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1.
Yakugaku Zasshi ; 140(10): 1213-1224, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999200

RESUMO

In basic pharmaceutical sciences to achieve drug development, research on the efficient chemical synthesis of small molecules having cyclic skeletons is important. We have been engaged in the development of artificial catalysts for asymmetric ring formation reactions that exclusively synthesize right-handed or left-handed cyclic compounds and have achieved the construction of optically active cyclic skeletons using our original catalysts. The synthesis of biologically active compounds was facilitated through six-membered ring construction by Diels-Alder reaction of Danishefsky diene; however, no asymmetric variant of the reaction has been achieved. We approached this unresolved issue using multi-coordinated lanthanide metals. A new chiral lanthanide catalyst was developed, and the catalytic asymmetric Diels-Alder reaction of Danishefsky diene was realized for the first time. By modifying the chemical structure of Danishefsky diene, we applied the lanthanide catalyst to the syntheses of polycyclic compounds and biologically active compounds. We achieved the asymmetric synthesis of natural products, antibacterial and antimalarial compounds, and an anti-obesity drug lead compound. Moreover, the novel catalyst exhibited higher performance than the previously reported ones. The latest generation of the catalyst can be handled stably in air at room temperature. Furthermore, we succeeded in the development of new catalysts by focusing on the properties of its metal precursors, such as nickel and indium, and achieved the construction of polycyclic skeletons by using these catalysts.


Assuntos
Compostos Heterocíclicos/síntese química , Compostos Policíclicos/síntese química , Alcenos/química , Antibacterianos/síntese química , Fármacos Antiobesidade/síntese química , Antimaláricos/síntese química , Produtos Biológicos/síntese química , Catálise , Reação de Cicloadição , Desenvolvimento de Medicamentos , Índio , Elementos da Série dos Lantanídeos/química , Níquel , Estereoisomerismo
2.
Yakugaku Zasshi ; 140(10): 1225-1233, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999201

RESUMO

This article describes our stereoselective and site-selective chemical methods for exploiting cationic heterocycles as electron-withdrawing groups (EWGs). We envisioned that the phosphoramide N-H proton of a pyridyl phosphoramide 3 would be activated by the cationic pyridinium moiety that is formed upon protonation. The resulting imide-like N-H proton and the acidic pyridinium proton of the pyridinium phosphoramide 3⋅HX cooperate together, making 3⋅HX a highly acidic dual Brønsted acid. The catalytic ability of 3⋅HX was demonstrated in the development of the first asymmetric Diels-Alder reaction between 1-amide dienes and maleimides. Focusing on the activation of N-bromosuccinimide (NBS) because of its structural similarity to maleimides, the enantioselective bromolactonization of trisubstituted olefinic acids was accomplished utilizing pyridyl phosphoramide 3f as a Brønsted base catalyst bearing an acidic N-H proton. Lastly, our strategy for the site-selective acylation of polyol compounds is described. In our system, a pyridine aldoxime ester 10, used as a mild acylating reagent, was activated by a catalytic amount of Lewis acid via the inductive effect of the cationic pyridinium moiety. The resulting metal complex preferentially attracted the alcohol with a Lewis basic site, thereby facilitating selective acylation via a template effect. This metal-template-driven strategy allowed for the site-selective acylation of diverse α-hydroxyamides, including unprotected N-glycolyl aminosugars.


Assuntos
Cátions/química , Cátions/síntese química , Química Orgânica/métodos , Desenvolvimento de Medicamentos/métodos , Elétrons , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Acilação , Amidas/química , Catálise , Complexos de Coordenação/química , Reação de Cicloadição , Ésteres/química , Compostos de Pralidoxima/química , Estereoisomerismo
3.
J Oleo Sci ; 69(8): 871-882, 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32641614

RESUMO

In this study, an N-heterocyclic carbene (NHC)-based metal coordinate surfactant (MCS), NHC-Au-MCS, in which the NHC framework afforded the bonding of the Au(I) at the linkage of the hydrophilic and hydrophobic moieties, was synthesized. The structure of NHC-Au-MCS was confirmed by 1H and 13C NMR spectroscopic measurements together with elemental analysis. Matrix-assisted laser desorption/ionization (MALDI), laser desorption/ionization (LDI), and electrospray ionization mass spectrometry (ESI-MS) indicated the distinct reactivity of NHC-Au-MCS, such as the exchange of Br to Cl and the formation of a cationic Au complex, where the two NHC ligands were coordinated to an Au(I) center upon laser activation. The surface tension and dynamic light scattering (DLS) measurements revealed that the coordination of Au(I) to NHC reduced the critical micelle concentration (CMC) of NHC-Au-MCS (1.3×10-5 M), which resulted in the formation of micelles at concentrations higher than the CMC in water. We also confirmed that the surface-active Au(I) complex of NHC-Au-MCS catalyzed the hydration of 1-dodecyne to 2-dodecanone in water in the absence of an organic solvent. On the basis of the detailed mechanistic investigations regarding the reactivity of NHC-Au-MCS, we revealed that NHC-Au-MCS partially translated into Au nanoparticles (AuNPs), which facilitated alkyne hydration. These mechanistic studies were supported by UV-vis measurements, transmission electron microscopy (TEM), and LDI-MS.


Assuntos
Alquinos/química , Ouro/química , Compostos Heterocíclicos/síntese química , Nanopartículas Metálicas/química , Metano/análogos & derivados , Tensoativos/síntese química , Catálise , Compostos Heterocíclicos/química , Hidrogenação , Interações Hidrofóbicas e Hidrofílicas , Metano/síntese química , Metano/química , Micelas , Tensoativos/química , Água
4.
Org Biomol Chem ; 18(15): 2793-2812, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32239033

RESUMO

The current review summarizes the latest achievements in the synthesis of piperidine-2,4-dione-type azaheterocycles. Two main groups traditional (carbonyl compound transformations) and novel (anionic enolate rearrangements) of complementary methods for the simple and effective preparation of structurally diverse compounds in racemic and enantiopure forms have been reported. Due to the specific structure and appropriate reactivity profiles of dione-type molecules, they are a convenient modern platform for the construction of functionalized piperidine-type systems possessing high synthetic and medicinal potential. This potential is successfully realized by the creation of highly active pharmaceutically relevant compounds and the synthesis of natural products.


Assuntos
Compostos Aza/síntese química , Produtos Biológicos/síntese química , Desenvolvimento de Medicamentos , Compostos Heterocíclicos/síntese química , Piperidonas/síntese química , Compostos Aza/química , Produtos Biológicos/química , Compostos Heterocíclicos/química , Estrutura Molecular , Piperidonas/química
5.
Nat Commun ; 11(1): 638, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005825

RESUMO

The discovery of modern medicine relies on the sustainable development of synthetic methodologies to meet the needs associated with drug molecular design. Heterocycles containing difluoromethyl groups are an emerging but scarcely investigated class of organofluoro molecules with potential applications in pharmaceutical, agricultural and material science. Herein, we developed an organophotocatalytic direct difluoromethylation of heterocycles using O2 as a green oxidant. The C-H oxidative difluoromethylation obviates the need for pre-functionalization of the substrates, metals and additives. The operationally straightforward method enriches the efficient synthesis of many difluoromethylated heterocycles in moderate to excellent yields. The direct difluoromethylation of pharmaceutical moleculars demonstrates the practicability of this methodology to late-stage drug development. Moreover, 2'-deoxy-5-difluoromethyluridine (F2TDR) exhibits promising activity against some cancer cell lines, indicating that the difluoromethylation methodology might provide assistance for drug discovery.


Assuntos
Compostos Heterocíclicos/síntese química , Catálise , Desenho de Fármacos , Descoberta de Drogas , Compostos Heterocíclicos/química , Estrutura Molecular , Oxirredução , Oxigênio/química
6.
Org Biomol Chem ; 18(7): 1279-1336, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32025682

RESUMO

Enantio- and diastereodivergent routes to marine-origin natural products with different sizes of cyclic ethers and lactones have been used in order to assign stereochemical features. Kainoid amino acids such as isodomoic acids have been synthesized using diastereodivergent routes. The bis(indole) alkaloid dragmacidin F has been prepared by enantiodivergent strategies as well as furanoterpenes and the tetracyclic agelastatin A. Natural products containing five-membered lactones like quercus lactones, muricatacins, goniofufuranones, methylenolactocins and frenolicin B have been synthesized using stereodivergent routes. Macrolides are very abundant lactones and have been mainly prepared from the corresponding seco-acids by lactonization, such as lasiodiplodin, zaeralanes, macrosphelides and haloprins, or by ring-closing metathesis, such as aspercyclides, microcarpalides, macrolides FD-891 and 892, and tetradic-5-en-9-olides. Other natural products including cyclic ethers (such as sesamin, asarinin, acetogenins, centrolobines and nabilones), alcohols (such as sulcatol), esters (such as methyl jasmonates), polycyclic precursors of fredericamycin, amino alcohols (such as ambroxol and sphingosines), isoprostanes, isofurans, polyketide precursors of anachelins, brevicomins, gummiferol, shikimic acid and the related compounds, and the pheromone disparlure have been synthesized stereodivergently. Heterocyclic systems such as epoxides, theobroxides and bromoxones, oxetan-3-ones, 5- to 8-membered cyclic ethers, azetidones, γ-lactams, oxazolidinones, bis(oxazolines), dihydropyridoisoindolines and octahydroisoquinolines have been prepared following stereodivergent routes. Stereodivergent routes to unnatural compounds such as alkenes, dienes, allenes, cyclopropanes, alcohols, aldols, amines, amino alcohols, ß-amino acids, carboxylic acids, lactones, nitriles and α-amino nitriles have been considered as well.


Assuntos
Produtos Biológicos/síntese química , Compostos Heterocíclicos/síntese química , Lactonas/síntese química , Álcoois/síntese química , Álcoois/química , Alcenos/síntese química , Alcenos/química , Aminas/síntese química , Aminas/química , Aminoácidos/síntese química , Aminoácidos/química , Produtos Biológicos/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Compostos Heterocíclicos/química , Lactonas/química , Estrutura Molecular , Nitrilos/síntese química , Nitrilos/química , Estereoisomerismo
7.
Molecules ; 25(2)2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31936773

RESUMO

Unique eleven-membered rings containing silicon, germanium, and tin were synthesized in good yields by the reactions of the corresponding 1,2-bis((2-bromothiophen-3-yl)methoxy)benzenes with (C6H5)2ECl2 where E = Sn, Ge, Si. The Sn and Ge congeners were crystallized, but the conformers that these rings crystallized in, were quite different. As confirmed by Density Functional Theory (DFT) calculations, (C28H22O2S2Sn) assumes a unique crystal structure that leaves more room around the tetrel atom as compared to the crystal structure of the corresponding Ge compound. In the latter, the central cavity is quite open, whereas in the former, one of the methylene groups can fold inwards. Another consequence is the influence on the planes of the aromatic rings flanking the heterocycle. In the Ge case, the benzene ring is folded away from the central cavity, whereas in the Sn case, it is almost parallel to the imaginary axis through the center of the ring. Thermal analysis investigations (TGA and DSC methods) of these eleven-membered rings suggested the loss of a phenyl group in the first decomposition step. The decomposition temperature decreased from the Si containing heterocycle to Ge and was lowest for the Sn containing heterocycle.


Assuntos
Germânio/química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Modelos Moleculares , Silício/química , Estanho/química , Cristalografia por Raios X
8.
Chem Rev ; 120(4): 1981-2048, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-31967451

RESUMO

In this contribution, we provide a comprehensive overview of C-H activation methods promoted by NHC-transition metal complexes, covering the literature since 2002 (the year of the first report on metal-NHC-catalyzed C-H activation) through June 2019, focusing on both NHC ligands and C-H activation methods. This review covers C-H activation reactions catalyzed by group 8 to 11 NHC-metal complexes. Through discussing the role of NHC ligands in promoting challenging C-H activation methods, the reader is provided with an overview of this important area and its crucial role in forging carbon-carbon and carbon-heteroatom bonds by directly engaging ubiquitous C-H bonds.


Assuntos
Técnicas de Química Sintética/métodos , Compostos Heterocíclicos/química , Metano/análogos & derivados , Compostos Organometálicos/química , Paládio/química , Compostos Heterocíclicos/síntese química , Imidazóis/química , Metano/química , Oxazóis/química , Tiazóis/química
9.
Molecules ; 25(3)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973234

RESUMO

A new series of nitrogen and sulfur heterocyclic systems were efficiently synthesized by linking the following four rings: indole; 1,2,4-triazole; pyridazine; and quinoxaline hybrids. The strength of the acid that catalyzes the condensation of 4-amino-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1 with aromatic aldehydes controlled the final product. Reflux in glacial acetic acid yielded Schiff bases 2-6, whereas concentrated HCl in ethanol resulted in a cyclization product at C-3 of the indole ring to create indolo-triazolo-pyridazinethiones 7-16. This fascinating cyclization approach was applicable with a wide range of aromatic aldehydes to create the target cyclized compounds in excellent yield. Additionally, the coupling of the new indolo-triazolo-pyridazinethiones 7-13 with 2,3-bis(bromomethyl)quinoxaline, as a linker in acetone and K2CO3, yielded 2,3-bis((5,6-dihydro-14H-indolo[2,3-d]-6-aryl-[1,2,4-triazolo][4,3-b]pyridazin-3 ylsulfanyl)methyl)quinoxalines 19-25 in a high yield. The formation of this new class of heterocyclic compounds in high yields warrants their use for further research. The new compounds were characterized using nuclear magnetic resonance (NMR) and mass spectral analysis. Compound 6 was further confirmed by the single crystal X-ray diffraction technique.


Assuntos
Compostos Heterocíclicos/síntese química , Indóis/síntese química , Nitrogênio/química , Piridazinas/síntese química , Quinoxalinas/síntese química , Enxofre/química , Triazóis/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Compostos Heterocíclicos/química , Ligação de Hidrogênio , Indóis/química , Conformação Molecular , Espectroscopia de Prótons por Ressonância Magnética , Piridazinas/química , Quinoxalinas/química , Triazóis/química , Difração de Raios X
10.
Molecules ; 25(2)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963527

RESUMO

Aromatic heterocycles are ubiquitous building blocks in bioactive natural products, pharmaceutical and agrochemical industries. Accordingly, the carborane-fused heterocycles would be potential candidates in drug discovery, nanomaterials, metallacarboranes, as well as photoluminescent materials. In recent years, the transition metal catalyzed B-H activation has been proved to be an effective protocol for selective functionalization of B-H bond of o-carboranes, which has been further extended for the synthesis of polyhedral borane cluster-fused heterocycles via cascade B-H functionalization/annulation process. This article summarizes the recent progress in construction of polyhedral borane cluster-fused heterocycles via B-H activation.


Assuntos
Boranos/química , Compostos Heterocíclicos/síntese química , Elementos de Transição/química , Catálise , Compostos Heterocíclicos/química , Hidrogênio/química , Estrutura Molecular
11.
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
12.
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
13.
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
14.
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
15.
DNA Repair (Amst) ; 86: 102765, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31846836

RESUMO

Cancer, also called malignancy, is a disease which is closely related with the oxidative stress instigated by the overproduction of vulnerable oxygen and nitrogen species. Available drugs are relatively painful and toxic and so are trailing their captivation. Keeping this in mind, we have attempted to reach a novel anti-cancer drug by taking a set of nineteen ligands which are hybrids of Indole-chalcone and triazole. These ligands were allowed to interact with the DNA dodecamer 5'(CGCGAATTCGCG)3' one by one using various docking protocols of Glide. Better docked complexes screened through docking scores and reported activity data were selected and exposed to molecular dynamics run of 20 ns. The dynamical pathways were investigated for each complex comparing the pre- and post- dynamics run. The outcome of the work is discussed in this paper. Among the better hybrids of this series, one of the molecules has shown interesting features, confirming its non-toxic nature and working as intercalator as well minor groove binder, perhaps making it suitable as a potent drug for further pharmacological use.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Chalconas/química , Compostos Heterocíclicos/farmacologia , Indóis/química , Triazóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular
16.
Drug Test Anal ; 12(3): 297-315, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31854124

RESUMO

Synthetic cannabinoid receptor agonists (SCRAs) first appeared on the international recreational drug market in the early 2000s in the form of SCRA-containing herbal blends. Due to the cannabimimetic effects associated with the consumption of SCRAs, they have acquired an ill-informed reputation for being cheap, safe, and legal alternatives to illicit cannabis. Possessing high potency and affinity for the human cannabinoid receptor subtype-1 (CB1 ) and -2 (CB2 ), it is now understood that the recreational use of SCRAs can have severe adverse health consequences. The major public health problem arising from SCRA use has pressed legislators around the world to employ various control strategies to curb their recreational use. To circumvent legislative control measures, SCRA manufacturers have created a wide range of SCRA analogs that contain, more recently, previously unencountered azaindole, γ-carbolinone, or carbazole heterocyclic scaffolds. At present, little information is available regarding the chemical syntheses of these newly emerging classes of SCRA, from a clandestine perspective. When compared with previous generations of indole- and indazole-type SCRAs, current research suggests that many of these heterocyclic SCRA analogs maintain high affinity and efficacy at both CB1 and CB2 but largely evade legislative control. This review highlights the importance of continued research in the field of SCRA chemistry and pharmacology, as recreational SCRA use remains a global public health issue and represents a serious control challenge for law enforcement agencies.


Assuntos
Agonistas de Receptores de Canabinoides/química , Agonistas de Receptores de Canabinoides/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Animais , Agonistas de Receptores de Canabinoides/síntese química , Compostos Heterocíclicos/síntese química , Humanos , Drogas Ilícitas/síntese química , Drogas Ilícitas/química , Drogas Ilícitas/farmacologia , Estrutura Molecular
17.
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
18.
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
19.
Molecules ; 24(23)2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31757097

RESUMO

An effective approach for amino protection and construction of a seven-membered ring has been developed. The method uses imidazolium chloride to carry out the Michael addition reaction at low temperatures and perform amino deprotection or construction of a seven-membered ring at high temperatures.


Assuntos
Compostos Heterocíclicos , Imidazóis/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química
20.
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
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