Synthesis of Some New Pyrazolo[3,4-b]Pyridlne and Pyrazolo[3,4-d]Pyrimidine Derivatives1

Several pyrazolo[3,4-b]pyridine (3,4) and pyrazolo-[3,4-d]pyrimidine (5-13) derivatives were prepared using 5-amino-l-(5-ethyl-5H-1,2,4-triazino[5,6-b]-indol-3-yl)-lH-pyrazole-4-carbonitrile (2) . The pyridine derivatives 3 and 4 were obtained by reaction of 2 with malononitrile and ethyl cyanoacetate, respectively, while pyrimidine analogs 5-13 were synthesized cither by a one-step or multi-step sequence.     

Novel Synthesis of N-Arylpyrrole,Pyrrolo[1,2-a]quinazoline,and Pyrrolo[3,4-d]pyridazine Derivatives

Phenacyl-malononitrile derivatives 1a,b react with dimethyl formamide dimethyl acetal (DMFDMA) in refluxing toluene to afford the enaminones 2a,b respectively. Compounds 2a and 2b react with the aromatic amines (aniline, p-toluidine, p-anisidine) in refluxing ethanol to afford the pyrroles 4a–f and with anthranilonitrile and methyl anthranilate to afford the pyrrolo[1,2-a]quinazolines 5a,b and 6a,b respectively. The pyrrole derivatives 4a–f react with hydrazine hydrate and phenyl hydrazine in refluxing ethanol to afford the pyrrolo[3,4-d] pyridazine derivatives 7a–f and 8a–f respectively.     

Reactions with Naphthoylhydroxlmoyl Chlorides: Synthesis of Derivatives of Isoxazole,Pyrrolidino[3,4-d]isoxazoiin-4,6-dione,lmidazo[1,2-a]pyridine,lmidazo[1,2-a]pyrimidine,Benzotriazine and Benzothiadiazine

Hydroximoyl chlorides 3 react with acrylonitrile, N-arylmaleimide and maleic anhydride to give isoxazolines 5 , pyrrolidino[3,4-d]isoxazolines 8 , and furolidino[3,4-d]isoxazolines 9 , respectively. 3 reacted with 2-aminopyridine, 2-aminopyrimidine, o-phenylenediamine and o-aminothiophenol to yield 3-ni-trosoimidazo[1,2-α]pyridines 20 , 3-nitrosopyrimidines 22 , 3-naphthoyl-1,4-dihydrobenzo-1,2,4-triazines 24 , and 3-naphthoyl-4H-1,3,4-benzothiadiazine 27 , respectively. Compound 3 reacted with benzoylacetonitrile, acetoacetanilide, thiophenol, benzencsulfinic acid in ethanolic sodium ethoxide solution to give the corresponding isoxazoles 12–13 and oximes 16–17 , respectively. The structures of these products were confirmed by elemental analyses, spectral data and, wherever possible, alternative synthesis.     

Synthesis and Biological Evaluation of Novel 5,7-Diphenylimidazo[1,2-a]pyridine Derivatives

A series of novel 5,7-diphenylimidazo[1,2-a]pyridine derivatives was designed and synthesized. The in vitro cytotoxic activities of all the target compounds against human colorectal cancer（HT-29）, human lung can- cer（H460）, human gastric cancer（MKN45） and human breast cancer（MDA-MB-231） cell lines were evaluated. The pharmacological results indicated that most of the target compounds showed moderate to excellent activities against the tested cell lines. The most promising compound 4h（0.20, 0.006, 0.08, 0.021 μmol/L） was 2.6, 5.1, 3.6 and 21.9 times more active than EPC2407（0.52, 0.031, 0.29, 0.46 μmol/L） against HT-29, H460, MKN45 and MDA-MB-231 cell lines, respectively.     

含1,3,4-噻二唑环吡唑并[3,4-d]嘧啶类化合物的合成及生物活性

通过5-氨基-4-氰基-1-苯基吡唑与甲酸发生环合、再经氯化和芳香族亲核取代反应,合成了12种新的含1,3,4-噻二唑环吡唑并[3,4-d]嘧啶类化合物.目标化合物的结构经红外光谱、核磁共振氢谱、质谱和元素分析方法予以确认.初步的生物活性测定试验表明,在50 mg/L浓度下,大部分目标化合物对小麦纹枯病菌(Rhizoctonia cerealis)表现出较好的杀菌活性,其中化合物5b,5d和5j的抑菌率超过90%.     

Formylation of Furyl-substituted Imidazo[1,2-a]pyridine, Imidazo[1,2-a]pyrimidine and Imidazo[2,1-b]thiazole

Vilsmeier formylation of 2-(2-furyl)-substituted imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine, and also 6-(2-furyl)imidazo[2,1-b]thiazole with 1 mole of reagent occurs at the free position of the imidazole ring, while with an excess of the reagent it also occurs at the position 5 of the furyl group.     

含吲哚的吡唑并[3,4-d]嘧啶衍生物的设计合成及其生物活性研究

利用药物设计中的生物活性基团拼接原理,设计合成了13个含吲哚的吡唑并[3,4-d]嘧啶衍生物.目标化合物均经核磁共振氢谱(1H NMR)、核磁共振碳谱(13C NMR)和高分辨质谱仪(HRMS)进行了结构确证.对4株肿瘤细胞(HeLa、MGC-803、MCF-7、BEL-7404)的体外抗增殖活性实验结果表明,目标化合物均表现出一定的抗肿瘤活性,MCF-7、MGC-803肿瘤细胞株敏感度高于HeLa和BEL-7404.其中, 6-[(6-甲氧羰基吲哚-3-基)硫基]-1-苯基-吡唑并[3,4-d]嘧啶-4-酮(5m)表现出较好的体外肿瘤抑制活性,对MCF-7、MGC-80和HeLa细胞的IC50均小于30μmol·L^-1,对MCF-7的IC50值为(4.02±0.92)μmol·L^-1,优于对照药物依托泊苷(10.1±0.62μmol·L^-1)和羟喜树碱(5.93±0.56μmol·L^-1).拓扑异构酶抑制实验结果表明,此类化合物对TopoII有选择性抑制活性,所有化合物对TopoⅡ表现出不同程度抑制活性,对Topo Ⅰ未表现出抑制活性.     

Synthesis and anti-inflammatory activity of imidazo [1,2-a] pyrimidine derivatives

A series of imidazo[1,2-a]pyrimidine derivatives substituted adjacently with two aryls at positions 2 and 3 were designed and synthesized in order to improve their anti-inflammatory activities. Biological tests suggested that these compounds have antiinflammatory activities with COX-2 selectivity to some extent.     

Design,Synthesis, and Anticancer Screening for Repurposed Pyrazolo[3,4-d]pyrimidine Derivatives on Four Mammalian Cancer Cell Lines

The present study reports the synthesis of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to mono-, di-, and trimethoxy benzylidene moieties through hydrazine linkages. First, in silico docking experiments of the synthesized compounds against Bax, Bcl-2, Caspase-3, Ki67, p21, and p53 were performed in a trial to rationalize the observed cytotoxic activity for the tested compounds. The anticancer activity of these compounds was evaluated in vitro against Caco-2, A549, HT1080, and Hela cell lines. Results revealed that two (5 and 7) of the three synthesized compounds (5, 6, and 7) showed high cytotoxic activity against all tested cell lines with IC₅₀ values in the micro molar concentration. Our in vitro results show that there is no significant apoptotic effect for the treatment with the experimental compounds on the viability of cells against A549 cells. Ki67 expression was found to decrease significantly following the treatment of cells with the most promising candidate: drug 7. The overall results indicate that these pyrazolopyrimidine derivatives possess anticancer activity at varying doses. The suggested mechanism of action involves the inhibition of the proliferation of cancer cells.     

Synthesis of Some New Biologically Active Sulfur Compounds Containing Pyrazolo[3,4-d] pyrimidine Moiety

A novel series of the pyrazolo[3,4-d]pyrimidines having biologically active sulfur moieties 3-20 were prepared via reaction of 4-mercapto-1-phenyl-1 H -pyrazolo[3,4-d]pyrimidine 3 with different reagents. Identification of the new compounds was established by elemental analyses, IR, 1 H-NMR, and mass spectral data. Some of the obtained compounds showed the interesting antimicrobial activity comparable to antibiotic chloramphenicol as standard antibacterial agent and Terbinafin as a standard antifungal agent.     

One-Pot Synthesis of Novel Spiro Pyrano[2,3-d][1,3]thiazolo[3,2-a]pyrimidine Derivatives

In a one-pot synthesis, 1′-methyl-2,3″-dioxo-5″-aryl-1,2,5a″,7″,8″,9a″-hexahydro-5″H,6″H-dispiro[indole-3,2′-pyrrolidine-3′,2″-pyrano[2,3-d][1,3]thiazolo[3,2-a]pyrimidine]-4′-carboxylic acid methyl ester was prepared via the sequential reaction of 4-aryl-octahydro-pyrano[2,3-d]pyrimidine-2-thione, dimethyl acetylenedicarboxylate (DMAD), and a mixture of isatin and sarcosine. All the novel spiro compounds, in moderate yields, were characterized thoroughly by infrared, NMR, mass spectromentry, and elemental analysis together with x-ray crystallographic analysis.     

新型吡唑并[1,5-a]嘧啶-氮芥衍生物的设计、合成及抗肿瘤活性研究

吡唑并嘧啶是一类具有广泛生物活性的杂环结构母体,同时,氮芥类药物被广泛应用于临床治疗癌症.本文基于药物设计的拼合原理,以简单易得的原料制备了取代吡唑并[1,5-a]嘧啶中间体,通过将其与苯胺氮芥组分进行拼接,合成了一系列新型吡唑并[1,5-a]嘧啶-氮芥化合物,并评估了目标化合物对五种不同肿瘤细胞(HepG2、SH-S...     

A New Efficient Synthesis of 4-Alkoxy-1,6-diaryl-1H-pyrazolo[3,4-d]pyrimidine Derivatives

A new synthesis of 4-methoxy (or ethoxy)-1,6-diaryl-1H-pyrazolo[3,4-d]pyrimidine derivatives is described. An efficient one-step methodology for the title compounds was achieved by using 5-amino-1-aryl-1H-pyrazole-4-carbonitriles with arylaldehydes in CH₃OH or C₂H₅OH and NaOH at 60 °C. The new compounds were obtained in moderate to good yields as stable solids and easily purified by filtration.     

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.     

Novel Synthesis of Some New Pyridazine and Pyridazino[4,5-d]pyridazine Derivatives

Phenacyl-malononitrile derivatives 1a and b react with dimethylformamide dimethylacetal (DMFDMA) in refluxing toluene to afford the enaminones 2a and b respectively. Compounds 2a and 2b react with the hydrazine hydrate 3a and phenyl hydrazine 3b in refluxing ethanol to afford the pyridazine derivatives 5a–d, presumably via the intermediates 4. Compounds 5a–d, react with hydrazine hydrate 3a to afford the pyridazino[4,5-d]pyridazines 6a–d respectively. The pyridazines 5a and b and the pyridazino[4,5-d] pyridazines 6a and b could be oxidized into the full aromatic systems 7a and b and 8a and b respectively. Compounds 7a and b react also with hydrazine hydrate 3a to afford 8a and b respectively.

An Efficient Synthesis of Pyrazolo[3,4-b]pyridine Derivatives in Ionic Liquid

A series of 3-methyl-1,4,6-triaryl-1H-pyrazolo[3,4-b]pyridines was synthesized via the reaction of 3-methyl-1-phenyl-1H-pyrazol-5-amine and α,β-unsaturated ketones in ionic liquid without any catalyst. This protocol has the advantages of easier work-up, milder reaction conditions, high yields and environmentally benign procedure.     

Synthesis and antiviral activity of 4H-[1,2,5]oxadiazolo-[3,4-d]pyrimidine-5,7-dione 1-oxide nucleosides

A series of 4H-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7-dione 1-oxide nucleosides was designed,synthesized and evaluated against vesicular stomatitis virus(VSV)in Wish cell.The antiviral activities of all compounds were stronger than those of acyclovir,while their toxicities were similar to those of acyclovir.     

Synthesis and Vasodilatory Activities of New Pyrazolo[3,4—d] pyrimidin—4—one Derivatives

A series of pyrazole[3,4-d] pyrimidin-4-one derivatives were synthesized and tested for vasodilatory activities. All of them were new compounds and their structures were confirmed by IR,^1H NMR,MS and elemental analysis.     

微波辐射下硅磺酸催化的香豆素并[4,3-d]吡唑并[3,4-b]吡啶的高效合成

在硅磺酸催化下,通过微波辐射的3-酰基香豆素与5-氨基吡唑的反应,一步高产率地合成了一系列香豆素并[4,3-d]吡唑并[3,4-b]吡啶衍生物.该方法具有反应时间短(20~30 min)、选择性好、产率高、操作简单和环境友好等优点.产物的结构经红外光谱、核磁共振谱及高分辨质谱予以确定.