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1.
Chemistry ; 26(9): 1922-1927, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31738451

RESUMO

The synthesis of a diverse range of heterobiaryls has been achieved by a transition-metal-free sp2 -sp2 cross-coupling strategy using lithiated heterocycle, aryl or heteroaryl boronic ester and an electrophilic halogen source. The construction of heterobiaryls was carried out through electrophilic activation of the aryl-heteroaryl boronate complex, which triggered 1,2-migration from boron to the carbon atom. Subsequent oxidation of the intermediate boronic ester afforded heterobiaryls in good yield. A comprehensive 11 B NMR study has been conducted to support the mechanism. The cross coupling between two nucleophilic cross coupling partners without transition metals reveals a reliable manifold to procure heterobiaryls in good yields. Various heterocycles like furan, thiophene, benzofuran, benzothiophene, and indole are well tolerated. Finally, we have successfully demonstrated the gram scale synthesis of the intermediates for an anticancer drug and OLED material using our methodology.


Assuntos
Ácidos Borônicos/química , Compostos Heterocíclicos/química , Catálise , Compostos Heterocíclicos/síntese química , Paládio/química , Teoria Quântica , Elementos de Transição/química
2.
Eur J Med Chem ; 186: 111908, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31791643

RESUMO

Artemisinin and its analogs have shown potent anticancer activity in primary cancer cultures and cell lines by inhibiting cancer proliferation, metastasis, and angiogenesis. Despite its apparent compatibility to normal cells and low IC50 values in comparison to the commonly used anticancer drugs, the underlying mechanisms behind their cytotoxic effects are not yet fully understood. Surprisingly, the efficacy of synthetic 1,2,4-trioxanes against cancer has not been explored yet. Given the high antitumor activity of artemisinin dimers in comparison to their monomers, we report here the synthesis of simple 1,2,3-triazole conjugated 1,2,4-trioxanes and their potential antitumor activity by studying their inhibitory effect on osteopontin (OPN) expression in MDA-MB-435 breast cancer cells. It may be noted that despite being a strong marker to identify human tumor metastasis, no study on effect of artemisinin and its synthetic and semisynthetic derivatives on OPN expression has ever been studied. Although our initial studies did not notice any straight-line relationship between the number of trioxane units in a molecule to the extent of inhibition of OPN protein expression, we could observe better results in some cases in comparison to artemisinin. We have observed that artemisinin did not show appreciable OPN downregulation in MDA-MB-435 cancer cells, but dihydroartemisinin (DHA) and some synthetic 1,2,4-trioxane monomers and dimers showed downregulation of OPN expression. Therefore, these compounds may act as an anti-metastatic agent in controlling breast cancer cells metastasis.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Compostos Heterocíclicos/farmacologia , Osteopontina/antagonistas & inibidores , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Estrutura Molecular , Osteopontina/biossíntese , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
3.
Chem Rec ; 20(2): 120-141, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31250972

RESUMO

Fluorine-containing organic scaffolds are of significant interest in medicinal chemistry. The incorporation of fluorine into biomolecules can lead to remarkable changes in their physical, chemical, and biological properties. There are already many drugs on the market, which contain at least one fluorine atom. Saturated functionalized azaheterocycles as bioactive substances have gained increasing attention in pharmaceutical chemistry. Due to the high biorelevance of organofluorine molecules and the importance of N-heterocyclic compounds, selective stereocontrolled procedures to the access of new fluorine-containing saturated N-heterocycles are considered to be a hot research topic. This account summarizes the synthesis of functionalized and fluorine-containing saturated azaheterocycles starting from functionalized cycloalkenes and based on oxidative ring cleavage of diol intermediates followed by ring expansion with reductive amination.


Assuntos
Compostos Aza/química , Compostos Heterocíclicos/química , Aldeídos/química , Azepinas/síntese química , Azepinas/química , Ciclização , Flúor/química , Compostos Heterocíclicos/síntese química , Oxirredução , Estereoisomerismo
4.
Eur J Med Chem ; 186: 111888, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31787359

RESUMO

Targeting L858R/T790M/C797S mutant EGFR is a major challenge in the new-generation EGFR tyrosine kinase inhibitors development for conquering drug resistant NSCLC. In this study, a series of novel 9-heterocyclyl substituted 9H-purine derivatives were designed as EGFRL858 R/T790 M/C797S tyrosine kinase inhibitors. Among these compounds, D4, D9, D11 and D12 showed significantly potent anti-proliferation and EGFRL858 R/T790 M/C797S inhibition activity. In particular, the most potent compound D9 showed anti-proliferation against HCC827 and H1975 cell lines with the IC50 values of 0.00088 and 0.20 µM, respectively. And D9 inhibited the EGFRL858R/T790M/C797S with an IC50 value of 18 nM. Furtherly, D9 could significantly suppress the EGFR phosphorylation, induce the apoptosis, arrest cell cycle at G0/G1, and inhibit colony formation in HCC827 cell line by a concentration-dependent manner. Molecular docking indicated that the introduction of a cyclopropylsulfonamide group in D9 led to the formation of additional two hydrogen bonds with mutant Ser797 which played key roles in generating efficient EGFRL858 R/T790 M/C797S inhibitory activity. These findings strongly indicated that 9-heterocyclyl substituted 9H-purine derivatives were promising L858R/T790M/C797S mutant EGFR-TKIs. The introduction of extra hydrogen bond interaction with mutant Ser797 is efficient method for the design of the fourth-generation EGFR-TKIs.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Compostos Heterocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Purinas/síntese química , Purinas/química , Relação Estrutura-Atividade
5.
Chem Pharm Bull (Tokyo) ; 67(12): 1259-1270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787652

RESUMO

The biary unit having heteroatom as important scaffolds widely exist in a large number of biologically active compounds and functional organic molecules. Since the cross-coupling is a useful synthetic method for constructing biaryl and heterobiaryl structures, the development of novel cross-coupling methods has been studied intensively. The oxidative biaryl coupling reaction of aromatic compounds having heteroatoms is an attractive method since they do not require the prefunctionalization of arenes. This report describes recent advances in hypervalent iodine(III) induced metal-free synthesis of biaryls having heteroatoms.


Assuntos
Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Iodo/química , Estrutura Molecular , Oxirredução
6.
Chem Pharm Bull (Tokyo) ; 67(12): 1314-1323, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787658

RESUMO

Condensation of rhodanine (1) with pyrazol-3(2H)-one derivatives (2a-f) gave 5-substituted-2-thioxo-1,3-thiazolidin-4-one derivatives (3a-f). Reaction of compound (1) with 2-arylmethylidene-malononitrile (4a-d) yielded the unexpected derivatives (5a-d). The latter compounds were subjected to cyclization reactions with malononitrile under different basic conditions, hydroxylamine hydrochloride and/or thiourea to furnish the fused thiazole derivatives (6a-d) and (8-10a-d). Coupling of (1) with diazotized aromatic amines (11a-c) in pyridine afforded the arylhydrazones (12a-c). Fusion of latter compounds with malononitrile afforded the thiazolopyridazine derivatives (13a-c). The structures of the newly synthesized compounds were elucidated via spectral data and elemental analyses. The in-vitro cytotoxic activity of compounds (3a-f) against the cell line MCF-7 was evaluated. Also, the synthesized products were investigated for their antibacterial and antifungal activities against six standard organisms including the G+ bacteria, Staphylococcus aureus and Bacillus subtilis, G- bacteria, Escherichia coli and Proteus vulgaris in addition to fungi, Candida albicans and Aspergillus flavus.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Compostos Heterocíclicos/farmacologia , Tiazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Aspergillus flavus/efeitos dos fármacos , Bacillus subtilis/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Células MCF-7 , Testes de Sensibilidade Microbiana , Proteus vulgaris/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Tiazóis/química
7.
Molecules ; 24(19)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581424

RESUMO

A one-pot route to 2-alkyl and 2-aryl-4H-benzo[d][1,3]oxazin-4-ones (also known as 4H-3,1-benzoxazin-4-ones) has been developed and studied. The method involves the reaction of aryl-substituted anthranilic acids with orthoesters in ethanol catalyzed by acetic acid. Additionally, we have also investigated the reaction under microwave conditions. Not all of the substrates were successful in yielding the target heterocycles as some of the reactions failed to undergo the final elimination. This process led to the isolation of (±)-2-alkyl/aryl-2-ethoxy-1,2-dihydro-4H-benzo[d][1,3]oxazin-4-ones. The formation of the dihydro analogs correlated with the electron density on the aromatic ring: Electron-donating groups favored the 4H- benzo[d][1,3]oxazin-4-ones, while electron-withdrawing groups tended to favor the dihydro product. Substituting a pyridine ring for the benzene ring in the substrate acid suppressed the reaction.


Assuntos
Benzoatos/síntese química , Oxazinas/química , ortoaminobenzoatos/química , Benzoatos/química , Catálise , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Estrutura Molecular , Relação Estrutura-Atividade
8.
Molecules ; 24(19)2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31590462

RESUMO

The reaction of pyridines with trifluoroacetylated acetylenes was investigated. It was found that the reaction of various pyridines with two molecules of CF3CO-acetylenes proceeds under mild metal-free conditions. As a result, efficient stereoselective synthesis of 3-arylethynyl-3-trifluoromethyl-1,3-oxazinopyridines was elaborated. Target heterocycles can be prepared in up to quantitative yields.


Assuntos
Alquinos/química , Compostos Heterocíclicos/síntese química , Piridinas/química , Halogenação , Compostos Heterocíclicos/química , Estrutura Molecular
9.
Molecules ; 24(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640196

RESUMO

Herein, we report the synthesis of 5,12-dihydropyrazino[2,3-c:5,6-c']difuro[2,3-c:4,5-c']-diquinoline-6,14(5H,12H)diones, 2-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-1,4-diphenyl- butane-1,4-diones and 4-(benzo-[d]oxazol-2-yl)-3-hydroxy-1H-[4,5]oxazolo[3,2-a]pyridine-1-one. The new candidates were synthesized and identified by different spectroscopic techniques, and X-ray crystallography.


Assuntos
Compostos Heterocíclicos/síntese química , Quinolonas/química , Cristalografia por Raios X , Compostos Heterocíclicos/química , Hidroxiquinolinas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular
10.
Eur J Med Chem ; 181: 111562, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31377592

RESUMO

The interaction between G-Protein coupled receptor CXCR4 and its natural ligand CXCL12 has been linked to inflammation experienced by patients with Irritable Bowel Disease (IBD). Blocking this interaction could potentially reduce inflammatory symptoms in IBD patients. In this work, several thiophene-based and furan-based compounds modeled after AMD3100 and WZ811-two known antagonists that interrupt the CXCR4-CXCL12 interaction-were synthesized and analyzed. Fifteen hit compounds were identified; these compounds exhibited effective concentrations (EC) lower than 1000 nM (AMD3100) and inhibited invasion of metastatic cells by at least 45%. Selected compounds (2d, 2j, 8a) that inhibited metastatic invasion at a higher rate than WZ811 (62%) were submitted for a carrageenan inflammation test, where both 8a and 2j reduced inflammation in the same range as WZ811 (40%) but did not reduce inflammation more than 40%. Select compounds were also modeled in silico to show key residue interactions. These preliminary results with furan-based and thiophene-based analogues contribute to the new class on heterocyclic aromatic-based CXCR4 antagonists.


Assuntos
Furanos/farmacologia , Compostos Heterocíclicos/farmacologia , Inflamação/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Tiofenos/farmacologia , Animais , Carragenina/administração & dosagem , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Membro Posterior/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores CXCR4/metabolismo , Relação Estrutura-Atividade , Tiofenos/química
11.
Eur J Med Chem ; 182: 111601, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31445233

RESUMO

The cyclic enaminone moiety has been identified as a new scaffold for selective inhibition of cyclooxygenase-2 with anti-inflammatory and analgesic activities. The designed cyclic enaminones have been synthesized conveniently through the development of a new catalyst-free methodology and evaluated for cyclooxygenase (COX-1 and COX-2) inhibitory activities. Three compounds 7d, 8, and 9 predominantly inhibited COX-2 with selectivity index of 74.09, 19.45 and 108.68, respectively, and were assessed for in vivo anti-inflammatory activity in carrageenan induced rat paw edema assay. The anti-inflammatory activity of 7d was comparable to that of celecoxib at a dose of 12.5 mg/kg. However, the compounds 8 and 9 were more/equally effective as anti-inflammatory agent compared to celecoxib at the doses of 12.5 mg/kg and 25 mg/kg and also exhibited anti-inflammatory activity comparable to that of diclofenac. The therapeutic potential of the most active compound 9 was further assessed by performing in vivo thermal and mechanical hyperalgesia tests using various models that revealed its analgesic activity. The in vivo non-ulcerogenicity of 9 revealed the gastrointestinal safety as compared to the non-selective COX inhibitor indomethacin. The in vitro antioxidant activity and in vivo experiments on heart rate and blood pressure provided the cardiovascular safety profile of 9. The molecular docking studies rationalize the COX-2 selectivity of the newly found anti-inflammatory compounds 7d, 8, and 9.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Compostos Heterocíclicos/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/química , Carragenina , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 182: 111618, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31434041

RESUMO

The α7 nicotinic acetylcholine receptor (α7 nAChR) has emerged as a promising therapeutic target for schizophrenia. In our previous work, a novel series of α7-nAChR agonists bearing scaffold of indolizine were discovered. To explore the effect of aromaticity on the activity and find more active agents, herein, fused heterocyclic carboxamide derivatives were designed and synthesized in this study. Based on the evaluation by two-electrode voltage clamp in Xenopus oocytes, 27 of the synthesized compounds showed obvious agonism of α7 nAChR. Particularly, compounds 10a and 10e showed significantly higher Emax than EVP-6124. The result illustrated the importance of aromaticity to the activity of agonism. Compound 10a, which showed EC50 of 1.88 µM and Emax of 72.4%, was further characterized comprehensively, including co-application with type II positive allosteric modulator PNU-120596, selectivity with other closely related ligand-gated ion channel, etc. The results showed that 10a showed moderate selectivity over other subtypes such as α4ß2 and α3ß4 nAChR. 10a evoked α7-like currents that were inhibited by MLA and enhanced in the presence of the α7 PAM PNU-120596. The analysis of binding mode and understanding of structure-activity relationship provided insights to develop more potent novel α7-nAChR agonists.


Assuntos
Descoberta de Drogas , Compostos Heterocíclicos/farmacologia , Indolizinas/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Relação Dose-Resposta a Droga , Feminino , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Indolizinas/síntese química , Indolizinas/química , Estrutura Molecular , Relação Estrutura-Atividade , Xenopus laevis
13.
J Enzyme Inhib Med Chem ; 34(1): 1534-1543, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31452407

RESUMO

A new series of triarylpyrazole derivatives having different heterocycle terminal groups have been designed and synthesised. Compounds 1h-j and 1l exhibited the highest mean percentage inhibition against the 58 cancer cell lines at a concentration of 10 µM, and thus were next examined in 5-dose testing mode to detect their IC50 value. The four compounds showed stronger antiproliferative activities upon comparing their results with sorafenib as a reference compound. Among them, compounds 1j and 1l possessing N-ethylpiperazinyl and N-benzylpiperazinyl terminal moiety through ethylene linker showed the greatest values of mean percentage inhibition (97.72 and 107.18%, respectively) over the 58-cell line panel at 10 µM concentration. The IC50 values of compound 1j over several cancer cell lines were in submicromolar scale (0.26 ∼ 0.38 µM). Moreover, the compounds 1j and 1l showed highly inhibitory activities (99.17 and 97.92%) against V600E-B-RAF kinase.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Compostos Heterocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
14.
Chem Biodivers ; 16(11): e1900291, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31469234

RESUMO

A convenient and facile methodology for N-sulfonylation of heteroaryl amines with ethyl chlorosulfonylacetate in the presence of dispersed sodium in THF under ultrasonication is reported. The corresponding heteroaryl sulfonamido esters are directly condensed with heteroaryl amines to get amido sulfonamido heteroaromatics in the presence of a mild base in THF under ultrasonication. Utilization of easy reaction conditions, shorter reaction times, and isolation of products in high yields under ultrasonication make this process as economically viable. The compounds 12c, 12d, 12f and 13f are potential antibacterial agents against B. subtilis and the compounds 12f, 13c and 13f are potential antifungal agents against A. niger.


Assuntos
Amidas/farmacologia , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Compostos Heterocíclicos/farmacologia , Sulfonamidas/farmacologia , Ultrassom , Amidas/síntese química , Amidas/química , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Aspergillus niger/efeitos dos fármacos , Bacillus subtilis/efeitos dos fármacos , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
15.
Chem Asian J ; 14(18): 3154-3160, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31318481

RESUMO

An aerobic radical approach for the synthesis of unsymmetrical heteroaryl ketones is described herein. The reaction involves cross-dehydrogenative coupling between aldehydes and heteroaromatic bases with molecular oxygen (O2 ). The key aspect of the method is the generation of reactive acyl radical via homolytic activation of aldehyde C-H bond using O2 as the sole oxidant. The reaction has a good substrate scope with respect to aldehydes and functionalized nitrogen heterocycles. Based on our mechanistic studies, a radical chain pathway is suggested for the reaction. A synthetic application of the method is demonstrated in the formal synthesis of natural alkaloid (±) angustureine.


Assuntos
Aldeídos/química , Compostos Heterocíclicos/química , Nitrogênio/química , Acilação , Radicais Livres/síntese química , Radicais Livres/química , Compostos Heterocíclicos/síntese química , Estrutura Molecular , Oxirredução
16.
Top Curr Chem (Cham) ; 377(4): 21, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31332546

RESUMO

The present review highlights the most important recent contributions toward the synthesis of functionalized fused heteroaromatic rings via intramolecular C-H activation mediated or catalyzed by transition metals. This type of reaction constitutes a versatile strategy to obtain a great variety of fused heterocyclic systems through the formation of carbon-carbon (C-C) and C-heteroatom bonds from direct coupling between two adjacent C-H bonds or C-H/H-X bonds. The  revision is focused on the synthesis of fused heterocycles through two chemical processes: (1) metal-catalyzed intramolecular oxidative C-H activation, and (2) intramolecular C-H activation mediated by metallic Lewis acids.


Assuntos
Cobre/química , Compostos Heterocíclicos/síntese química , Paládio/química , Catálise , Compostos Heterocíclicos/química , Estrutura Molecular , Elementos de Transição
17.
Eur J Med Chem ; 180: 486-508, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31330449

RESUMO

From many decades, S-heterocycles have maintained their status as an important part and core of FDA approved drugs and medicinally active compounds. With exhaustive exploration of nitrogen heterocycles in medicinal chemistry, researchers have shifted their interest towards other heterocycles, especially, S-heterocycles. Thus several attempts have been made to synthesize a variety of new sulphur containing compounds with high medicinal value and low toxicity profile, in comparison to previous N-heterocycles. Till today, S-heterocycle containing compounds have been largely reported as anticancer, antidiabetic, antimicrobial, antihypertension, antivral, antinflammatory etc. In this review, the authors have tried to provide a critical analysis of synthesis and medicinal attributes of sulphur containing heterocycles such as thiirane, thiophene, thiazole, thiopyran, thiazolidine etc reported within last five years to emphasize the significance and usefulness of these S-heterocycles in the drug discovery process.


Assuntos
Compostos Heterocíclicos/farmacologia , Enxofre/farmacologia , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Química Farmacêutica , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Enxofre/química
18.
Arch Pharm (Weinheim) ; 352(9): e1900107, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31359502

RESUMO

Recent studies on histamine receptor (HR) subtypes identified imidazolyl butyl cyanoguanidines, like UR-PI376, as highly potent agonists at the human histamine H4 receptor (hH4 R). While imidazole-containing compounds display drawbacks in pharmacokinetics, we studied the possibility of replacing the heteroaromatic cycle by nonaromatic six-membered heterocycles (piperidine, morpholine, thiomorpholine, and N-methylpiperazine) as potential bioisosteres. Beyond that, this approach should give more information about the indispensability of the aromatic ring as a basic head group. Besides these changes, a variation of the spacer length (C3 -C5 ) connecting the heterocycle and the cyanoguanidine moiety has been made to possibly trigger the selectivity towards the respective HRs. Investigations in radioligand-binding assays exhibited only very weak activity at the hH1 R and hH3 R, while nearly all compounds were inactive at the hH2 R and hH4 R. In the case of piperidine-containing compounds, moderate affinities at the hH3 R over the single-digit micromolar range were detected.


Assuntos
Guanidinas/síntese química , Compostos Heterocíclicos/síntese química , Agonistas dos Receptores Histamínicos/síntese química , Receptores Histamínicos/metabolismo , Guanidinas/química , Guanidinas/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Agonistas dos Receptores Histamínicos/química , Agonistas dos Receptores Histamínicos/farmacologia , Humanos , Ligantes , Ensaio Radioligante , Relação Estrutura-Atividade
19.
Bioconjug Chem ; 30(7): 1969-1978, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31251559

RESUMO

The ortho-hydroxy-protected aryl sulfate (OHPAS) linker is composed of a diaryl sulfate backbone equipped with a latent phenol moiety at the ortho position of one of the aryl units. The Ar-OH released when the ortho phenol undergoes intramolecular cyclization and displaces the second aryl unit can be viewed as a payload. We have shown in the preceding paper that the OHPAS linkers are highly stable chemically and in various plasmas, yet release payloads when exposed to suitable triggering conditions. As an extension of the OHPAS system, we employed a para-hydroxy benzyl (PHB) spacer for coupling to nonphenolic payloads; this tactic again provided a highly stable system capable of smooth release of appended payloads. The PHB modification works beautifully for tertiary amine and N-heterocycle payloads.


Assuntos
Aminas/química , Compostos de Benzil/química , Compostos Heterocíclicos/química , Fenol/química , Sulfatos/química , Álcoois/síntese química , Álcoois/química , Aminas/síntese química , Compostos de Benzil/síntese química , Ciclização , DNA/síntese química , DNA/química , Compostos Heterocíclicos/síntese química , Fenol/síntese química , RNA/síntese química , RNA/química , Sulfatos/síntese química
20.
Top Curr Chem (Cham) ; 377(3): 13, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31054016

RESUMO

Graphene-based carbocatalysts owing to numerous amazing properties such as large specific surface area, high intrinsic mobility, excellent thermal and electrical conductivities, chemical stability, ease of functionalization, simple method of preparation, effortless recovery and recyclability have gained a superior position amongst the conventional homogeneous and heterogeneous catalysts. In this review, an endeavor has been made to highlight the syntheses of diverse heterocyclic compounds catalyzed by graphene-based catalysts. Further, the study also reveals that all the catalysts could be reused several times without significant loss in their catalytic activity. Additionally, most of the reactions catalyzed by graphene-based carbocatalysts were carried out at ambient temperature and under solvent-free conditions. Thus, the graphene-based catalysts do not merely act as efficient catalysts but also serve as sustainable, green catalysts. This review is divided into various sub-sections, each of which comprehensively describes the preparation of a particular heterocyclic scaffold catalyzed by graphene-derived carbocatalyst in addition to synthesis of graphene oxide and reduced graphene oxide, functionalization, and structural features governing their catalytic properties. Synthesis of heterocycles catalyzed by graphene-based carbocatalysts.


Assuntos
Técnicas de Química Sintética/métodos , Grafite/química , Compostos Heterocíclicos/síntese química , Catálise , Compostos Heterocíclicos/química
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