated that the interaction between the pyrazolone ring and ferrous ion, and the hydrophobic interaction of quinazolone with its surrounding residues, such as Phe347 and Phe364, contributed greatly to the high potency of these inhibitors. Therefore, compounds 3h and 3u could be potentially useful for the treatment of type I tyrosinemia and other diseases with defects in tyrosine degradation. © 2014 Elsevier Ltd. All rights reserved.
语种:
英文
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Synthesis and Herbicidal Evaluation of Triketone-Containing Quinazoline-2,4-diones
作者:
Wang, Da-Wei;Lin, Hong-Yan;Cao, Run-Jie;Yang, Sheng-Gang;Chen, Qiong;...
期刊:
Journal of Agricultural and Food Chemistry ,2014年62(49):11786-11796 ISSN:0021-8561
通讯作者:
Yang, Wen-Chao
作者机构:
[Yang, Guang-Fu; Yang, Sheng-Gang; Yang, Wen-Chao; Chen, Qiong; Wang, Da-Wei; Lin, Hong-Yan; Cao, Run-Jie; Hao, Ge-Fei] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Hubei, Peoples R China.;[Yang, Guang-Fu] Collaborat Innovat Ctr Chem Sci & Engn, Tianjin 30071, Peoples R China.
通讯机构:
[Yang, Wen-Chao] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Hubei, Peoples R China.
关键词:
4-hydroxyphenylpyruvate dioxygenase;crop selectivity;herbicidal activity;quinazoline-2,4-dione;synthesis
摘要:
Exploring novel 4-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) inhibitors is one of the most promising research directions in herbicide discovery. To discover new triketone herbicides with broad-spectrum weed control as well as excellent crop selectivity, a series of (total 52) novel triketone-containing quinazoline-2,4-dione derivatives were synthesized and further bioevaluated. The greenhouse testing indicated that many of the newly synthesized compounds showed better or excellent herbicidal activity against broadleaf and monocotyledonous weeds at the dosages of 37.5-150 g of active ingredient (ai)/ha. The structure and activity relationship in this study indicated that the triketone-containing quinazoline-2,4-dione motif has possessed great impact on herbicide activity and may be used for further optimization. Among the new compounds, III-b and VI-a-VI-d displayed a broader spectrum of weed control than mesotrione. In addition, the compound III-b also demonstrated comparatively superior crop selectivity to mesotrione, thus possessing great potential for weed control in the field. © 2014 American Chemical Society.
语种:
英文
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Hexahydrophthalimide-benzothiazole hybrids as a new class of protoporphyrinogen oxidase inhibitors: synthesis, structure-activity relationship, and DFT calculations
作者:
Wu, Qiong-You;Jiang, Li-Li;Yang, Sheng-Gang;Zuo, Yang;Wang, Zhi-Fang;...
期刊:
New Journal of Chemistry ,2014年38(9):4510-4518 ISSN:1144-0546
通讯作者:
Xi, Zhen
作者机构:
[Yang, Guang-Fu; Yang, Sheng-Gang; Wu, Qiong-You; Jiang, Li-Li; Zuo, Yang; Wang, Zhi-Fang] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Xi, Zhen] Collaborat Innovat Ctr Chem Sci & Engn, Tianjin 30071, Peoples R China.
通讯机构:
[Xi, Zhen] C;Collaborat Innovat Ctr Chem Sci & Engn, Tianjin 30071, Peoples R China.
摘要:
Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) has attracted continuous interest during the last few decades not only because of its unique biochemical characteristics but also because of its biomedical significance. As a continuation of our research work on the development of new PPO inhibitors, N-(benzothiazol-5-yl)-hexahydro-2H-isoindole-1,3-dithione (1a–j) and N-(benzothiazol-5-yl)-octahydro-3-thioxoisoindol-1-one derivatives (2a–i) were designed and synthesized. These newly prepared compounds were characterized by elemental analyses, 1H NMR and ESI-MS spectroscopy. The in vitro assay indicated that these compounds displayed good inhibition activity against human PPO (hPPO) with Ki values ranging from 0.38 μM to 6.83 μM. Notably, most of the monothionated products (1a–j) displayed a higher or comparable PPO-inhibition activity compared with the commercial control sulfentrazone. The comparison of the dihedral angles of the representative compound with that of acifluorfen (ACF) complexed with hPPO clearly indicated that the dihedral angle between the thionyl amide or carbonyl amide ring and the benzothiazole ring was closely related to the variation of the PPO inhibition activity of different types of inhibitors.
语种:
英文
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Synthesis, In Vitro Protoporphyrinogen Oxidase Inhibition, and Herbicidal Activity of N-(Benzothiazol-5-yl)hexahydro-1H-isoindole-1,3-diones and N-(Benzothiazol-5-yl)hexahydro-1H-isoindol-1-ones
作者:
Wu, Qiong-You;Jiang, Li-Li;Zuo, Yang;Wang, Zhi-Fang;Xi, Zhen;...
期刊:
Chemical Biology & Drug Design ,2014年84(4):431-442 ISSN:1747-0277
通讯作者:
Yang, Guang-Fu
作者机构:
[Yang, Guang-Fu; Wu, Qiong-You; Jiang, Li-Li; Zuo, Yang; Wang, Zhi-Fang] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Yang, Guang-Fu; Xi, Zhen] Collaborat Innovat Ctr Chem Sci & Engn, Tianjin 30071, Peoples R China.
通讯机构:
[Yang, Guang-Fu] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
关键词:
benzothiazole hexahydro-1H-isoindole-1,3(2H)-dione;herbicidal activity;hexahydro-1H-isoindol-1-one;protoporphyrinogen oxidase
摘要:
Protoporphyrinogen oxidase (EC 1.3.3.4) is one of the most significant targets for a large family of herbicides. As part of our continuous efforts to search for novel protoporphyrinogen oxidase-inhibiting herbicides, N-(benzothiazol-5-yl)tetrahydroisoindole-1,3-dione was selected as a lead compound for structural optimization, leading to the syntheses of a series of novel N-(benzothiazol-5-yl)hexahydro-1H-isoindole-1,3-diones (1a-o) and N-(benzothiazol-5-yl)hexahydro-1H-isoindol-1-ones (2a-i). These newly prepared compounds were characterized by elemental analyses, 1H NMR, and ESI-MS, and the structures of 1h and 2h were further confirmed by X-ray diffraction analyses. The bioassays indicated that some compounds displayed comparable or higher protoporphyrinogen oxidase inhibition activities in comparison with the commercial control. Very promising, compound 2a, ethyl 2-((6-fluoro-5-(4,5,6,7-tetrahydro-1-oxo-1H-isoindol-2(3H)-yl)benzo[d]thiazol-2-yl)-sulfanyl)acetate, was recognized as the most potent candidate with Ki value of 0.0091 μm. Further greenhouse screening results demonstrated that some compounds exhibited good herbicidal activity against Chenopodium album at the dosage of 150 g/ha. © 2014 John Wiley & Sons A/S.
语种:
英文
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Design and synthesis of novel quinazoline-2,4-dione derivatives as potent 4-HPPD inhibitors
作者:
Wang, Da-Wei;Chen, Qiong;Yang, Wen-Chao;Yang, Guang-Fu
( 杨光富 )
作者机构:
[Yang, Guang-Fu; Yang, Wen-Chao; Chen, Qiong; Wang, Da-Wei] Cent China Normal Univ, Dept Chem, Wuhan 430079, Hubei, Peoples R China.
会议名称:
248th National Meeting of the American-Chemical-Society (ACS)
会议时间:
AUG 10-14, 2014
会议地点:
San Francisco, CA
语种:
英文
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Synthesis and fungicidal activity of novel ametoctradin derivates
作者:
Zhu, Xiao Lei;Zhang, Meng Meng;Yang, Guang-Fu
( 杨光富 )
作者机构:
[Yang, Guang-Fu; Zhang, Meng Meng; Zhu, Xiao Lei] Ctr China Normal Univ, Dept Chem, Wuhan 430079, Hubei, Peoples R China.
会议名称:
248th National Meeting of the American-Chemical-Society (ACS)
会议时间:
AUG 10-14, 2014
会议地点:
San Francisco, CA
语种:
英文
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一种制备取代联苯的方法
申请/专利权人:
华中师范大学
申请/专利号:
CN201310228937.X
申请时间:
2013-6-8
公开号:
CN104230719A
公开时间:
2014-12-24
主申请人地址:
430079 湖北省武汉市洪山区珞瑜路152号
摘要:
本发明公开了一种制备式1所示取代联苯的方法,该方法包括在钯催化剂、L1-L8所示配体中的至少一种和碱性物质存在下,使式2所示化合物和式3所示化合物在溶剂中接触。本发明具有反应条件温和,钯催化剂用量少等优点。<img file="DDA00003322724800011.TIF" wi="1520" he="760" />
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Recent Developments in the Synthesis and Applications of Isatins
作者:
Liu, Yu-Chao;Zhang, Rui;Wu, Qiong-You;Chen, Qiong;Yang, Guang-Fu
* ( 杨光富 )
期刊:
Organic Preparations and Procedures International ,2014年46(4):317-362 ISSN:0030-4948
通讯作者:
Yang, Guang-Fu
作者机构:
[Yang, Guang-Fu; Wu, Qiong-You; Liu, Yu-Chao; Zhang, Rui; Chen, Qiong] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
通讯机构:
[Yang, Guang-Fu] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
摘要:
Isatin (1H-indole-2,3-dione, ) was first obtained by Erdman and Laurent in 1841 as a product from the oxidation of indigo by nitric and chromic acids.1 Since then, isatin and its derivatives have b...
语种:
英文
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Computational discovery of novel agrochemicals: A case study
作者:
Yang, Guang-Fu
( 杨光富 ) ;Hao, Ge-Fei;Yang, Sheng-Gang;Zhu, Xiao-Lei
作者机构:
[Yang, Guang-Fu; Yang, Sheng-Gang; Zhu, Xiao-Lei; Hao, Ge-Fei] Cent China Normal Univ, Coll Chem, Wuhan, Peoples R China.
会议名称:
248th National Meeting of the American-Chemical-Society (ACS)
会议时间:
AUG 10-14, 2014
会议地点:
San Francisco, CA
语种:
英文
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Design, Synthesis and Herbicidal Activity of Novel Quinazoline-2,4-Diones
作者:
Da-Wei Wang;Qiong Chenn;Wen-Chao Yang;Guang-Fu Yang
( 杨光富 )
作者机构:
[Guang-Fu Yang; Da-Wei Wang; Qiong Chenn; Wen-Chao Yang] Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University,Wuhan 430079, P.R.China
会议名称:
中国化学会全国第十一届有机合成化学学术研讨会
会议时间:
2014-10-16
会议地点:
上海
会议主办单位:
中国化学会
会议论文集名称:
中国化学会全国第十一届有机合成化学学术研讨会论文集
关键词:
4-hydroxyphenylpyruvate dioxygenase;crop selectivity;herbicidal activity;quinazoline-2,4-dione;triketone-containing
摘要:
4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is an important enzyme in the catabolism oftyrosine, which converts 4-hydroxyphenylpyruvate (HPPA) into homogentisate (HGA).In plants, HGA is an important precursor for the biosynthesis of tocopherol and plastoquinone, two compounds crucial for the normal growth of plants.When HPPD is inhibited, the plant will be severely damaged by sunlight, becoming bleached and eventually undergoing necrosis and death.[1-3] Inhibition of HPPD is one of the most promising modes of action of herbicides.It is widely reported that quinazoline-2,4-dione is an important chemical scaffolds, because these derivatives often posses a variety of biological activities, such as antitumor, anti-inflammatory, antidiabetic, anti-infective, and antiobesity properties.[4] Although the derivatives of quinazoline-2,4-dione are extensively studied in medical chemistry,the research of them in agrochemicals is very scare, especially the herbicidal activity of them need to be further explored.To explore the herbicidal activity of quinazoline-2,4-dione derivatives, and study their HPPD-inhibiting activity, we designed and synthesized a series of novel triketone-containing quinazoline-2,4-diones.The in vitro tests indicated that many of the newly synthesized compounds displayed good AtHPPD inhibitory activity with Ki values ranging from 0.005 to 0.668 μM.In addition, the greenhouse experiments indicated that most of the synthesized compounds showed good or excellent herbicidal activity against broadleaf and monocotyledonous weeds at the dosages of 37.5-150 g ai/ha.Most promisingly, some compounds showed significantly improved crop selectivity compared with mesotrione.
语种:
英文
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Discovery of novel 4-hydroxyphenylpyruvate dioxygenase inhibitors as potential herbicides
作者:
Yang, Wen-Chao;Xu, Yu-Ling;Lin, Hong-Yan;Yang, Guang-Fu
( 杨光富 )
作者机构:
[Yang, Guang-Fu; Xu, Yu-Ling; Yang, Wen-Chao; Lin, Hong-Yan] Cent China Normal Univ, Dept Chem, Wuhan 430079, Hubei, Peoples R China.
会议名称:
248th National Meeting of the American-Chemical-Society (ACS)
会议时间:
AUG 10-14, 2014
会议地点:
San Francisco, CA
语种:
英文
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Activity of a novel strobilurin fungicide benzothiostrobin against Sclerotinia sclerotiorum
作者:
Xu, Congying;Hou, Yiping;Wang, Jianxin;Yang, Guangfu
( 杨光富 ) ;Liang, Xiaoyu;...
期刊:
Pesticide Biochemistry and Physiology ,2014年115:32-38 ISSN:0048-3575
通讯作者:
Zhou, Mingguo
作者机构:
[Xu, Congying; Liang, Xiaoyu; Hou, Yiping; Zhou, Mingguo; Wang, Jianxin] Nanjing Agr Univ, Coll Plant Protect, Key Lab Pesticide, Nanjing 210095, Jiangsu, Peoples R China.;[Yang, Guangfu] Cent China Normal Univ, Coll Chem, Wuhan 430079, Hubei Province, Peoples R China.
通讯机构:
[Zhou, Mingguo] N;Nanjing Agr Univ, Coll Plant Protect, Key Lab Pesticide, Nanjing 210095, Jiangsu, Peoples R China.
关键词:
Sclerotinia sclerotiorum;Benzothiostrobin;Oxygen consumption;Biological activity
摘要:
Benzothiostrobin is a novel strobilurin fungicide. In this study, baseline sensitivity of Sclerotinia sclerotiorum (Lib.) de Bary to benzothiostrobin was determined using 100 strains collected during 2012 and 2013 from different geographical regions in Jiangsu Province of China, and the average EC50 value was 0.0218 ( +/- 0.0111)mu g/mL for mycelial growth. After benzothiostrobin treatment, hyphae were contorted with offshoot of top increasing and cell membrane permeability increased markedly, while sclerotial production and oxalic acid content significantly decreased. Benzothiostrobin strongly inhibited mycelial respiration within 12 h and the oxygen consumption of the mycelia could not be inhibited after 24 h. On detached rapeseed leaves, the protective and curative activity test of benzothiostrobin suggested that benzothiostrobin had good control efficiency against S. sclerotiorum, and protective activity was better than curative activity. These results will contribute to us evaluating the potential of the new strobilurin fungicide benzothiostrobin for management of diseases caused by S. sclerotiorum and understanding the mode of action of benzothiostrobin against S. sclerotiorum. (C) 2014 Elsevier Inc. All rights reserved.
语种:
英文
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Design and synthesis of benzo[d]oxazol-5-yl)-1-methyl-1H-pyrazole-4-carboxamides as complex II inhibitors
作者:
Xiong, Li;Zhu, Xiao Lei;Yang, Guang Fu
( 杨光富 )
作者机构:
[Yang, Guang Fu; Xiong, Li; Zhu, Xiao Lei] Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Hubei, Peoples R China.
会议名称:
248th National Meeting of the American-Chemical-Society (ACS)
会议时间:
AUG 10-14, 2014
会议地点:
San Francisco, CA
语种:
英文
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Syntheses of coumarin–tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase
作者:
Sun, Qi;Peng, Da-Yong;Yang, Sheng-Gang;Zhu, Xiao-Lei;Yang, Wen-Chao* ;...
期刊:
Bioorganic & Medicinal Chemistry ,2014年22(17):4784-4791 ISSN:0968-0896
通讯作者:
Yang, Wen-Chao
作者机构:
[Yang, Guang-Fu; Yang, Sheng-Gang; Zhu, Xiao-Lei; Yang, Wen-Chao; Sun, Qi; Peng, Da-Yong] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Yang, Guang-Fu] Collaborat Innovat Ctr Chem Sci & Engn, Tianjin 30071, Peoples R China.
通讯机构:
[Yang, Wen-Chao] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
关键词:
Acetylcholinesterase inhibitor;Alzheimer's disease;Butylcholinesterase inhibitor;Coumarin
摘要:
Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (Ki = 16.7 nM) against human AChE and about 2-fold lower potency (Ki = 16.1 nM) against BChE than tacrine (Ki = 35.7 nM for AChE, Ki = 8.7 nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both Aβ aggregation and β-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery. © 2014 Elsevier Ltd. All rights reserved.
语种:
英文
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Editorial (Thematic Issue: Structure-Based Drug Design: Strategies and Challenges)
期刊:
Current Pharmaceutical Design ,2014年20(5):685-686 ISSN:1381-6128
通讯作者:
Yang, Guang-Fu
作者机构:
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P.R. China.,China;[Yang, Guang-Fu] Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P.R. China.,China
通讯机构:
Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, China
语种:
英文
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Comparative Kinetics of Q(1) Site Inhibitors of Cytochrome bc(1) Complex: Picomolar Antimycin and Micromolar Cyazofamid
作者:
Li, Hui;Zhu, Xiao-Lei;Yang, Wen-Chao;Yang, Guang-Fu
* ( 杨光富 )
期刊:
Chemical Biology & Drug Design ,2014年83(1):71-80 ISSN:1747-0277
通讯作者:
Yang, Guang-Fu
作者机构:
[Yang, Guang-Fu; Zhu, Xiao-Lei; Yang, Wen-Chao; Li, Hui] Cent China Normal Univ, Minist Educ, Coll Chem, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
通讯机构:
[Yang, Guang-Fu] C;Cent China Normal Univ, Minist Educ, Coll Chem, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
关键词:
Cytochrome bc1 complex;antimycin;cyazofamid;enzyme inhibitor;succinate-cytochrome c reductase
摘要:
Antimycin and cyazofamid are specific inhibitors of the mitochondrial respiratory chain and bind to the Qi site of the cytochrome bc 1 complex. With the aim to understand the detailed molecular inhibition mechanism of Qi inhibitors, we performed a comparative investigation of the inhibitory kinetics of them against the porcine bc 1 complex. The results showed that antimycin is a slow tight-binding inhibitor of succinate-cytochrome c reductase (SCR) with Ki = 0.033 ± 0.00027 nm and non-competitive inhibition with respect to cytochrome c. Cyazofamid is a classical inhibitor of SCR with Ki = 12.90 ± 0.91 μm and a non-competitive inhibitor with respect to cytochrome c. Both of them show competitive inhibition with respect to substrate DBH2. Further molecular docking and quantum mechanics calculations were performed. The results showed that antimycin underwent significant conformational change upon the binding. The energy barrier between the conformations in the crystal and in the binding pocket is ~13.63 kcal/mol. Antimycin formed an H-bond with Asp228 and two water-bridged H-bonds with Lys227 and His201, whereas cyazofamid formed only one H-bond with Asp228. The conformational change and the different hydrogen bonding network might account for why antimycin is a slow tight-binding inhibitor, whereas cyazofamid is a classic inhibitor. In this paper, a comparative investigation of the inhibitory kinetics of antimycin and cyazofamid against the porcine bc1 complex was performed. The resulsts show that antimycin was a slow tight-binding inhibitor and cyazofamid was a typical classical inhibitor. Combined with molecular docking and quantum mechanics calculations, the detailed mechanism of inhibition by Qi inhibitors was obtained. © 2013 John Wiley & Sons A/S.
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英文
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