Sulfonylurea类ALS/AHAS抑制剂作用方式的分子对接研究和新抑制剂的虚拟筛选

采用Dock5和Autodock3的组合, 从乙酰乳酸合成酶(ALS)的晶体结构出发, 对五个磺酰脲分子和三个类磺酰脲分子与ALS的相互作用方式进行了详细的分子对接研究, 并结合对ALS与氯嘧磺隆(类磺酰脲)共结晶的复合物晶体结构的分析得出了一个简化的药效团模型, 与前人利用其它手段得到的药效团模型一致. 结合此药效团模型并根据sulfonylurea类分子与ALS的作用机理, 我们对425个具有不同除草和杀虫作用的已知农药和ALS进行了分子对接研究和筛选, 从中发现了一些可能对ALS有抑制作用的农药分子. 此结果可以很好地解释这类农药的结构和活性的关系, 对设计、开发新ALS抑制剂的先导化合物提供依据和指导.     

单嘧磺隆原药组成的定性和定量分析

磺酰脲类除草剂作用于乙酰乳酸合成酶(ALS),对温血动物几乎无毒,磺酰脲活性分子必须含有胍桥,在胍桥间位须为双取代,而对位不能有任何取代基,分子中还须有一个杂环系统,前文从室内筛选出发,发现部分单一取代杂环的磺酰脲化合物也具有足够的除草活性,     

N-[2-(4-甲基)嘧啶基]-N′-2-硝基苯磺酰脲的合成、晶体结构、生物活性及其与酵母AHAS的分子对接

合成了磺酰脲化合物N-[2-(4-甲基)嘧啶基]-N′-2-硝基苯磺酰脲,用元素分析、红外、核磁共振氢谱对产物进行了表征,培养并测定了其晶体结构.晶体属三斜晶系,P1空间群,晶胞参数a=0.54159(1)nm,b=1.1533(3)nm,c=1.1857(4)nm,α=83.907(6)°,β=81.048(5)°,γ=77.637(4)°,V=0.7126(4)nm3,Dc=1.572g/cm3,Z=2,F(000)=348,R=0.0659,wR=0.1217.在晶体结构中,杂环上的一个N原子与脲桥上邻近的N原子上的H构成分子内氢键.测定了对酵母AHAS的离体抑制活性,其抑制常数Ki为(2.48±0.35)×10-7mol/L.用分子对接方法,将目标化合物晶体结构对接到靶酶酵母AHAS的活性位点,发现对接完毕目标化合物的构象与复合物晶体中的磺酰脲分子构象接近,并得到了合理的生物活性预测值.该研究为进一步理解磺酰脲类的分子结构、药物活性并设计新的分子提供了帮助和指导.     

4,5,6-三取代嘧啶苯磺酰脲类化合物的生物活性、分子对接与3D-QSAR关系研究

用柔性分子对接方法(FlexX)将15个4,5,6-三取代嘧啶苯磺酰脲化合物以及3个不含5-位取代嘧啶苯磺酰脲化合物(分别为4,6-双取代嘧啶和4-取代嘧啶)和乙酰羟酸合成酶(AHAS)活性口袋进行了对接, 对接程序预测的抑制剂和酶之间的相互作用能与抑制活性之间有一定的相关性, 相关系数为0.660. 然后采用比较分子相似性指数分析(CoMSIA)对27个新型4,5,6-三取代嘧啶苯磺酰脲类化合物的除草活性进行三维定量构效关系(3D-QSAR)研究. 建立了三维定量构效关系CoMSIA模型, 立体场、静电场和氢键的贡献分别为47.3%, 32.8%, 19.9%. 交叉验证系数q2值为0.520. 根据CoMSIA模型的立体场、静电场、氢键给体场三维等值线图不仅直观地解释了结构与活性的关系, 并且与用FlexX预测的结合模式相一致, 证明了我们预测的结合模式是可靠的, 为进一步设计高活性的标题化合物提供较好的理论指导.     

以ALS为靶标的新型除草剂的分子设计、合成及生物活性研究——Ⅴ.磺酰脲、稠杂磺酰胺类除草剂与受体的初级作用模型

采用X射线衍射分析、量子药理学分析以及QSAR分析 ,从空间构象、电子结构和物化性能等 3个方面系统地研究了磺酰脲和稠杂磺酰胺类除草剂的结构与活性关系 ,发现这两类除草剂的结构与活性间的关系是非常一致的 .杂环及磺酰基是它们共同的药效基团 ,可能作用于受体的同一位点 .在此基础上 ,提出了这两类除草剂与ALS的初级作用模型     

N-[2-(4-甲基)嘧啶基]-N′-2-硝基苯磺酰脲的合成、晶体结构、生物活性及其与酵母AHAS的分子对接

合成了磺酰脲化合物N-[2-(4-甲基)嘧啶基]-N′-2-硝基苯磺酰脲, 用元素分析、红外、核磁共振氢谱对产物进行了表征, 培养并测定了其晶体结构. 晶体属三斜晶系, 空间群, 晶胞参数a＝0.54159(1) nm, b＝1.1533(3) nm, c＝1.1857(4) nm, α＝83.907(6)°, β＝81.048(5)°, γ＝77.637(4)°, V＝0.7126(4) nm³, D_c＝1.572 g/cm³, Z＝2, F(000)＝348, R＝0.0659, wR＝0.1217. 在晶体结构中, 杂环上的一个N原子与脲桥上邻近的N原子上的H构成分子内氢键. 测定了对酵母AHAS的离体抑制活性, 其抑制常数K_i为(2.48±0.35)×10^－7 mol/L. 用分子对接方法, 将目标化合物晶体结构对接到靶酶酵母AHAS的活性位点, 发现对接完毕目标化合物的构象与复合物晶体中的磺酰脲分子构象接近, 并得到了合理的生物活性预测值. 该研究为进一步理解磺酰脲类的分子结构、药物活性并设计新的分子提供了帮助和指导.     

新型含三唑啉酮的磺酰脲类化合物的合成、晶体结构及除草活性研究

为了进一步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,将三唑啉酮杂环引入到分子中,合成了23个未见文献报道的新型磺酰脲化合物,通过1H NMR、高分辨质谱以及X射线单晶衍射确定了其结构.经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,化合物5h具有优秀的除草活性,其对油菜的IC50值与对照药醚苯磺隆和醚磺隆相近,在3.75 g/ha浓度下对单子叶杂草稗草具有优异的盆栽抑制活性.     

含磺酰胺的苯氧乙(丙)酸酯的合成与除草活性

磺酰脲(胺)作为一类抑制乙酰乳酸合成酶(ALS)活性的除草剂,具有剂量小,选择性强,杀草谱广,对哺乳动物毒性低,在环境中不易积聚等特点,成为除草剂研究的热点[1-4].本文采用"亚结构连接法",将含饱和杂环(芳环)磺酰胺引入到芳氧羧酸中,试图降低药物对作物产生的毒副作用与抗药性,同时提高其除草活性.8个目标化合物的合成路线如下:     

应用CoMFA研究磺酰脲类化合物的三维构效关系

用比较分子力场分析 (CoMFA)方法研究了磺酰脲类除草剂结构与活性的三维定量构效关系 ( 3D QSAR) ,并在此基础上对原有分子结构进行修饰改造 ,以获得较高活性的化合物 .并在三维等值线图的基础上得到了此类除草剂作用靶标ALS酶的模拟作用模型 ,为进一步合成出全新结构的ALS酶抑制剂的先导化合物提供了有益的启示和帮助 .     

N-(4-取代嘧啶-2-基)苄基磺酰脲和苯氧基磺酰脲的3D-QSAR研究

采用比较分子力场分析(CoMFA)方法,对两类单取代嘧啶类似物、6个N-(4-取代嘧啶-2-基)-2-甲氧羰基苄基磺酰脲(1a～1f)和14个N-(4-取代嘧啶-2-基)-2-取代苯氧基磺酰脲(2a～2n)进行三维定量构效关系(3D-QSAR)研究.建立了一个较为可靠的预测模型.结果表明,分子中苯环邻位、嘧啶环形成氢键的N原子处以及嘧啶环4位和6位附近负电荷增加;苯环邻位乙氧基的CH₂CH₃附近选择带正电的原子;苯环邻位乙氧基附近空间体积增加,而嘧啶环4位甲氧基稍远处取代基的立体位阻不超过此位置,将有利于提高活性.最后解释了修饰磺酰脲的除草剂仍具有较高活性的原因.     

Different hydrogen-bonding patterns in two [Zn(ENTPP)] complexes with water or methanol as ligands

We have synthesized zinc complexes of H₂ENTPP (5-(8-ethoxycarbonyl-1-naphthyl)-10,15,20-triphenyl porphyrin) as a model to study hydrogen-bonding interactions. When water or methanol is a ligand, crystals of [Zn(ENTPP)(CH₃OH)] or [Zn(ENTPP)(H₂O)]?·?C₆H₅CH₃ were obtained. In both structures, the ligand has hydrogen-bonding interactions, but in different patterns. In [Zn(ENTPP)(CH₃OH)], the methanol oxygen and carboxylate oxygen in the naphthyl group form an intermolecular hydrogen bond. In [Zn(ENTPP)(H₂O)]?·?C₆H₅CH₃, there are two independent molecules A and B. In molecule B, there is an intramolecular hydrogen bond between the water oxygen and the carboxylate oxygen, while in molecule A, besides the intramolecular hydrogen bond, there is an intermolecular hydrogen bond between the water oxygen and the carboxylate oxygen. ¹H NMR spectra suggest the binding of methanol or water to zinc are equilibrium processes in solution. Equilibrium constant has been determined by UV-Vis measurements, and it suggests the binding affinity of zinc to methanol has been moderately increased.     

Mechanistic studies of the formation of different states of oxygen on irradiated ZrO2 and the photocatalytic nature of photoprocesses from determination of turnover numbers

The photoadsorption of oxygen (photoreduction on electron surface-active centers) and the photoadsorption of hydrogen (photooxidation on hole surface-active centers) as well as the photooxidation of hydrogen in the presence of oxygen were examined over irradiated zirconia (ZrO2) specimens by thermoprogrammed desorption spectroscopy (TPD) and kinetically to assess the states (forms) of oxygen species formed on the surface of zirconia. The three TPD spectral maxima observed inferred three oxygen species of varying activity in the photooxidation of hydrogen. The number of surface-active sites on the zirconia surface were quantitatively estimated (ca. 1 x 10(16) centers), thereby permitting an estimate of the turnover numbers (TON) for the photooxidation of hydrogen (TON > 14.5) and for the photoreduction of oxygen (TON > 6.6). These demonstrate for the first time that a photoreaction occurring on the surface of a metal-oxide photocatalyst is truly photocatalytic.     

Conformation and stability of the hydrogen-bonded complex 6-oxabicyclo

The hydrogen-bonded complex between 6-oxabicyclo[3.1.0]hexane and hydrogen chloride was investigated by microwave spectroscopy in a supersonic jet. A dual flow pulsed valve was used to preclude chemical reaction between the monomers. Only the equatorial conformer was observed and the spectra of three isotopomers, (C5H8O, H35Cl), (C5H8O, H37Cl) and (C5H8O, D35Cl), were measured. The derived structure of the complex has Cs symmetry with the hydrogen chloride pointing to the domain of the equatorial lone pair of electrons at the oxygen atom. The three atoms involved in the hydrogen bond adopt a bent arrangement with a O...H distance of 1.77(4) A, a (O...H-Cl) angle of 115(4)degrees, and a deviation of 15.4(14)degrees of the hydrogen bond from collinearity. In agreement with the experimental results, ab initio calculations predict the equatorial form to be the most stable one.     

高岭石-水体系中水分子结构的分子动力学模拟

以Hendricks模型为初始结构, 利用CLAYFF力场对高岭石-水体系进行无晶体学限制的分子动力学模拟. 结果表明, 层间水有三种类型: I型类似于Costanzo提出的“洞水”分子, 其HH矢量(水分子中从一个氢原子位置指向另一个氢原子位置的方向矢量)平行于(001)平面, 而C2轴稍微倾斜于(001)面法线; II型类似于“连接水”, 一个氢氧键指向临近的层间四面体氧形成氢键, 另一个氢氧键与(001)面近似平行; III型水分子在层间近似保持为竖直状, 一个氢与层间四面体氧形成氢键, 而另一个氢与对面层的羟基氧形成氢键. 高岭石羟基氢沿(001)晶面法线的浓度曲线显示一部分羟基指向变为近似平行于(001)面, 羟基氧因此能够暴露出来与层间水分子氢形成氢键. 此外, 模拟中还观察到部分II型水分子氧偏离于层间的平均位置而更靠近四面体层, 这和Costanzo的实验结果一致, 可能是X射线谱图中(002)弱衍射峰出现的原因.     

N,N',N″-三-(2-羟基丙基)-1,4,7-三氮杂环癸烷钴(Ⅱ)配合物的合成及其结构表征

合成了侧臂带有醇羟基的十元环大环三胺衍生物配体N,N',N″-三-(2-羟基丙基)-1,4,7-三氮杂环癸烷(L)及它的过渡金属配合物[CoL][ClO_4]_2,利用元素分析、红外光谱以及热重分析等技术手段对其结构进行了表征,并测定了配合物的晶体结构。解析结果表明,配合物属于Monoclinic晶系,P2(1)/n空间群,中心的Co(Ⅱ)原子为六配位,处于一个畸变的三棱柱配位环境。其中6个配位原子分别来自配体的3个N原子和3个O原子。平均的Co—N键长和Co—O键长分别为:0.2114(6)和0.2097(6)nm。高氯酸根中的3个氧原子分别与邻近的配合物阳离子中的3个O原子通过氢键O…H—O连接起来,形成了一个具有规则结构的超分子网络结构。     

Time‐dependent density functional theory study on the absorption spectrum of Coumarin 102 and its hydrogen‐bonded complexes

The effect of both solvent polarity and hydrogen bonding (HB) on the electronic transition energy of Coumarin 102 (C102) has been examined using the time‐dependent density functional theory (TDDFT). Solvent effect on both geometry and electronic transition energy is evaluated using the polarizable continuum model (PCM). A linear relation of the absorption maximum of C102 with the solvent polarity function Δf is found using the TDDFT‐PCM method for all solvents except dimethyl sulfoxide. The solvent polarity and the type B HB between the carbonyl oxygen and solvent hydrogen atom make the absorption wavelength redshift, whereas the type A HB between the amino nitrogen atom and solvent hydrogen atom has an opposite effect on the absorption wavelength. The calculated absorption wavelengths of C102 with two type B HB between the carbonyl oxygen and solvent hydrogen atom are in excellent agreement with experimental measurements. The solvatochromism of C102 is analyzed in terms of the Kamlet–Taft equation and the parameters s and a are discussed. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011.     

Electrochemical catalysis of styrene epoxidation with films of MnO(2) nanoparticles and H(2)O(2)

Films of polyions and octahedral layered manganese oxide (OL-1) nanoparticles on carbon electrodes made by layer-by-layer alternate electrostatic adsorption were active for electrochemical catalysis of styrene epoxidation in solution in the presence of hydrogen peroxide and oxygen. The highest catalytic turnover was obtained by using applied voltage -0.6 V vs SCE, O(2), and 100 mM H(2)O(2). (18)O isotope labeling experiments suggested oxygen incorporation from three different sources: molecular oxygen, hydrogen peroxide, and/or lattice oxygen from OL-1 depending on the potential applied and the oxygen and hydrogen peroxide concentrations. Oxygen and hydrogen peroxide activate the OL-1 catalyst for the epoxidation. The pathway for styrene epoxidation in the highest yields required oxygen, hydrogen peroxide, and a reducing voltage and may involve an activated oxygen species in the OL-1 matrix.     

Synthesis, solid-state structures, and aggregation motifs of phosphines and phosphine oxides bearing one 2-pyridone ring

Three phosphines and their corresponding oxides bearing one 2-pyridone ring and two benzene rings were synthesized. Their single-crystal X-ray analyses exhibited three kinds of molecular aggregation: bimolecular aggregates, chiral one-dimensional structures, and achiral one-dimensional structures. In the bimolecular aggregate of (2-oxo-1, 2-dihydro-x-pyridyl)diphenylphosphines (x = 3: 2a and 6: 2c), cyclic dimers that are derived from two 2-pyridone rings are observed. In contrast, (2-oxo-1,2-dihydro-5-pyridyl)diphenylphosphine (2b) molecules form a chiral one-dimensional chain via intermolecular hydrogen bonding. In the case of phosphine oxides, their oxygen always acts as a hydrogen acceptor of the hydrogen bonding. Thus, (2-oxo-1,2-dihydro-x-pyridyl)diphenylphosphine oxides (x = 3: 3a and 5: 3b) form hydrogen bonds intermolecularly between the oxygen atom on the phosphoryl group and the hydrogen atom on nitrogen to construct a chiral or an achiral one-dimensional chain. Interestingly, (2-oxo-1,2-dihydro-6-pyridyl)diphenylphosphine oxide (3c) exists as a 2-hydroxypyridine form (enol form) in a crystalline state, and intermolecular hydrogen bonds between the phosphoryl oxygen and the hydroxy proton construct an achiral one-dimensional chain.     

The Combustion of SiCl4 in Hot O2/H2 Flames

A simple kinetic model describing the molecular gas phase reactions during the formation of fumed silica (AEROSIL®) was developed. The focus was on the formation of molecular SiO₂, starting from SiCl₄, hydrogen and oxygen. Wherever available, kinetic and thermodynamic parameters were taken from the literature. All other parameters are based on quantum chemical calculations. From these data, an adiabatic model for the combustion reaction has been developed. It was found that a significant amount of molecular SiO₂ forms after about 0.1 and 0.6 ms at starting temperatures between 1000 and 2000 K. The initial reaction of the SiCl₄ combustion in a hydrogen/oxygen flame was found to be different from the combustion in air: The high reactivity of SiCl₄ towards water is favored over the SiCl₄ dissociation, which is the initial and rate‐determining step during the combustion of SiCl₄ in air.