基于支持向量机、支持向量回归和分子对接的CYP450 1A2抑制剂的发现研究

支持向量机,支持向量回归和分子对接的计算方法已广泛应用于化合物的药理活性计算。为了提高计算的准确性和可靠性,拟以细胞色素P450酶1A2为研究载体,运用建立的联合SVM-SVR-Docking计算模型预测潜在的CYP1A2抑制剂。其中,建立的最优SVM定性模型训练集,内部测试集和外部测试集的准确率分别为99.432%,97.727%和91.667%。最优SVR定量模型训练集和测试集的R和MSE分别为0.763,0.013和0.753,0.056。实验表明两个模型具有较高的准确性和可靠性。通过对SVM和SVR模型结果的比较分析,发现连接性指数、分子构成描述符和官能团数目等分子描述符可能与CYP1A2抑制剂的辨识和活性预测密切相关。随后利用分子对接技术分析化合物与CYP1A2的结合构象及相互作用的稳定性。形成氢键相互作用的关键氨基酸包括THR124,ASP320;形成疏水相互作用的关键氨基酸包括ALA317和GLY316。所获得模型可用于天然产物化学成分中CYP1A2潜在抑制剂的活性计算及其介导的药物-药物相互作用预测提供理论指导,也为合理联合用药提供一定参考。共获得20个对CYP1A2具有潜在抑制活性的化合物。部分结果与文献结果相互印证,进一步说明了模型的准确性和联合计算策略的可靠性.     

A reinvestigation of the acid-promoted heterocyclization of 2-(2-oxo-2-arylethyl)malononitriles in the presence of amines

The reinvestigation of the acid-promoted cyclization of 2-(2-oxo-2-arylethyl)malononitriles, in the presence of benzylamine or aniline, in ethanol or acetonitrile, has confirmed that this is a long-time reaction process for a low-yielding synthesis of 2-amino-5-arylfuran-3-carbonitriles (2), or 2-amino-5-aryl-1-phenyl-1H-pyrrole-3-carbonitriles (4), depending on the base used. However, the microwave-assisted synthesis of 2-amino-5-(4′-methoxyphenyl)furan-3(4)-(di)carbonitriles (2c and 3c) proceeds in shorter reaction times and higher yields than does the classical thermal heating protocol. In these reactions we have observed for the first time, and characterized by their spectroscopic data and X-ray analysis, the unexpected formation of 2-amino-5-aryl-3 (4)-(di)carbonitriles (3), whose formation has been rationalized by density functional theory (DFT) analysis of the proposed reaction mechanism.     

Spectral Characteristics of the Reaction Products of 5-Phenyl-2,3,4-furantrione with o-Diamines

The ¹H and ¹³C NMR and mass spectra of 2-(2-amino-4,5-dimethylphenylcarbamoyl)-3-(hydroxyphenylmethyl)-6,7-dimethylqinoxaline (2), 3-(hydroxyphenylmethyl)-6,7-dimethylquinoxalin-2-carboxylic-γ-lactone (5), 3-(hydroxyphenylmethyl)-6,7-dimethylquinoxalin-2-carboxylic acid phenylhydrazide (6), 3-[2-hydroxy-2-phenyl-1-(phenylhydrazono)ethyl]-6,7-dimethyl-2(1H)-quinoxalinone (7), 2,3-dihydro-6,7-dimethyl-3-phenylhydrazono-2-phenylfuro[2,3-b]auinoxaline (8), 3-(hydroxyphenylmethyl)-6,7-dimethyl-1-phenylflavazole (9), and 3-(acetoxyphenylmethyl)-6,7-dimethyl-1-phenylflavazole (10) have been studied.     

Vibrational spectra,X‐ray and molecular structure of 1H‐ and 3H‐imidazo[4,5‐b]pyridine and their methyl derivatives: DFT quantum chemical calculations

Molecular structure, vibrational energy levels and potential energy distribution of 1H‐imidazo[4,5‐b]pyridine, 3H‐imidazo[4,5‐b]pyridine, 5‐methyl‐1H‐imidazo[4,5‐b]pyridine, 6‐methyl‐1H‐imidazo[4,5‐b]pyridine and 7‐methyl‐3H‐imidazo[4,5‐b]pyridine were determined using density functional theory (DFT) at the B3LYP/6‐31G(d,p) level. The optimised bond lengths and bond angles are in good agreement with the X‐ray data of 5‐methyl‐1H‐imidazo[4,5‐b]pyridine obtained in the present work (Pbca space group; a = 8.660(2), b = 11.078(2), c = 11.078(3) Å, Z = 8). The N⁺H group plays the role of a proton donor in a medium strong hydrogen bond of the type N H…N, linking the N‐atom of the pyridine with the adjacent molecule related by the symmetry operation: 1/2 − x, y − 1/2, z(N…N = 2.869(25) Å). The presence of hydrogen bond is confirmed by appearance in the IR spectra of a very broad and strong contour in the 2000–3100 cm⁻¹ range. The place of substitution of the methyl group at the pyridine ring influences the proton position of the NH group at the imidazole unit. Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis of highly substituted 2,3-dihydropyrimido[4,5-<Emphasis Type="Italic">d</Emphasis>]pyrimidin-4(1<Emphasis Type="Italic">H</Emphasis>)-ones from 4,6-dichloro-5-formylpyrimidine,amines and aldehydes

A practical strategy was developed for the preparation of highly substituted 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones from 4,6-dichloro-5-formylpyrimidine, primary amines, and aldehydes. The key step for this synthesis entails a cyclization reaction involving an intramolecular amide addition to an iminium intermediate formed in situ from 4-amino-pyrimidine-5-carboxamide 2 and aldehydes to form the pyrimido[4,5-d]pyrimidine core with a strategically placed 5-Cl group for further derivatization. The utility of this methodology was demonstrated through the preparation of a 27-membered library of representative 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones in moderate to good yields.     

A combined experimental and theoretical study of the alkylation of 3,5‐dithioxo‐[1,2,4]triazepines

The chemo‐ and regioselective alkylation reactions of 3,5‐dithioxo[1,2,4]triazepine 1 in a basic medium with α,ω‐dibromoalkanes 2a – c , Br(CH₂)_nBr (n = 1–3), are studied experimentally and theoretically. These alkylations, which occur at the thioxo sulfur atom in position 5, afford mainly 5‐bromomethylthio‐2,7‐dimethyl‐ 2,3‐dihydro‐ 4H[1,2,4]triazepin‐3‐one 3 for n = 1, 6,8‐dimethyl‐5‐thioxo‐2,3,4,5‐tetrahydro‐6H[1,3]thiazolo[4,5‐d][1,2,4]triazepine 4 for n = 2 and 7,9‐dimethyl‐6‐thioxo‐2,3,4,5,6,7‐hexahydro[1,3]thiazino [4,5‐d][1,2,4]triazepine 5 for n = 3. Theoretical calculations have been carried out at the B3LYP/6‐31G* and B3LYP(benzene)/6‐311+G*//B3LYP/6‐31G* levels, in order to rationalize the experimental observations. Both chemo‐ and regio‐selectivities of the alkylation reactions are analyzed. Copyright © 2008 John Wiley & Sons, Ltd.     

Parallel and automated library synthesis of 2-long alkyl chain benzoazoles and azole[4,5-<Emphasis Type="BoldItalic">b</Emphasis>]pyridines under microwave irradiation

Summary A versatile route to 40-membered library of 2-long alkyl chain substituted benzoazoles (1 and 2) and azole[4,5-b]pyridines (3 and 4) via microwave-assisted combinatorial synthesis was developed. The reactions were carried out in both monomode and multimode microwave oven. With the latter, all reactions were performed in high-throughput experimental settings consisting of an 8×5 combinatorial library designed to synthesize 40 compounds. Each step, from the addition of reagents to the recovery of final products, was automated. The microwave-assisted N-long chain alkylation reactions of 2-alkyl-1H-benzimidazole (1) and 2-alkyl-1H-benzimidazole[4,5-b] pyridines (3) were also studied.     

Dimer radical cation of 4‐thiouracil: a pulse radiolysis and theoretical study

Pulse radiolysis with optical absorption detection has been used to study the reactions of hydroxyl radical (OH^?) with 4‐thiouracil (4TU) in aqueous medium. The transient absorption spectrum for the reaction of OH^? with 4TU is characterized by λ_max 460 nm at pH 7. A second‐order rate constant k_(4TU+OH) of 1.7 × 10¹⁰ M^?1 s^?1 is determined via competition kinetics method. The transient is envisaged as a dimer radical cation [4TU]₂^?+, formed via the reaction of an initially formed radical cation [4TU]^?+ with another 4TU. The formation constant of [4TU]₂^?+ is 1.8 × 10⁴ M^?1. The reactions of dibromine radical ion (Br₂^??) at pH 7, dichlorine radical ion (Cl₂^??) at pH 1, and azide radical (N₃^?) at pH 7 with 4TU have also produced transient with λ_max 460 nm. Density functional theory (DFT) studies at BHandHLYP/6–311 + G(d,p) level in aqueous phase showed that [4TU]₂^?+ is characterized by a two‐centerthree electron (2c‐3e) [?S∴S?] bond. The interaction energy of [?S∴S?] bond in [4TU]₂^?+ is ?13.01 kcal mol^?1. The predicted λ_max 457 nm by using the time‐dependent DFT method for [4TU]₂^?+ is in agreement with experimental λ_max. Theoretical calculations also predicted that compared with [4TU]₂^?+, 4‐thiouridine dimer is more stable, whereas 4‐thiothymine dimer is less stable. Copyright © 2013 John Wiley & Sons, Ltd.     

Spectrophotometric determination of some amino heterocyclic donors through charge transfer complex formation with chloranilic acid in acetonitrile

The present study is directed toward a development of simple, rapid and accurate spectrophotometric method for determination of some amino heterocyclic donors. The Charge transfer (CT) interactions between 3-aminopyrazole (AP), 3,5-dimethyl-pyrazole (DMP), 3-amino-5-methyl-pyrazole (AMP), 2-amino-4-methyl-thiazole (AMT), 2-amino-5-methyl-1,3,4-thiadiazole (AMTD) and 2-amino-5,6-dimethyl-1,2,4-triazine (ADMT) with chloranilic acid (CLA) as π-acceptor have been investigated spectrophotometrically in acetonitrile. Factors controlling the CT-reactions were also studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients were identified with high accuracy and precision. Job's method of continuous variation, spectrophotometric and conductometric titrations were used to identify the composition of the formed CT-complexes. Benesi-Hildebrand (BH) equation has been used to calculate the formation constants of the charge transfer reactions K_CT and the molar extinction coefficients ε. Free energy change (ΔG^o), oscillator strength (f), transition dipole moment (µ), ionization potential (I_P) and charge transfer energy of the formed CT-complexes (E_CT) were also determined and evaluated.     

NMR Studies of Drugs. Enantiomeric Excess Determination of N-acetylcathinone with Eu(HFC)3

A technique for determination of enantiomeric excess of cathinone, 2-amino-1-phenyl-1-propanone, by use of the chiral lanthanide shift reagent (LSR), tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium (III), Eu (HFC)₃, is described. The hydrochloride salt of the cathinone sample is first converted directly to the N-acetyl derivative without need for isolation of the potentially unstable cathinone free base. Addition of Eu (HFC)₃ to the crude acetylated cathinone resulted in near-baseline resolution of the CH ₃CO resonances of the enantiomers. Analytical utility and the sense of magnetic nonequivalence of this signal were demonstrated using “spiked” non-racemic samples.     

Synthesis and Spectral Studies of Novel Co(II), Ni(II), Cu(II), Cd(II), and Fe(II) Metal Complexes with N-[5′-Amino-2,2′-bis(1,3,4-thiadiazole)-5-yl]-2-hydroxybenzaldehyde Imine (HL)

Co(II), Ni(II), Cu(II), Cd(II), and Fe(II) complexes with Schiff base derived from 2-amino-5-(2-amino-1,3,4-thiadiazolyl)-1,3,4-thiadiazole (1) and salicylaldehyde have been prepared. The ligand and its complexes have been characterized by IR, ¹H NMR spectra, elemental analyses, magnetic susceptibility, UV-Vis. and thermogravimetry–differential thermal analysis (TGA-DTA). The analytical data show 1:2 metal-to-ligand ratio for Co(II), Ni(II), Cd(II), and Fe(II) and 2:2 metal-to-ligand ratio for Cu(II) complexes. The suggested structures for the N-[5′-Amino-2,2′-bis(1,3,4-thiadiazole)-5-yl]-2-hydroxybenzaldehyde Imine (HL) complexes of Fe(II), Co(II), and Cd(II) are octahedral, for the Ni(II) complex is tetrahedral, and for the Cu(II) complex is square-planar     

Chemo- and stereoselective reaction between alkyl isocyanides and dimethyl 1,3-acetonedicarbocxylate in the presence of acetylenic esters

The reaction of alkyl isocyanides with dimethyl 1,3-acetonedicarboxylate in the presence of dialkyl acetylenedicarboxylates in CH₂Cl₂ at ambient temperature leads to highly functionalized 2-amino-4H-pyrans and 1,2-dialkyl 4,6-dimethyl-(1E, 3E)-3 (alkylamino)-5-oxo-1,3-hexadiene-1,2,4,6-tetracarboxylates.     

Levels in Gd158 from the (d,p) reaction

The nuclear spectroscopy of Gd¹⁵⁸ has been investigated by deuteron stripping with magnetic analysis of the resulting protons. Over fifty levels have been observed. Comparison is made of observed and theoretical relative cross sections. Two new rotational bands have been observed; one band based on the 2+ two-quasiparticle state [521 +] – [521?] at 2333.6 keV and a second band based on the 1 + two-quasiparticle state [521 +] – [521?] at 2494 keV. The ground state (d,p)Q-value was found to beQ _o=5706± 5 keV.     

Influence of Co(III) Polypyridyl Complexes on Luminescence Behavior,DNA Binding,Photocleavage, Antimicrobial Activity and Molecular Docking Studies

A new ligand FIPB?=?5-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)furan-2-yl-2-boronic acid, having three cobalt(III) polypyridyl complexes [Co(phen)₂(FIPB)]³⁺(1) {FIPB?=?5-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)furan-2-yl-2-boronic acid}, (phen?=?1,10-Phenanthroline), [Co(bpy)₂(FIPB)]³⁺(2) (bpy?=?2,2’bipyridyl), [Co(dmb)₂(FIPB)]³⁺(3) (dmb?=?4, 4′-dimethyl 2, 2′-bipyridine) have been synthesized and characterized by elemental analysis, ES-MS,¹H-NMR, ¹³C-NMR, UV-Vis and FTIR. Their DNA binding behavior has been explored by various spectroscopic titrations and viscosity measurements, which indicated that all the complexes bind to calf thymus DNA by means of intercalation with different binding strengths. The binding properties of these all three complexes towards calf-thymus DNA (CT-DNA) have been investigated by UV-visible, emission spectroscopy and viscosity measurements.The experimental results suggested that three Co(III) complexes can intercalate into DNA base pairs,but with different binding affinities. Photo induced DNA cleavage studies have been performed and results indicate that three complexes efficiently cleave the pBR322-DNA in different forms. The three synthesized compounds were tested for antimicrobial activity by using Staphylococcus aureus and Bacillus subtilis organisms, these results indicated that complex 1 was more activity compared to other two complexes against both tested microbial strains. The in vitro cytotoxicity of these complexes was evaluatedby MTT assay, and complex 1 shows higher cytotoxicity than complex 2 and 3 on HeLa cells.

     

To what extent can a conjugation between two pairs of peri‐nitro and peri‐amino groups be realized through the naphthalene core?

Through‐conjugation for a wide range of 1,8‐diamino‐4,5‐dinitronaphthalenes (N‐acylated, N‐alkylated, N,N′‐bridged, N‐heterocyclic, and N‐deprotonated compounds) was for the first time quantified in solution by means of ultraviolet–visible and proton nuclear magnetic resonance spectroscopy and compared with that of the simpler naphthalene and benzene push‐pull systems. Surprisingly, an extent of conjugation in 1,8‐diamino‐4‐nitro‐ and 1,8‐diamino‐4,5‐dinitronaphthalenes measured in dimethyl sulfoxide is commensurable. On the whole, the repulsive peri‐interactions between the amino groups in systems with N‐alkylated and N‐deprotonated amino groups are more favorable for an effective D‐π‐A charge transfer than in N,N′‐bridged compounds (perimidines, 2,3‐dihydroperimidines and perimidin‐2‐ones). The best electron donors from peri‐positions are pyrrolidin‐1‐yl and methylamido groups. The conclusions obtained from solution studies were deepened by solid‐ state X‐ray experiments for a number of push–pull naphthalenes, including 6,7‐dinitroperimidine N‐anion and two representatives of 4,5‐diaminonaphthalene‐1,8‐dicarbaldehydes. In particular, they helped to trace changes in the bond order redistribution and twisting of the naphthalene core. The latter reaches a record value of 27° for 4,5‐dinitro‐1,8‐di(pyrrolidin‐1‐yl)naphthalene. Copyright © 2013 John Wiley & Sons, Ltd.     

Directly Oxidized Chemiluminescence of 2-Substituted-4,5-di(2-Furyl)-1<Emphasis Type="Italic">H</Emphasis> -Imidazole by Acidic Potassium Permanganate and its Analytical Application for Determination of Albumin

In the paper, 2,4,5-tri(2-furyl)-1H-imidazole (TFI) and 2-phenyl-4,5-di(2-furyl)-1H-imidazole (PDFI), were chosen to investigate chemiluminescence (CL) properties of 2-substituted-4,5-di(2-furyl)-1H-imidazoles. The directly oxidized CL of analytes by potassium permanganate (KMnO₄) was in detail studied. The KMnO₄ could directly oxidize TFI/PDFI to produce strong CL emission in acidic solution. The effects of experimental conditions were investigated. Under the optimal conditions, the effect of albumin on the TFI/PDFI-KMnO₄ system was investigated. It was found that the addition of albumin into the system could induce enhancement of CL signal, and the enhanced CL intensity is linearly related to the logarithm of concentration of albumin. Based on this study, a novel CL method has been developed for the determination of albumin with high sensitivity and good selectivity. The method was applied to the determination of albumin in human serum samples, and the results were in agreement with those obtained by the bromcresol green (BCG) method. The relative errors for the analytical results were from −5.8% to 4.2%. These new phenomena would further enable people to exploit more CL analytical application of the heterocyclic imidazole derivatives.     

Theoretical and antimicrobial activity study for ethyl{4-[3-(1H-imidazole-1-yl)propyl]-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate

Ethyl{4-[3-(1H-imidazole-1-yl)propyl]-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}-acetate (I) was synthesized as described in the literature and studied by proton and carbon-13 nuclear magnetic resonance, Fourier transform infrared spectroscopic techniques. Theoretical calculations were performed by the density functional method with 6-311G(d,p) and 6-311++G(d,p) basis sets. Structural parameters of compound I, vibrational frequencies, and chemical shift values were determined. The antimicrobial activity of compound I was tested for seven standard bacteria; Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, Yersinia enterocolitica, Listeria monocytogenes, Shigella flexneri, Pseudomonas aeruginosa, and one standard fungi isolate by microdilution broth assay with Alamar Blue Dye. The in vitro results show that compound I has antimicrobial activity against to two standard bacteria, Shigella flexneri and Listeria monocytogenes. And also, the antifungal activity was not detected against selected fungi isolate, Candida tropicalis.