Synthesis of pyrazole and pyrazolo [4,3-d] pyrimidinone derivatives. II

Three new series of pyrazolic and pyrazolo-pyrimidinonic derivatives (II a-g), (III a-g) and (IV a-g), containing the substituted phenyl-hydrazide moiety were prepared and studied in order to check some information on the analgesic and antipyretic activity of an analogous series obtained in a previous work. Some derivatives (II b), (II d), (II f), (III b), (III c) and (IV d) show interesting analgesic activity.     

Synthesis of pyrazolo [4,3-c] pyridazine and isoxazolo [3,4-d] pyridazine derivatives

Arylhydrazones of diethyl acetonedicarboxylate3 was treated with formaldehyde to give 1-aryl-1,4,5,6-tetrahyeheypyridazine derivatives4a-f Cyclization of compound4a-f by hydroxylamine afforded [3,4-d] 1,4,5,6-tetrahydropyridazine derivatives5a-f. Also cyclization of compound4c with semicarbazide gave pyrazolote [4,3-c] pyridazine6. On the other hand compound 3 reacted with ethylorthoformate to give diethyl-1,4-dihydro-1-arylpyridazine-4-one-3,5 dicarboxylate7, which on treatment with hydrazine, semicarbazide and thiosemicarbzide gave pyridazine, amido and thioamido derivatives. The spectral and antimicrobial data of these compounds1–8 were studied.     

Synthesis of substituted pyrimidines, pyrazole[3,4-d]pyrimidines and imidazo[4,5-d]pyrimidines and evaluation of their antifungal activity

Some pyrimidines, pyrazolo[3,4-d]pyrimidines and imidazo[4,5-d]pyrimidines bearing the 5-nitro- and 5-aminothienyl-2-sulfide functionalities on the pyrimidine nucleus were synthesized and evaluated for their antifungal activity against several strains of yeasts and dermatophytes. 4-Amino-2-pyrimidinyl-5'-nitro-2'-thienylsulfide (Va) resulted active against both yeasts and dermatophytes (about 30 fold less potent than Miconazole). Compds. (II b), (V b) and (VIII b) showed only a slight activity against dermatophytes, while the other compounds were inactive.     

磷酸二酯酶抑制剂吡唑并[4,3-d]嘧啶-7-酮类衍生物的研究

目的 寻找新型磷酸二酯酶抑制剂，设计合成未见文献文献报道的吡唑[4,3-d]嘧啶－7－酮类衍生物。方法 合成了8个新的衍生物，结构经IR,^1H-NMR和MS确证，并进行离体主动脉条和离体气管螺旋条药理实验。结果 目标化合物均具有一定的血管扩张作用和支气管扩经作用，其中Ⅸc的血管扩张作用优于对照药维拉帕米，Ⅸa的支握管扩张作用强于对照药氨茶碱。结论 吡唑并[4,3-d]嘧啶－7－酮类衍生物有可能开发成为新型选择性磷酸二酯酶抑制剂。     

新型吡唑并[4,3-d]嘧啶衍生物的合成和抗炎活性

目的为了研发新型抗炎药,设计合成了一种新的吡唑并[4,3-d]嘧啶衍生物,并揭示了新化合物可能的抗炎机制。方法在显微镜下观察细胞的形态变化;通过Griess法测定新型化合物对脂多糖刺激的RAW264.7细胞中NO产生的影响;通过qRT-PCR评估TNF-α、IL-6和IL-1β的基因相对转录水平;通过qRT-PCR和Western blot测量环氧化酶-2表达,以及对NF-κB/NLRP3炎症小体信号通路进行检测。小鼠体内实验通过HE染色观察肺组织变化。结果该新型化合物借助NF-κB/NLRP3炎症小体信号通路可有效抑制RAW264.7细胞中NO的产生以及COX-2、TNF-α、IL-6和IL-1β的表达。同时,它还可以改善细胞的形态和缓解小鼠急性肺损伤。结论新型吡唑并[4,3-d]嘧啶衍生物通过NF-κB/NLRP3炎症小体信号通路来产生抗炎活性。     

Pyrazoles and pyrazolo[3,4-d]pyrimidines as biologically active agents.

Syntheses of the pyrazole derivatives 2a-c by different routes and cyclisation of the products to pyrazolo [3,4-d] pyrimidines are reported. The structures of the compounds were confirmed by spectroscopy. A few of them were screened as pesticides.     

Pyrazole-related nucleosides. Synthesis and antiviral/antitumor activity of some substituted pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides.

Several pyrazole and pyrazolo[4,3-d]-1,2,3-triazin-4-one ribonucleosides were prepared and tested for antiviral/antitumor activities. Appropriate heterocyclic bases were prepared by standard methodologies. Glycosylation of pyrazoles 6a-e,g,i and of pyrazolo[4,3-d]-1,2,3-triazin-4-ones 12f-1 mediated by silylation with hexamethyldisilazane, with 1-beta-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose, gave in good yields the corresponding glycosides 7a-e,g, 8g,i, 13f,h,k, and 14f, but could not be applied to compounds 12g,i,j,l. To overcome this occurrence, a different strategy involving the preparation, diazotization, and in situ cyclization of opportune pyrazole glycosides 9 and 10 was required. Moreover derivatives having the general formula 5 were considered not only as synthetic intermediates in the synthesis of 3 but also as carbon bioisosteres of ribavirin 4. All compounds were evaluated in vitro for cytostatic and antiviral activity. The pyrazolo[4,3-d]-1,2,3-triazin-4-one nucleosides that resulted were substantially devoid of any activity; only 15h,k showed a moderate cytostatic activity against T-cells. However, pyrazole nucleosides 9b,c,e were potent and selective cytotoxic agents against T-lymphocytes, whereas 9e showed a selective, although not very potent, activity against coxsackie B1.     

Facile one-pot synthesis and antimycobacterial evaluation of pyrazolo[3,4-d]pyrimidines

The present article describes a facile one-pot synthesis of a series of eight pyrazolo[3,4-d]pyrimidines 4a-h which were evaluated for their in-vitro antibacterial activity against Mycobacterium tuberculosis H37Rv using the Alamar-Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in mg/mL. The compounds 4b, 4c, 4d, and 4g exhibited the best results (1.2 microg/mL) when compared with first-line drugs such as isoniazid (INH) and rifampicin (RIP). Therefore, this class of compounds could be a good starting point to develop new lead compounds in the treatment of multidrug-resistant tuberculosis.     

Synthesis and anti-tubercular evaluation of some novel pyrazolo[3,4-d]pyrimidine derivatives

A series of phenothiazine clubbed pyrazolo[3,4-d]pyrimidines have been synthesized by using the Biginelli multi-component cyclocondensation reaction and their ability to inhibit growth of Mycobacterium tuberculosis in vitro have been determined. The results show that compounds 4b, 4d, and 4f exhibited excellent anti-tubercular activity with percentage inhibition of 93, 91, and 96, respectively, at a minimum inhibitory concentration (MIC) of <6.25?μg/ml, whereas compounds 4a, 4c, 4e, 4g, and 4h exhibited moderate to good anti-tubercular activity with percentage inhibition of 75, 68, 74, 54, and 63, respectively at a MIC of >6.25?μg/ml.     

Synthesis and structure-activity relationships of pyrazolo[4,3-d]pyrimidin-7-ones as adenosine receptor antagonists

A series of 21 1,3-dialkylpyrazolo[4,3-d]pyrimidin-7-ones substituted in the 5-position with various phenyl substituents has been synthesized and found to have affinity for the adenosine A1 receptor. The potency pattern due to substituents of the phenyl ring was found to parallel that found in a previously reported 1,3-dialkyl-8-phenylxanthine series. A quantitative structure-activity relationship was developed between these two series that correctly predicted the potencies of six additional 5-substituted pyrazolo[4,3-d]pyrimidines that were synthesized during the course of the analysis. With use of the correlation as a guide, one additional 5-phenylpyrazolo[4,3-d]pyrimidine containing a 4-[[(dimethylamino)ethyl]amino]sulfonyl substituent to improve aqueous solubility was prepared. On the basis of the high correlation between adenosine binding affinities of analogously substituted xanthines and pyrazolo-[4,3-d]pyrimidines and the close superposition of the heterocyclic rings and substituents that is apparent from molecular models of these two series, it is hypothesized they fit the receptor in an analogous fashion.     

Synthesis,biological evaluation of certain pyrazolo[3,4-d]pyrimidines as novel anti-inflammatory and analgesic agents

In the present study, a series of pyrazolo[3,4-d]pyrimidin-4(5H)-ones linked at 5-position to thiazoline or thiazolidinone ring systems through imino linkage (5–8) was designed and synthesized. The compounds were assessed for their anti-inflammatory activity and analgesic in vivo. Also, their ability to inhibit ovine COX-1/COX-2 isozymes was evaluated using in vitro cyclooxygenase (COX) inhibition assay. The newly synthesized compounds 7, 8d, and 8e showed potent anti-inflammatory and analgesic activity. Moreover, compound 7 displayed preferential COX-2 inhibitory potency (IC₅₀ = 0.53 µM and COX-2 selectivity index = 10.07) which is more potent than the standard drug meloxicam. Interestingly, the tested compounds showed excellent gastrointestinal safety profile and were well tolerated by experimental animals with high safety margins than the reference drug meloxicam.     

吡唑并[1，5-α]嘧啶类化合物的合成及其抗肿瘤活性

目的设计合成新的吡唑并[1,5-a]嘧啶类化合物,并评价其抗肿瘤活性。方法根据吡唑并[1,5-a]嘧啶类抗肿瘤药物的基本结构设计了一系列5-胺甲基-7-苯胺基吡唑并[1,5-a]嘧啶类化合物,并以丙二腈和原甲酸三乙酯为起始原料,经5步反应得到目标产物。采用MTT法,以顺铂为阳性对照药,以Bel-7402和HT-1080为测试细胞株对目标化合物的抗肿瘤活性进行评价。结果与结论合成了11个未见文献报道的化合物,结构经质谱和核磁共振氢谱确证。化合物6显示出很好的抗肿瘤活性。     

Microwave-assisted, divergent solution-phase synthesis of 1,3,6-trisubstituted pyrazolo[3,4-d]pyrimidines

A concise and highly divergent synthetic route has been developed to rapidly access 1,3,6-trisubstituted pyrazolopyrimidines. The synthesis features a microwave assisted one-pot N1-alkylation/Suzuki-Miyaura reaction as the key step. The sequence of the synthetic scheme can be varied to selectively modify the N1, C3, or C6 position at a late synthetic stage, thereby providing a highly efficient approach to explore the structure-activity relationships of pyrazolopyrimidine derivatives. The scope of these reactions has also been explored.     

Synthesis, DNA-binding, and antiviral activity of certain pyrazolo[3,4-d]pyrimidine derivatives

Some new pyrazolo[3,4-d]pyrimidine derivatives have been prepared and tested for their antiviral and DNA-binding activities. Compounds 4, 5, and 6 showed high binding affinity to DNA at concentrations of 19, 27, and 28 micrograms/ml, respectively. On the other hand, compounds 6 and 10 reduced the number of viral plaques of Herpes simplex type-1 (HSV-1) by 66 and 41%, respectively. The detailed synthesis and spectroscopic and biological data are reported.