Synthesis of (2S,4S)-2-Substituted-3- (3-Sulfanylpropanoyl)-6- Oxohexahydropyrimidine-4-Carboxylic Acids as Potential Antihypertensive Drugs

Proceeding from natural amino acid L-asparagine and commercially available aldehydes a stereoselective synthesis was developed of (2S,4S)-2-alkyl(aryl)-3-(3-sulfanylpropanoyl)-6-oxohexahy- dropyrimidine-4-carboxylic acids, potential antihypertensive drugs, inhibitors of the angiotensin converting enzyme.

QSAR and Pharmacophore Studies of Thiazolidine-4-carboxylic Acid Derivatives as Novel Influenza Neuraminidase Inhibitors Using HQSAR, Topomer CoMFA and CoMSIA

In order to understand the chemical-biological interactions governing their activities toward neuraminidase （NA）, QSAR models of 28 thiazolidine-4-carboxylic acid derivatives with inhibitory influenza A virus were developed. The obtained HQSAR （hologram quantitative structure activity relationship）, Topomer CoMFA and CoMSIA （comparative molecular similarity indices analysis） models were robust and had good exterior predictive capabilities. Moreover, QSAR modeling results elucidated that hydrogen bonds highly contributed to the inhibitory activity, then electrostatic and hydrophobic factors. Squared multiple correlation coefficients （R2） of HQSAR, Topomer CoMFA and CoMSIA models were 0.994, 0.978 and 0.996, respectively. Squared cross-validated correlation coefficients （Q2） of HQSAR, Topomer CoMFA and CoMSIA models were in turn 0.951, 919 and 0.820. Furthermore, squared multiple correlation coefficients for the test set （R2test） of HQSAR, CoMFA and CoMSIA models were 0.879, 0.912 and 0.953, respectively. Squared cross-validated correlation coefficients for the test set （Q2ext） of HQSAR, Topomer CoMFA and CoMSIA models were 0.867, 0.884 and 0.899, correspondingly.

LC-MS/MS analysis of 2-aminothiazoline-4-carboxylic acid as a forensic biomarker for cyanide poisoning

AIM: To demonstrate the potential of using 2-aminothiazoline-4-carboxylic acid(ATCA) as a novel biomarker/forensic biomarker for cyanide poisoning. METHODS: A sensitive method was developed and employed for the identification and quantification of ATCA in biological samples, where the sample extraction and clean up were achieved by solid phase extraction(SPE). After optimization of SPE procedures, ATCA was analyzed by high performance liquid chromatographytandem mass spectrometry. ATCA levels following the administration of different doses of potassium cyanide(KCN) to mice were measured and compared to endogenous ATCA levels in order to study the significance of using ATCA as a biomarker for cyanide poisoning.RESULTS: A custom made analytical method was established for a new(mice) model when animals were exposed to increasing KCN doses. The application of this method provided important new information on ATCA as a potential cyanide biomarker. ATCA concentration in mice plasma samples were increased from 189 ± 28 ng/mL(n = 3) to 413 ± 66 ng/mL(n = 3) following a 10 mg/kg body weight dose of KCN introduced subcutaneously. The sensitivity of this analytical method proved to be a tool for measuring endogenous level of ATCA in mice organs as follows: 1.2 ± 0.1 μg/g for kidney samples, 1.6 ± 0.1 μg/g for brain samples, 1.8 ± 0.2 μg/g for lung samples, 2.9 ± 0.1 μg/g for heart samples, and 3.6 ± 0.9 μg/g for liver samples. CONCLUSION: This finding suggests that ATCA has the potential to serve as a plasma biomarker / forensic biomarker for cyanide poisoning.

Highly Efficient Synthesis of Novel Fluorine Bearing Quinoline-4-carboxylic Acid and the Related Compounds as Amylolytic Agents

Highly efficient syntheses of novel fluorine bearing quinoline-4-carboxylic acids and the related compounds had been achieved from cyclocondensation of 2-amino-5-fluorophenyl glyoxylic acid 1 with benzoyle asetanilides 2 in boiling DMF, to give the target 3. Decarboxylation of 3 produced 6-fluoro-2-phenyl-3-(substituted amino)-keto-quinolines 4, while that reaction underwent refluxing, afforded 7-fluoro-1-(aryl)-3-phenyl-pyrrolo[3,4-c] quinoline-2,9-diones 5. Structure of the products has been established from their elemental and spectral analysis. All targets exhibited a high to moderate activity against some Aspergillus fungi as amylolytic agents.

Esterification and Chemoselective Synthesis of R-Tetrahydrothiazo-2-thione-4-carboxylic Esters Catalyzed by TiCl_4

A series of esters of R-tetrahydrothiazo-2-thione-4-carboxylic acid [ R-TTCA ] was synthesized by direct esterifica- tion of R-TTCA with alcohols（CH3OH, C2H5OH, n-C3HTOH, i-C3HTOH, n-C4H9OH, sec-C4H9OH） in the presence of TiCl4 as the catalyst at room temperature without using any other solvent or dehydrant in high yields, 91.6%-99.1% for primary alcohols and 55%- 80% for secondary alcohols. The catalyst has a strong chemoselec-tive activity for the esterification of primary alcohols with R-TTCA in the presence of secondary alcohols. Owing to high yield, high chemoselectivity, and mild conditions used, this is an efficient method for the esterification of prima-ry alcohols with R-TTCA.

Structure and Luminescent Property of a Novel 4-Hydroxyquinoline-2-carboxylate Based Zn(Ⅱ) Complex

A 3D coordination polymer [Zn2（hqc）2（H2O）]n has been obtained from the reaction of 4-hydroxyquinoline-2-carboxylic acid （H2hqc） with zinc（II） salt under hydrothermal condition, and characterized by elemental analysis, IR, TGA, PXRD and X-ray single-crystal diffraction. The complex crystallizes in the monoclinic system, space group P21/c with a = 14.305（2）, b = 9.132（2）, c = 15.356（2）, β = 103.586（7）o, V = 1949.9（4）3, Z = 4, Dc = 1.782 g/cm3, μ = 2.508 mm-1, Mr = 523.06, F（000） = 1048, T = 293（2） K, λ（MoKα） = 0.71073, S = 1.008, the final R = 0.0329 and wR = 0.0745 for 3849 observed reflections （I 〉 2σ（I））. The title complex features a 3D framework via Zn（2） linking the 1D {Zn1（hqc）2}n chains. Thermogravimetric analysis shows that its framework is highly thermally stable up to 556 ℃ in the solid state.

Synthesis and Crystal Structure of a Novel Ethyl 5-(4-(2-Phenylacetamido)phenyl)-1H-pyrazole-3-carboxylate as an Acrosin Inhibitor

The title compound （ethyl5-（4-（2-phenylacetamido）phenyl）-lH-pyrazole-3-carboxylate, C20H19N3O3） was synthesized by the reaction of Claisen condensation, cyclization, reduction and acylation. The structure was characterized by X-ray diffraction, MS, NMR and IR. It belongs to the monoclinic system, space group C2/c with a = 22.723（9）, b = 9.324（4）, c = 18.890（8） A, β = 114.259（6）°, V = 3649（3） A^3, Dc = 1.272 Mg·m^3, Z = 8, Mr = 349.38, p = 0.087 mm^-1, F（000） = 1472, the final R = 0.0615 and wR = 0.1643. The biological test shows that the title compound has a moderate acrosin inhibition activity.

Syntheses and Characterization of Two New Alkaline Earth Metal-organic Topological Frameworks with 3-Amino-1H-1,2,4-triazole-5-carboxylate

Two new alkaline earth metal coordination polymers constructed from the deriva-tive of 1,2,4-triazole are presented herein,namely,{[Sr（AmTAZAc）2（H2O）]}（1） and {[Ba（AmTAZAc）2（H2O）]}（2）（AmTAZAc = 3-amino-1H-1,2,4-triazole-5-carboxylate）,which have been synthesized by using the layering method and structurally characterized by elemental analysis,IR,and single-crystal X-ray diffraction.Complexes 1 and 2 are isostructural,and both crystallize in the orthorhombic system,space group Fdd2.X-ray structural analysis shows that 1 or 2 has an intriguing 3-D infinite network of（318.438.510） topology based on a 2-D sheet structure of（4,4） net.The result shows that noncovalent interactions play an important role in strengthening the whole structures of the compounds.

Synthesis and Structural Characterization of a New Hydrogen-bonded Polyrotaxane of [Co(H_2O)_6]_(2+) with 1,1′-(Propane-1,3-diyl)dipyridinium-4-carboxylate

A new double betaine 1,1′-（propane-1,3-diyl）dipyridinium-4-carboxylate L has been synthesized. Reaction of 1, 1′-（propane-1,3-diyl）dipyridinium-4-carboxylate tetrahydrate 1 with Co（ClO4）2-6H2O leads to the formation of a new Co（Ⅱ） coordination compound, namely [Co（H2O）6]-2H2O-2L-2ClO4 2. The crystal structures of 1 and 2 have been determined by single-crystal X-ray diffraction method. Crystal data for 1. monoclinic, space group C2/c, a = 18.945（4）, b = 7.700（2）, c = l 1.888（2）A,β = 101.67（3）°, V = 1698.3（6） A^3, Z = 4, F（000） = 760.0, Dc = 1.402 g/cm^3, the final R = 0.0607 and wR = 0.1607 for 950 observed reflections （1 〉 2σ（I））; and those for 2： monoclinic, space group P21/c, a = 17.982（1）, b = 15.879 （1）, c = 7.0716（5）/A,β= 100.675（1）°, V= 1984.3（3） ,A^3 Z= 4, F（000） = 1010.0, Dc = 1.631 g/cm^3, the final R = 0.0316 and wR = 0.0896 for 3784 observed reflections （1 〉20（I））. Crystal structure analysis indicates that in 1, molecules of L in a ＂V-shaped＂ conformation are linked to chains sustained by O-H…O hydrogen bonds between carboxylate groups and solvent water molecules. The chains are joined by O-H…O and C-H…O hydrogen bonds to further expand into a three-dimensional structure. For 2, molecules of L in a ＂Z-shaped＂ conformation are linked by hydrogen bonds between carboxylate groups and aqua ligands to form a chain of loops running down the b axis. The （2D→2D） polythreading in compound 2 represents the mode of parallel interpenetration of 2D sheets, having polyrotaxane character.

Synthesis and Crystal Structure of Methyl 2-(Diphenylamino)-4-phenyl-1,3-thiazole-5-carboxylate

The title compound, methyl 2-（diphenylamino）-4-phenyl-1,3-thiazole-5-carboxylate, was synthesized and studied by single-crystal X-ray diffraction method. The structure of the product was confirmed by IR, 1H- and 13C-NMR spectroscopy and elemental analysis. These experimental studies were supported by quantum mechanical calculations. The structure was solved in monoclinic, space group P21/c with a = 9.573（3）, b = 19.533（7）, c = 9.876（3）, β = 92.35（4）°, V = 1845.2（10）3, T = 85（2） K, Z = 4, R = 0.040 and wR = 0.089 for 6424 observed reflections with I2σ（I）.

Synthesis and Quantum Chemistry Studies of (R)-N-(Propionylthiazolidine-2-thione-4-methoxycarbonyl)germanium Sesquioxide

(R)-N-(β-Trichlorogermyl propionyl)thiazolidine-2-thione-4-carboxylic methyl ether(1) and its sesquioxide(2) were synthesized. The crystal structure of 1 was determined by means of X-ray diffraction analysis, which shown that the >CO and >CS groups are located in the opposite sides of C(4)—N—C(3) bond with transconfiguration. The electronic structures and optimized configurations of compounds 1 and 2 were studied with MNDO method.

A Facile Synthesis of 9,10-Dimethoxybenzo[6,7]- ox-epino[3,4-<i>b</i>]quinolin-13(6<i>H</i>)-one and Its Derivatives

A concise and efficient method for the synthesis of novel 9,10-imethoxybenzo[6,7]oxepino[3,4-b]quinolin13(6H)-one and its derivatives 7a-p has been developed via the intramolecular Friedel-Crafts acylation reactions of 6,7-dimethoxy-2-(phenoxymethyl)quinoline-3-carboxylic acids 6a-p with polyphosphoric acid (PPA) as catalyst and solvent under mild conditions. The key intermediates 6a-p were prepared through the in situ formation of ethyl 6,7-dimethoxy-2-(phenoxymethyl)quinoline-3-carboxylates 5a-p followed by hydrolysis with aqueous ethanolic sodium hydroxide solution. The novel synthetic method has the advantages of good yields, easy work-up, and environmentally friendly character, which may provide a novel highly efficient process for making quinoline and related azaheterocycle libraries.

Synthesis, Reactions and Characterization of 1,1’-(1,4-Phenylenebis(3-amino-6-methyl-1H-pyrazolo[3,4-b]pyridine-4,5-diyl))bis(ethan-1-one)

Reaction of 4,4’-(1,4-phenylene)bis(5-acetyl-6-methyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile) (1) with methyl iodide afforded the 4,4’-(1,4-phenylene)bis(5-acetyl-6-methyl-2-(methylthio)nicotinonitrile) (2). The reaction of 2 with hydrazine hydrate followed by diazotization reaction af-forded the 1,1’-(1,4-phenylenebis(3-amino-6-methyl-1H-pyrazolo[3,4-b]pyridine-4,5-diyl))bis(e-than-1-one) (3) and 1,1’-(1,4-phenylenebis(3-(chlorodiazenyl)-6-methyl-1H-pyrazolo[3,4-b]-pyridine-4,5-diyl))bis(ethan-1-one) (4) respectively. On the other hand, reaction of 4 with malononitrile, 2-cyanoethanethioamide, ethyl acetoacetate, acetyl acetone, ethyl benzoylacetate, diethylmalonate, ethyl cyanoacetate and phenacylbromide aiming to build up pyrazolotriazine or pyrazole ring on the ring system of 4. Structures of all newly synthesized heterocyclic compounds in the present study were confirmed by considering the data of IR, 1H NMR, mass spectra as well as that of elemental analyses.

Design, Synthesis, Antifungal Activities and SARs of （R）-2-Aryl-4,5-dihydrothiazole-4-carboxylic Acid Derivatives

Based on the structure of natural product 2-aryl-4,5-dihydrothiazole-4-carboxylic acid, a series of novel （R）-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives were designed and synthesized. Their structures were characterized by ^1H NMR, ^13C NMR and HRMS. The single crystal structure of compound 9b was determined by X-ray diffraction analysis. The antifungal activities were evaluated for the first time. The bioassay results indicated that most compounds exhibited moderate to good antifungal activities. The antifungal activities of compound 13a （against Cercospora arachidicola Hori）, 13d （against Alternaria solani）, and 16e （against Cercospora arachidieola Hori） were 61.9%, 67.3% and 61.9%, respectively, which are higher than those of the commercial fungicides chlorothalonil and carbendazim. Moreover, compound 13d exhibited excellent antifungal activities against 7 kinds of the fungi tested （66.7%, 77.3%, 63.0%, 87.9%, 70.0%, 70.0% and 80.0% at 50 μg/mL）. Therefore, 13d can be used as a new lead structure for the development of antifungal agents.

Application of L-thiazolidine-4-carboxylic acid monolayer in electrochemical determination of copper(Ⅱ)

L-Thiazolidine-4-carboxylic acid monolayer was prepared on gold electrodes through the self-assembly approach.Such novel thioether-based monolayer could efficiently preconcentrate Cu2+,which provided a simple,stable and reproducible method for the determination of Cu2+.The modified electrodes were stable enough to be continuously used for one week(more than 30 times regeneration) with lower than 10% decrease in the response.They retained their initial activity for more than one month if used once a day.The calibration curve was linear for Cu2+ from 0.6 to 158.8 μg L?1 with a detection limit of 0.38 μg L?1.The relative standard deviation was 3.2% for a series of six successive measurements.The proposed method was applied in the determination of Cu2+ in mineral water and human hair samples.

QSAR and Docking Studies of Thiazolidine-4-carboxylic Acid Derivatives as Neuraminidase Inhibitors

In order to understand the chemical-biological interactions governing their activities toward neuraminidase(NA),QSAR models of 28 thiazolidine-4-carboxylic acid derivatives with inhibitory influenza A virus were developed.Here a quantitative structure activity relationship(QSAR)model was built by three-dimensional holographic atomic vector field(3D-HoVAIF)and multiple linear regression(MLR).The estimation stability and prediction ability of the model were strictly analyzed by both internal and external validations.The correlation coefficient(R2)of established MLR model was 0.984,and the cross-validated correlation coefficient(Q2)of MLR model was 0.947.Furthermore,the cross-validated correlation coefficient for the test set(Qext 2)was 0.967.The binding mode pattern of the compounds to the binding site of integrase enzyme was confirmed by docking studies.The results of present study indicated that this model can aid in designing more potent neuraminidase inhibitors.

Three component reactions: An efficient and green synthesis of 3, 4-dihydropyrimidin-2-(1H)-ones and thiones using silica gel-supported L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate

An environmentally benign aqueous protocol for the synthesis of 3,4-dihydropyrimidin-2-（ 1 H）-ones and thiones promoted by a green catalyst, silica gel-supported L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate, has been developed. The use of nontoxic, thermally stable and inexpensive amino acid catalyst makes the process simple with minimal amount of chemical waste. Compared with classical Biginelli reaction conditions, this new method has the advantages of high yields and simple workup procedures.

Drug discovery based on the structure of FKBP12: Design, synthesis and evaluation of L-1,4-thiazane-3-carboxylic acid derivatives as neuroimmunophilin ligands

By choosing neuroimmunophilin FKBP12 as a therapeutical target, we have attempted to discover a new structural drug for treating neurodegenerative disease. This drug should possess neurotrophic activity and not affect the immune system. Based on the crystal structure of FKBP12, FK506 and Calcineurin complex, a series of small organic molecules were designed. These molecules were to have the ability of binding to FKBP12 in a virtual screening. By using a solution parallel synthetic method, these compounds were synthesized. The neuroprotective and neuroregenerative activities of these compounds were evaluated by binding assays, PC12 cells survival and neurite outgrowth model, chick dorsal root ganglion cultures (DRG) and 6-OHDA lesioned mice sympathetic nerve endings model. The evaluation results of these compounds showed that compound N308 has great promise as a candidate for a neuroprotective and neuroregenerative agent.