一类新型N型钙通道阻滞剂的比较定量构效关系研究

使用结构和量子化学参数对一系列N取代N-甲基二肽衍生物的N型钙通道阻滞活性进行了定量构效关系研究, 并使用SOMFA方法建立了三维定量构效关系模型. 结果表明分子的范德华体积和最低未占据轨道能量是影响化合物生物活性的主要因素. N原子上取代基的溶剂可及面积也对化合物的钙通道阻滞活性有重要影响. 三维定量构效关系模型进一步支持了以上结果. 这些研究结果可为设计更高活性的N型钙通道阻滞剂提供有价值的参考信息.     

N1位取代的喹诺酮类化合物分子设计与合成研究

在抗感染化疗药物研究领域中,喹诺酮类抗菌药由于有许多优良特性,近年来得到迅速发展。喹诺酮类的基本骨架如图1。而1位取代基的演变实际是喹诺酮类化合活性改进的写照。N1位早期研究表明以乙基及与其体积相似的乙烯基为最佳,大于或小于乙烯基均使活性降低。本文通过对15个N1位取代的该类化合物的抗菌活性进行定量构效关系研究,得到4个QSAR关系式,并对所设计的新化合物进行活性预测、合成、抗菌活性测定。结果表明,新化合物具有良好活性,且实验值与预测值基本相符。     

2-(4-取代-苯基)-3-异噻唑啉酮抗菌活性的定量构效关系研究

用密度泛函理论和逐步回归分析方法对22种新合成的2-(4-取代-苯基)-3-异噻唑啉酮化合物进行了结构与抗菌活性研究. 通过对平衡几何构型、前线轨道组成和Mulliken电荷分布的分析得出: S(1), N(2)原子是该类化合物的主要活性部位, 且5位氯取代的化合物抗菌活性较好. 通过回归分析, 筛选了影响抗菌活性的主要因素, 建立了定量构效关系方程. 结果表明, 硫原子的亲核前线电子密度、3D-Balaban指数、S(1)-N(2) Wiberg键级和Schultz分子价拓扑指数是影响异噻唑啉酮类化合物抗大肠杆菌活性的主要因素, 所得模型对化合物抗菌活性有较好的预报能力.     

2(1H)-喹啉-2,4-二酮类化合物抗小麦锈病的3D-QSAR研究

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)方法研究了21个2(1H)-喹啉-2,4-二酮类化合物抗小麦锈病的三维定量构效关系(3D-QSAR),发现用CoMFA方法可以找到最佳的3D-QSAR模型,并通过量子化学从头计算的方法研究了不同活性化合物的前线轨道及静电势分布图的差异.所得构效关系模型为发现更高活性的化合物提供理论指导.     

4, 6-二芳基-2-氨基嘧啶类衍生物的合成与生物活性

合成并表征了5种4,6-二芳基-2-氨基嘧啶类化合物。 测试了它们对大肠肝菌甲硫酰胺肽酶(EcMetAP)的抑制作用及对CXCR4受体的拮抗作用。 发现5种化合物均对EcMetAP酶活有抑制作用,除化合物2外均对CXCR4受体有拮抗作用。 利用FieldTemplater和FieldAlign软件对化合物1～5的上述活性构效关系进行了分析,初步认为化合物的嘧啶环3位N原子及4位取代苯环上若引入给电子基团,可增强这类化合物的EcMetAP酶抑制活性;在嘧啶环2位引入负电性较强的基团取代,改造2个苯环和嘧啶环的4、5、6位Ｃ原子的结构可增强其CXCR4受体拮抗活性。     

2(1H)-吡啶酮互变异构体系取代效应的理论计算

取代的2（1H）-吡啶酮团类化合物常具有诱人的生物活性[1，2]．由于其酮式和醇式结构的互变异构化性质，确定互变异构平衡体系中的优势结构及研究取代基对平衡体系的影响，对阐明该类化合物的构效关系有着重要的意义．实验发现2（1H）-吡啶酮的6-位H被取代后对其互变异构平衡有     

2-羟基-1-萘甲醛缩-N(4)-取代氨基硫脲的合成与抑菌活性

苯胺或取代苯胺、二硫化碳与水合肼在氢氧化钾催化下经加成与取代反应合成了10种N(4)-取代氨基硫脲,随后在浓盐酸催化下分别与2-羟基-1-萘甲醛加成合成了10种未见报道的2-羟基-1-萘甲醛缩-N(4)-取代氨基硫脲.通过IR、1 H NMR与13 C NMR对标题化合物进行了结构表征;采用离体法初步测试了标题化合物对6种常见农作物真菌病源菌的抑菌活性,并推测其可能的构效关系.结果表明,标题化合物对水稻纹枯病菌、小麦赤霉病菌、番茄早疫病菌、黄瓜枯萎病菌、马铃薯晚疫病菌及辣椒疫霉病菌均表现出一定的抑菌活性,其抑菌活性大小与标题化合物N(4)-取代基中苯环所连取代基的类型与位置有关.     

5-甲氧基色胺苯基哌嗪衍生物的合成及其α1-受体拮抗活性

α1-受体拮抗剂是目前临床治疗良性前列腺增生的一类有效药物,现有的α1-受体拮抗剂主要有喹唑啉类、哌啶类、苯基哌嗪类和苯乙胺类.综合已有的几类α1-受体拮抗剂的构效关系,我们发现多数苯基哌嗪类药物均具有较好的尿道组织选择性和α1-受体亚型选择性.     

2-氰基-3-(2-氟吡啶-5-基)甲氨基-3-甲硫基氰基丙烯酸酯类化合物的合成及除草活性

设计合成了系列光系统II (PS-II)电子传递抑制剂2-氰基-3-(2-氟吡啶-5-基)甲氨基-3-甲硫基氰基丙烯酸酯类化合物. 其结构经¹H NMR、元素分析确证. 生物活性测定表明: 部分化合物显示出很好的除草活性. 其中活性最好的化合物在150 g/ha, 对阔叶杂草的防效在90%以上. 构效关系研究表明: 氰基丙烯酸酯的3位取代基对它们的活性影响较大. 3位由(2-氟吡啶-5-基)甲氨基取代的氰基丙烯酸酯和相应的氯取代的氰基丙烯酸酯的除草活性相当或稍高.     

1-环丙基-6-氟-7-取代喹诺酮抗HIV活性的定量构效关系

用量子化学AM1法对一系列1-环丙基-6-氟-7-取代-1,4-二氢-4-氧-喹啉-3-羧酸的定量构效关系进行了研究,结果表明该类化合物在对HIV的抑制过程中是一很好的电子给予体,给电子的部位主要是7-位哌嗪基末端氮原子,并进一步提出从抗C^+和G^-菌活性差的喹诺酮中有望筛选出好的抗HIV化合物。     

An unexpected product from the cyclodesulfurization of 5-[1-(3-methoxycarbonyl)thioureido]-1-(β-D-ribofuranosyl)imidazole-4- carboxamide with dicyclohexylcarbodiimide

The treatment of 5-[1-(3-methoxycarbonyl)thioureido]-1-(β-D-ribofuranosyl)imidazole-4-carboxamide with N,N'-dicyclohexylcarbodiimide in N,N-dimethylformamide has afforded 4-cyano-5-[1-(3-methoxycarbonyl)-ureido]-1-(β-D-ribofuranosyl)imidazole.     

The crystal structure of 1-(4-chlorophenyl)-3-(4-methylbenzoyl)thiourea

1-(4-Chlorophenyl)-3-(4-methylbenzoyl)thiourea was synthesized and characterized by IR,¹H and ¹³C NMR, mass spectroscopy and the elemental analysis. The crystal structure was confirmed from single crystal X-ray diffraction data. It crystallizes in the monoclinic space group P2₁/c with unit cell dimensions a=12.038(3), b=6.330(6), c=18.912(5) Å and β=100.32(3)°. There is a strong intramolecular hydrogen bond of the type N?H...O, with distance N1...O1=2.659(3) Å. The structure is composed of dimers related by inversion centers. The dimers are formed by intermolecular interactions of the type N?H...S with N...S separation of 3.440(2) Å. The mass fragmentation pattern has also been discussed.     

QSAR analyses of 3-(4-benzylpiperidin-1-yl)-N-phenylpropylamine derivatives as potent CCR5 antagonists

CCR5 receptor binding affinity of a series of 3-(4-benzylpiperidin-1-yl)propylamine congeners was subjected to QSAR study using the linear free energy related (LFER) model of Hansch. Appropriate indicator variables encoding different group contributions and different physicochemical variables such as hydrophobicity (pi), electronic (Hammett sigma), and steric (molar refractivity, STERIMOL values) parameters of phenyl ring substituents of the compounds were used as predictor variables. The Hansch analysis explores the importance of the lipophilicity and electron-donating substituents for the binding affinity. However, this method could not give more insight into the structure-activity relationships because of the diverse molecular features in the data set. 3D-QSAR analyses of the same data set using Molecular Shape Analysis (MSA), Receptor Surface Analysis (RSA), and Molecular Field Analysis (MFA) techniques were also performed. The best model with acceptable statistical quality was derived from the MSA, which showed the importance of the relative negative charge (RNCG): substituents with a high RNCG value have more binding affinity than the unsubstituted piperidine and phenyl (R1 position) congeners. The relative negative charge surface area (RNCS) is detrimental (e.g. R2 = 3,4-Cl2) for the activity. An increase in the length of the molecule in the Z dimension (Lz) is conducive (e.g. R3 = sulfonylmorpholino), while an increase in the area of the molecular shadow in the XZ plane (Sxz) is detrimental (e.g. R1 = N-c-hexylmethyl-5-oxopyrrolidin-3-yl) for the binding affinity. The presence of a chiral center makes the molecule less active (e.g. R1 = N-methyl-5-oxopyrrolidin-3-yl). An increase in the van der Waals area, the molecular volume, and the difference between the volume of the individual molecule and the shape reference compound are conducive (e.g. R3 = (CH3)2NSO2-) for the binding affinity. Substituents with higher JursFPSA_2 values (fractional charged partial surface area) like the N-methylsulfonylpiperidin-4-yl (R1 position) group have better binding affinity than the substituents such as 4-chlorophenylamino (R1 position). Unsubstituted piperidines (R1 position) with less JursFNSA_1 values have lower binding affinity than the 4-chlorophenyl substituted compounds. The MFA derived equation shows interaction energies at different grid points, while the RSA model shows the importance of hydrophobicity and charge at different regions of the molecules. The models were validated through the leave-one-out, leave-15%-out, and leave-25%-out cross-validation techniques. The developed models were also subjected to a randomization test (99% confidence level). Although the MSA derived models had excellent statistical qualities both for the training as well as test sets, RSA and MFA results for the test sets are not comparable statistically with the MSA derived models.     

Competition and selectivity in the reaction of nitriles on ge(100)-2x1

We have experimentally investigated bonding of the nitrile functional group (R-Ctbd1;N:) on the Ge(100)-2x1 surface with multiple internal reflection infrared spectroscopy. Density functional theory calculations are used to help explain trends in the data. Several probe molecules, including acetonitrile, 2-propenenitrile, 3-butenenitrile, and 4-pentenenitrile, were studied to elucidate the factors controlling selectivity and competition on this surface. It is found that acetonitrile does not react on the Ge(100)-2x1 surface at room temperature, a result that can be understood with thermodynamic and kinetic arguments. A [4+2] cycloaddition product through the conjugated pi system and a [2+2] C=C cycloaddition product through the alkene are found to be the dominant surface adducts for the multifunctional molecule 2-propenenitrile. These two surface products are evidenced, respectively, by an extremely intense nu(C=C=N), or ketenimine stretch, at 1954 cm(-)(1) and the nu(Ctbd1;N) stretch near 2210 cm(-)(1). While the non-conjugated molecules 3-butenenitrile and 4-pentenenitrile are not expected to form a [4+2] cycloaddition product, both show vibrational modes near 1954 cm(-)(1). Additional investigation suggests that 3-butenenitrile can isomerize to 2-butenenitrile, a conjugated nitrile, before introduction into the vacuum chamber, explaining the presence of the vibrational modes near 1954 cm(-)(1). Pathways directly involving only the nitrile functional group are thermodynamically unfavorable at room temperature on Ge(100)-2x1, demonstrating that this functional group may prove useful as a vacuum-compatible protecting group.     

Favorskii Rearrangement in the Reaction of 3-(1-Adamantyl)-1-chloro-2-propanone with Amines

The reaction of 3-(1-adamantyl)-1-chloro-2-propanone with amines [diethylamine, (1-adamantyl)methylamine, p-toluidine, and piperidine] in diethyl ether at room temperature involves the Favorskii rearrangement and yields N,N-disubstituted amides of 3-(1-adamantyl)propanoic acid.     

Probe of bending motion following the 1s(-1)pi* excitation of N2O

The doubly degenerate core-excited Pi state of N2O splits into two due to the static Renner-Teller effect. The lower state, A1, has a bent stable geometry and the molecule excited to this state starts to deform itself toward this bent geometry. To probe the effect of the potential energy surfaces of the core-excited A1 states on the nuclear motion, we measure the momenta of the three atomic ions in coincidence by means of the ion momentum imaging technique. We find that the potential energy surface affects the molecular deformation significantly. N2O in the terminal N 1s(-1)3piA1 excited state is observed to be bent more than that in the central N 1s(-1)3piA1 excited state. This means that N2O in the terminal N 1s(-1)3piA1 excited state bends faster than that in the central N 1s(-1)3piA1 excited state. When the excitation energy is decreased within the 1s(-1)3pi resonances, the nuclear motion in the A1 states becomes faster. This is interpreted by the notion that the excitation occurs onto the steeper slope part of the potential energy surface of the excited state for the lower excitation energy. The branching ratio of the A1 excitation increases with the decrease in the excitation energy.     

Mechanisms for NH3 decomposition on Si(100)-(2 x 1) surface: a quantum chemical cluster model study

In this paper, we present a detailed mechanism for the complete decomposition of NH3 to NHx(a) (x = 0-2). Our calculations show that the initial decomposition of NH3 to NH2(a) and H(a) is facile, with a transition-state energy 7.4 kcal mol-1 below the vacuum level. Further decomposition to N(a) or recombination-desorption to NH3(g) is hindered by a large barrier of approximately 46 kcal mol-1. There are two plausible NH2 decomposition pathways: 1) NH2(a) insertion into the surface Si-Si dimer bond, and 2) NH2(a) insertion into the Si-Si backbond. We find that pathway (1) leads to the formation of a surface Si = N unit, similar to a terminal Si = Nt pair in silicon nitride, Si3N4, while pathway (2) leads to the formation of a near-planar, subsurface Si3N unit, in analogy to a central nitrogen atom (Nc) bounded to three silicon atoms in the Si3N4 environment. Based on these results, a plausible microscopic mechanism for the nitridation of the Si(100)-(2 x 1) surface by NH3 is proposed.     

Transformations of 1-amino-2-(3-hydroxyalk-1-ynyl)-9,10-anthraquinones in the presence of amines

When heated in piperidine, 1-amino-2-(3-hydroxyalk-1-ynyl)-9,10-anthraquinones undergo cyclization into 2-(1-hydroxyalkyl)naphtho[2,3-g]indole-6,11-diones. In contrast, 1-amino-2-(3-hydroxy-3-phenylpropynyl)-9,10-anthraquinone reacts with primary and secondary amines to give the corresponding 1-amino-2-(1-amino-2-benzoylvinyl)-9,10-anthraquinones, which undergo cyclization into 4-dialkylamino- or 4-alkylamino-2-phenylnaphtho[2,3-h]quinoline-7,12-diones. Heating of the starting phenylpropynol with Et₃N causes its dehydrogenation and isomerization.     

Formation mechanism of 1,3-bis(2-oxopropyl)-3H-1,2,3-benzotriazolium triiodide in the alkylation reaction of 1,2,3-benzotriazole with 1-iodopropan-2-one

Within DFT (B3LYP) methods the potential surface of the interaction between 1-iodopropan-2-one and 1,2,3-benzotriazole resulting in the formation of 1,3-bis(2-oxopropyl)-3H-1,2,3-benzotriazolium triiodide is studied. A mechanism consisting of four steps (N1-alkylation of 1,2,3-benzotriazole, elimination of molecular iodine during partial reduction of 1-iodopropan-2-one with hydrogen iodide, formation of the triiodide structure, and formation of 1,3-bis(2-oxopropyl)-3H-1,2,3-benzotriazolium) is proposed. Thermodynamic and kinetic parameters of these steps are obtained.     

Ring-Transformationen bei der Umsetzung von 3-(Dimethylamino)-2,2-dimethyl-2H-azirin mit 1-substituierten Imidazolidin-2,4,5-trionen

Ring-Transformations in the Reaction of 3-(Dimethylamino)-2,2-dimethyl-2H-azirines with 1-Substituted Imidazolidine-2,4,5-triones Reaction of 1-substituted imidazolidine-2,4,5-triones ( = N-substituted parabanic acids; 2 ) and 3-(dimethylamino)-2,2-dimethyl-2H-azirine ( 1 ) in i-PrOH or MeCN at room temperature yields 5,6,7,7a-tetrahydro-3H-imidazo[3,4-a]imidazole-5,7-diones 3 (Scheme 1). By ¹⁵N-NMR studies, using (3-¹⁵N)- 2a , it has been shown that only N( 1 ) in (¹⁵N)- 3a is labelled and, hence, N(4) stems from 1 , e.g. the azirine reacts via cleavage of the N(1)=C(3) bond. In MeCN at room temperature, the azacyclols 3 rearrange slowly to give monocyclic 2H, 5H-imidazol-2-ones 4 (Scheme 3); the ¹⁵N-label in (¹⁵N)- 4a is in position 1. Both reactions proceed via deep-seated skeletal rearrangements, most probably via ring-expansion/ring-contraction processes.