Browse
Submit Data
Databases
API
Help

Dataset Information

13 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Design and synthesis of novel pyrazolo[4,3-d]pyrimidines as potential therapeutic agents for acute lung injury.

ABSTRACT: Four series of total 35 new pyrazolo[4,3-d]pyrimidine compounds were designed, synthesized and evaluated for their inhibitory activity against LPS-induced NO production in RAW264.7 macrophages. Among them, compound 4e was found to be the most potent inhibitor, which decreased the production of cytokines in vitro, such as NO, IL-6 and TNF-?, with IC50 values of 2.64, 4.38 and 5.63??M, respectively. Further studies showed that compound 4e inhibited cytokines secretion of macrophages through suppressing TLR4/p38 signaling pathway. Additionally, compound 4e showed in vivo anti-inflammatory activity in LPS-induced model of acute lung injury. These data suggested that compound 4e may be a promising lead structure for the treatment of ALI.

SUBMITTER: Wang BS

PROVIDER: S-EPMC6534230 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Design and synthesis of novel pyrazolo[4,3-d]pyrimidines as potential therapeutic agents for acute lung injury.

Wang Bao Shi BS Huang Xin X Chen Liu Zeng LZ Liu Ming Ming MM Shi Jing Bo JB

Journal of enzyme inhibition and medicinal chemistry 20191201 1

Four series of total 35 new pyrazolo[4,3-d]pyrimidine compounds were designed, synthesized and evaluated for their inhibitory activity against LPS-induced NO production in RAW264.7 macrophages. Among them, compound 4e was found to be the most potent inhibitor, which decreased the production of cytokines in vitro, such as NO, IL-6 and TNF-α, with IC50 values of 2.64, 4.38 and 5.63 μM, respectively. Further studies showed that compound 4e inhibited cytokines ...[more]

PMID: 31117832

Similar Datasets

Regioselective Synthesis of New 2,4-(Het)aryl-3H-pyrido[1',2':1,5]pyrazolo[4,3-d]pyrimidines Involving Palladium-Catalyzed Cross-Coupling Reactions.

Project description:The design of some novel di-(het)arylated-3H-pyrido[1',2':1,5]pyrazolo[4,3-d]pyrimidine derivatives is reported. The series was developed from 1-aminopyridinium iodide, which afforded the key intermediate bearing two thiomethyl and amide functions, each of them useful for palladium catalyzed cross coupling reactions by alkyl sulfur release and C-O activation, respectively. The two regioselective and successive cross-coupling reactions were first carried out in C-4 by in situ C-O activation and next in C-2 by a methylsulfur release. Process optimization furnished conditions leading to products in high yields. The scope and limitations of the methodologies were evaluated and the final compounds characterized.

| S-EPMC6278517 | biostudies-literature

Synthesis and biological evaluation of chalcone-linked pyrazolo[1,5-a]pyrimidines as potential anticancer agents.

Project description:A series of pyrazolo[1,5-a]pyrimidines substituted at C5 with 1-phenylprop-2-en-1-one (6a-q) and 3-phenylprop-2-en-1-one (7a-k) was synthesized and evaluated for antiproliferative activity. Among them, 6h was found to be the most active compound against the MDA-MB-231 cell line with an IC50 of 2.6 ?M . The antiproliferative activity of this series of compounds ranged from 2.6 to 34.9 ?M against A549 (lung cancer), MDA-MB-231 (breast cancer) and DU-145 (prostate cancer) cell lines. FACS analysis revealed that these hybrids arrest the cell cycle at the subG1 phase. Western blot analysis and an immunofluorescence assay showed the inhibition of the EGFR and STAT3 axis, which plays an important role in cell survival and apoptosis. Western blot and RT-PCR analyses that displayed an increase in apoptotic proteins such as p53, p21 and Bax and a decrease in the anti-apoptotic proteins Bcl-2 and procaspase-9 confirmed the ability of these hybrids to trigger cell death by apoptosis. Molecular docking studies described the binding of these hybrids to the ATP binding site of EGFR.

| S-EPMC6084153 | biostudies-literature

Structure-based design, synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo[4,3-c]pyridine inhibitors of fascin 1 as potential anti-metastatic agents.

Project description:Fascin is an actin binding and bundling protein that is not expressed in normal epithelial tissues but overexpressed in a variety of invasive epithelial tumors. It has a critical role in cancer cell metastasis by promoting cell migration and invasion. Here we report the crystal structures of fascin in complex with a series of novel and potent inhibitors. Structure-based elaboration of these compounds enabled the development of a series with nanomolar affinities for fascin, good physicochemical properties and the ability to inhibit fascin-mediated bundling of filamentous actin. These compounds provide promising starting points for fascin-targeted anti-metastatic therapies.

| S-EPMC6419574 | biostudies-literature

Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2H-pyrazolo[4,3-c]pyridines.

Project description:A library of 2,4,6,7-tetrasubstituted-2H-pyrazolo[4,3-c]pyridines was prepared from easily accessible 1-phenyl-3-(2-phenylethynyl)-1H-pyrazole-4-carbaldehyde via an iodine-mediated electrophilic cyclization of intermediate 4-(azidomethyl)-1-phenyl-3-(phenylethynyl)-1H-pyrazoles to 7-iodo-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridines followed by Suzuki cross-couplings with various boronic acids and alkylation reactions. The compounds were evaluated for their antiproliferative activity against K562, MV4-11, and MCF-7 cancer cell lines. The most potent compounds displayed low micromolar GI50 values. 4-(2,6-Diphenyl-2H-pyrazolo[4,3-c]pyridin-7-yl)phenol proved to be the most active, induced poly(ADP-ribose) polymerase 1 (PARP-1) cleavage, activated the initiator enzyme of apoptotic cascade caspase 9, induced a fragmentation of microtubule-associated protein 1-light chain 3 (LC3), and reduced the expression levels of proliferating cell nuclear antigen (PCNA). The obtained results suggest a complex action of 4-(2,6-diphenyl-2H-pyrazolo[4,3-c]pyridin-7-yl)phenol that combines antiproliferative effects with the induction of cell death. Moreover, investigations of the fluorescence properties of the final compounds revealed 7-(4-methoxyphenyl)-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridine as the most potent pH indicator that enables both fluorescence intensity-based and ratiometric pH sensing.

| S-EPMC8588486 | biostudies-literature

Design, synthesis and structure-activity relationship studies of 4-indole-2-arylaminopyrimidine derivatives as anti-inflammatory agents for acute lung injury.

Project description:Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), a clinically high mortality disease, has not been effectively treated till now, and the development of anti-acute lung injury drugs is imminent. Acute lung injury was efficiently treated by inhibiting the cascade of inflammation, and reducing the inflammatory response in the lung. A series of novel compounds with highly efficient inhibiting the expression of inflammatory factors were designed by using 4-indolyl-2-aminopyrimidine as the core skeleton. Totally eleven 4-indolyl-2-arylaminopyrimidine derivatives were designed and synthesized. As well, the related anti-ALI activity of these compounds was evaluated. Compounds 6c and 6h showed a superior activity among these compounds, and the inhibition rate of IL-6 and IL-8 release ranged from 62% to 77%, and from 65% to 72%, respectively. Furthermore, most of compounds had no significant cytotoxicity in vitro. The infiltration of inflammatory cells into lung tissue significantly reduced by using compound 6h (20 mg/kg) in the ALI mice model, which achieved the effect of protecting lung tissue and improving ALI. In addition, the inflammatory response was inhibited by using compound 6h through inhibiting phosphorylation of p-38 and ERK in MAPK signaling pathway, and resulted in protective effect on ALI. These data indicated that compound 6h showed good anti-inflammatory activity in vitro and in vivo, which was expected to become a leading compound for the treatment of ALI.

| S-EPMC8357485 | biostudies-literature

Synthesis of trifluoromethyl-substituted pyrazolo[4,3-c]pyridines - sequential versus multicomponent reaction approach.

Project description:A straightforward synthesis of 6-substituted 1-phenyl-3-trifluoromethyl-1H-pyrazolo[4,3-c]pyridines and the corresponding 5-oxides is presented. Hence, microwave-assisted treatment of 5-chloro-1-phenyl-3-trifluoromethylpyrazole-4-carbaldehyde with various terminal alkynes in the presence of tert-butylamine under Sonogashira-type cross-coupling conditions affords the former title compounds in a one-pot multicomponent procedure. Oximes derived from (intermediate) 5-alkynyl-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehydes were transformed into the corresponding 1H-pyrazolo[4,3-c]pyridine 5-oxides by silver triflate-catalyzed cyclization. Detailed NMR spectroscopic investigations ((1)H, (13)C, (15)N and (19)F) were undertaken with all obtained products.

| S-EPMC4142841 | biostudies-literature

Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents.

Project description:Three novel pyrazolo-[4,3-e][1,2,4]triazolopyrimidine derivatives (1, 2, and 3) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity against cervical and breast cancer cell lines. However, compound 1 showed the best antiproliferative activity against all tested tumor cell lines, including HCC1937 and HeLa cells, which express high levels of wild-type epidermal growth factor receptor (EGFR). Western blot analyses demonstrated that compound 1 inhibited the activation of EGFR, protein kinase B (Akt), and extracellular signal-regulated kinase (Erk)1/2 in breast and cervical cancer cells at concentrations of 7 and 11 µM, respectively. The results from docking experiments with EGFR suggested the binding of compound 1 at the ATP binding site of EGFR. Furthermore, the crystal structure of compound 3 (7-(4-bromophenyl)-9-(pyridin-4-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine) was determined by single crystal X-ray analysis. Our work represents a promising starting point for the development of a new series of compounds targeting EGFR.

| S-EPMC8271544 | biostudies-literature

Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines to develop functionalized ligands to target adenosine receptors: fluorescent ligands as an example.

Project description:A series of adenosine receptor antagonists bearing a reactive linker was developed. Functionalization of these derivatives is useful to easily obtain multi-target ligands, receptor probes, drug delivery systems, and diagnostic or theranostic systems. The pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold was chosen as a pharmacophore for the adenosine receptors. It was substituted at the 5 position with reactive linkers of different lengths. Then, these compounds were used to synthesise probes for the adenosine receptors by functionalization with a fluorescent moiety. Both series of compounds were evaluated for their binding at the four adenosine receptor subtypes. Different affinity and selectivity profiles were observed towards hA1, hA2A and hA3 adenosine receptors. In particular, fluorescent compounds behave as dual hA2A/hA3 ligands. Computational studies suggested different binding modes for developed compounds at the three receptors. Both molecular docking and supervised molecular dynamics (SuMD) simulations confirmed that the preferred binding mode at the single receptor was driven by the substitution present at the 5 position. Obtained results rationalized the compounds' binding profile at the adenosine receptors and pave the way for the development of more potent conjugable and conjugated ligands targeting these membrane receptors.

| S-EPMC6644567 | biostudies-literature

Synthesis and In Silico Docking of New Pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine-based Cytotoxic Agents.

Project description:To explore a new set of anticancer agents, a novel series of pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine derivativeshave been designed and synthesized viacyclocondensation reactions of pyrazolo-enaminone with a series of arylidenemalononitriles; compound 5 was obtained from 5-amino-4-cyanopyrazole. The structures of the target compounds were investigated by spectral techniques and elemental analysis (IR, UV-Vis, 1H NMR, 13C NMR and ESI-MS). All compounds were evaluated for their in vitro cytotoxicity employing a panel of different human tumor cell lines, A375, HT29, MCF7, A2780, FaDu as well as non-malignant NIH 3T3 and HEK293 cells. It has been found that the pyrazolo-pyrido-pyrimidine analog bearing a 4-Br-phenyl moiety was the most active toward many cell lines with EC50 values ranging between 9.1 and 13.5 µM. Moreover, in silico docking studies of the latter with six anticancer drug targets, i.e., DHFR, VEGFR2, HER-2/neu, hCA-IX, CDK6 and LOX5, were also performed, in order to gain some insights into their putative mode of binding interaction and to estimate the free binding energy of this bioactive molecule.

| S-EPMC8508785 | biostudies-literature

Synthesis, Structural Characterization, and Biological Activity of New Pyrazolo[4,3-e][1,2,4]triazine Acyclonucleosides.

Project description:A series of new pyrazolo[4,3-e][1,2,4]triazine acyclonucleosides 2-5 and 8 were prepared and evaluated for their anticancer activity against human cancer cell lines (MCF-7, K-562) and CDK2/E, as well as Abl protein kinases inhibitors. Lipophilicity of the compounds was determined using C-18 and immobilized artificial membrane (IAM) chromatography. In order to confirm the molecular structures and synthesis pathway of new acyclonucleosides, X-ray analysis was performed for model compound 3. Theoretical calculations at the DFT/B3LYP/6-311++G(d,p) level were used for the characterization of electronic structures of 1-8. The potential antiviral activity of acyclonucleosides 2-8 was tested in silico using molecular docking method.

| S-EPMC6982861 | biostudies-literature