Synthesis and ring transformation of pyrrolo[2,3-d][1,3]oxazine to pyrrolo[2,3-d]pyrimidines

A convenient route is reported for the synthesis of fused pyrrolo [2, 3-d] [1, 3]-oxazine and pyrrolo [2, 3-d]-pyrimidine derivatives from 2-amino-1-benzyl-3-t-butoxycarbonyl-4, 5-dimethylpyrrole.     

Ecofriendly synthesis of pyrano[2,3-d]pyrimidine derivatives and related heterocycles with anti-inflammatory activities

A versatile, efficient, clean, and facile method was used for the synthesis of pyrano[2,3-d]pyrimidine derivatives by the one-pot three-component condensation reaction of thiobarbituric acid and malononitrile with p-chlorobenzaldehyde, using Fe₃O₄ or ZnO or Mn₃O₄ as nanostructure catalysts. The catalyst could be easily recovered using an external magnet and reused for six cycles with almost a consistent activity. A series of polyheterocyclic compounds containing five and/or six rings fused with each other was designed. The anti-inflammatory activities for some of the newly synthesized compounds were evaluated. All the synthesized compounds were characterized on the basis of their elemental analyses and spectral data.     

Further modifications of 1H-pyrrolo[2,3-b]pyridine derivatives as inhibitors of human neutrophil elastase

Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes and is considered to be a multifunctional enzyme. HNE is also involved in a variety of pathologies affecting the respiratory system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrrolo[2,3-b]pyridine derivatives of our previously reported potent HNE inhibitors. Our results show that position 2 of the pyrrolo[2,3-b]pyridine scaffold must be unsubstituted, and modifications of this position resulted in loss of HNE inhibitory activity. Conversely, the introduction of certain substituents at position 5 was tolerated, with retention of HNE inhibitory activity (IC₅₀ = 15–51 nM) after most substitutions, indicating that bulky and/or lipophilic substituents at position 5 probably interact with the large pocket of the enzyme site and allow Michaelis complex formation. The possibility of Michaelis complex formation between Ser195 and the ligand carbonyl group was assessed by molecular docking, and it was found that highly active HNE inhibitors are characterized by geometries favorable for Michaelis complex formation and by relatively short lengths of the proton transfer channel via the catalytic triad.     

Synthesis of thiazolo[4,5-d]pyrimidine derivatives as potential antimicrobial agents

In this study, we report the synthesis and antimicrobial evaluation of several new thiazolo[4,5-d]pyrimidine derivatives, namely 7-substituted amino-5-methyl-3-phenylthiazolo[4,5-d]pyrimidine-2(3H)-thiones 4a-e, 8, 13, 15, ethyl 2-cyano-2-(7-substituted-5-methyl-3-phenylthiazolo [4,5-d]-pyrimidin-2(3H)-ylidene)acetates 5a-b, 2-(7-substituted-5-methyl-3-phenylthiazolo[4,5-d]pyrimidin-2(3H)-ylidene)malononitriles 6a-b, 5-methyl-7-morpholino-3-phenylthiazolo[4,5-d] pyrimidine-2(3H)-one 7, and 7-[4-(1-substituted-5-phenyl-4,5-dihydro-1H-pyrazolin-3-yl)anilino]-5-methyl-3-phenylthiazolo[4,5-d]pyrimidine-2(3H)-thiones 10-12. Some of the tested compounds were more active against C. albicans than E. coil and P. aeruginosa, and all were inactive against S. aureus.     

Design,synthesis, antitumor evaluation,and molecular docking of novel pyrrolo[2,3-d]pyrimidine as multi-kinase inhibitors

In the last twenty years, protein kinases have been identified as important targets for cancer therapy. In order to prevent unexpected toxicity, medicinal chemists have always focused on discovering selective protein kinase inhibitors. However, cancer is a multifactorial process and its formation and progression depend on different stimuli. Therefore, it is imperative to develop anticancer therapy that targets multiple kinases associated cancer progression. In this research a series of hybrid compounds was designed and synthesized successfully with the aim of producing anticancer activity through the induction of multiple protein kinase inhibition. The designed derivatives comprise isatin and pyrrolo[2,3-d]pyrimidine scaffolds in their structures with a hydrazine linking the two pharmacophores. Antiproliferative and kinase inhibition assays revealed promising anticancer and multi-kinase inhibitory effects of compound 7 with comparable results with the reference standards. Moreover, compound 7 suppressed cell cycle progression and induced apoptosis in HepG2 cells. Finally, molecular docking simulation was performed to investigate the potential types of interactions between the protein kinase enzymes and the designed hybrid compounds. The results of this research indicated the promising anticancer effect of compound 7 through the inhibition of a number of protein kinase receptors and the suppression of cell cycle and the induction of apoptosis.     

Synthesis and biological evaluation of some pyrrolo[2,3-d]pyrimidines

Pyrrolo[2,3-d]pyrimidine and tetrazolopyrimidine derivatives 2a, b-5a, b were prepared. Also, acyclic and cyclic C-nucleosides 7a, b-12a, b were prepared by treating compound 6 with some aldoses. All prepared products were tested for antiviral activity against hepatitis-A virus (HAV, MBB-cell culture adapted strain) and herpes simplex virus type-1 (HSV-1). Plaque reduction infectivity assay was used to determine virus count reduction as a result of treatment with tested compounds. Compound 2a showed the highest effect on HAV, while compound 11b showed the highest effect on the HSV-1 virus.     

Novel synthesis and antifungal activity of pyrrole and pyrrolo[2,3-d]pyrimidine derivatives containing sulfonamido moieties

Several sulfonamides containing pyrroles (2a-c, 6a-d, 8a-d), pyrrolo[2,3-d] pyrimidines (3a-c), acetanilides (11a-c) and tetrahydrobenzothiophenes (13a-c) were synthesized starting from N4-chloroacetylsulfanilamides (1a-d). The structures of synthesized compounds were elucidated by elemental analyses and spectral data. Compounds 2b, 3b, 6b, 8b and 8d exhibited a remarkable antifungal activity compared with the standard fungicide mycostatine.     

Synthesis and receptor binding of new thieno[2,3-d]-pyrimidines as selective ligands of 5-HT(3) receptors

With the aim to develop new potent and selective ligands of 5-HT(3)-type serotonin receptors and to acquire more information on their structure-affinity relationships, new thieno[2,3-d]pyrimidine derivatives 32-39 were synthesized and their binding to 5-HT(3) versus 5-HT(4 )receptors was studied. Some of these new compounds exhibit good affinity for cortical 5-HT(3) receptors, but not for 5-HT(4) receptors. Among these derivatives, 6-ethyl-4-(4-methyl-1-piperazinyl)-2-(methylthio)thieno[2,3-d]pyrimidine 32 is the most potent ligand (K(i) = 67 nM); it behaves as a competitive antagonist of the 5-HT(3) receptor function in the guinea pig colon. Its binding interactions with 5-HT(3A )receptors were analysed by using receptor modelling and comparative docking.     

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.     

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.     

Antitumor activity of novel pyrrolo[2,3-d]pyrimidin-4-ones

Pyrrolo[2,3-d]pyrimidine is known to have a broad spectrum of biological activities, including antitumor activity. The cytotoxic properties of six novel pyrrolo[2,3-d]pyrimidin-4-ones in vitro were investigated on four different human cancer cell lines. Meanwhile, the role of apoptosis was explored. Malignant cells were cultured in RPMI medium and incubated with different concentrations. Cell viability was quantitated by MTT assay. Apoptotic cells were determined using DAPI (4′-6-diamidino-2-phenylindole) and propidium iodide staining of DNA fragmentation by flow cytometry (sub-G1 peak). We have identified new analogs as a novel class of antiproliferative agents by a cell-based screening method. All compounds inhibited the growth of malignant cells in a dose-dependent manner. The IC₅₀ of compounds 4 and 5 as the two most potent analogs was determined as 122.4 and 106.7 μM in HeLa cells, respectively. Compounds 4 and 5 induced a sub-G1 peak in the flow-cytometry histogram of treated cells, compared to control, indicating that apoptotic cell death is involved in compound 4– and 5–induced toxicity. In conclusion, compounds 4 and 5 exert cytotoxic effects in different cancer cell lines in which apoptosis plays an important role. Thus, compounds 4 and 5 could be considered as potential chemotherapeutic agents.     

Fused Thiopyrano[2,3-d]thiazole Derivatives as Potential Anticancer Agents

rel-(5aR,11bR)-3,5a,6,11b-tetrahydro-2H,5H-chromeno[4′,3′:4,5]thiopyrano[2,3-d][1,3]thiazol-2-ones formed by the stereoselective Knoevenagel-hetero-Diels-Alder reaction were functionalized at the nitrogen in position 3 via reactions of alkylation, cyanoethylation, and acylation. The synthesized compounds were evaluated for their anticancer activity in NCI60 cell lines. Among the tested compounds, 3f was found to be the most active candidate with the greatest influence on leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, prostate cancer, and breast cancer subpanel cell lines with GI₅₀ values over a range of 0.37–0.67 μM.     

Synthesis and molluscicidal activity of some 1,3,4-triaryl-5-chloropyrazole, pyrano[2,3-c]pyrazole, pyrazolylphthalazine and pyrano[2,3-d]thiazole derivatives

2-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-ylmethylene)-malononitrile 1a reacts with the arylidenes of malononitrile 2a-d to afford the triaryl-5-chloropyrazoles 3a-d, respectively. 1a reacts with the active methylene pyrazolinones 5a, b and 12a, b to afford different products 8, 9, 10, 11, and 14a, b--depending on the substitution in the pyrazole ring. Compound 1a reacts also with the pyridazinone derivative 15 to afford the phthalazinone 16, and with the thiazolinones 17a-c to afford the pyrano[2,3-d]thiazoles 20a-c, respectively. It reacts also with the malononitrile dimer 21a and with ethyl cyanoacetate dimer 21b to yield the pyrazolyl pyridines 22a, b, respectively. The synthesized compounds showed a moderate molluscicidal activity towards Biomphalaria alexandrina snails.     

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.     

Pharmacophore modeling, 3D-QSAR,synthesis, and anti-lung cancer evaluation of novel thieno[2,3-d][1,2,3]triazines targeting EGFR

Two series of thieno[2,3-d][1,2,3]triazine derivatives were designed, synthesized, and biologically evaluated as potential epidermal growth factor receptor (EGFR) inhibitors targeting the non-small-cell lung cancer cell line H1299. Most of the synthesized compounds displayed IC₅₀ values ranging from 25 to 58 nM against H1299, which are superior to that of gefitinib (40 µM). 3-(5,6,7,8-Tetrahydro-7H-cyclohexa[4:5]thieno[2,3-d]-1,2,3-triazin-4-ylamino)benzene-1,3-diamine ( 6b ) achieved the highest cytotoxic activity against H1299 with an IC₅₀ value of 25 nM; it had the ability to decrease the EGFR concentration in H1299 cells from 7.22 to 2.67 pg/ml. In vitro, the IC₅₀ value of compound 6b was 0.33 nM against EGFR, which is superior to that of gefitinib at 1.9 nM and erlotinib at 4 nM. The three-dimensional quantitative structure–activity relationships and molecular modeling studies revealed comparable binding modes of compound 6b , gefitinib, and erlotinib in the EGFR active site. The in silico ADME (absorption, distribution, metabolism, and excretion) prediction parameters of this compound revealed promising pharmacokinetic and physicochemical properties. Moreover, DFT (density functional theory) calculations showed the high reactivity of compound 6b toward the EGFR compared with other compounds. The designed compound 6b might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR.     

Pyrrolo[2,1-a]isoquinoline and pyrrole alkaloids from Sinomenium acutum

Two pyrrolo[2,1-a]isoquinolines (1 and 2) and three pyrrole alkaloids (3?5), including three new ones, named sinopyrines A?C (1?3), were isolated from the 95% EtOH extract of the stems and rhizomes of Sinomenium acutum (Thumb.) Rehd. et Wils. The structures of the new compounds were elucidated on the basis of spectroscopic data. This is the first report of pyrrole-bearing natural compounds from the family Menispermaceae.     

Characterization and preliminary use of 1-, 2- and 3-methyl-5-phenyl-7-chloro-1,2,3-triazolo[4,5-d]pyrimidine as reaction intermediates

This paper reports synthesis and characterization, by spectroscopic methods, of three new N-methyl-5-phenyl-7-chloro-1,2,3-triazolo[4,5-d]pyrimidine isomers 3a, 3b and 3c. For comparison purpose the 3-benzyl-5-phenyl-7-chloro-1,2,3-triazolo[4,5-d]pyrimidine (7) was also prepared. Starting from the isomer mixture 3a-c and the chloroderivative 7, by nucleophilic substitution reaction with ethyl carbazate and subsequent intramolecular cyclization, the new tricyclic derivatives 5a-c and 9 were prepared and tested towards the benzodiazepine and adenosine A1 and A2A receptors.     

Dihydropyrrolo[2,3-d]pyrimidines: Selective Toll-Like Receptor 9 Antagonists from Scaffold Morphing Efforts

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