Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.193
Filtrar
1.
Molecules ; 26(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33672046

RESUMO

Substituted N-phenyl cinnamamide derivatives were designed and synthesized to confirm activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway by the electronic effect on beta-position of Michael acceptor according to introducing the R1 and R2 group. Compounds were screened using the Nrf2/antioxidant response element (ARE)-driven luciferase reporter assay. Compound 1g showed desirable luciferase activity in HepG2 cells without cell toxicity. mRNA and protein expression of Nrf2/ARE target genes such as NAD(P)H quinone oxidoreductase 1, hemeoxygenase-1, and glutamate-cysteine ligase catalytic subunit (GCLC) were upregulated by compound 1g in a concentration-dependent manner. Treatment with 1g resulted in increased endogenous antioxidant glutathione, showing strong correlation with enhanced GCLC expression for synthesis of glutathione. In addition, tert-butyl hydroperoxide (t-BHP)-generated reactive oxygen species were significantly removed by 1g, and the results of a cell survival assay in a t-BHP-induced oxidative cell injury model showed a cytoprotective effect of 1g in a concentration dependent manner. In conclusion, the novel compound 1g can be utilized as an Nrf2/ARE activator in antioxidative therapy.


Assuntos
Cinamatos/farmacologia , Citoproteção/efeitos dos fármacos , Glutationa/biossíntese , Hepatócitos/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Elementos de Resposta Antioxidante/genética , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Morte Celular/efeitos dos fármacos , Cinamatos/química , Glutationa/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Luciferases/metabolismo , Fator 2 Relacionado a NF-E2/agonistas , Substâncias Protetoras/farmacologia , terc-Butil Hidroperóxido
2.
ACS Appl Mater Interfaces ; 13(6): 7021-7036, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33539069

RESUMO

Implants can induce a foreign body reaction that leads to chronic inflammation and fibrosis in the surrounding tissue. Macrophages help detect the foreign material, play a role in the inflammatory response, and may promote fibrosis instead of the desired tissue regeneration around implants. Implant surface properties impact macrophage responses by changing the nature of the adsorbed protein layer, but conflicting studies highlight the complexity of this relationship. In this study, the effect of surface chemistry on macrophage behavior was investigated with poly(styrene) surfaces containing common functional groups at similar surface densities. The protein layer was characterized to identify the proteins that adsorbed on the surfaces from the medium and the proteins secreted onto the surfaces by adherent macrophages. Of the surface chemistries studied, carboxylic acid (COOH) groups promoted anti-inflammatory responses from unstimulated macrophages and did not exacerbate inflammation upon stimulation. These surfaces also enhanced the adsorption of proteins involved in integrin signaling and promoted the secretion of proteins related to angiogenesis, integrin signaling, and cytokine signaling, which have been previously associated with improved biomaterial integration. Therefore, this study suggests that surface modification with COOH groups may help improve the integration of implants in the body by enhancing anti-inflammatory macrophage responses through altered protein adsorption.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ácidos Carboxílicos/farmacologia , Citocinas/química , Macrófagos/efeitos dos fármacos , Adsorção , Animais , Anti-Inflamatórios não Esteroides/química , Ácidos Carboxílicos/química , Bovinos , Células Cultivadas , Citocinas/genética , Humanos , Tamanho da Partícula , Poliestirenos/síntese química , Poliestirenos/química , Poliestirenos/farmacologia , Proteômica , Propriedades de Superfície , Células THP-1
3.
J Med Chem ; 64(1): 481-515, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33382264

RESUMO

N-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is regarded as the main enzyme responsible for the biosynthesis of N-acylethanolamines (NAEs), a family of bioactive lipid mediators. Previously, we reported N-(cyclopropylmethyl)-6-((S)-3-hydroxypyrrolidin-1-yl)-2-((S)-3-phenylpiperidin-1-yl)pyrimidine-4-carboxamide (1, LEI-401) as the first potent and selective NAPE-PLD inhibitor that decreased NAEs in the brains of freely moving mice and modulated emotional behavior [Mock Nat Chem. Biol., 2020, 16, 667-675]. Here, we describe the structure-activity relationship (SAR) of a library of pyrimidine-4-carboxamides as inhibitors of NAPE-PLD that led to the identification of LEI-401. A high-throughput screening hit was modified at three different substituents to optimize its potency and lipophilicity. Conformational restriction of an N-methylphenethylamine group by replacement with an (S)-3-phenylpiperidine increased the inhibitory potency 3-fold. Exchange of a morpholine substituent for an (S)-3-hydroxypyrrolidine reduced the lipophilicity and further increased activity by 10-fold, affording LEI-401 as a nanomolar potent inhibitor with drug-like properties. LEI-401 is a suitable pharmacological tool compound to investigate NAPE-PLD function in vitro and in vivo.


Assuntos
Amidas/química , Ácidos Carboxílicos/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fosfatidiletanolaminas/química , Fosfolipases/antagonistas & inibidores , Pirimidinas/química , Ácidos Carboxílicos/farmacologia , Fosfolipases/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade
4.
J Anim Sci ; 98(9)2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32780110

RESUMO

The objective was to study the effects of microencapsulated organic acids (OA) and essential oils (EO) on growth performance, immune system, gut barrier function, nutrient digestion and absorption, and abundance of enterotoxigenic Escherichia coli F4 (ETEC F4) in the weaned piglets challenged with ETEC F4. Twenty-four ETEC F4 susceptible weaned piglets were randomly distributed to 4 treatments including (1) sham-challenged control (SSC; piglets fed a control diet and challenged with phosphate-buffered saline (PBS)); (2) challenged control (CC; piglets fed a control diet and challenged with ETEC F4); (3) antibiotic growth promoters (AGP; CC + 55 mg·kg-1 of Aureomycin); and (4) microencapsulated OA and EO [P(OA+EO); (CC + 2 g·kg-1 of microencapsulated OA and EO]. The ETEC F4 infection significantly induced diarrhea at 8, 28, 34, and 40 hr postinoculation (hpi) (P < 0.05) in the CC piglets. At 28 d postinoculation (dpi), piglets fed P(OA+EO) had a lower (P < 0.05) diarrhea score compared with those fed CC, but the P(OA+EO) piglets had a lower (P < 0.05) diarrhea score compared with those fed the AGP diets at 40 dpi. The ETEC F4 infection tended to increase in vivo gut permeability measured by the oral gavaging fluorescein isothiocyanate-dextran 70 kDa (FITC-D70) assay in the CC piglets compared with the SCC piglets (P = 0.09). The AGP piglets had higher FITC-D70 flux than P(OA+EO) piglets (P < 0.05). The ETEC F4 infection decreased mid-jejunal VH in the CC piglets compared with the SCC piglets (P < 0.05). The P(OA+EO) piglets had higher (P < 0.05) VH in the mid-jejunum than the CC piglets. The relative mRNA abundance of Na+-glucose cotransporter and B0AT1 was reduced (P < 0.05) by ETEC F4 inoculation when compared with the SCC piglets. The AGP piglets had a greater relative mRNA abundance of B0AT1 than the CC piglets (P < 0.05). The ETEC F4 inoculation increased the protein abundance of OCLN (P < 0.05), and the AGP piglets had the lowest relative protein abundance of OCLN among the challenged groups (P < 0.05). The supplementation of microencapsulated OA and EO enhanced intestinal morphology and showed anti-diarrhea effects in weaned piglets challenged with ETEC F4. Even if more future studies can be required for further validation, this study brings evidence that microencapsulated OA and EO combination can be useful within the tools to be implemented in strategies for alternatives to antibiotics in swine production.


Assuntos
Diarreia/veterinária , Escherichia coli Enterotoxigênica/crescimento & desenvolvimento , Infecções por Escherichia coli/veterinária , Microbioma Gastrointestinal/efeitos dos fármacos , Óleos Voláteis/farmacologia , Doenças dos Suínos/microbiologia , Animais , Antibacterianos/farmacologia , Ácidos Carboxílicos/farmacologia , Clortetraciclina/farmacologia , Diarreia/microbiologia , Dieta/veterinária , Composição de Medicamentos/veterinária , Escherichia coli Enterotoxigênica/efeitos dos fármacos , Infecções por Escherichia coli/microbiologia , Feminino , Imunidade , Jejuno/efeitos dos fármacos , Masculino , Nutrientes/metabolismo , Distribuição Aleatória , Suínos , Desmame
5.
J Med Chem ; 63(6): 2789-2801, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-31765155

RESUMO

A major resistance mechanism in Gram-negative bacteria is the production of ß-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent ß-lactamases can now confer resistance to other ß-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of ß-lactamase-producing multi-drug-resistant "superbugs" has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-ß-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided 20 (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum ß-lactamase inhibitor. In vitro and in vivo studies demonstrated that 20 restored the activity of ß-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum ß-lactamase inhibitor to enter clinical development.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Ácidos Borínicos/química , Ácidos Borínicos/farmacologia , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Ácidos Borínicos/síntese química , Ácidos Borínicos/uso terapêutico , Carbapenêmicos/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/uso terapêutico , Humanos , Camundongos , Modelos Moleculares , Resistência beta-Lactâmica , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/uso terapêutico
6.
Chem Commun (Camb) ; 56(8): 1179-1182, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31868184

RESUMO

We report unprecedented Friedel-Crafts arylation of chlorofullerenes C60Cl6 and C70Cl8 with unprotected carboxylic acids as an efficient single-step synthesis of the inherently stable water-soluble fullerene derivatives. Using this method, a series of previously unaccessible compounds was obtained without chromatographic purification in almost quantitative yields. Promising anti-HIV activity comparable to characteristics of commercial drugs was demonstrated for some of these compounds.


Assuntos
Fármacos Anti-HIV/farmacologia , Ácidos Carboxílicos/farmacologia , Fulerenos/farmacologia , Água/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Fulerenos/química , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Solubilidade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia
7.
Antiviral Res ; 174: 104671, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31812637

RESUMO

The management of Human Immunodeficiency Virus type 1 (HIV-1) infection requires life-long treatment that is associated with chronic toxicity and possible selection of drug-resistant strains. A new opportunity for drug intervention is offered by antivirals that act as allosteric inhibitors targeting two viral functions (dual inhibitors). In this work, we investigated the effects of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derivatives on both HIV-1 Integrase (IN) and Reverse Transcriptase associated Ribonuclease H (RNase H) activities. Among the tested compounds, the dihydroxyindole-carboxamide 5 was able to inhibit in the low micromolar range (1-18 µM) multiple functions of IN, including functional IN-IN interactions, IN-LEDGF/p75 binding and IN catalytic activity. Docking and site-directed mutagenesis studies have suggested that compound 5 binds to a previously described HIV-1 IN allosteric pocket. These observations indicate that 5 is structurally and mechanistically distinct from the published allosteric HIV-1 IN inhibitors. Moreover, compound 5 also inhibited HIV-1 RNase H function, classifying this molecule as a dual HIV-1 IN and RNase H inhibitor able to impair the HIV-1 virus replication in cell culture. Overall, we identified a new scaffold as a suitable platform for the development of novel dual HIV-1 inhibitors.


Assuntos
Ácidos Carboxílicos/farmacologia , Inibidores de Integrase de HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Ácidos Carboxílicos/química , Linhagem Celular , Descoberta de Drogas , Infecções por HIV/virologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
8.
Chemosphere ; 239: 124706, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31493754

RESUMO

The remediation effect of organic acids in heavy metal contaminated soil was widely studied. However, the comprehensive evaluation of organic acids on micro-ecological environment in heavy metal contaminated soil was less known. Herein, this experiment was conducted to investigate the impact of malic acid, citric acid and oxalic acid on soil fertility, cadmium (Cd) speciation and ecotoxicity in contaminated soil. Especially, to evaluate the ecotoxicity of Cd, high-throughput sequencing was used to investigate the soil bacterial community structure and diversity after incubation with organic acids. The results showed that obvious changes in soil pH were not observed. Whereas, the contents of available phosphorus (Olsen-P) and alkali hydrolysable nitrogen (Alkeline-N) evidently increased with a significant difference. Furthermore, compared to control, the proportion of acetic acid-extractable Cd increased by 3.06-6.63%, 6.11-9.43% and 1.91-6.22% respectively in the groups amended with malic acid, citric acid and oxalic acid, which indicated that citric acid did better in improving the availability of Cd than malic acid and oxalic acid. In terms of biological properties, citric acid did best in bacteria count increase, enzyme activities and bacterial community structure improvement. Accordingly, these results provided a better understanding for the influence of organic acids on the micro-ecological environment in Cd contaminated soil, based on physicochemical and biological analysis.


Assuntos
Cádmio/toxicidade , Ácidos Carboxílicos/farmacologia , Recuperação e Remediação Ambiental/métodos , Microbiologia do Solo , Poluentes do Solo/química , Bactérias/efeitos dos fármacos , Cádmio/análise , Cádmio/química , Ácidos Carboxílicos/química , Ácido Cítrico/química , Ácido Cítrico/farmacologia , Ecotoxicologia , Poluição Ambiental/análise , Malatos/química , Malatos/farmacologia , Ácido Oxálico/química , Ácido Oxálico/farmacologia , Solo/química , Poluentes do Solo/análise
9.
Eur J Med Chem ; 186: 111883, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761385

RESUMO

As part of a continuing study, we designed and synthesized four series of 1-phenylimidazole-4-carboxylic acid derivatives as xanthine oxidoreductase (XOR) inhibitors, evaluated their in vitro inhibitory potencies against XOR and hypouricemic effects in mice, and determined their structure-activity relationships (SARs). Most of the compounds exhibited in vitro XOR inhibition at the nanomolar level. In comparison to febuxostat (half-maximal inhibitory concentration [IC50] value of 7.0 nM), compounds Ie and IVa exhibited the most promising XOR inhibitory effects with IC50 values of 8.0 and 7.2 nM, respectively. In the potassium oxonate/hypoxanthine-induced acute and long-term hyperuricemia mouse models, compounds Ie and IVa displayed significant hypouricemic potencies (P < 0.05), that were slightly weaker than and similar to febuxostat, respectively. More interestingly, both compounds showed a capacity to improve kidney damage by decreasing creatinine and urea nitrogen levels compared to the long-term hyperuricemia mouse group (P < 0.05), while febuxostat showed no significant effect.


Assuntos
Ácidos Carboxílicos/farmacologia , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Xantina Desidrogenase/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Imidazóis/síntese química , Imidazóis/química , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Xantina Desidrogenase/metabolismo
10.
Sci Adv ; 5(12): eaay0044, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31840070

RESUMO

An immense demand in biomedical imaging is to develop efficient photoluminescent probes with high biocompatibility and quantum yield, as well as multiphoton absorption performance to improve penetration depth and spatial resolution. Here, iron selenide (FeSe) quantum dots (QDs) are reported to meet these criteria. The synthesized QDs exhibit two- and three-photon excitation property at 800- and 1080-nm wavelengths and high quantum yield (ca. 40%), which are suitable for second-window imaging. To verify their biosuitability, poly(ethylene glycol)-conjugated QDs were linked with human epidermal growth factor receptor 2 (HER2) antibodies for in vitro/in vivo two-photon imaging in HER2-overexpressed MCF7 cells and a xenograft breast tumor model in mice. Imaging was successfully carried out at a depth of up to 500 µm from the skin using a nonlinear femtosecond laser at an excitation wavelength of 800 nm. These findings may open up a way to apply biocompatible FeSe QDs to multiphoton cancer imaging.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Ácidos Carboxílicos/farmacologia , Ferro/farmacologia , Compostos Organosselênicos/farmacologia , Receptor ErbB-2/isolamento & purificação , Animais , Neoplasias da Mama/patologia , Ácidos Carboxílicos/química , Feminino , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Xenoenxertos , Humanos , Ferro/química , Células MCF-7 , Camundongos , Imagem Molecular , Compostos Organosselênicos/química , Pontos Quânticos/química , Receptor ErbB-2/genética
11.
Mol Cell Proteomics ; 18(12): 2433-2446, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31591263

RESUMO

Stable isotope-labeled standard (SIS) peptides are used as internal standards in targeted proteomics to provide robust protein quantification, which is required in clinical settings. However, SIS peptides are typically added post trypsin digestion and, as the digestion efficiency can vary significantly between peptides within a protein, the accuracy and precision of the assay may be compromised. These drawbacks can be remedied by a new class of internal standards introduced by the Human Protein Atlas project, which are based on SIS recombinant protein fragments called SIS PrESTs. SIS PrESTs are added initially to the sample and SIS peptides are released on trypsin digestion. The SIS PrEST technology is promising for absolute quantification of protein biomarkers but has not previously been evaluated in a clinical setting. An automated and scalable solid phase extraction workflow for desalting and enrichment of plasma digests was established enabling simultaneous preparation of up to 96 samples. Robust high-precision quantification of 13 apolipoproteins was achieved using a novel multiplex SIS PrEST-based LC-SRM/MS Tier 2 assay in non-depleted human plasma. The assay exhibited inter-day coefficients of variation between 1.5% and 14.5% (median = 3.5%) and was subsequently used to investigate the effects of omega-3 carboxylic acids (OM3-CA) and fenofibrate on these 13 apolipoproteins in human plasma samples from a randomized placebo-controlled trial, EFFECT I (NCT02354976). No significant changes were observed in the OM3-CA arm, whereas treatment with fenofibrate significantly increased apoAII and reduced apoB, apoCI, apoE and apoCIV levels. The reduction in apoCIV following fenofibrate treatment is a novel finding. The study demonstrates that SIS PrESTs can facilitate the generation of robust multiplexed biomarker Tier 2 assays for absolute quantification of proteins in clinical studies.


Assuntos
Apolipoproteínas/sangue , Ácidos Carboxílicos/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Fenofibrato/farmacologia , Marcação por Isótopo , Espectrometria de Massas em Tandem/métodos , Adulto , Idoso , Biomarcadores/sangue , Estudos de Coortes , Método Duplo-Cego , Humanos , Marcação por Isótopo/normas , Pessoa de Meia-Idade , Fragmentos de Peptídeos , Proteínas Recombinantes , Reprodutibilidade dos Testes
12.
Chem Biodivers ; 16(11): e1900403, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31515947

RESUMO

The antibacterial and antibiofilm activities of two new ruthenium complexes against E. coli, S. aureus, P. aeruginosa PAO1 (laboratory strain) and P. aeruginosa LES B58 (clinical strain) were evaluated. Complexes, mer-[RuIII (2-bimc)3 ] ⋅ H2 O (1) and cis-[RuIV Cl2 (2,3-pydcH)2 ] ⋅ 4H2 O (2), were obtained using aromatic carboxylic acid ligands, namely, 1H-benzimidazole-2-carboxylic acid (2-bimcH) and pyridine-2,3-dicarboxylic acid (2,3-pydcH2 ). Compounds were physicochemically characterized using X-ray diffraction, Hirshfeld surface analysis, IR and UV/VIS spectroscopies, as well as magnetic and electrochemical measurements. Structural characterization revealed that Ru(III) and Ru(IV) ions in the complexes adopt a distorted octahedral geometry. The intermolecular classical and weak hydrogen bonds, and π⋅⋅⋅π contacts significantly contribute to structure stabilization, leading to the formation of a supramolecular assembly. Biological studies have shown that the Ru complexes inhibit the growth of bacteria and biofilm formation by the tested strains and the complexes seem to be a potential as antimicrobial agents.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Ácidos Carboxílicos/farmacologia , Compostos Organometálicos/farmacologia , Rutênio/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Ácidos Carboxílicos/química , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Pseudomonas aeruginosa/efeitos dos fármacos , Rutênio/química , Staphylococcus aureus/efeitos dos fármacos
13.
Molecules ; 24(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509949

RESUMO

The amount of boron accumulated in tumor tissue plays an important role regarding the success of the boron neutron capture therapy (BNCT). In this article, we report a modular system, combining readily available starting materials, like glycine, 1,3,5-triazine and the well-known 9-mercapto-1,7-dicarba-closo-dodecaborane(12), as well as α-d-galactopyranose for increased hydrophilicity, with a novel boron-rich tris-meta-carboranyl thiol.


Assuntos
Terapia por Captura de Nêutron de Boro , Boro/farmacologia , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Boro/química , Compostos de Boro/síntese química , Compostos de Boro/química , Compostos de Boro/farmacologia , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Ésteres/química , Glicina/química , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Estrutura Molecular , Neoplasias/patologia , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Triazinas/química , Triazinas/farmacologia
14.
J Exp Bot ; 70(21): 6293-6304, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31504728

RESUMO

Agrochemicals provide vast potential to improve plant productivity, because they are easy to implement at low cost while not being restricted by species barriers as compared with breeding strategies. Despite the general interest, only a few compounds with growth-promoting activity have been described so far. Here, we add cis-cinnamic acid (c-CA) to the small portfolio of existing plant growth stimulators. When applied at low micromolar concentrations to Arabidopsis roots, c-CA stimulates both cell division and cell expansion in leaves. Our data support a model explaining the increase in shoot biomass as the consequence of a larger root system, which allows the plant to explore larger areas for resources. The requirement of the cis-configuration for the growth-promoting activity of CA was validated by implementing stable structural analogs of both cis- and trans-CA in this study. In a complementary approach, we used specific light conditions to prevent cis/trans-isomerization of CA during the experiment. In both cases, the cis-form stimulated plant growth, whereas the trans-form was inactive. Based on these data, we conclude that c-CA is an appealing lead compound representing a novel class of growth-promoting agrochemicals. Unraveling the underlying molecular mechanism could lead to the development of innovative strategies for boosting plant biomass.


Assuntos
Cinamatos/farmacologia , Desenvolvimento Vegetal/efeitos dos fármacos , Arabidopsis/efeitos dos fármacos , Arabidopsis/crescimento & desenvolvimento , Ácidos Carboxílicos/farmacologia , Cinamatos/química , Ciclopropanos/farmacologia , Ácidos Indolacéticos/farmacologia , Isomerismo , Tabaco/efeitos dos fármacos , Tabaco/crescimento & desenvolvimento
15.
ChemMedChem ; 14(21): 1863-1872, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31549492

RESUMO

We report the synthesis and biological evaluation of phenylcarboxylic acid and phenylboronic acid containing HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. Inhibitors bearing bis-THF ligand as P2 ligand and phenylcarboxylic acids and carboxamide as the P2' ligands, showed very potent HIV-1 protease inhibitory activity. However, carboxylic acid containing inhibitors showed very poor antiviral activity relative to carboxamide-derived inhibitors which showed good antiviral IC50 value. Boronic acid derived inhibitor with bis-THF as the P2 ligand showed very potent enzyme inhibitory activity, but it showed lower antiviral activity than darunavir in the same assay. Boronic acid containing inhibitor with a P2-Crn-THF ligand also showed potent enzyme Ki but significantly decreased antiviral activity. We have evaluated antiviral activity against a panel of highly drug-resistant HIV-1 variants. One of the inhibitors maintained good antiviral activity against HIVDRV R P20 and HIVDRV R P30 viruses. We have determined high resolution X-ray structures of two synthetic inhibitors bound to HIV-1 protease and obtained molecular insight into the ligand-binding site interactions.


Assuntos
Fármacos Anti-HIV/farmacologia , Ácidos Borônicos/farmacologia , Ácidos Carboxílicos/farmacologia , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Linhagem Celular , Cristalografia por Raios X , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular
16.
J Enzyme Inhib Med Chem ; 34(1): 1414-1425, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401901

RESUMO

The emergence of drug-resistant pathogenic bacteria is occurring due to the global overuse and misuse of ß-lactam antibiotics. Infections caused by some bacteria which secrete metallo-ß-lactamases (enzymes that inactivate ß-lactam antibiotics) are increasingly prevalent and have become a major worldwide threat to human health. These bacteria are resistant to ß-lactam antibiotics and MBL-inhibitor/ß-lactam antibiotic combination therapy can be a strategy to overcome this problem. So far, no clinically available inhibitors of metallo-ß-lactamases (MBLs) have been reported. In this study, L-benzyl tyrosine thiol carboxylic acid analogues (2a-2k) were synthesized after the study of computational simulation by adding of methyl, chloro, bromo and nitro groups to the benzyl ring for investigation of SAR analysis. Although the synthesized molecules 2a-k shows the potent inhibitory effects against metallo-ß-lactamase (IMP-1) with the range of Kic values of 1.04-4.77 µM, they are not as potent as the candidate inhibitor.


Assuntos
Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Compostos de Sulfidrila/química , Tirosina/química , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ácidos Carboxílicos/química , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/enzimologia , Serratia marcescens/efeitos dos fármacos , Serratia marcescens/enzimologia , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/química
17.
Eur J Med Chem ; 181: 111559, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376568

RESUMO

Xanthine oxidase is an important target for the treatment of hyperuricemia, gout and other related diseases. Analysis of the high-resolution structure of xanthine oxidase with febuxostat identified the existence of a subpocket formed by the residues Leu648, Asn768, Lys771, Leu1014 and Pro1076. In this study, we designed and synthesized a series of 2-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives (8a-8z) with a tetrazole group targeting this subpocket of the xanthine oxidase active site, and they were further evaluated for their inhibitory potency against xanthine oxidase in vitro. The results showed that all the tested compounds (8a-8z) exhibited an apparent xanthine oxidase inhibitory potency, with IC50 values ranging from 0.0288 µM to 0.629 µM. Among them, compound 8u emerged as the most potent xanthine oxidase inhibitor, with an IC50 value of 0.0288 µM, which was comparable to febuxostat (IC50 = 0.0236 µM). The structure-activity relationship results revealed that the hydrophobic group at the 4'-position was indispensable for the inhibitory potency in vitro against xanthine oxidase. A Lineweaver-Burk plot revealed that the representative compound 8u acted as a mixed-type inhibitor for xanthine oxidase. Furthermore, molecular modeling studies were performed to gain insights into the binding mode of 8u with xanthine oxidase and suggested that the tetrazole group of the phenyl unit was accommodated in the subpocket, as expected. Moreover, a potassium oxonate-induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 8u, and the result demonstrated that compound 8u could effectively reduce serum uric acid levels at an oral dose of 5 mg/kg. In addition, acute oral toxicity study in mice indicated that compound 8u was nontoxic and tolerated at a dose up to 2000 mg/kg. Thus, compound 8u could be a potential and efficacious agent in treatment of hyperuricemia with low toxicity.


Assuntos
Ácidos Carboxílicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Hiperuricemia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xantina Oxidase/metabolismo
18.
Molecules ; 24(16)2019 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-31405197

RESUMO

Psoromic acid (PA), a bioactive lichen-derived compound, was investigated for its inhibitory properties against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), along with the inhibitory effect on HSV-1 DNA polymerase, which is a key enzyme that plays an essential role in HSV-1 replication cycle. PA was found to notably inhibit HSV-1 replication (50% inhibitory concentration (IC50): 1.9 µM; selectivity index (SI): 163.2) compared with the standard drug acyclovir (ACV) (IC50: 2.6 µM; SI: 119.2). The combination of PA with ACV has led to potent inhibitory activity against HSV-1 replication (IC50: 1.1 µM; SI: 281.8) compared with that of ACV. Moreover, PA displayed equivalent inhibitory action against HSV-2 replication (50% effective concentration (EC50): 2.7 µM; SI: 114.8) compared with that of ACV (EC50: 2.8 µM; SI: 110.7). The inhibition potency of PA in combination with ACV against HSV-2 replication was also detected (EC50: 1.8 µM; SI: 172.2). Further, PA was observed to effectively inhibit HSV-1 DNA polymerase (as a non-nucleoside inhibitor) with respect to dTTP incorporation in a competitive inhibition mode (half maximal inhibitory concentration (IC50): 0.7 µM; inhibition constant (Ki): 0.3 µM) compared with reference drugs aphidicolin (IC50: 0.8 µM; Ki: 0.4 µM) and ACV triphosphate (ACV-TP) (IC50: 0.9 µM; Ki: 0.5 µM). It is noteworthy that the mechanism by which PA-induced anti-HSV-1 activity was related to its inhibitory action against HSV-1 DNA polymerase. Furthermore, the outcomes of in vitro experiments were authenticated using molecular docking analyses, as the molecular interactions of PA with the active sites of HSV-1 DNA polymerase and HSV-2 protease (an essential enzyme required for HSV-2 replication) were revealed. Since this is a first report on the above-mentioned properties, we can conclude that PA might be a future drug for the treatment of HSV infections as well as a promising lead molecule for further anti-HSV drug design.


Assuntos
Antivirais , Benzoxepinas , Ácidos Carboxílicos , DNA Polimerase Dirigida por DNA , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 2/fisiologia , Líquens/química , Simulação de Acoplamento Molecular , Proteínas Virais , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacologia , Benzoxepinas/química , Benzoxepinas/farmacologia , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Chlorocebus aethiops , DNA Polimerase Dirigida por DNA/química , DNA Polimerase Dirigida por DNA/metabolismo , Humanos , Inibidores da Síntese de Ácido Nucleico/química , Inibidores da Síntese de Ácido Nucleico/farmacologia , Células Vero , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/química , Proteínas Virais/metabolismo
19.
ChemMedChem ; 14(21): 1856-1862, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31454168

RESUMO

The parasitic disease schistosomiasis is the cause of more than 200 000 human deaths per year. Although the disease is treatable, there is one major shortcoming: praziquantel has been the only drug used to combat these parasites since 1977. The risk of the emergence of resistant schistosomes is known to be increasing, as a reduced sensitivity of these parasites toward praziquantel has been observed. We developed a new class of substances, which are derived from inhibitors of human aldose reductase, and which showed promising activity against Schistosoma mansoni couples in vitro. Further optimisation of the compounds led to an increase in anti-schistosomal activity with observed phenotypes such as reduced egg production, vitality, and motility as well as tegumental damage and gut dilatation. Here, we performed structure-activity relationship studies on the carboxylic acid moiety of biarylalkyl carboxylic acids. Out of 82 carboxylic acid amides, we identified 10 compounds that are active against S. mansoni at 25 µm. The best five compounds showed an anti-schistosomal activity up to 10 µm and induced severe phenotypes. Cytotoxicity tests in human cell lines showed that two derivatives had no cytotoxicity at 50 or 100 µm. These compounds are promising candidates for further optimisation toward the new anti-schistosomal agents.


Assuntos
Amidas/farmacologia , Ácidos Carboxílicos/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Amidas/síntese química , Amidas/química , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
20.
J Med Chem ; 62(18): 8544-8556, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31454231

RESUMO

The bicyclic boronate VNRX-5133 (taniborbactam) is a new type of ß-lactamase inhibitor in clinical development. We report that VNRX-5133 inhibits serine-ß-lactamases (SBLs) and some clinically important metallo-ß-lactamases (MBLs), including NDM-1 and VIM-1/2. VNRX-5133 activity against IMP-1 and tested B2/B3 MBLs was lower/not observed. Crystallography reveals how VNRX-5133 binds to the class D SBL OXA-10 and MBL NDM-1. The crystallographic results highlight the ability of bicyclic boronates to inhibit SBLs and MBLs via binding of a tetrahedral (sp3) boron species. The structures imply conserved binding of the bicyclic core with SBLs/MBLs. With NDM-1, by crystallography, we observed an unanticipated VNRX-5133 binding mode involving cyclization of its acylamino oxygen onto the boron of the bicyclic core. Different side-chain binding modes for bicyclic boronates for SBLs and MBLs imply scope for side-chain optimization. The results further support the "high-energy-intermediate" analogue approach for broad-spectrum ß-lactamase inhibitor development and highlight the ability of boron inhibitors to interchange between different hybridization states/binding modes.


Assuntos
Ácidos Borínicos/farmacologia , Boro/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Ácidos Carboxílicos/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/química , Anti-Infecciosos/farmacologia , Domínio Catalítico , Cristalografia por Raios X , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Klebsiella pneumoniae/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Oxigênio/química , Solventes
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...