Facile Synthesis of [1,2,4]Triazolo[4,3-a]pyrazin-3-amines via Oxidative Cyclization of 1-(Pyrazin-2-yl)guanidine Derivatives

In this study, we applied a novel, mild, and convenient synthetic method involving the oxidative cyclization of 1-(pyrazin-2-yl)guanidine derivatives to produce [1,2,4]triazolo[4,3-a ]pyrazin-3-amines. We optimized the reaction procedure to easily obtain 5-chloro-[1,2,4]triazolo[4,3-a ]pyrazin-3-amine. Various types of halogenated pyrazines can successfully undergo this process. We synthesized a series of 1-(pyrazin-2-yl)guanidines and [1,2,4]triazolo[4,3-a ]pyrazin-3-amines, and then elucidated their structures based on their ~1H-NMR, ^(13)C-NMR, ESI-HRMS, and nuclear Overhauser effect spectra.

Synthesis,Crystal Structure,DFT Studies and Biological Activity of a Novel Schiff Base Containing Triazolo[4,3-a]pyridine Moiety

The novel Schiff base（E）-8-chloro-NA-（4-（dimethylamino）benzylidene）-[1,2,4]triazolo[4,3-a]pyridine-3-carbohydrazide was synthesized and characterized by ^1H NMR,MS,elemental analysis and X-ray diffraction.The compound crystallizes in the monoclinic space group P2_1/c with a = 7.091（2）,b = 10.750（3）,c = 21.380（6） A,β = 96.299（6）°,V = 1619.7（8） A^3,Z = 4 and R = 0.0351.Theoretical calculation of the title compound was carried out with the B3LYP/6-31 G basis set.The frontier orbital energy and atomic net charges were discussed.It is found that the experimental data show good agreement with the calculated values.And the compound exhibits good antifungal activity against Stemphylium lycopersici（Enjoji） Yamamoto.

Synthesis and Crystal Structure of 1-(4-Fluorophenyl)-2-hexylthiobenzo[4,5]-furo[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-5(1H)-one

The crystal structure of the title compound 1-（4-fluorophenyl） -2-hexylthio-benzo [4,5]furo[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-5（1H） -one（C23H21FN4O2S,Mr = 436.5） has been prepared and determined by single-crystal X-ray diffraction. The crystal is of monoclinic,space group P21/n with a = 13.9854（3） ,b = 17.2678（4） ,c = 18.1828（5）A,β = 99.364（2） °,V = 4332.58（18） A^3,Z = 4,Dc = 1.338,F（000） =1824,μ = 0.185 mm^-1,MoKa radiation（λ = 0.71073） ,R = 0.0538 and wR = 0.1162 for 4728 observed reflections with I 〉 2σ（I） . X-ray diffraction analysis reveals the fused rings of benzo[4,5]furo[3,2-d]-1,2,4-triazolo[1,5-a] pyrimidin-5（1H） -one system are nearly coplanar. The crystal packing is mainly stabilized by weak intermolecular C-H···O hydrogen bond and π-π interactions.

Synthesis,Crystal Structure and Antifungal Activity of 8-Chloro-3-((4-chlorobenzyl)-thio)[1,2,4]triazolo[4,3-a]pyridine

The title compound 8-chloro-3-（（4-chlorobenzyl）thio）-[1,2,4]triazolo[4,3-a]pyridine was prepared from 1-chloro-4-（chloromethyl）benzene and 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3（2H）-thione in the presence of Na OH, and its structure was determined by X-ray diffraction analysis. The crystal is of triclinic system, space group P1 with a = 6.8264（6）, b = 7.5890（4）, c = 13.0960（7） A, α = 93.447（4）, β = 98.772（6）, γ = 92.615（6）o, V = 668.26（8） A3, Z = 2, the final R = 0.035 and wR = 0.09 for 2259 observed reflections with I 〉 2σ（I）. The preliminary biological test showed that the title compound has activities against Stemphylium lycopersici（Enjoji） Yamamoto, Fusarium oxysporum. sp. cucumebrium, and Botrytis cinerea with inhibitory to be 51.19%, 62.02% and 15.56%, respectively.

Studies on Condensed Heterocyclic Compounds(Ⅲ)——Synthesis and Antibacterial Activity of 3-(4-Pyridyl)-6-Alkyl/Aromatic Heterocyclyl-s-Triazolo[3,4-b]-1, 3,4-Thiadiazoles and 1,4-Bis [6-(4-Pyridyl)-s-Triazolo [3,4-b]-1, 3,4-Thiadiazol-3-yl]-n-Butane

In recent years, fused heterocycles have been reported to possess important properties in synthesis and pharmacology. Especially, s-triazolo, 3,4-thiadiazole derivatives have been attracting much attention for chemists and pharmacologists because they show broad spectra of biological activities, such as antifungal, antibacterial, hy-

Crystal and Molecular Structure of 2-(2-Methoxycarboxyl)phenyloxy-5 ,7-dim ethyl-1 ,2 ,4-triazolo〔1 ,5-a〕pyrimidine

The crystal structure of the title compound has been determined by single crystal X ray diffraction analysis. C 15 H 14 N 4O 3, M r =298.30, monoclinic, space group P2 1/n, a=9.483(9), b=11.078(9), c=13.700(9), β=100.19(7)°, V=1417(4) 3, Z=4, D x =1.399 g.cm -3 , μ =0.0942 mm -1 ; F (000)=624, final R =0.074 and R w =0.074 for 1502 observed reflections〔 I≥3σ(I )〕. The results show that all ring atoms in the triazolopyrimidinyl moiety were coplanar with strong tensile force, which might be an important active site.

Synthesis and electrochemical properties of 2,6-bis(6-aryl-[1,2,4]- triazolo[3,4-b][1,3,4]-thiadiazole-3-yl)pyridines

By the condensation of 2,6-bis（4-amino-5-mercapto-[1,2,4]-triazoles-2）pyridine with aromatic acid in the presence of phosphorus oxychloride. Compounds of 2,6-bis（6-aryl-[1,2,4]-triazolo[3,4-b][1,3,4]-thiadiazole-3-yl）pyridines were synthesized. Their structures were confirmed by IR, ^1H NMR spectroscopies and elemental analysis. Their electrochemical behavior and cyclic voltammogram also were be studied. The results showed that they have high ionization potentials and good affinity.

Phase Transfer Catalyzed Synthesis and Antibacterial Activity of Water-soluble S-Triazolo[3,4-b][1,3,4]thiadiazoles Containing Piperazine Group

6/3-（4-Chlorophenyl）-s-triazolo[3, 4-b][1, 3, 4]thiadiazoles （2,a-e） and （Sa-e） were synthesized respectively by intermolecular cyclization of 5-aryl / 4-chlorophenyl-4-amino-3- mercapto-1, 2, 4-triazoles （la-e） and （4） with 4-chlorobenzoic acid / aryl acids, which were condensed with piperazine under phase transfer catalyst TBAB to yield the corresponding free bases of monopiperazine derivatives and followed to form water-soluble salts （3a-e） and （6a-e） with hydrochloric acid in good yields. The in vitro biological results showed that piperazine group conjugated with the above fused heterocycles played an important role in antibacterial activity. The structures of novel compounds were confirmed by IR, ＇H NMR, MS and elemental analysis.

Preparation and Spectral Characterization of 3-Benzyl-6-aryl-1,2,4-triazolothiadiazoles

Benzyl 4 amino 5 mercapto 1,2,4 triazole reacted with aromatic acids in the presence of phosphorus oxychloride, yielding a series of new compounds, i.e. , 3 benzyl 6 aryl 1,2,4 triazolothiadiazoles, each of which has an active methylene at 3 position. The structures of all the title compounds were confirmed by elementary analysis, IR, 1H NMR and 13 C NMR spectra.

Crystal and Molecular Structure of 2-(2, 6-Dinitro-4-Trifluoromethyl) phenylthio-5, 7-Dimethyl-1,2,4-Triazolo [1, 5-a] Pyrimidine

The crystal structure of the title compound has been determined bysingle crystal X-ray diffraction analysis. C14H9F3N6O4S, Mr = 414. 32, monoclinic,space group P21/n, a=8. 287(3), b= 24. 972(4), c= 8. 617(3)A, β= 108. 36(3)°,V= 1693(2) A3, Z=4, Dx=1. 626 g. cm-3, μ=0. 2481 mm-1; F(000) =840, finalR = 0. 057 and Rw= 0. 057 for 1169 observed reflections [I≥3σ(I)]. The results showthat all ring atoms in the triazolopyrimidinyl moiety were coplanar with strong tensileforce, which might be an important active site.

Syntheses and Crystal Structures of 4-Amino-3-(3-hydroxypropyl)-1H-1,2,4-triazole-5(4H)-thione and 6-(4-Biphenylyl)-3-(3-hydroxypropyl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazine

Starting with y-butyrolactone, 4-amino-3-（3-hydroxypropyl）-1H-1,2,4-triazole-5-（4H） thione 1 was prepared, and cyclization of it with 4-phenylbromoacetophenone gave 6-（4-biphenylyl）- 3-（3-hydroxypropyl）-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazine Ⅱ. The structures of Ⅰ and Ⅱ were determined by elemental analyses, IR, ^1H NMR, ^13C NMR, and X-ray diffraction. Crystal data for 1： C5H10N4OS, Mr = 174.23, monoclinic system, space group P21/c, a =8.4568（6）, b = 22.8905（16）, c = 9.2625（6） A, β= 114.172（1）°, V= 1635.82（19） A^3, F（000） = 736, Z= 8, Dc = 1.415 g/cm^3, 2 λ=0.71073 A,μ = 0.346 mm^-1 and the final R = 0.0603 for 2870 unique reflections with 1993 observed ones （I 〉 2σ（I）. Crystal data for Ⅱ： C19H18N4OS, Mr = 350.43, monoclinic system, space group P21/c, a = 6.7481（7）, b = 8.2647（8）, c = 30.075（3） A, β= 94.445（2）°, V= 1672.3（3） A3, F（000） = 736, Z = 4, Dc = 1.392 g/cm^3, λ=0.71073 A,μ= 0.209 mm^-1 and the final R = 0.0667 for 3000 unique reflections with 2534 observed ones （I 〉 2σ（I））. In the crystal of compound Ⅱ, the five-membered triazole ring and two benzene rings are coplanar, while the six-membered thiadiazine ring is slightly distorted, with an r.m.s deviation of 0.227（1） A. Some hydrogen bonding interactions are observed and π-π stacking interactions between adjacent molecules are found in the packing diagrams of the two compounds.

2D/3D-QSAR Studies of [1,2,4]Triazolo[1,5-a]pridinylpyridine Derivatives as Potent Anticancer Agents

By using a combined method of density functional theory(DFT), molecular mechanics(MM2) and statistics for two-dimensional(2D), as well as the comparative molecular field analysis(Co MFA) and comparative molecular similarity index analysis(Co MSIA) methods for three-dimensional(3D), theoretical studies on 2D/3D quantitative structure-activity relationships(QSAR) of 22 novel compounds of [1,2,4]triazolo[1,5-a] pyridinylpyridines acting as PI3 K inhibitors against the human colon carcinoma cell line(HCT-116) have been performed. Both the 2D- and 3D-QSAR models established from the random 18 compounds in training set show significant statistical quality and satisfactory predictive ability(R2 = 0.821, q2 = 0.773 for 2D-QSAR, R2 = 0.966, q2 = 0.668 for Co MFA, R2 = 0.979, q2 = 0.753 for Co MSIA). The combined 2D- and 3D-QSAR studies suggest that the moderate-size, hydrophilic and electron-withdrawing group at R1 position, the bulky and hydrophobic group at R2 position, and the minor, hydrophobic, H-bond donor and electron-donating group at R3 position would enhance the anticancer activities. These obtained results help to insight into the action mechanism, and will serve as a basis for the design of new potent anticancer agents.

Design,synthesis and antiproliferative activity of novel 2,7-disubstituted triazolo[1,5-a]pyrimidines

In our efforts to identify novel potent anticancer agents, we synthesized a series of 2,7-disubstituted triazolo[1,5-a]pyrimidines （6-16）. Their antiproliferative activity against Bel-7402, HT- 1080 and WI-38 cell lines was tested by MTT assay in vitro. Four of the compounds （9-11 and 16） displayed promising antiproliferative activity superior to gefitinib, especially compound 9. A preliminary SAR study of these derivatives was performed.

Synthesis and Crystal Structure of 3-Benzyl-6-trichloromethyl-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazole

The title compound 3-benzyl-6-trichloromethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole I （C11HTC13N4S, Mr = 333.62） has been synthesized, and its structure was determined by elemental analyses, IR, ^1H NMR, ^13C NMR, and X-ray diffractions. The crystal is of triclinic, space group P1^-, with a = 5.898（3）, b = 10.510（4）, c = 11.580（5） A, α = 74.936（7）, β= 75.476（7）, γ = 79.647（7）°, V= 665.9（5）/A^3, F（000） = 336, Z= 2, Dc = 1.664 g/cm^3, 2 = 0.71073A, p = 0.834 mm^-1, the final R = 0.0605 and wR = 0.0900. The secondary bonding interactions （SBIs） S…N and π-π stacking interactions are found in the crystal structure and they link the molecules into a three-dimensional network.

Synthesis and Antiproliferative Activity of Novel [1,2,4]Triazolo[1,5-a]pyrimidine-7-amine Derivatives

A series of novel N-anilino-2-substituted-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-7-amine derivatives was prepared and evaluated for their in vitro antiproliferative activity against two cancer cell lines,Bel-7402 and HT-1080.Most of the compounds inhibited the cell proliferation at a low concentration.Seven compounds,VI5,VI7,VI10,and VI12―VI15,possessed marked antiproliferative activity superior to that of cisplatin.Of these seven initial hits,compound VI10 was the most active.

Synthesis of 5,7-Dimethyl-2-(5-Substituted-1,3,4-Oxadiazole-2-yl)- Methylenethio-1,2,4-Triazolo[1,5-a]Pyrimidines as Potential Fungicides

A series of diheterocyclic compounds containing 1,2,4-triazolo [1,5-a]pyrimidine and 1, 3,4-oxadiazole were designed and synthesized starting from 2-mercapto-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine. The structure of all compounds prepared were confirmed by H-1 NMR spectroscopy and elemental analysis. The preliminary bioassay indicated that the title compounds displayed good fungicidal activity against Rhizoctonia solani.

Reactivity of 1-methylisoquinoline synthesis of pyrazolyl triazoloisoquinoline and thia-diazolyl isoquinoline derivatives

The reaction of 1-methylisoquinoline 1 with hy-drazonoyl halides 2 in ethanol in the presence of chitosan under microwave irradiation affords triazoloisoquinoline 4. Product 4 reacts with dimethylformamide-dimethylacetal to give ena- minones 7 which react with hydrazonoyl halides to give pyrazolyl triazoloisoquinoline 13. Also, 1-methylisoquinoline 1 reacts with arylisothio-cyanate to give thioanilide 15 which reacts with hydrazonoyl halides to give the corresponding thiadiazolyl isoquinoline derivatives 20, 24.