Synthesis and Biological Evaluation of a Series of Substituted Pyrazolo[3,4-d]-1,2,3-triazoles and Pyrazolo[3,4-d]oxazoles

In view of the biological relevance of triazole-based heterocyclic structures as antifungal, antiviral, and antitumor agents, we have synthesized a series of substituted pyrazolo[3,4-d]-1,2,3-triazoles ( 2e–h, 2j, 4b ) which we evaluated for their cytostatic and antiviral (HIV-1 included) activity and for their capability to inhibit the multiplication of various human pathogenic fungi and bacteria. Moreover, the biological activities of a few compounds, namely pyrazolo[3,4-d]oxazoles ( 3a–e ) and pyrazolo[3,4-d]-1,2,3-triazoles ( 2a–d, 4a, 5 ), previously obtained by us but not investigated for their biological activity, were also studied. Only compounds 3a–e were endowed with a significative antiproliferative activity on the human lymphoblastoid cell line MT-4 cells. All pyrazole derivatives proved ineffective in protecting cell cultures against the HIV-1-induced cytopathogenicity, and none of the compounds was active against the bacteria and fungi tested.     

Synthesis,Anti-Inflammatory,and Ulcerogenicity Studies of Novel Substituted and Fused Pyrazolo[3,4-d]pyrimidin-4-ones

In the present investigation, some new pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives (7–12) as well as fused pyrazolo[3′,4′:4,5]pyrimido[1,2-b]pyridazin-4(1H)-one (14–16) and 7,8,9,10-tetrahydropyrazolo[3′,4′:4,5]pyrimido[1,2-b]-cinnolin-4(1H)-one (17) ring systems were synthesized using the starting compound 5-amino-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (5). The structures of the newly synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis. The theoretical calculation of their lipophilicity as C log P was performed. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw edema test in rats using indomethacin as the reference drug. Ulcer indices for the most active compounds were calculated. Seven compounds (10b, 11a–f) showed consistently good anti-inflammatory activity. In particular, 5-{[4-(4-bromophenyl)-3-(4-chlorophenyl)-1,3-thiazol-2(3H)-ylidene]amino}-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (11e) and its 3,4-bis(4-chlorophenyl) analog (11f) were found to be the most effective among the other derivatives, showing activity comparable to that of indomethacin with minimal ulcerogenic effects. Correlation of the biological data of the active compounds with their theoretically calculated C log P values revealed that lipophilicity influences the biological response.     

Design and Synthesis of Novel Pyrazolo[3,4-d]Pyrimidines: In Vitro Cytotoxic Evaluation and Free Radical Scavenging Activity Studies

Pharmaceutical Chemistry Journal - With evident biological importance, a new series of pyrazolo[3,4-d]pyrimidines 3a,3b and 4a,4b were synthesized via the formation of pyrazol-3-one 2a and 2b...     

Pyrazolo[3,4-d]pyrimidine analogues: synthesis, characterization and their in vitro antiamoebic activity

Pyrazolo[3,4-d]pyrimidine analogues were synthesized by treating 3-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4-amine with different sulfonyl chlorides and triethylamine in dry dichloromethane. The structure of all the compounds was elucidated by spectral data and their purity was confirmed by elemental analysis. In vitro antiamoebic activity was performed against HM1:IMSS strain of Entamoeba histolytica and two compounds, 4 (IC₅₀ = 0.57) and 6 (IC₅₀ = 0.68), were found better inhibitors than the reference drug metronidazole (IC₅₀ = 1.80). Further, both the compounds (4 and 6) were low cytotoxic against the human breast cancer MCF-7 cell line in the concentration range of 2.5–250 μM. These preliminary results reveal that pyrazolo[3,4-d]pyrimidine analogues could help in designing better molecules with enhanced antiamoebic activity.     

Synthesis,Characterization, and Cytotoxicity of Some New 5-Aminopyrazole and Pyrazolo[1,5-a]pyrimidine Derivatives

5-Amino-N-aryl-3-[(4-methoxyphenyl)amino]-1H-pyrazole-4-carboxamides 4a–c were synthesized by the reaction of N-(aryl)-2-cyano-3-[(4-methoxyphenyl)amino]-3-(methylthio)acrylamides 3a–c with hydrazine hydrate in ethanol. The reaction of 5-amino-N-aryl-1H-pyrazoles 4a–c with acetylacetone 5 or 2-(4-methoxybenzylidene)malononitrile 8 yielded the pyrazolo[1,5-a]pyrimidine derivatives 7a–c and 10a–c, respectively. The structures of the synthesized compounds were established based on elemental analysis and spectral data (IR, MS, ¹H-NMR, and ¹³C-NMR). Representative examples of the new synthesized products were screened for their in vitro cytotoxic activity against Ehrlich Ascites Carcinoma (EAC) cells.     

Synthesis and antineoplastic effects of furo[3,4-d]pyrimidine derivatives

Furo[3,4-d]pyrimidine was obtained in the reaction of 2-phenyl-4-phenylamino-6-methyl-5-pyrimidinecarboxylic acid with SOCl2. This compound, heated with aliphatic amines, yielded mono- and diamino-derivatives. Some of the obtained compounds exhibited a potent antineoplastic activity.     

抗肿瘤前药-姜黄素衍生物的设计合成及初步活性测试

目的:为了提高姜黄素的抗癌活性及选择性,考虑将之做成前药形式.方法:从几种氨基酸出发,经过马来酸酐活化后与姜黄素结合,得到四个化合物.利用MTT法对四个目标化合物进行了体外抗肿瘤活性评价.结果与结论:其结构经IR,1HNMR和13CNMR确证.目标化合物对胰腺癌细胞株SW-1990和膀胱癌细胞株T24的抑制试验结果表明,四个化合物对这两种细胞的抑制作用均优于阳性对照药5-Fu.     

Design, Synthesis and Biological Evaluation of Novel Pyrimido[4,5-d]pyrimidine CDK2 Inhibitors as Anti-Tumor Agents

A series of 2,5,7-trisubstituted pyrimido[4,5-d]pyrimidine cyclin-dependent kinase (CDK2) inhibitors is designed and synthesized. 6-Amino-2-thiouracil is reacted with an aldehyde and thiourea to prepare the pyrimido[4,5-d]-pyrimidines. Alkylation and amination of the latter ones give different amino derivatives. These compounds show potent and selective CDK inhibitory activities and inhibit in vitro cellular proliferation in cultured human tumor cells.     

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.     

Novel Water-Soluble Substituted Pyrrolo[3,2-d]pyrimidines: Design, Synthesis, and Biological Evaluation as Antitubulin Antitumor Agents

Purpose

To study the effects of a regioisomeric change on the biological activities of previously reported water soluble, colchicine site binding, microtubule depolymerizing agents.

Methods

Nine pyrrolo[3,2-d]pyrimidines were designed and synthesized. The importance of various substituents was evaluated. Their abilities to cause cellular microtubule depolymerization, inhibit proliferation of MDA-MB-435 tumor cells and inhibit colchicine binding to tubulin were studied. One of the compounds was also evaluated in the National Cancer Institute preclinical 60 cell line panel.

Results

Pyrrolo[3,2-d]pyrimidine analogs were more potent than their pyrrolo[2,3-d]pyrimidine regioisomers. We identified compounds with submicromolar potency against cellular proliferation. The structure-activity relationship study gave insight into substituents that were crucial for activity and those that improved activity. The compound tested in the NCI 60 cell line is a 2-digit nanomolar (GI₅₀) inhibitor of 8 tumor cell lines.

Conclusion

We have identified substituted pyrrolo[3,2-d]pyrimidines that are water-soluble colchicine site microtubule depolymerizing agents. These compounds serve as leads for further optimization.     

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.     

Pyrazolo[3,4-d]pyrimidine scaffold: A review on synthetic approaches and EGFR and VEGFR inhibitory activities

The pyrazolo[3,4-d]pyrimidine core has received a lot of interest from the medicinal chemistry community as a promising framework for drug design and discovery. It is an isostere of the adenine ring of adenosine triphosphate, which allows it to mimic kinase active site hinge region binding contacts. This scaffold has a wide pharmacological and biological value, one of which is as an anticancer agent. Many successful anticancer medicines have been designed and synthesized using pyrazolo[3,4-d]pyrimidine as a key pharmacophore. The main synthetic routes of pyrazolo[3,4-d]pyrimidines as well as their recent developments as promising anticancer agents acting as endothelial growth factor receptors and vascular endothelial growth factor receptor inhibitors, published in the time frame from 1999 to 2022, are summarized in this review to set the direction for the design and synthesis of novel pyrazolo[3,4-d]pyrimidine derivatives for clinical deployment in cancer treatment.     

Pyrazoles and Pyrazolo[3,4-d]pyrimidines as Biologically Active Agents,II

Pyrazoles with bio-active substituents at different positions are prepared and cyclised to the corresponding pyrazolo[3,4-d]pyrimidines in order to establish structure-activity relationships. The structure of the compounds is established by micro-analyses and spectroscopic studies.