2-[4-(2-Thienyl)-1,3-thiazol-2-yl]ethanenitrile in Heterocyclic Synthesis of Biological Interist

Abstract

Thiazolylacetonitrile was used in the synthesis of coumarin, pyrazolo[4,3]pyrimidines, 1,3,4-thiadiazolines, aminothiophenes, and thiazoles in a good yields. Also, pyrazolo[4,5-d]triazolino[4,5-a]pyrimidines, pyrazolo[4,5-d]thiazolino[3,2-a]pyrimidines, and pyrazolo[4,5-d]tetrazolino[1,5-a]pyrimidines were synthesized from pyrazolo[4,5-d]pyrimidine. Structures of the newly synthesized were elucidated by elemental analysis, spectral data, and alternative synthesis routes whenever possible. Some synthesized compounds were tested for their antimicrobial activity.     

1,3-Disubstitutedpyrazole-4-caboxaldehyde in Heterocyclic Synthesis: A Novel Synthesis of Pyridine-2(1H)-thione and Fused Nitrogen and/or Sulfur Heterocyclic Derivatives

Pyridine-2(1H)-thione 5 was synthesized from the reaction of 3-[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-1-phenylpropenone (3) and cynothioacetamide (4). Compound 5 reacted with halogented compounds 6a–e to give 2-S-alkylpyridine derivatives 7a–e, which could be in turn cyclized into the corresponding thieno[2,3-b]-pyridine derivatives 8a–e. Compound 8a reacted with hydrazine hydrate to give 9. The latter compound reacted with acetic anhydride (10a), formic acid (10b), acetic acid, ethyl acetoacetate, and pentane-2,4-dione to give the corresponding pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidine 13a,b, pyrazolo[3′,4′:4,5]thieno[3,2-d]pyridine 14 and thieno[2,3-b]-pyridine derivatives 18 and 20, respectively. Alternatively, 8c reacted with 10a,b and nitrous acid to afford the corresponding pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 24a,b and pyrido[3′,2′:4,5]thieno[3,2-d][1,2,3]triazine 26 derivatives, respectively. Finally compound 5 reacted with methyl iodide to give 2-methylthiopyridine derivative 27, which could be reacted with hydrazine hydrate to yield the corresponding pyrazolo[3,4-b]-pyridine derivative 29.     

6-烷基-7-亚胺基-2-硫代-2,3,6,7-四氢噻唑并[4,5-d]嘧啶的合成、晶体结构与生物活性

通过3-苯基-5-氰基-2-硫代-2,3-二氢-4-乙氧亚甲胺基噻唑(5)与伯胺反应, 经中间体甲脒关环, 合成了10种新的噻唑并[4,5-d]嘧啶类化合物6a～6j. 所有化合物的结构均经1H NMR, IR和元素分析进行了表征, 并且采用X射线单晶衍射分析方法进一步测定了化合物6i的结构. 初步的生物活性试验表明, 部分标题化合物具有一定的杀菌或除草活性.     

Novel Synthesis of 2-(2-(3-Hydroxy-5-oxo-4-phenylthiophen-2(5H)-ylidene)-2-phenylacetamido)propanoic Acid Analogues and Their Anti-Inflammatory Properties

This article describes the reaction of 3,6-diphenyl-thieno[3,2-b]furan-2,5-dione 1 with different amino acids 2a–j in glacial acetic acid which afforded the 2-(2-(3-hydroxy-5-oxo-4-phenylthiophen-2(5H)-ylidene)-2-phenylacetamido)propanoic acid analogues 3a–j and also describes the reaction of 3,6-diphenyl-thieno[3,2-b]thiophene-2,5-dione 4 with different amino acids 5a–e in acidic medium to give 2-(2-(3-mercapto-5-oxo-4-phenylthiophen-2(5H)-ylidene)-2-phenylacetamido)propanoic acid analogues 6a–e. All the compounds have been screened for their anti-inflammatory activity against the carrageenan induced rat paw edema in albino rats. In the primary screening, some of the compounds exhibited appreciable activity.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Cyanothioacetanilide Intermediates in Heterocyclic Synthesis,Part 1: Synthesis and Biological Evaluation of Some Novel Thiazole,Thiophene, Pyrazole,and Pyrazolo[1,5-a]Pyrimidine Derivatives

Some novel thiophenes (4a,b, 5, and 9a,b) were obtained from the cycloalkylation of the thiocarbamoyl group in the cyanothioacetanilide derivative (1) with α-halocarbonyl compounds. Also, the reaction of cyanothioacetanilide derivative with phenyl isothiocyanate in the presence of potassium hydroxide followed by in situ heterocyclization of the resulting adduct with α-halocarbonyl compounds furnished the corresponding thiazole (12, 14, and 15), pyrazole (19), and pyraozlo[1,5-a]pyrimidine (22, 25, and 26) derivatives. Compounds (4b, 5, 9a, 12, 13, 18, 22, 25, and 26) were tested to evaluate their antimicrobial activity.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Studies on the Synthesis of New 3-(3,5-Diamino-1-substituted-pyrazol-4-yl)azo-thieno[2,3-b]pyridines and 3-(2-Amino-5,7-disubstituted-pyrazolo[1,5-a]pyrimidine-3-yl)azothieno[2,3-b]pyridines

Coupling the diazonium salt of 3-amino-2-cyano-4,6-dimethylthieno[2,3-b]pyridine 1 with malononitrile 2 gave 2-cyano-3-(hydrazonomalononitrile)-4,6-dimethylthieno[2,3-b]pyridine 3 which then reacted with hydrazine compounds 4a-4h to yield corresponding 2-cyano-3-(3,5-diamino-1-substituted-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 5a-5h. The 2-cyano-3-(2-amino-5,7-disubstituted-pyrazolo-[1,5-a]pyrimidine-3-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 7a-7f were obtained in good yield by the cyclocondensation reaction of 2-cyano-3-(3,5-diamino-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridine 5a with the appropriate 1,3-diketones 6a-6f under acidic condition.     

Synthesis and Neurotropic Activity of New Heterocyclic Systems: Pyridofuro[3,2-d]pyrrolo[1,2-a]pyrimidines,Pyridofuro[3,2-d]pyrido[1,2-a]pyrimidines and Pyridofuro[3′,2′:4,5]pyrimido[1,2-a]azepines

Background: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. Objective: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. Methods: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. Results: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of “open field” and “elevated plus maze” (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of “forced swimming” (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABA_A receptor with a value of the scoring function that estimates free energy of binding (ΔG) at −7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT_1A receptor. Conclusions: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.     

Convenient and Practical Synthesis of 6-Chloro-2-(chloromethyl)-thiazolo[5,4-b]pyridine

A high-yielding and practical synthesis of 6-chloro-2-(chloromethyl)-thiazolo[5,4-b]pyridine starting from 2-amino-5-chloropyridine has been accomplished in a sequence of five steps.     

Synthesis of 6-oxopyrimidin-1(6H)-yl benzamide derivatives and evaluation of their antibacterial and cytotoxic activity

A series of novel 2-alkylamino and 2, 4-dialkyl amino 6-oxopyrimidin-1(6H)-yl) benzamide derivatives were prepared in good yields from a base-catalyzed ring opening of oxadiazolo[3,2-a]pyrimidin-5-one and evaluated for their antibacterial and cytotoxicity. Most of the compounds exhibited antibacterial activity. In particular, compounds 5b and 5k exhibited considerable antibiotic activity against Klebsiella pneumonia and Bacillus cereus. In addition, compounds 5g and 5i also inhibited the growth of two human tumor cell lines (A549 and H460) at micromolar concentrations.     

Efficient Synthesis,Crystal Structure and Antibacterial Activity of Two Novel Thieno [2,3-d] pyrimidin-4(3H)-one Derivatives

Two new thieno[2,3-d]pyrimidin-4(3H)-one derivatives,C24H22 Cl N3O2S(5a) and C25H25N3O2S(5b),have been synthesized via a tandem aza-Wittig reaction.This tandem reaction has many attractive aspects such as easily accessible and versatile starting materials,mild conditions and high yields.Both compounds have been characterized by elemental analysis,HR-MS,IR,NMR spectra and X-ray single-crystal diffraction.Compound 5a crystallizes in monoclinic,space group P21/c with a = 9.986(3),b = 14.263(4),c = 15.530(5)?,β = 93.806(5)o,V = 2207.1(11) ?3,Mr = 451.96,Z = 4,Dc = 1.360 g/cm3,F(000) = 944,μ = 0.294 mm-1,Mo Kα radiation(λ = 0.71073 ?),the final R = 0.0444 and w R = 0.1219 for 3407 observed reflections with I 2σ(I).Compound 5bcrystallizes in triclinic,space group P1 with a = 8.974(4),b = 10.766(5),c = 12.260(6) ?,β = 93.047(7)o,V = 1122.1(9) ?3,Mr = 431.54,Z = 2,Dc = 1.277 g/cm3,F(000) = 456,μ = 0.170 mm-1,Mo Kα radiation(λ = 0.71073 ?),the final R = 0.0378 and w R = 0.1072 for 3806 observed reflections with I 2σ(I).The preliminary antibacterial activities of 5a and 5b were investigated.Compound 5a showed 71.3% and 79.2% in vitro inhibition against Fusarium oxysporium and Rhizoctonia solani,respectively.Compound 5b showed 75.3% in vitro inhibition against Rhizoctonia solani.     

Heteroannulated Quinazoline and Quinazolinone Derivatives from (Z)-2-[1-Benzamido-2-(3,4,5-trimethoxyphenyl)]vinyl-3,1-benzoxazin-4(3H)-one

The title compound 1 was prepared and allowed to react with a series of nitrogen nucleophiles to afford the quinazoline and quinazolinone derivatives 2–12 and tetrazole derivative 13. The IR, ¹H NMR, ¹³C NMR, and mass spectra of all the synthesized compounds were discussed.     

Studies on the Chemistry of Thienoannelated O , N - and S , N -Containing Heterocycles, 28 [1]. Synthesis of Imidazo[1,5- d ]thieno[2,3- b ][1,4]thiazine Derivatives as GABA -Receptor Ligands

Summary.  GABA-receptor-ligands are still very interesting in drug-development. Usually benzodiazepines are used in the treatment but they have serious side-effects. Thus, a recently synthesized quioxaline derivative which showed reduced side-effects in an animal model was used as a model-substance. The cyclus was modified to optimize the pharmacological profile. Accordingly, a series of imidazo-thieno-thiazines was synthesized starting from 5-acetyl-2-chloro-3-nitrothiophene to yield 6-ethyl-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-2-one. Reaction with potassium tert-butoxide and diethylchlorophosphate gave an intermediate, which resulted in the desired ring system after adding the corresponding isocyanides and potassium tert-butoxide. Corresponding author. E-mail: thomas.erker@univie.ac.at Received August 6, 2002; accepted August 13, 2002     

10-氯-5-二乙氧基甲基-1,3-二甲基色烯并[4,3-d]吡唑并[3,4-b]吡啶-6(3H)-酮的合成和晶体结构

利用L-脯氨酸催化的5-氯水杨醛(1)与6-甲基-4-羟基吡喃酮(2)的缩合反应及硫酸铜催化下与1,3-二甲基-5-氨基吡唑(3)的串联反应,合成得到了10-氯-1,3-二甲基-5-(2-氧代丙基)色烯并[4,3-d]吡唑并[3,4-b]吡啶-6(3H)-酮(4)和10-氯-5-二乙氧基甲基-1,3-二甲基色烯并[4,3-d]吡唑并[3,4-b]吡啶-6(3H)-酮(5).化合物5的结构通过单晶X射线衍射法确定:晶体属于三斜晶系,空间群P-1;相对分子质量Mr=803.68;晶胞参数a=1.03160(10)nm,b=1.42900(13)nm,c=1.44268(15)nm;V=1.9448(3)nm~3;Z=2;晶胞密度Dc=1.372g/cm~3;吸收系数μ=0.228mm-1;单胞中电子的数目F(000)=840.晶体结构用直接法解出,经全矩阵最小二乘法对原子参数进行修正,最终的偏离因子为R=0.0681,w R=0.2051.在晶体结构中色烯环与吡啶环及吡唑环近似于共平面.     

N-(1,2,4-三唑并[1,5-a]嘧啶-2-基)-N′-芳酰基硫脲的合成与生物活性

通过2-氨基-5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶同芳酰基异硫氰酸酯反应, 合成了12种新的含杂环基的芳酰基硫脲, 用红外光谱、核磁共振氢谱和元素分析确证了其结构, 初步的生物活性测定试验表明部分目标化合物具有良好的生物活性, 尤其是对于双子叶植物表现出较高的除草活性.     

6-烷氨(氧)基-3-甲硫基-1H-吡唑并[3,4-d]嘧啶-4(5H)-酮衍生物的合成与生物活性

用六氯乙烷、三苯基膦和5-氨基吡唑衍生物一锅法合成关键中间体膦亚胺。 再利用串联aza-Wittig反应,加入对氯苯基异氰酸酯,进一步和烷基胺或取代酚反应合成了11个未见文献报道的6-烷氨（氧）基-3-甲硫基1H-吡唑并[3,4-d]嘧啶-4(5H)-酮衍生物。 通过1H NMR、EI-MS、IR和元素分析等方法对所合成的化合物进行了结构表征,并测试了它们的杀菌和除草活性。 测试结果表明,部分化合物对稗草(barnyard grass)和油菜(Rape)均表现出了较好的抑制活性。     

One-Pot,Multicomponent Condensation Reaction in Neutral Conditions: Synthesis,Characterization, and Biological Studies of Fused Thiazolo[2,3-b]quinazolinone Derivatives

A new series of 12-(2-chloro-6-quinoline-3-yl)-3,3,8-substituted-2,3,4,12-tetrahydro-benzo[4,5]thiazolo[2,3-b]quinazolin-1-ones 4 was synthesized in one pot by condensing various 2-chloro-3-formylquinolines 1, 2-amino-6-substituted-benzothiazoles 2, and 1,3-cyclohexanedione 3 in ethanol. All the compounds were characterized by IR, ¹H NMR, ¹³C NMR spectra and elemental analysis. All the synthesized compounds were screened for their antibacterial activity against Grampositive bacterial species Bacillus cereus and Bacillus substilus, Gram-negative bacterial species Escherichia coli, and their fungicidal activity against Aspergillus niger, Fuserium oxisporum, and Rhizopus species.     

Synthesis,Characterization and In Vitro Evaluation of Novel 5-Ene-thiazolo[3,2-b][1,2,4]triazole-6(5H)-ones as Possible Anticancer Agents

The present paper is devoted to the search for drug-like molecules with anticancer properties using the thiazolo[3,2-b][1,2,4]triazole-6-one scaffold. A series of 24 novel thiazolo-[3,2-b][1,2,4]triazole-6-ones with 5-aryl(heteryl)idene- and 5-aminomethylidene-moieties has been synthesized employing three-component and three-stage synthetic protocols. A mixture of Z/E-isomers was obtained in solution for the synthesized 5-aminomethylidene-thiazolo[3,2-b]-[1,2,4]triazole-6-ones. The compounds have been studied for their antitumor activity in the NCI 60 lines screen. Some compounds present excellent anticancer properties at 10 μM. Derivatives 2h and 2i were the most active against cancer cell lines without causing toxicity to normal somatic (HEK293) cells. A preliminary SAR study had been performed for the synthesized compounds.     

Synthesis of 1-Amino-6,7-dihydro-7-(hydroxymethyl)-4-nitro-pyrrolo[1,2-f]pyrimidin-3-(5H)-one from 2-Amino-6-methylpyrimidin-3-one

The synthesis of previously unreported 1-amino-6,7-dihydro-7-(hydroxymethyl)-4-nitropyrrolo[1,2-f]pyrimidin-3-(5H)-one starting from 2-amino-6-methylpyrimidin-3-one is described.     

Synthesis,Reactions, and Characterization of 6-Amino-4-(Benzo[b]Thiophen-2-YL)-2-Thioxo-1, 2-Dihydropyridine-3, 5-Dicarbonitrile

Abstract

Benzothiophene -2- carbaldehyde 1 reacted with 2-cyanoethanethioamide 2 in 1:2 molar ratios to give the corresponding 6-amino-4-(benzo[b]thiophen-2-yl)-2-thioxo-1, 2-dihydropyridine-3,5-dicarbonitrile 6. The synthetic potentiality of compound 6 was investigated via its reaction with active halogen-containing reagents to afford the corresponding thieno[2,3-b]pyridine derivatives 11a,b, 14, 16, and 19. Also, compound 6 reacted with hydrazine hydrate to give the pyrazolo[3,4-b]pyridine derivative 21. Compound 21 condensed with 4-(2-thienyl)benzaldehyde to afford pyrazolo[3,4-b]pyridine derivative 23. Structural elucidation of all the newly synthesized heterocyclic compounds was based on elemental analyses, IR, ¹H NMR, and mass spectra.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

3,6-二取代-5,6-二氢-1,2,4-三唑并[3,4-b]-1,3,4-噻二唑的合成及生物活性

以３－芳基－４－氨基－５－巯基－１,２,４－三唑为原料,在酸催化下与醛类发生分子内的Ｍａｎｎｉｃｈ反应,合成了１４个标题化合物,其结构经元素分析、ＩＲ、＾１ＨＮＭＲ和ＭＳ确证。研究了反应条件。生物活性测定结果表明,部分化合物具有较强的生物活性。