新型苯环5-(取代)苯甲酰胺基苯磺酰脲类化合物的比较定量构效关系研究

采用比较分子力场分析(CoMFA)方法, 对26个新型苯环5-(取代)苯甲酰胺基苯磺酰脲类化合物的除草活性进行了三维定量构效关系(3D-QSAR)研究, 建立了三维定量构效关系CoMFA模型(R²=0.948, F=91.364, SE=0.141). 结果表明, 此类磺酰脲类化合物的除草活性与苯环5位取代基的立体结构和电场性质密切相关. 根据CoMFA模型的立体场和静电场三维等值线图不仅直观地解释了结构与活性的关系, 而且为进一步设计高活性的目标化合物提供理论依据.     

新磺酰脲类化合物除草活性的3D-QSAR分析

用比较分子力场分析 (CoMFA) 方法和比较分子相似性指数分析 (CoMSIA) 方法对所合成的新磺酰脲类化合物的除草活性进行了较为系统的3D-QSAR分析.两种方法所建立的模型对化合物的除草活性预测能力均较好,所得三维等值线图为合成高活性的化合物能提供指导作用     

HEPT类逆转录酶抑制剂的三维定量构效关系

利用比较分子力场分析(CoMFA)方法对32个HEPT类HIV-1逆转录酶抑制剂(RTIs)的三维定量构效关系(3D-QSAR)进行了分析,建立了HIV-1逆转录酶抑制剂的3种3D-QSAR模型,发现影响其生物活性的主要因素为立体场因素,这与HIV-1RT的非底物结合部位(NNBS)的疏水性环境相吻合.进一步分析表明,适当长度的1-位侧链对保持化合物的抗病毒活性致关重要;增大5-位取代基的体积可增强生物活性;在1-位苄氧甲基的对位引入大体积基团有利于提高活性.同时考察立体场、静电场与生物活性的关系,表明,CoMFA模型为最佳预测模型,其交叉验证系数R_CV²=0.870,传统相关系数R²=0.986,标准偏差SE=0.146,F=294.546.用此模型预测了检验组3个HEPT类化合物的-lgEC₅₀,R_pred²=0.850,表明模型具有很好的预测能力,可为HEPT类HIV-1逆转录酶抑制剂的结构优化提供理论指导.     

HIV-1逆转录酶抑制剂的三维定量构效关系

采用比较分子力场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)对一系列非核苷类HIV-1逆转录酶抑制剂(苯磺酰基亚胺噻唑类化合物)进行了三维定量构效关系的研究,获得了高可靠性的CoMFA和CoMSIA模型,其交叉验证相关系数q2值分别为0.748和0.607.通过对CoMFA和CoMSIA模型三维等势图的分析,确定了该类化合物抗HIV-1活性的结构要求.研究结果表明,对苯磺酰基亚胺噻唑类化合物而言,在苯环的C-5位引入体积大和电负性强的基团能增加其抑制活性;苯环的C-2位的氢键给体基团对活性有利;噻唑环的R2取代基疏水性增大会降低生物活性.研究结果表明,可以指导新HIV-1逆转录酶抑制剂的设计和合成.     

含芳氧乙酰基和间-三氟甲基苯基的双酰胺化合物的合成及其除草活性

通过组合不同除草作用机制的活性基团,采用芳氧乙酸为酸组分的Ugi四组分反应合成了一系列芳氧乙酰基和间三氟甲基苯基片段的双酰胺化合物3a~3v,采用IR、¹H NMR、EI-MS和元素分析等技术手段对其结构进行了表征。 温室盆栽测试结果表明,部分目标化合物对油菜、反枝苋、稗草和马唐表现出中等至良好的除草活性,如化合物3r在温室盆栽时,在1.5 kg/ha剂量下,在苗前处理时对反枝苋和马唐显示出100%的抑制活性;在苗后处理时对马唐显示出100%的抑制活性。 初步探讨了目标化合物的构效关系。     

磺酰脲类化合物除草活性的QSAR研究

采用密度泛函理论方法, 在B3LYP/6-31G(d)水平下, 计算了23种磺酰类化合物的分子极化率及分子骨架中各原子的Milliken电荷. 提出了一种新的QSAR建模方法, 并据此对其中18种化合物进行多元线性回归分析, 建立了除草活性的预测模型(R=0.96, R2=0.92, r2adj=0.88, F=26.26, q2=0.71, p<0.01, SE=0.36), 对剩余五种化合物进行预测, 结果吻合. 该模型从化合物的亲水性、分子几何特征的角度对如何提高磺酰脲类化合物的除草活性进行了分析, 并对提高化合物除草活性的方法做出预测: 提高苯环和嘧啶环取代基的亲水性, 增加N13周围的电子云密度, 为苯环接入较小的取代基团, 在嘧啶环上接入较大取代基团都可提高化合物的除草活性. 预测结果与3D-QSAR方法的预测结果一致.     

抗癌性吲哚喹唑啉衍生物3D-QSAR研究及其分子设计

吲哚喹唑啉衍生物是近年来发现的一类具有良好抗癌活性的化合物. 作者在最近报道的二维定量构效关系(2D-QSAR)的基础上, 采用比较分子力场方法(CoMFA)进一步对该系列化合物进行三维定量构效关系(3D-QSAR)研究, 建立了3D-QSAR的CoMFA模型, 其非交叉验证相关系数r2=0.986, 标准偏差SD=0.084, 统计方差比F=114.6, 交叉验证相关系数q2=0.695, 表明该模型合理、可信, 并具有良好的预测能力. 研究结果表明: (1) 取代基R1的部位上静电效应起主要作用, 并且确保取代基R1的第一个原子具有较大的净正电荷, 对提高化合物的抗癌活性十分重要. 这与2D-QSAR研究结果相一致. (2) 取代基R2的部位上立体效应起主要作用, R2的体积大小要适中. 应用这些规律进行了分子设计, 在理论上获得了一些具有较高抗癌活性的新的吲哚喹唑啉衍生物, 并期待实验证实. 该QSAR的研究结果可为实验工作者合成新药提供理论参考.     

氟喹诺酮均三唑衍生物抗肿瘤活性的CoFMA研究

通过比较分子力场分析方法(CoMFA)研究氟喹诺酮均三唑衍生物对人肝癌细胞(SMMC-7721)、鼠白血病细胞(L1210)和人白血病细胞(HL60)的体外增值抑制活性的三维定量结构-活性相关(3D-QSAR).根据CoMFA模型的立体场和静电场三维等势线图可知,外部苯环的4-位引入的近正远负大体积基团,有利于提高氟喹诺酮均三唑衍生物的抗肿瘤活性.     

含有单取代嘧啶的新型磺酰脲类化合物的设计、合成及除草活性

为了寻找高效的磺酰脲类除草剂, 以商品化磺酰脲类除草剂为基础, 将单取代嘧啶结构引入到分子中, 合成了一系列新型磺酰脲类化合物, 并通过¹H NMR和高分辨质谱确定了其结构. 采用盆栽法和平皿法测试了所有化合物的除草活性以及部分化合物对油菜的IC₅₀值. 结果表明, 一些化合物具有一定的除草活性, 其中化合物7b和7d对油菜和反枝苋具有较好的抑制活性.     

磷酸二酯酶4b抑制剂定量构效关系及分子对接研究

磷酸二酯酶 4( PDE4)是第二信使环磷酸腺苷( cAMP)选择性高亲和力的水解酶,影响气道平滑肌、炎性细胞和免疫细胞的功能,选择性 PDE4b 抑制剂作为抗炎药治疗哮喘和慢性阻塞性肺病( COPD) 因为不会引起恶心呕吐等副反应而受到极大的关注。本文使用比较分子场( CoMFA) 方法,对系列嘧啶二芳基取代的 PDE4b 抑制剂构建了合理的三维定量构效关系( 3D-QSAR) 模型,使用分子对接方法研究了抑制剂与酶的相互作用,发现该系列化合物的嘧啶环 2 位引入带有较大电负性基团取代的五元环状烃基可提升活性;嘧啶环 4 位、5 位两个碳原子上建议保留小体积取代基;嘧啶环 6 位引入带有氢键给体或氢键受体取代的芳烃基可增加化合物活性。本研究可为后续合理设计高效的 PDE4b 抑制剂提供理论指导。     

N-Fluorinated phenyl-N＇-pyrimidyl urea derivatives： Synthesis,biological evaluation and 3D-QSAR study

With the increase of herbicide-resistant weeds, novel, more selective and even more potent herbicides to control weeds are needed. In this paper, a series of N-fluorinated phenyl-N＇-pyrimidyl urea derivatives were synthesized and screened for their herbicidal activities against Amaranthus retroflexus （AR） and Setaria viridis （ SV）. Compound 2S （N-（3-trifluoromethylphenyl）-N＇-（2-amino-4-chloro-6-methylpyr- imidyl） urea） exhibited marked herbicidal activity against SV（IC50 =11.67 mg/L） and is more potent than bensulfuron （IC50= 27.45 mg/L）, a commercially available herbicide. A statistically significant CoMFA model with high prediction abilities （q2 = 0.869, r2 = 0.989） was obtained.     

Synthesis and biological activity of novel N-(3-furan-2-yl-1-phenyl-1H-pyrazol-5-yl) amides derivatives

A series of novel N-(3-furan-2-yl-1-phenyl-1H-pyrazol-5-yl) amides derivatives were designed and synthesized. Their structures were confirmed by ¹H NMR, ¹³C NMR and HRMS. All title compounds were evaluated for their herbicidal and antifungal activities. Preliminary bioassay results indicated that the title compounds showed good to moderate herbicidal activity at 1000 mg/L. Compound 6q presented the best activity against Digitaria sanguinalis (L) Scop., Amaranthus retroflexus L. and Arabidopsis thaliana with an inhibition degree of five. Compound 6d also showed an inhibition degree of five against D. sanguinalis. In addition, at 50 mg/L, most compounds exhibited good in vitro antifungal activity against Sclerotinia sclerotiorum, with compound 6c showing over 90% antifungal activity against S. sclerotiorum and Pellicularia sasakii.     

Design,synthesis and SAR study of novel sulfonylurea derivatives containing arylpyrimidine moieties as potential anti-phytopathogenic fungal agents

Three series of novel sulfonylureas (SUs) 9-11 containing aromatic-substituted pyrimidines were designed and synthesized. The 3D-QASR and molecular docking studies showed that SUs should be considered as potential antiphytopathogenic fungal agents.     

Design,synthesis and SAR study of novel sulfonylurea derivatives containing arylpyrimidine moieties as potential anti-phytopathogenic fungal agents

Acetohydroxyacid synthase(AHAS) was considered as a promising target for antifungal agents.Herein,three series of novel sulfonylureas(SUs) 9-11 containing aromatic-substituted pyrimidines were designed and synthesized according to pharmacophore-combination and bioisosterism strategy.The in vitro fungicidal activities against ten phytopathogenic fungi indicated that most of the title compounds exhibited broad-spectrum and excellent fungicidal activities.Based on the preliminary fungicidal activities,a CoMFA model was constructed and the 3 D-QSAR analysis indicated that either a bulky group around the 5-position of the pyrimidine ring or electropositive group around the 2-position of the benzene ring would be favour to fungicidal activities.In order to study interaction mechanism,10 k was automatically docked into yeast AHAS and it further indicated that bearing bulky groups-aryl at the pyrimidine ring was critical to enhance antifungal activities.It revealed that the antifungal activity of derivatives 9-11 probably results from the inhibition of fungal AHAS.Thus,the present results strongly showed that SUs should be considered as lead compounds or model molecules to develop novel antiphyt o pathogenic fungal agents.     

Synthesis,bioactivities and 3D-QSAR of novel avermectin B2a aglycon derivatives

Fourteen avermectin B2 a aglycon derivatives were designed and synthesized after removing the oleandrose disaccharide of avermectin B2 a.Their structures were characterized by’H NMR,13 C NMR,HMRS.Preliminary bioassays indicated that these compounds exhibited good insecticidal activity against diamondback moth at 200 mg/L,with mortality no less than 90%.Compounds 10 b,12 a,12 c,17 demonstrated good acaricidal activity against the adult mites,larvae,and good inhibition rate of hatching to mite eggs of Tetranychus cinnabarinus.Compounds 5,10 b,10 c exhibited excellent fungicidal activity against fourteen fungal pathogens in vitro.3 D-QSAR analysis showed that the fungicidal activity of avermectin B2 a aglycon derivatives would be increased when a negatively charged and bulky group was introduced at 13-position,which will be instructive for the further modification of avermectin B2 aaglycon.     

新型含吡唑环的N-甲氧基氨基甲酸甲酯类化合物的设计、合成及生物活性

以苯(吡啶)乙/丙酮类化合物为原料, 经酯化、环化和缩合三步制得新型含吡唑环的N-甲氧基氨基甲酸甲酯类化合物3a~3r, 化合物及其中间体的化学结构经红外光谱、核磁共振谱及元素分析确认. 生物活性结果表明, 化合物3在400 mg/L下分别对水稻稻瘟病、黄瓜霜霉病和小麦白粉病具有很好的防治效果. 对水稻稻瘟病, R₁为甲基或甲氧基取代的苯基时活性最好; 对于黄瓜霜霉病和小麦白粉病, R₁为苯基或甲基取代苯基的化合物杀菌活性优于其它化合物, R₂为甲基的化合物杀菌活性优于R₂为氢的化合物.     

Synthesis and Antiviral Activity of N-Adamantyl-2-amino(or 2-phenoxy)-acylamides

New N-adamantyl-2-amino-acylamides(3a―3f) and N-adamantyl-2-phenoxy-acetamides(6a―6d) were designed and synthesized by the modification of the amino group of amantadine 1 and the structures were confirmed by mass spectra(MS) and ¹H NMR spectra. The antiviral potencies of the synthesized compounds were evaluated against the replication of influenza virus A/H₃N₂ subtype in Madin-Darby canine kidney(MDCK) cells. Among the amantadine derivatives, compound 3a had the strongest antiviral potency and showed activity similar to that of amantadine. Interestingly, the bulky and extended lipophilic moieties on the α-position of the carbonyl group resulted in decreases in potency.     

5-苄基-4-叔丁基-2-苄亚氨基噻唑的合成与杀菌活性

5-苄基-4-叔丁基-2-氨基噻唑与水杨醛衍生物反应制备了12种5-苄基-4-叔丁基-2-苄亚氨基噻唑类新化合物。初步测试了25种5-苄基-4-叔丁基-2-苄亚氨基噻唑的杀菌活性。结果表明,化合物1a(500mg/L)对水稻纹枯病菌抑制率为95%;化合物1i、1j、1l、1p、1q和1s(25mg/L)对小麦赤霉病菌的抑制率分别为55.1%、55.1%、51.3%、51.5%、51.5%和51.5%;化合物1i、1l和1s(25mg/L)对辣椒疫霉病菌抑制率分别为51.1%、51.9%和64.9%;化合物1h和1j(25mg/L)对黄瓜灰霉病菌抑制率为53.1%和61.2%;化合物1t、1o和1r(25mg/L)对油菜菌核病菌的抑制率分别为56.1%、56.1%和65.4%;化合物1w(25mg/L)对烟草赤星病菌的抑制率为52.6%。