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2.
Chem Biodivers ; 16(10): e1900377, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31436917

RESUMO

The series of novel Mannich bases were synthesized and evaluated for their in vitro antibacterial activity against Gram-positive and Gram-negative bacterial strains. The results showed that all compounds were less active than the drugs used as reference, but some of them had moderate potency against Staphylococcus epidermidis ATCC 12228 and Bacillus subtilis ATCC 6633. The presence of a phenyl ring in the position 4 of piperazine seems to be necessary for antibacterial activity in this class of compounds.


Assuntos
Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Bases de Mannich/química , Staphylococcus epidermidis/efeitos dos fármacos , Triazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Triazóis/síntese química , Triazóis/química
3.
Eur J Med Chem ; 179: 449-469, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271958

RESUMO

In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4ß2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [18F] radiolabelled derivatives. It can be expected from our results that some of these compounds will be suitable for further developments and will have effects on cognitive disorders.


Assuntos
Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/tratamento farmacológico , Radioisótopos de Flúor/química , Marcação por Isótopo , Agonistas Nicotínicos/farmacologia , Tomografia por Emissão de Pósitrons , Quinuclidinas/farmacologia , Triazóis/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Transtornos Cognitivos/metabolismo , Relação Dose-Resposta a Droga , Ligantes , Estrutura Molecular , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Quinuclidinas/síntese química , Quinuclidinas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Células Tumorais Cultivadas , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
4.
J Enzyme Inhib Med Chem ; 34(1): 1210-1217, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31286781

RESUMO

In this study, a series of 4,5-bis(substituted phenyl)-4H-1,2,4-triazol-3-amine compounds was designed, synthesised, and evaluated to determine their potential as anti-lung cancer agents. According to the results of screening of lung cancer cell lines A549, NCI-H460, and NCI-H23 in vitro, most of the synthesised compounds have potent cytotoxic activities with IC50 values ranging from 1.02 to 48.01 µM. Particularly, compound 4,5-bis(4-chlorophenyl)-4H-1,2,4-triazol-3-amine (BCTA) was the most potent anti-cancer agent, with IC50 values of 1.09, 2.01, and 3.28 µM against A549, NCI-H460, and NCI-H23 cells, respectively, meaning many-fold stronger anti-lung cancer activity than that of the chemotherapeutic agent 5-fluorouracil. We also explored the effects of BCTA on apoptosis in lung cancer cells by flow cytometry and western blotting. Our results indicated that BCTA induced apoptosis by upregulating proteins BAX, caspase 3, and PARP. Thus, the potential application of compound BCTA as a drug should be further examined.


Assuntos
Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Triazóis/síntese química , Triazóis/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Triazóis/química
5.
Eur J Med Chem ; 179: 182-195, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254920

RESUMO

A series of (1,2,4)triazole[4,3-a]pyridine (TZP) derivatives have been designed and synthesized. Compound 8d was identified as having the most potent inhibitory activity on NO release in response to lipopolysaccharide (LPS) stimulation and inhibition of the migration induced by MCP-1 protein on RAW264.7 macrophages. Based on the screening data, an immunofluorescence assay and a real-time qPCR assay were conducted, indicating that compound 8d suppressed NF-κB p65 translocation and expression of inflammatory genes by concanavalin A (Con A)-induced RAW264.7 macrophages. More importantly, 8d also exhibited potent efficacy, alleviating Con A-induced hepatitis by downregulating the levels of plasma alanine transaminase (ALT), aspartate transaminase (AST) and inflammatory infiltration in a mouse autoimmune hepatitis (AIH) model. In addition, the flow cytometry (FCM) data showed that compound 8d inhibited the accumulation of MDSCs in the liver of Con A-induced mice. These findings raise the possibility that compound 8d might serve as a potential agent for the treatment of AIH.


Assuntos
Concanavalina A/antagonistas & inibidores , Hepatite/tratamento farmacológico , Piridinas/farmacologia , Triazóis/farmacologia , Animais , Sobrevivência Celular , Células Cultivadas , Concanavalina A/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Drogas , Feminino , Hepatite/metabolismo , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Óxido Nítrico/análise , Óxido Nítrico/biossíntese , Piridinas/síntese química , Piridinas/química , Células RAW 264.7 , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
6.
Eur J Med Chem ; 177: 362-373, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158750

RESUMO

Inhibiting the decomposition of carbohydrates into glucose or promoting glucose conversion is considered to be an effective treatment for type 2 diabetes. Herein, a series of novel xanthone-triazole derivatives were designed, synthesized, and their α-glucosidase inhibitory activities and glucose uptake in HepG2 cells were investigated. Most of the compounds showed better inhibitory activities than the parental compound a (1,3-dihydroxyxanthone, IC50 = 160.8 µM) and 1-deoxynojirimycin (positive control, IC50 = 59.5 µM) towards α-glucosidase. Compound 5e was the most potent inhibitor, with IC50 value of 2.06 µM. The kinetics of enzyme inhibition showed that compounds 5e, 5g, 5h, 6c, 6d, 6g and 6h were noncompetitive inhibitors, and molecular docking results were consistent with the noncompetitive property that these compounds bind to allosteric sites away from the active site (Asp214, Glu276 and Asp349). On the other hand, the glucose uptake assays exhibited that compounds 5e, 6a, 6c and 7g displayed high activities in promoting the glucose uptake. The cytotoxicity assays showed that most compounds were low-toxic to human normal hepatocyte cell line (LO2). These novel xanthone triazole derivatives exhibited dual therapeutic effects of α-glucosidase inhibition and glucose uptake promotion, thus they could be use as antidiabetic agents for developing novel drugs against type 2 diabetes.


Assuntos
Glucose/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , Triazóis/farmacologia , Xantonas/farmacologia , Sítios de Ligação , Desenho de Drogas , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/toxicidade , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/metabolismo , Hipoglicemiantes/toxicidade , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/toxicidade , Xantonas/síntese química , Xantonas/metabolismo , Xantonas/toxicidade , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
7.
J Agric Food Chem ; 67(22): 6143-6149, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31083983

RESUMO

Strigolactones (SLs) are one of the plant hormones that control several important agronomic traits, such as shoot branching, leaf senescence, and stress tolerance. Manipulation of the SL biosynthesis can increase the crop yield. We previously reported that a triazole derivative, TIS108, inhibits SL biosynthesis. In this study, we synthesized a number of novel TIS108 derivatives. Structure-activity relationship studies revealed that 4-(2-phenoxyethoxy)-1-phenyl-2-(1 H-1,2,4-triazol-1-yl)butan-1-one (KK5) inhibits the level of 4-deoxyorobanchol in roots more strongly than TIS108. We further found that KK5-treated Arabidopsis showed increased branching phenotype with the upregulated gene expression of AtMAX3 and AtMAX4. These results indicate that KK5 is a specific SL biosynthesis inhibitor in rice and Arabidopsis.


Assuntos
Reguladores de Crescimento de Planta/antagonistas & inibidores , Terpenos/antagonistas & inibidores , Triazóis/química , Triazóis/farmacologia , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Oryza/efeitos dos fármacos , Oryza/genética , Oryza/metabolismo , Reguladores de Crescimento de Planta/biossíntese , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Terpenos/metabolismo , Triazóis/síntese química
8.
Molecules ; 24(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067640

RESUMO

Copper(II) complexes of bis(pyrazol-1-yl)- and bis(triazol-1-yl)-acetate heteroscorpionate ligands have been synthesized. The copper(II) complexes [HC(COOH)(pzMe2)2]Cu[HC(COO)(pzMe2)2]·ClO4, [HC(COOH)(pz)2]2Cu(ClO4)2 (pzMe2 = 3,5-dimethylpyrazole; pz = pyrazole) were prepared by the reaction of Cu(ClO4)2·6H2O with bis(3,5-dimethylpyrazol-1-yl)acetic acid (HC(COOH)(pzMe2)2) and bis(pyrazol-1-yl)acetic acid (HC(COOH)(pz)2) ligands in ethanol solution. The copper(II) complex [HC(COOH)(tz)2]2Cu(ClO4)2·CH3OH (tz = 1,2,4-triazole) was prepared by the reaction of Cu(ClO4)2·6H2O with bis(1,2,4-triazol-1-yl)acetic acid (HC(COOH)(tz)2) ligand in methanol solution. The synthesized Cu(II) complexes, as well as the corresponding uncoordinated ligands, were evaluated for their cytotoxic activity in monolayer and 3D spheroid cancer cell cultures with different Pt(II)-sensitivity. The results showed that [HC(COOH)(pzMe2)2]Cu[HC(COO)(pzMe2)2]·ClO4 was active against cancer cell lines derived from solid tumors at low IC50 and this effect was retained in the spheroid model. Structure and ultra-structure changes of treated cancer cells analyzed by Transmission Electron Microscopy (TEM) highlighted the induction of a cytoplasmic vacuolization, thus suggesting paraptotic-like cancer cell death triggering.


Assuntos
Complexos de Coordenação/química , Pirazóis/química , Triazóis/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cobre/química , Cristalografia por Raios X , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/farmacologia , Esferoides Celulares/efeitos dos fármacos , Triazóis/síntese química , Triazóis/farmacologia
9.
Eur J Med Chem ; 173: 274-281, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31009913

RESUMO

Antibiotics are commonly used to fight against bacterial infections, but bacteria have already been resistant to almost all antibiotics due to abuse of antibiotics. 1,2,4-Triazole derived compounds possess chemotherapeutic effects including potential antibacterial activities against drug-sensitive as well as drug-resistant pathogens. Hybridization displays a high potential to develop novel drugs with the capacity to overcome drug resistance, reduce toxicity and improve pharmacokinetic profiles. More effective antibacterial candidates might be obtained by the hybridization of 1,2,4-triazole with other antibacterial pharmacophores. This review summarizes the recent advances of 1,2,4-triazole derivatives as potential antibacterial compounds, and the structure-activity relationship is also discussed.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Triazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
10.
Eur J Med Chem ; 171: 372-382, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928709

RESUMO

Two new series of 1,2-benzisothiazol-3(2H)-one-1,1-dioxide derivatives containing either five membered heterocyclic rings or aryl hydrazones were synthesized and evaluated for their in vitro COX-1/COX-2 inhibitory activity. In vivo anti-inflammatory evaluation revealed that benzenesulfonamides bearing pyrazole moiety 19, 20 and its cyclized form 23 exhibited the highest anti-inflammatory activity with comparable potency to celecoxib. Furthermore, the ulcerogenic activity evaluation showed that compounds 19, 20 and 23 exerted the minimal ulcer index in comparison to indomethacin as a reference drug. Docking studies of the most selective COX-2 derivatives were also carried out against COX-2 active site. Benzenesulfonamide derivatives 19 and 20 displayed higher predicted binding affinities inside the COX-2 active site. Molecular modelling simulation and drug likeness studies showed good agreement with the obtained biological evaluation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Sulfonamidas/farmacologia , Triazóis/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Triazóis/síntese química , Triazóis/química
11.
Biosci Trends ; 13(2): 197-203, 2019 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-31019142

RESUMO

Histone deacetylase is an important member of epigenetics and a well validated target for anti-cancer drug discovery. In this study, we designed and synthesized a series of twenty-one novel hydroxamic acid-based histone deacetylase inhibitors with 4-piperidin-4-yl-triazole as the core skeleton. Most target compounds displayed excellent inhibition rates toward histone deacetylases at the concentration of 1 µM. Among them, the inhibition rates of two compounds MH1-18 and MH1-21 exceeded 90%. Furthermore, these two compounds selectively inhibited the activity of histone deacetylase 6 with low IC50 values. The high potency of them toward histone deacetylase 6 was rationalized by molecular docking studies. We found that MH1-18 and MH1-21 moderately inhibited the proliferation of four human cancer cell lines SGC-7901, NCI-H226, MCF-7, and HL-60. However, MH1-21 showed potent efficacy in suppressing the migration of MCF-7 cells. Results obtained in the current study shed light on designing potent HDAC6 inhibitors as anti-cancer agents.


Assuntos
Desenho de Drogas , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Triazóis/química
12.
Microb Pathog ; 131: 227-233, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30943433

RESUMO

Baicalein, an isolate of secutellaria baicalensis is known for its anti-inflammatory activity. In the present study, 12-triazole derivatives of baicalein were synthesized and evaluated against RSV infected BEAS-2B cells in vitro and in mice model in vivo. The preventive effect of most active compound 5f against RSV infection was studied in detail. The compound 5f treatment increased IFN-ß1 expression in BEAS-2B cells infected with RSV. In BEAS-2B cells treatment with compound 5f inhibited RSV-induced secretion of interleukin-6 and -8 cytokines. It decreased RSV-induced nitric oxide & malondialdehyde production and inhibited the RSV-mediated activation of NF-κB, COX-2, Stat3 and MAPK. The p38 phosphorylation was enhanced significantly in RSV infected cells by compound 5f pre-treatment. RT-qPCR showed that compound 5f treatment of the RSV-infected mice significantly (P < 0.05) decreased viral load through reduction in the viral replication. In the mice model of RSV-infection compound 5f treatment decreased interleukin-6, -8 and tumor necrosis factor-α expression. The level of MPO, nitric oxide and malondialdehyde was also decreased significantly by compound 5f in the RSV infected mice BALF. It also reduced the infiltration of neutrophils and lymphocytes in the BALF of RVS-infected mice. In summary, compound 5f inhibits RSV-infection and prevents pulmonary airway inflammation through the activation of IFN signalling pathway.


Assuntos
Flavanonas/farmacologia , Estresse Oxidativo , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Infecções Respiratórias/prevenção & controle , Triazóis/farmacologia , Animais , Citocinas/metabolismo , Feminino , Flavanonas/síntese química , Interferon beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Neutrófilos/metabolismo , Pneumonia/prevenção & controle , Pneumonia/virologia , Infecções Respiratórias/virologia , Ribavirina/farmacologia , Fator de Transcrição STAT3/metabolismo , Triazóis/síntese química , Fator de Necrose Tumoral alfa/metabolismo , Replicação Viral/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Eur J Med Chem ; 172: 62-70, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30947122

RESUMO

In the present study a library of thiophenol-formaldehyde-triazole (TFT) derivatives was synthesized and screened against CAOV3, CAOV4 and ES-2 ovary cancer cell lines. Initial screening revealed that five-compounds 5a, 5b, 5j, 5h and 5i inhibited the viability of tested cell lines. Analysis of apoptosis revealed that increase in compound 5a (most active) concentration from 0.25 to 2.0 µM enhanced apoptotic cell proportion. Transwell assay showed reduction in invasive potential of CAOV3 cells on treatment with compound 5a. In wound healing assay increasing the concentration of compound 5a from 0.5 to 2.0 µM caused a significant (P < 0.05) decrease in the migration potential. Western blotting showed that compound 5a treatment markedly decreased the level of matrix metalloproteinase (MMP)-2 and -9 in CAOV3 cells. Treatment of CAOV3 cells with compound 5a caused a marked decrease in Focal Adhesion Kinase (FAK) activation. Tumor growth was inhibited in the compound 5a treated mice markedly than those of untreated group. The tumor metastasis to liver, intestine, spleen and peritoneal cavity was markedly decreased in mice treated with 10 mg/kg dose of compound 5a. Examination of Von Willebrand factor (vWF) expression in liver, intestinal and pulmonary lesions showed a marked decrease in the compound 5a-treated mice. The infiltration of macrophages in the metastatic lesions showed a significant decrease in compound 5a-treated mice. In conclusion, the compound 5a inhibited ovary cancer cell viability and induced apoptosis through decrease in expression of vWF and metalloproteinase, suppression of FAK activation and decrease in infiltration of macrophages. The compound 5a therefore can be investigated further for the treatment of ovary cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Formaldeído/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Fenóis/farmacologia , Compostos de Sulfidrila/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Formaldeído/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Fenóis/química , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Triazóis/síntese química , Triazóis/química , Células Tumorais Cultivadas
14.
Artigo em Inglês | MEDLINE | ID: mdl-30968733

RESUMO

A series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3'-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidines (20-49) was synthesized by means of phosphorylation of 3'-[4-aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidines (7-11) with 4-chlorophenyl phosphoroditriazolide (14), followed by a reaction with the appropriate amine. The synthesized compounds 7-11 and 20-49 were evaluated along with four known anticancer compounds for their cytotoxic activity in human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), osteosarcoma (143B) (only selected compounds 20, 24, 28, 32-36, 38, 40, 46) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Among 3'-[4-aryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidines (7-11) the highest activity in all the investigated cancer cells was displayed by 3'-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3'-deoxythymidine (9) (IC50 in the range of 2.58-3.61 µM) and its activity was higher than that of cytarabine. Among phosphoramidates 20-49 the highest activity was demonstrated by N-n-propyl phosphoramidate of 3'-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3'-deoxythymidine (35) in all the cancer cells (IC50 in the range of 0.97-1.94 µM). Also N-ethyl phosphoramidate of 3'-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3'-deoxythymidine (33) exhibited good activity in all the used cell lines (IC50 in the range of 4.79-4.96 µM).


Assuntos
Amidas/química , Antineoplásicos/síntese química , Ácidos Fosfóricos/química , Timidina/análogos & derivados , Timidina/síntese química , Triazóis/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Drogas , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Timidina/farmacologia , Triazóis/farmacologia
15.
Eur J Med Chem ; 170: 203-224, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30901686

RESUMO

Clostridioides (formerly Clostridium) difficile is a Gram-positive anaerobic bacterial pathogen that causes severe gastrointestinal infection in humans. The current chemotherapeutic options are vastly inadequate, expensive and limited; this results in an exorbitant medical and financial burden. New, inexpensive chemotherapeutic treatments for C. difficile infection with improved efficacy are urgently needed. A streamlined synthetic pathway was developed to allow access to 38 novel mono- and di-cationic biaryl 1,2,3-triazolyl peptidomimetics with increased synthetic efficiency, aqueous solubility and enhanced antibacterial efficacy. The monocationic arginine derivative 28 was identified as a potent, Gram-positive selective antibacterial with MIC values of 4 µg/mL against methicillin-resistant Staphylococcus aureus and 8 µg/mL against C. difficile. Furthermore, the dicationic bis-triazole analogue 50 was found to exhibit broad-spectrum activity with substantial Gram-negative efficacy against Acinetobacter baumannii (8 µg/mL), Pseudomonas aeruginosa (8 µg/mL) and Klebsiella pneumoniae (16 µg/mL); additionally, compound 50 displayed reduced haemolytic activity (<13%) in an in vitro haemolysis assay. Membrane-disruption assays were conducted on selected derivatives to confirm the membrane-active mechanism of action inherent to the synthesized amphiphilic compounds. A comparative solubility assay was developed and utilized to optimize the aqueous solubility of the compounds for in vivo studies. The biaryl peptidomimetics 28 and 67 were found to exhibit significant efficacy in an in vivo murine model of C. difficile infection by reducing the severity and slowing the onset of disease.


Assuntos
Antibacterianos/química , Antibacterianos/uso terapêutico , Infecções por Clostridium/tratamento farmacológico , Clostridium difficile/efeitos dos fármacos , Peptidomiméticos/química , Peptidomiméticos/uso terapêutico , Animais , Antibacterianos/síntese química , Antibacterianos/farmacologia , Cátions/síntese química , Cátions/química , Cátions/farmacologia , Cátions/uso terapêutico , Humanos , Masculino , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Peptidomiméticos/síntese química , Peptidomiméticos/farmacologia , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologia , Triazóis/uso terapêutico
16.
Artigo em Inglês | MEDLINE | ID: mdl-30856058

RESUMO

The chemical ribosylation pathways of 5-substituted-1,2,4-triazole-3-carboxylates are discussed. For the products of the chemical synthesis of the 3(5)-alkyl- or 3(5)-aryl-substituted ribavirin analogues the anomer configuration and isomer composition were determined.


Assuntos
Ácidos Carboxílicos/síntese química , Ribavirina/análogos & derivados , Ribavirina/síntese química , Triazóis/síntese química , Catálise , Isomerismo , Estrutura Molecular , Relação Estrutura-Atividade
17.
Int J Biol Macromol ; 130: 928-937, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844456

RESUMO

Chitosan copper (II) oxide nanocomposite was synthesized, characterized and used to synthesize [1,2,3]triazoles. Nanocomposite was characterized by using FTIR, XRD, FESEM, and EDS techniques, which reflected rough morphology. The powerful catalytic activity of hybrid nanocomposite was utilized to synthesize chalcones (3a-p) in relatively high yields (82%-98%) and multicomponent regio-selective cycloaddition of chalones, aryl halides (4), and sodium azide to afford the expected N-2-aryl[1,2,3]triazoles (5a-h) (80%-95% yield) rather than N-1-aryl[1,2,3]-triazoles (6a-h). The performance of nanomaterial was optimized by several variables. The capability of the nanocomposite was compared with previous work and the nanocomposite was found more efficient, economic and reproducible. The hybrid nanocomposite could be easily isolated form the reaction mixture and recycled four times without any significant loss of its catalytic activity. The reported catalyst is an inexpensive for good yields of the triazoles and may be used at industrial production for the reported compounds.


Assuntos
Quitosana/química , Cobre/química , Química Verde , Nanocompostos/química , Triazóis/química , Azidas/química , Catálise , Chalcona/química , Reação de Cicloadição , Modelos Moleculares , Conformação Molecular , Triazóis/síntese química
18.
Mini Rev Med Chem ; 19(16): 1298-1368, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30864516

RESUMO

Triazole is a valuable platform in medicinal chemistry, possessing assorted pharmacological properties, which could play a major role in the common mechanisms associated with various disorders like cancer, infections, inflammation, convulsions, oxidative stress and neurodegeneration. Structural modification of this scaffold could be helpful in the generation of new therapeutically useful agents. Although research endeavors are moving towards the growth of synthetic analogs of triazole, there is still a lot of scope to achieve drug discovery break-through in this area. Upcoming therapeutic prospective of this moiety has captured the attention of medicinal chemists to synthesize novel triazole derivatives. The authors amalgamated the chemistry, synthetic strategies and detailed pharmacological activities of the triazole nucleus in the present review. Information regarding the marketed triazole derivatives has also been incorporated. The objective of the review is to provide insights to designing and synthesizing novel triazole derivatives with advanced and unexplored pharmacological implications.


Assuntos
Neoplasias/tratamento farmacológico , Triazóis/química , Triazóis/farmacologia , Humanos , Infecção/tratamento farmacológico , Inflamação/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Convulsões/tratamento farmacológico , Triazóis/síntese química
19.
An Acad Bras Cienc ; 91(suppl 1): e20180751, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785471

RESUMO

The chemistry of 1,2,3-triazoles gained much attention since the discovery of the copper catalyzed Alkyne-azide cycloaddition (CuAAC) reaction which delivers exclusively the 1,4-regioisomer in high yields. On the other hand there is still no universal methodology capable of delivering the N2 substituted regioisomer. The unique properties of these N2-substituted 1,2,3-triazoles have stimulated synthetic efforts on the developments of methodologies capable of delivering it in high yield and selectivity. These efforts are the subject of the presented review.


Assuntos
Triazóis/química , Catálise , Reação de Cicloadição , Estrutura Molecular , Triazóis/síntese química
20.
Eur J Med Chem ; 167: 388-401, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30780087

RESUMO

The histone lysine specific demethylase 1 (LSD1/KDM1A) is implicated in the development of cancers, targeting LSD1 has been recognized as a promising strategy for cancer therapy. To date, some small-molecule inhibitors are currently being investigated in clinical trials. Herein we report the design, synthesis and biochemical characterization of [1,2,4]triazolo[1,5-a]pyrimidine derivatives as new LSD1 inhibitors. Of these compounds, compound C26 inhibited LSD1 in a reversible manner (IC50 = 1.72 µM) and showed selectivity to LSD1 over MAO-A/B. Besides, compound C26 displayed FAD-competitive binding to LSD1. Interestingly, C26 did not inhibit horseradish peroxidase (HRP) and quench H2O2, thus excluding the possibility that LSD1 inhibition by C26 was due to the HRP inhibition and consumption of H2O2. In LSD1 overexpressed A549 cells, compound C26 concentration-dependently induced accumulation of H3K4me1/me2 and H3K9me2 and showed cellular target engagement to LSD1. Additionally, compound C26 significantly inhibited migration of A549 cells in a concentration-dependent manner, further western blot analysis showed that C26 increased expression levels of epithelial cell markers E-Cadherin and Claudin-1, down-regulated mesenchymal cell marker N-Cadherin and the upstream transcription factors Snail and Slug. Docking studies were also performed to rationalize the potency of C26 toward LSD1. To conclude, the [1,2,4]triazolo[1,5-a]pyrimidine could serve as a promising scaffold for the development of new LSD1 inhibitors.


Assuntos
Desenho de Drogas , Inibidores Enzimáticos/síntese química , Histona Desmetilases/antagonistas & inibidores , Pirimidinas/farmacologia , Triazóis/farmacologia , Ligação Competitiva , Caderinas/metabolismo , Claudina-1/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo , Triazóis/síntese química
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