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1.
Eur J Med Chem ; 178: 341-351, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31200236

RESUMO

Cancer is one of the main causes of death throughout the world. The anticancer agents are indispensable for the treatment of various cancers, but most of them currently on the market are not specific, resulting in series of side effects of chemotherapy. Moreover, the emergency of drug-resistance towards cancers has already increased up to alarming level in the recent decades. Therefore, it's imperative to develop novel anticancer candidates with excellent activity against both drug-susceptible and drug-resistant cancers, and low toxicity as well. Tetrazole is the bioisoster of carboxylic acid, and its derivatives demonstrated promising anticancer activity. Hybridization of tetrazole with other anticancer pharmacophores may provide novel candidates with anticancer potency. The present review described the anticancer activity of tetrazole hybrids, and the structure-activity relationship (SAR) is also discussed to provide an insight for rational designs of tetrazole anticancer candidates with higher efficiency.


Assuntos
Antineoplásicos/farmacologia , Tetrazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
2.
Microb Pathog ; 132: 59-65, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31002962

RESUMO

The present study was aimed to synthesize and evaluate tetrazoles of baicalin against Pneumocystis carinii pneumonia in the rat model. Among the seven synthesized baicalin tetrazoles, one with trifloromethyl group in the aromatic ring was found to be most potent during the initial study. The mechanism of preventive effect of most potent compound 4c against Pneumocystis carinii pneumonia was investigated in detail. The compound 4c decreased the parasitic load by almost 99% in the rats. It significantly (P < 0.05) decreased mortality rate of the rats, prevented pulmonary tissue damage and aggregation of inflammatory cytokines. In Pneumocystis carinii infected rats compound 4c treatment inhibited production of interleukin-18, interleukin-1ß and TNF-α significantly (P < 0.05) in the BALF and pulmonary tissues. Treatment of the pneumocystis carinii-infected rats with compound 4c inhibited up-regulation of mRNA expression corresponding NLRP3, ASC and caspase-1. The compound 4c treatment of the pneumocystis carinii-infected rats significantly (P < 0.02) suppressed the level of NLRP3 and ASC proteins. Moreover, the enhancement of caspase-1 activation by pneumocystis carinii-infection in rats was also suppressed by compound 4c. The results from present study demonstrate that compound 4c protects pneumocystis carinii induced pneumonia through suppression of inflammatory cytokines and NLRP3 activation. Therefore, compound 4c can be of therapeutic importance for the treatment of pneumocystis carinii induced pneumonia.


Assuntos
Antifúngicos/farmacologia , Flavonoides/farmacologia , Hospedeiro Imunocomprometido , Pneumocystis carinii/efeitos dos fármacos , Pneumonia por Pneumocystis/prevenção & controle , Tetrazóis/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antifúngicos/química , Líquido da Lavagem Broncoalveolar/química , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/metabolismo , Citocinas , Modelos Animais de Doenças , Flavonoides/síntese química , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Pulmão/patologia , Mortalidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia por Pneumocystis/patologia , RNA Mensageiro/metabolismo , Ratos , Tetrazóis/síntese química , Fator de Necrose Tumoral alfa/metabolismo
3.
Bioorg Med Chem Lett ; 29(6): 791-796, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30718161

RESUMO

The present study describes the discovery and characterization of a series of 5-aryl-2H-tetrazol-3-ylacetamides as G protein-gated inwardly-rectifying potassium (GIRK) channels activators. Working from an initial hit discovered during a high-throughput screening campaign, we identified a tetrazole scaffold that shifts away from the previously reported urea-based scaffolds while remaining effective GIRK1/2 channel activators. In addition, we evaluated the compounds in Tier 1 DMPK assays and have identified a (3-methyl-1H-pyrazol-1-yl)tetrahydrothiophene-1,1-dioxide head group that imparts interesting and unexpected microsomal stability compared to previously-reported pyrazole head groups.


Assuntos
Acetamidas/farmacologia , Descoberta de Drogas , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/agonistas , Pirazóis/farmacologia , Tetrazóis/farmacologia , Acetamidas/síntese química , Acetamidas/química , Animais , Células HEK293 , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
4.
Mol Pharm ; 16(3): 1255-1271, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30681344

RESUMO

Renin-angiotensin aldosterone system inhibitors are for a long time extensively used for the treatment of cardiovascular and renal diseases. AT1 receptor blockers (ARBs or sartans) act as antihypertensive drugs by blocking the octapeptide hormone Angiotensin II to stimulate AT1 receptors. The antihypertensive drug candesartan (CAN) is the active metabolite of candesartan cilexetil (Atacand, CC). Complexes of candesartan and candesartan cilexetil with 2-hydroxylpropyl-ß-cyclodextrin (2-HP-ß-CD) were characterized using high-resolution electrospray ionization mass spectrometry and solid state 13C cross-polarization/magic angle spinning nuclear magnetic resonance (CP/MAS NMR) spectroscopy. The 13C CP/MAS results showed broad peaks especially in the aromatic region, thus confirming the strong interactions between cyclodextrin and drugs. This experimental evidence was in accordance with molecular dynamics simulations and quantum mechanical calculations. The synthesized and characterized complexes were evaluated biologically in vitro. It was shown that as a result of CAN's complexation, CAN exerts higher antagonistic activity than CC. Therefore, a formulation of CC with 2-HP-ß-CD is not indicated, while the formulation with CAN is promising and needs further investigation. This intriguing result is justified by the binding free energy calculations, which predicted efficient CC binding to 2-HP-ß-CD, and thus, the molecule's availability for release and action on the target is diminished. In contrast, CAN binding was not favored, and this may allow easy release for the drug to exert its bioactivity.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Benzimidazóis/química , Compostos de Bifenilo/química , Composição de Medicamentos/métodos , Pró-Fármacos/química , Tetrazóis/química , Proteínas Adaptadoras de Transdução de Sinal/química , Benzimidazóis/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Células HEK293 , Humanos , Ligações de Hidrogênio , Conformação Molecular , Simulação de Dinâmica Molecular , Sistema Renina-Angiotensina , Espectrometria de Fluorescência , Espectrometria de Massas por Ionização por Electrospray , Tetrazóis/síntese química
5.
Eur J Med Chem ; 164: 562-575, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30634084

RESUMO

Nuclear receptor RXRα plays an important role in many biological and pathological processes. The nongenomic action of RXRα is implicated in many cancers. K-8008, a non-canonical RXRα ligand derived from sulindac, inhibits the TNFα-activated PI3K/AKT pathway by mediating the interaction between a truncated form of RXRα (tRXRα) and the p85α regulatory subunit of PI3K and exerts potent anticancer activity in animal model. Herein we report our studies of a novel series of K-8008 analogs as potential anticancer agents targeting RXRα. Two compounds 8b and 18a were identified to have slightly stronger binding to RXRα and improved apoptotic activities in breast cancer cells.


Assuntos
Antineoplásicos/síntese química , Desenho de Drogas , Receptor X Retinoide alfa , Tetrazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Humanos , Ligantes , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tetrazóis/síntese química , Tetrazóis/química , Tetrazóis/metabolismo , Fator de Necrose Tumoral alfa
6.
Bioorg Med Chem Lett ; 29(2): 172-178, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30528695

RESUMO

A series of novel tetrazole analogues of resveratrol were synthesized and evaluated for their anti-leukemic activity against an extensive panel of human cancer cell lines and against the MV4-11 AML cell line. These molecules were designed as drug-like derivatives of the resveratrol analogue DMU-212 and its cyano derivatives. Four compounds 8g, 8h, 10a and 10b exhibited LD50 values of 4.60 µM, 0.02 µM, 1.46 µM, and 1.08 µM, respectively, against MV4-11 leukemia cells. The most potent compounds, 8h and 10b, were also found to be active against an extensive panel of human hematological and solid tumor cell lines; compound 8h was the most potent compound with GI50 values <10 nM against more than 90% of the human cancer cell lines in the 60-cell panel. Analogues 8g, 8h, 10a and 10b were also tested for their ability to inhibit the polymerization of tubulin, and compound 8h was found to be the most potent analogue. Molecular modeling studies demonstrated that 8h binds to the colchicine binding site on tubulin. Thus, compound 8h is considered to be a lead druglike molecule from this tetrazole series of compounds.


Assuntos
Antineoplásicos/farmacologia , Tetrazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
7.
Eur J Med Chem ; 163: 404-412, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30530192

RESUMO

Tetrazole, a bioisostere of the carboxylic acid group, can replace the carboxyl group in drugs to increase the lipophilicity, bioavailability and reduce side effects. Tetrazole derivatives possess a broad-spectrum of biological properties including anti-tubercular and anti-malarial activities, and some tetrazole-based compounds have already been used in clinics for the treatment of various diseases. Therefore, tetrazole is an important pharmacophore in the development of new drugs. This review covers the recent advances of tetrazole derivatives as potential anti-tubercular and anti-malarial agents, and the structure-activity relationship is also discussed for the further rational design of tetrazole derivatives.


Assuntos
Antimaláricos/química , Antituberculosos/química , Tetrazóis/farmacocinética , Animais , Antimaláricos/farmacologia , Antituberculosos/farmacologia , Humanos , Relação Estrutura-Atividade , Tetrazóis/efeitos adversos , Tetrazóis/síntese química , Tetrazóis/farmacologia
8.
J Enzyme Inhib Med Chem ; 34(1): 144-149, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30427224

RESUMO

Recently, we have described a method for evaluation of plasma amine oxidase (PAO) inhibitors, which monitors the formation of 6-(5-phenyl-2H-tetrazol-2-yl)hexanal from the corresponding amine substrate by HPLC with UV-detection using purified bovine PAO. We now investigated, whether crude bovine plasma can be used as enzyme source in this assay instead of the purified enzyme. With the aid of specific inhibitors, it was ensured that there was no detectable activity of other important amine oxidases in the plasma, namely monoamine oxidase (MAO) A and B and diamine oxidase (DAO). For a series of ω-(5-phenyl-2H-tetrazol-2-yl)alkan-1-amine substrates similar conversion rates were measured for both the purified PAO and crude plasma. The inhibition values determined for the PAO inhibitor 2-(4-phenylphenyl)acetohydrazide (16) under different conditions also corresponded. Additionally, inhibition data of the known PAO inhibitor 2-amino-N-(3-phenylbenzyl)acetamide (17) and a newly synthesised meta-substituted derivative of 16 were determined, which together reflect the two-step inhibition mechanism of these covalent inhibitors.


Assuntos
Cromatografia Líquida de Alta Pressão , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/sangue , Monoaminoxidase/metabolismo , Plasma/enzimologia , Tetrazóis/farmacologia , Raios Ultravioleta , Animais , Bovinos , Relação Dose-Resposta a Droga , Estrutura Molecular , Monoaminoxidase/isolamento & purificação , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
9.
Bioorg Med Chem Lett ; 29(1): 66-72, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30455151

RESUMO

A series of novel Benzofuran-tetrazole derivatives were successfully synthesised by integrating multicomponent Ugi-azide reaction with the molecular hybridization approach. Interestingly, a number of synthesized derivatives (5c, 5d, 5i, 5l, 5q and 5s) exhibited significant reduction of aggregation of "human" amyloid beta peptide, expressing on transgenic Caenorhabditis elegans (C. elegans) strain CL4176. Further, in silico docking results have evidenced the exquisite interaction of active compounds with the help of TcAChE-E2020 complex. These findings underscore the potential of these hybrids as lead molecules against Alzheimers's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzofuranos/farmacologia , Inibidores da Colinesterase/farmacologia , Simulação de Dinâmica Molecular , Tetrazóis/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/microbiologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Benzofuranos/síntese química , Benzofuranos/química , Caenorhabditis elegans/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
10.
Eur J Med Chem ; 163: 481-499, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30544037

RESUMO

The Escherichia coli neutral M1-aminopeptidase (ePepN) is a novel target identified for the development of antimicrobials. Here we describe a solid-phase multicomponent approach which enabled the discovery of potent ePepN inhibitors. The on-resin protocol, developed in the frame of the Distributed Drug Discovery (D3) program, comprises the implementation of parallel Ugi-azide four-component reactions with resin-bound amino acids, thus leading to the rapid preparation of a focused library of tetrazole-peptidomimetics (TPMs) suitable for biological screening. By dose-response studies, three compounds were identified as potent and selective ePepN inhibitors, as little inhibitory effect was exhibited for the porcine ortholog aminopeptidase. The study allowed for the identification of the key structural features required for a high ePepN inhibitory activity. The most potent and selective inhibitor (TPM 11) showed a non-competitive inhibition profile of ePepN. We predicted that both diastereomers of compound TPM 11 bind to a site distinct from that occupied by the substrate. Theoretical models suggested that TPM 11 has an alternative inhibition mechanism that doesn't involve Zn coordination. On the other hand, the activity landscape analysis provided a rationale for our findings. Of note, compound TMP 2 showed in vitro antibacterial activity against Escherichia coli. Furthermore, none of the three identified inhibitors is a potent haemolytic agent, and only two compounds showed moderate cytotoxic activity toward the murine myeloma P3X63Ag cells. These results point to promising compounds for the future development of rationally designed TPMs as antibacterial agents.


Assuntos
Aminopeptidases/antagonistas & inibidores , Antibacterianos/síntese química , Descoberta de Drogas , Escherichia coli/enzimologia , Peptidomiméticos/síntese química , Tetrazóis/síntese química , Animais , Antibacterianos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Escherichia coli/efeitos dos fármacos , Humanos , Camundongos , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Técnicas de Síntese em Fase Sólida
11.
ACS Sens ; 4(1): 44-51, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30540170

RESUMO

Photoclickable fluorogenic probes will enable visualization of specific biomolecules with precise spatiotemporal control in their native environment. However, the fluorogenic tagging of DNA with current photocontrolled clickable probes is still challenging. Herein, we demonstrated the fast (19.5 ± 2.5 M-1 s-1) fluorogenic labeling and imaging of DNA in vitro and in vivo with rationally designed coumarin-fused tetrazoles under UV LED photoirradiation. With a water-soluble, nuclear-specific coumarin-fused tetrazole (CTz-SO3), the metabolically synthesized DNA in cultured cells was effectively labeled and visualized, without fixation, via "photoclick" reaction. Moreover, the photoclickable CTz-SO3 enabled real-time, spatially controlled imaging of DNA in live zebrafish.


Assuntos
Cumarínicos/química , DNA/análise , Corantes Fluorescentes/química , Tetrazóis/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Click , Cumarínicos/síntese química , Cumarínicos/efeitos da radiação , Reação de Cicloadição , DNA/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Humanos , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Tetrazóis/síntese química , Tetrazóis/efeitos da radiação , Raios Ultravioleta , Peixe-Zebra
12.
Eur J Med Chem ; 163: 690-709, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30572179

RESUMO

To develop novel therapeutic agents with anticancer activities, two series of novel 7-amino-[1,2,4]triazolo[4,3-f]pteridinone, and 7-aminotetrazolo[1,5-f]pteridinone derivatives were designed and synthesized. All compounds were tested for anti-proliferative activities against five cancer cell lines. The structure-activity relationships (SARs) studies were conducted through the variation in two regions, the moiety of A ring and the terminal aniline B on pteridinone core. 1-Methyl-1,2,4-triazole derivative L7 with 2,6-dimethylpiperazine showed the most potent antiproliferative activity against A549, PC-3, HCT116, MCF-7 and MDA-MB-231 cell lines with IC50 values of 0.16 µM, 0.30 µM, 0.51 µM, 0.30 µM, and 0.70 µM, respectively. Combined with the results of the molecular docking and enzymatic studies, the PLK1 was very likely to be one of the drug targets of compound L7. Furthermore, to clarify the anticancer mechanism of compound L7, further explorations in the bioactivity were conducted. The results showed that compound L7 obviously inhibited proliferation of A549 cell lines, induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells, suppressed the migration of tumor cells, and arrested G1 phase of A549 cells.


Assuntos
Antineoplásicos/química , Desenho de Drogas , Pteridinas/farmacologia , Tetrazóis/farmacologia , Triazóis/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Simulação de Acoplamento Molecular , Pteridinas/síntese química , Relação Estrutura-Atividade , Tetrazóis/síntese química , Triazóis/síntese química
13.
Eur J Med Chem ; 164: 106-120, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30594027

RESUMO

The increase of opportunistic fungal infections raises the need for design and synthesis of new antifungal agents. Taking into account that tetrazole derivatives exhibit antifungal activity, and some of them are in the phase of clinical trials, new tetrazole derivatives bearing pyrrolidine moiety were synthesized in order to present their action mode against C. albicans. The target compounds were obtained by N-alkylation of various 2-arylpyrrolidines with several 1-(3-chloropropyl)-5-aryl-2H-tetrazoles. Regardless of the substituents at tetrazole or pyrrolidine rings reactions took place in 48 h and with satisfactory yields ranging from 53 to 70%. We performed screen of the synthesized compounds to identify these nontoxic inhibiting the C. albicans planktonic and sessile cells, and conducted a series of follow up studies to examine the in vitro and in vivo activity of the most potent antifungals. The leading antifungal inhibitor: 2-{3-[2-(3-Methylphenyl)pyrrolidin-1-yl]propyl}-5-phenyl-2H-tetrazole (3aC) and the randomly selected ones: 5-phenyl-2-[3-(2-phenylpyrrolidin-1-yl)propyl]-2H-tetrazole (3aA), 5-(4-chlorophenyl)-2-{3-[2-(4-fluorophenyl)pyrrolidin-1-yl]propyl}-2H-tetrazole (3cD), and 5-(4-chlorophenyl)-2-{3-[2-(4-chlorophenyl)pyrrolidin-1-yl]propyl}-2H-tetrazole (3cE) showed little to no toxicity against the Vero cell line and Galleria mellonella. 3aC and 3aD, the most active against biofilm in vitro, demonstrated in vivo activity in the invertebrate model of disseminated candidiasis. Flow cytometry analysis showed that necrotic cell death was generated under 3aC due to its interactions with the fungal membrane; this confirmed by the mitochondrial damage (XTT assay) and reduced adhesion to the TR-146 cell line at 46.05 µM. Flow cytometry was used to directly measure the redox state of the treated cells with the fluorescent DCFH probe. Pro-necrotic tetrazole derivatives (3aA, 3aC, 3cD) are unable to induce ROS production in the C. albicans cells. Moreover, CLSM analyses revealed that the tetrazole derivatives (principally 3aC, 3aD, and 3aE) inhibit C. albicans' ability to neutralize macrophages; a more effective phagosomes organisation was observed. 3aC's and 3aD's activity reflected in an attenuation of virulence in disseminated candidiasis in vivo.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Pirrolidinas/farmacologia , Tetrazóis/farmacologia , Alquilação , Animais , Antifúngicos/síntese química , Antifúngicos/química , Biofilmes/efeitos dos fármacos , Candidíase/tratamento farmacológico , Linhagem Celular , Necrose/induzido quimicamente , Pirrolidinas/química , Relação Estrutura-Atividade , Tetrazóis/síntese química , Virulência/efeitos dos fármacos
14.
Acta Crystallogr C Struct Chem ; 74(Pt 11): 1413-1419, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30398196

RESUMO

3,5-Bis[(1H-tetrazol-5-yl)methyl]-4H-1,2,4-triazol-4-amine (H2L) associates under deprotonation with CuSO4 in aqueous medium to form a new waisted barrel-shaped M6L4 cluster, namely hexaaquatetrakis{µ4-3,5-bis[(1H-tetrazol-5-yl)methyl]-4H-1,2,4-triazol-4-amine}-µ4-sulfato-hexacopper(II) sulfate hydrate, [Cu6(SO4)(C6H6N12)4(H2O)6]SO4·nH2O (n = ∼23) (1). Cluster 1 resembles concave cucurbit[6]uril and has one disordered sulfate anion trapped inside the cage, which additionally stabilizes the Cu6 unit. The CuII ions have either a square-pyramidal or a distorted octahedral geometry. The equatorial positions are filled by N atoms from the L2- ligand, while the axial positions are occupied by coordinated water molecules and O atoms of the sulfate counter-ion. In the solid state, the Cu6 clusters are connected through a large number of hydrogen bonds formed by uncoordinated water molecules and an additional sulfate anion. The compound shows good antimicrobial activity against E. coli tested with the Kirby Bauer approach. In addition, the cell viability towards HeLa and L-929 cells was studied.


Assuntos
Antibacterianos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Complexos de Coordenação/farmacologia , Tetrazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/toxicidade , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Cobre/química , Cristalografia por Raios X , Escherichia coli/efeitos dos fármacos , Células HeLa , Humanos , Ligações de Hidrogênio , Ligantes , Camundongos , Estrutura Molecular , Tetrazóis/síntese química , Tetrazóis/química , Tetrazóis/toxicidade , Água/química
15.
ACS Chem Biol ; 13(9): 2585-2594, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30138566

RESUMO

Indole-3-acetic acid (auxin) is considered one of the cardinal hormones in plant growth and development. It regulates a wide range of processes throughout the plant. Synthetic auxins exploit the auxin-signaling pathway and are valuable as herbicidal agrochemicals. Currently, despite a diversity of chemical scaffolds all synthetic auxins have a carboxylic acid as the active core group. By applying bio-isosteric replacement we discovered that indole-3-tetrazole was active by surface plasmon resonance spectrometry, showing that the tetrazole could initiate assembly of the Transport Inhibitor Resistant 1 (TIR1) auxin coreceptor complex. We then tested the tetrazole's efficacy in a range of whole plant physiological assays and in protoplast reporter assays, which all confirmed auxin activity, albeit rather weak. We then tested indole-3-tetrazole against the AFB5 homologue of TIR1, finding that binding was selective against TIR1, absent with AFB5. The kinetics of binding to TIR1 are contrasted to those for the herbicide picloram, which shows the opposite receptor preference, as it binds to AFB5 with far greater affinity than to TIR1. The basis of the preference of indole-3-tetrazole for TIR1 was revealed to be a single residue substitution using molecular docking, and assays using tir1 and afb5 mutant lines confirmed selectivity in vivo. Given the potential that a TIR1-selective auxin might have for unmasking receptor-specific actions, we followed a rational design, lead optimization campaign, and a set of chlorinated indole-3-tetrazoles was synthesized. Improved affinity for TIR1 and the preference for binding to TIR1 was maintained for 4- and 6-chloroindole-3-tetrazoles, coupled with improved efficacy in vivo. This work expands the range of auxin chemistry for the design of receptor-selective synthetic auxins.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Proteínas F-Box/metabolismo , Herbicidas/metabolismo , Ácidos Indolacéticos/metabolismo , Reguladores de Crescimento de Planta/metabolismo , Receptores de Superfície Celular/metabolismo , Tetrazóis/metabolismo , Arabidopsis/crescimento & desenvolvimento , Halogenação , Herbicidas/síntese química , Herbicidas/química , Ácidos Indolacéticos/síntese química , Ácidos Indolacéticos/química , Simulação de Acoplamento Molecular , Reguladores de Crescimento de Planta/síntese química , Reguladores de Crescimento de Planta/química , Ligação Proteica , Tetrazóis/síntese química , Tetrazóis/química
16.
Org Biomol Chem ; 16(29): 5241-5244, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-29995029

RESUMO

A panel of sterically shielded tetrazoles with different N-aryl groups were synthesized and subsequently evaluated in the photoinduced tetrazole-alkene cycloaddition reaction. It was found that increase in the HOMO energy of the corresponding nitrile imines leads to a faster cycloaddition reaction along with a red shift in the fluorescence emission of the pyrazoline cycloadduct.


Assuntos
Química Click , Corantes Fluorescentes/química , Tetrazóis/química , Ciclização , Fluorescência , Pirazóis/química , Tetrazóis/síntese química
17.
Bioorg Chem ; 79: 201-211, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29772470

RESUMO

5-Aryl-1H-tetrazoles (1-24) were synthesized and screened for their xanthine oxidase (XO) inhibitory activity using allopurinol as standard inhibitor (IC50 = 2.0 ±â€¯0.01 µM). Six compounds 3, 4, 5, 9, 21, and 24 exhibited significant to weak activities with IC50 values in the range of 7.4-174.2 µM. Active compounds were further subjected to kinetic and molecular docking studies to deduce their modes of inhibition, and to study their interactions with the protein (XO) at atomic level, respectively. Interestingly, all these compounds showed a competitive mode of inhibition. Docking studies identified several important interactions between the ligand and the receptor protein (XO). Some of these interactions were similar to that exhibited by clinical inhibitors of XO (allopurinol, and febuxostat). This study identifies 5-aryl-1H-tetrazoles as a new class of xanthine oxidase inhibitors, which deserves to be further, investigated for the treatment of hyperuricemia and gout.


Assuntos
Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Tetrazóis/farmacologia , Xantina Oxidase/antagonistas & inibidores , Alopurinol/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Cinética , Estrutura Molecular , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química , Xantina Oxidase/metabolismo
18.
Chem Commun (Camb) ; 54(35): 4449-4452, 2018 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-29652063

RESUMO

Three γ-heteroatom-substituted N-methylpyrroletetrazole-lysines (mPyTXKs) were synthesized and subsequently incorporated into proteins site-specifically via genetic code expansion. The γ-seleno-substituted derivative, mPyTSeK, showed excellent incorporation efficiency in Escherichia coli and allowed site-selective photo-cross-linking of the GST dimer. Furthermore, the mPyTSeK-cross-linked GST dimer can be cleaved under mild oxidative conditions. The incorporation of mPyTXKs into proteins in mammalian cells was also demonstrated. Lastly, the recombinantly expressed mPyTSeK-encoded Grb2 was shown to covalently capture its interaction partner, EGFR, in mammalian cell lysate, which was subsequently released after treatment with H2O2.


Assuntos
Reagentes para Ligações Cruzadas/efeitos da radiação , Glutationa Transferase/genética , Lisina/análogos & derivados , Lisina/genética , Engenharia de Proteínas , Tetrazóis/efeitos da radiação , Animais , Reagentes para Ligações Cruzadas/síntese química , Reagentes para Ligações Cruzadas/toxicidade , Receptores ErbB/química , Receptores ErbB/genética , Receptores ErbB/efeitos da radiação , Escherichia coli , Proteína Adaptadora GRB2/química , Proteína Adaptadora GRB2/genética , Proteína Adaptadora GRB2/efeitos da radiação , Glutationa Transferase/química , Glutationa Transferase/efeitos da radiação , Células HEK293 , Humanos , Peróxido de Hidrogênio/química , Lisina/efeitos da radiação , Lisina/toxicidade , Schistosoma japonicum , Tetrazóis/síntese química , Tetrazóis/toxicidade , Raios Ultravioleta
19.
Chembiochem ; 19(12): 1326-1333, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29385317

RESUMO

BODIPY-linked bithiophene-tetrazoles were designed and synthesized for bioorthogonal photoclick reactions in vitro and in vivo. The reactivity of these tetrazoles toward dimethyl fumarate was found to depend on the BODIPY attachment site, with the meta-linked BODIPY-tetrazole being the most reactive. The resulting pyrazoline cycloadduct showed drastically reduced BODIPY fluorescence. However, BODIPY fluorescence recovered after treatment with hydrogen peroxide. This turn-on effect was attributed to conversion from the pyrazoline to a pyrazole. Finally, we showed that this unique BODIPY-tetrazole off-on fluorescence probe can be used to detect hydrogen peroxide inside HeLa cells.


Assuntos
Compostos de Boro/química , Corantes Fluorescentes/química , Peróxido de Hidrogênio/análise , Tetrazóis/química , Compostos de Boro/síntese química , Química Click/métodos , Fluorescência , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Microscopia Confocal/métodos , Imagem Óptica/métodos , Tetrazóis/síntese química
20.
Org Lett ; 20(5): 1275-1278, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29466017

RESUMO

Direct oxidative deamination of glyoxal-derived Ugi-azide and Ugi three-component reaction products readily affords vicinal tricarbonyls (α,ß-diketoamides) and α,ß-diketotetrazoles with two diversity elements. This significant extension of our previously described multicomponent reaction-oxidative deamination methodology is proposed to proceed through a mechanistically distinct SeO2-mediated C-N oxidation derived from an active enol of α-amino-ß-ketone systems, effectively an aza-Riley oxidation. This methodology accesses diverse VTC systems from prototypical amines, glyoxaldehydes, and isocyanide building blocks in a mere two steps.


Assuntos
Amidas/síntese química , Azidas/química , Cetonas/síntese química , Tetrazóis/síntese química , Álcoois/química , Aldeídos/química , Aminas/química , Cianetos/química , Desaminação , Estrutura Molecular , Oxirredução , Óxidos de Selênio/química , Temperatura Ambiente
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