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1.
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
2.
J Enzyme Inhib Med Chem ; 34(1): 1426-1438, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401883

RESUMO

Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, 10g. 10g displayed exceptional enzymatic activities (<0.5 nM of IC50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5 nM of IC50) and displays excellent selectivity over c-Met. Moreover, 10g strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, 10g engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Apoptose/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida , Cristalografia por Raios X , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Pirazóis/química , Piridinas/química , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
3.
J Enzyme Inhib Med Chem ; 34(1): 1380-1387, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401884

RESUMO

Novel sulfonamide-dithiocarbamate hybrids were designed and synthesised via the molecular hybridisation strategy. Among them, compound 13d displayed a potent activity with IC50 values of 0.9, 0.7, 1.9 and 2.6 µM against UM-UC-3, RT-112, RT4 and T24. Compound 13d inhibited the migration and regulated the migration-related markers (E-cadherin, N-cadherin, Vimentin, Snail and Slung) against RT-112 cells in a concentration dependent manner. By the tubulin polymerisation assay in vitro and immunostaining assay, compound 13d was identified as a novel tubulin polymerisation inhibitor. Intragastric administration of compound 13d could inhibit the growth of RT-112 cells in vivo in a xenograft mouse model with the low toxicity, indicating that it may be a leading candidate with antitumor properties to treat bladder cancer.


Assuntos
Antineoplásicos/farmacologia , Sulfonamidas/farmacologia , Moduladores de Tubulina/farmacologia , Neoplasias da Bexiga Urinária/patologia , Animais , Antineoplásicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectrometria de Massas , Camundongos , Camundongos Nus , Espectroscopia de Prótons por Ressonância Magnética , Sulfonamidas/química , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Enzyme Inhib Med Chem ; 34(1): 1457-1464, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31411080

RESUMO

Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial metalloenzymes that are involved in diverse bioprocesses. We report the synthesis and biological evaluation of novel series of benzenesulfonamides incorporating un/substituted ethyl quinoline-3-carboxylate moieties. The newly synthesised compounds were in vitro evaluated as inhibitors of the cytosolic human (h) isoforms hCA I and II. Both isoforms hCA I and II were inhibited by the quinolines reported here in variable degrees: hCA I was inhibited with KIs in the range of 0.966-9.091 µM, whereas hCA II in the range of 0.083-3.594 µM. The primary 7-chloro-6-flouro substituted sulphfonamide derivative 6e (KI = 0.083 µM) proved to be the most active quinoline in inhibiting hCA II, whereas, its secondary sulfonamide analog failed to inhibit the hCA II up to 10 µM, confirming the crucial role of the primary sulphfonamide group, as a zinc-binding group for CA inhibitory activity.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Inibidores da Anidrase Carbônica/química , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Sulfonamidas/química
5.
J Enzyme Inhib Med Chem ; 34(1): 1465-1473, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31411081

RESUMO

In this investigation, we studied a family of compounds with an oxathiazolidine-4-one-2,2-dioxide skeleton and their amide synthetic precursors as new anticonvulsant drugs. The cyclic structures were synthesized using a three-step protocol that include solvent-free reactions and microwave-assisted heating. The compounds were tested in vivo through maximal electroshock seizure test in mice. All the structures showed activity at the lower doses tested (30 mg/Kg) and no signs of neurotoxicity were detected. Compound encoded as 1g displayed strong anticonvulsant effects in comparison with known anticonvulsants (ED50 = 29 mg/Kg). First approximations about the mechanisms of action of the cyclic structures were proposed by docking simulations and in vitro assays against sodium channels (patch clamp methods).


Assuntos
Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Desenho de Drogas , Imidas/química , Imidas/farmacologia , Tiazóis/química , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Imidas/síntese química , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.1/efeitos dos fármacos , Óxidos/química , Técnicas de Patch-Clamp , Espectroscopia de Prótons por Ressonância Magnética
6.
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
7.
Chem Commun (Camb) ; 55(64): 9444-9447, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31287465

RESUMO

A new mitochondrion targetable molecular probe for carbon monoxide (CO)-specific detection based on palladium-free mediated opening of spirolactam was designed. The turn-on red fluorescence caused by CO enables a safe and powerful method for unravelling the function of CO in biological systems to be established.


Assuntos
Monóxido de Carbono/análise , Corantes Fluorescentes/química , Mitocôndrias/química , Imagem Óptica/métodos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Lactamas/química , Espectroscopia de Prótons por Ressonância Magnética , Frações Subcelulares/química
8.
SAR QSAR Environ Res ; 30(7): 477-490, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31155931

RESUMO

Selection of key descriptors is very important in QSPR analysis. Presence of noise in the subset of descriptors reduces the quality of predictions. A complete set is considered as perfect when it does not include irrelevant or redundant elements. This paper reports complete sets of descriptors used to develop QSPR models for 1786 13C NMR chemical shifts (δC parameters) of carbon atoms in 125 diverse chemical compounds. PBE1PBE/6-311G(2d,2p) and B3LYP/6-31G(d) basis sets were used for quantum chemistry calculations after the molecular structures were optimized with semi-empirical AM1 and B3LYP/6-31G(d). The two complete sets consisting of magnetic shielding elements (σXX, σYY, σZZ) and the chemical shift principal values (σ11, σ22, σ33) were used as the inputs for support vector machine (SVM) models of δC parameters. The four SVM models obtained have the mean root mean square (rms) errors of about 4.5-4.6 ppm. The results suggest that SVM models are accurate and acceptable compared with previous models, although our models are based on a relatively large set of compounds. Our approach is valuable in the selection of important descriptors for QSPR studies of δC parameters.


Assuntos
Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Compostos Orgânicos/química , Relação Quantitativa Estrutura-Atividade , Algoritmos , Modelos Moleculares , Estrutura Molecular , Teoria Quântica , Máquina de Vetores de Suporte
9.
J Enzyme Inhib Med Chem ; 34(1): 1193-1198, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31237157

RESUMO

A series of histamine bis-Schiff bases and bis-spinaceamine derivatives were synthesised and investigated as activators of four human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic hCA I, II and VII, and the membrane-associated hCA IV. All isoforms were effectively activated by the new derivatives, with activation constants in the range of 4.73-10.2 µM for hCA I, 6.15-42.1 µM for hCA II, 2.37-32.7 µM for hCA IV and 32 nM-18.7 µM for hCA VII, respectively. The nature of the spacer between the two histamine/spinaceamine units of these molecules was the main contributor to the diverse activating efficacy, with a very different fine tuning for the diverse isoforms. As CA activators recently emerged as interesting agents for enhancing cognition, in the management of CA deficiencies, or for therapy memory and artificial tissues engineering, our compounds may be considered as candidates for such applications.


Assuntos
Aminas/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Histamina/metabolismo , Isoenzimas/antagonistas & inibidores , Bases de Schiff/metabolismo , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier
10.
Molecules ; 24(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071946

RESUMO

This work incorporates a variety of conjugated donor-acceptor (DA) co-monomers such as 2,6-diaminopurine (DP) into the structure of a polymeric carbon nitride (PCN) backbone using a unique nanostructure co-polymerization strategy and examines its photocatalytic activity performance in the field of photocatalytic CO2 reduction to CO and H2 under visible light irradiation. The as-synthesized samples were successfully analyzed using different characterization methods to explain their electronic and optical properties, crystal phase, microstructure, and their morphology that influenced the performance due to the interactions between the PCN and the DPco-monomer. Based on the density functional theory (DFT) calculation result, pure PCN and CNU-DP15.0 trimers (interpreted as incorporation of the co-monomer at two different positions) were extensively evaluated and exhibited remarkable structural optimization without the inclusion of any symmetry constraints (the non-modified sample derived from urea, named as CNU), and their optical and electronic properties were also manipulated to control occupation of their respective highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). Also, co-polymerization of the donor-acceptor 2,6-diamino-purine co-monomer with PCN influenced the chemical affinities, polarities, and acid-base functions of the PCN, remarkably enhancing the photocatalytic activity for the production of CO and H2 from CO2 by 15.02-fold compared than that of the parental CNU, while also improving the selectivity.


Assuntos
Dióxido de Carbono/química , Elétrons , Luz , Nitrilos/química , Polímeros/química , Adsorção , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Catálise/efeitos da radiação , Eletroquímica , Nitrogênio/química , Oxirredução , Espectroscopia Fotoeletrônica , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
11.
Eur J Med Chem ; 175: 349-356, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096155

RESUMO

Twelve 2,3-dihydro-[1,4]-dioxino[2,3-f]quinazoline derivatives were designed and evaluated as vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors. The most half-maximal inhibitory concentration (IC50) values of them were less than 10 nM. Among these compounds, 13d displayed highly effective inhibitory activity against VEGFR-2 (IC50 = 2.4 nM) and excellent antiproliferative activities against human umbilical vein endothelial cells (HUVECs) (IC50 = 1.2 nM). When anti-tumor animal experiments were carried out in mice, the tumor almost disappeared (TGI = 133.0%) after six days of administration of 13d. Therefore, 13d was a potential and effective anticancer agent. The binding conformations were respectively compared between VEGFR-2 with 13d and leading compound lenvatinib, and shows that they have similar binding modes.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Quinazolinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/química , Animais , Antineoplásicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Quinazolinas/química , Quinolinas/química , Quinolinas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Ureia/química , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Eur J Med Chem ; 175: 187-200, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078866

RESUMO

The inability to discover novel class of antibacterial agents, especially against Gram-negative bacteria (GNB), compel us to consider a broader non-conventional approach to treat infections caused by multidrug-resistant (MDR) bacteria. One such approach is the use of adjuvants capable of revitalizing the activity of current existing antibiotics from resistant pathogens. Recently, our group reported a series of tobramycin (TOB)-based hybrid adjuvants that were able to potentiate multiple classes of legacy antibiotics against various MDR GNB. Herein, we report the modification of TOB-based hybrid adjuvants by replacing TOB domain by the pseudo-disaccharide nebramine (NEB) through selective cleavage of the α-d-glucopyranosyl linkage of TOB. Potent synergism was found for combinations of NEB-based hybrid adjuvants with multiple classes of legacy antibiotics including fluoroquinolones (moxifloxacin and ciprofloxacin), tetracyclines (minocycline), or rifamycin (rifampicin) against both wild-type and MDR P. aeruginosa clinical isolates. We also demonstrated that a combination of the optimized NEB-CIP hybrid 1b and rifampicin protects Galleria mellonella larvae from the lethal effects of extensively drug-resistant (XDR) P. aeruginosa. Mechanistic evaluation of NEB-based hybrid adjuvants revealed that the hybrids affect the outer- and inner membranes of wild-type P. aeruginosa PAO1. This study describes an approach to optimize aminoglycoside-based hybrids to yield lead adjuvant candidates that are able to resuscitate the activity of partner antibiotics against MDR GNB.


Assuntos
Antibacterianos/farmacologia , Dissacarídeos/química , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Piranos/química , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Sinergismo Farmacológico , Quimioterapia Combinada , Células HEK293 , Hemólise/efeitos dos fármacos , Humanos , Larva/efeitos dos fármacos , Lepidópteros/crescimento & desenvolvimento , Lepidópteros/microbiologia , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética , Pseudomonas aeruginosa/efeitos dos fármacos , Rifampina/administração & dosagem , Espectrometria de Massas por Ionização por Electrospray , Suínos
13.
Eur J Med Chem ; 175: 49-62, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31075608

RESUMO

Antibiotic resistance remains a pressing medical challenge for which novel antibacterial agents are urgently needed. The phenylthiazole scaffold represents a promising platform to develop novel antibacterial agents for drug-resistant infections. However, enhancing the physicochemical profile of this class of compounds remains a challenging endeavor to address to successfully translate these molecules into novel antibacterial agents in the clinic. We extended our understanding of the SAR of the phenylthiazoles' lipophilic moiety by exploring its ability to accommodate a hydrophilic group or a smaller sized hetero-ring with the objective of enhancing the physicochemical properties of this class of novel antimicrobials. Overall, the 2-thienyl derivative 20 and the hydroxyl-containing derivative 31 emerged as the most promising antibacterial agents inhibiting growth of drug-resistant Staphylococcus aureus at a concentration as low as 1 µg/mL. Remarkably, compound 20 suppressed bacterial undecaprenyl pyrophosphatase (UppP), the molecular target of the phenylthiazole compounds, in a sub nano-molar concentration range (almost 20,000 times more potent than the lead compounds 1a and 1b). Compound 31 possessed the most balanced antibacterial and physicochemical profile. The compound exhibited rapid bactericidal activity against S. aureus, and successfully cleared intracellular S. aureus within infected macrophages. Furthermore, insertion of the hydroxyl group enhanced the aqueous solubility of 31 by more than 50-fold relative to the first-generation lead 1c.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Lipídeos/química , Pirofosfatases/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Animais , Antibacterianos/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular , Cromatografia Líquida , Macrófagos/microbiologia , Espectrometria de Massas , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 175: 201-214, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078867

RESUMO

Herein we report the design, synthesis, molecular docking study and evaluation of antimicrobial activity of ten new dithioloquinolinethiones. The structures of compounds were confirmed by 1H NMR, 13C NMR and HPLC-HRMS. Before evaluation of their possible antimicrobial activity prediction of toxicity was performed. All compounds showed antibacterial activity against eight Gram positive and Gram negative bacterial species. All compounds appeared to be more active than ampicillin and almost all than streptomycin. The best antibacterial activity was observed for compound 8c 4,4,8-trimethyl-5-{[(4-phenyl-5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)thio]acetyl}-4,5-dihydro-1H-[1,2]dithiolo[3,4c]quino lone-1-thione). The most sensitive bacterium En.cloacae followed by S. aureus, while L.monocytogenes was the most resistant. All compounds were tested for antifungal activity also against eight fungal species. The best activity was expressed by compound 8d (5-[(4,5-Dihydro-1,3-thiazol-2-ylthio)acetyl]-4,4-dimethyl-4,5-dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thione). The most sensitive fungal was T. viride, while P. verrucosum var. cyclopium was the most resistant one. All compounds were more potent as antifungal agent than reference compound bifonazole and ketoconazole. The docking studies indicated a probable involvement of E. coli DNA GyrB inhibition in the anti-bacterial mechanism, while CYP51ca inhibition is probably responsible for antifungal activity of tested compounds. It is interesting to mention that docking results coincides with experimental.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Antibacterianos/síntese química , Antifúngicos/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cromatografia Líquida de Alta Pressão , Desenho de Drogas , Fungos/classificação , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Quinolinas/síntese química , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 175: 162-171, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082763

RESUMO

We have designed novel tropinone-thiazole derivatives that showed high antiproliferative activity against a variety of cancer cell lines via caspase 3/7 activation mechanism. Among the derivatives, compounds 3b-3h were found to exhibit high activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast carcinoma (MCF-7), and skin melanoma (B16-F10) cancer cell lines, with IC50 values of 5.43-11.06 µM. The lead compound 3g increases caspase 3/7 activity in A549 cells 25 times more than the control, and 2 times more than reference drug camptothecin. We have also found that tropinone-thiazole derivatives exhibit high tyrosinase inhibitory activity. The lead compounds 3g and 3h showed tyrosinase inhibition effect, with IC50 values 3.22 and 3.51 µM, respectively. These inhibitory activities are 22 times higher than the activity of kojic acid (IC50 72.27 µM) and 120 times higher than activity of ascorbic acid (IC50 386.5 µM). For compounds 3g and 3h, the experimentally determined lipophilicity correlates very well with their enzymatic activities. These data suggest that presented compounds could constitute lead anticancer drug candidates.


Assuntos
Caspase 3/metabolismo , Caspase 7/farmacologia , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Ativadores de Enzimas/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Tiazóis/química , Tropanos/química , Células 3T3 , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Caspase 7/química , Linhagem Celular Tumoral , Cromatografia Líquida/métodos , Ensaios de Seleção de Medicamentos Antitumorais , Ativadores de Enzimas/química , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray/métodos , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 175: 172-186, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082764

RESUMO

Due to the limitations of existing anti-EV71 targets, we have been eager to discover a new anti-EV71 agent based on mTOR (the mammalian target of rapamycin), which is an important target for finding antiviral agents based on host cells. Torin2 is a second-generation ATP competitive mTOR kinase inhibitor (IC50 = 0.25 nM). Our research team tested the anti-EV71 activity of Torin2 in vitro for the first time. The result showed that Torin2 had significant anti-EV71 activity (IC50 = 0.01 µM). In this study, thirty novel Torin2 derivatives were synthesized and evaluated for anti-EV71 activity. Among them, 11a, 11b, 11d, 11e and 11m displayed similar activity to Torin2. 11e displayed the most potent activity, with an IC50 value of 0.027 µM, which was closest to Torin2, and displayed potent mTOR kinase inhibitory activity. A molecular modeling study showed that 11e interacted with Val2240 and Lys2187 via hydrogen bonds and had a good match with the receptor. Additionally, a mechanism study showed that most of the compounds had significant inhibition for the mTOR pathway substrates p70S6K and Akt. The water solubility test of compounds with potent activity revealed that 11a and 11m were improved by approximately 5-15-fold compared to Torin2. These data suggest that 11a and 11m may be potential candidates for anti-EV71 treatment.


Assuntos
Antivirais/química , Antivirais/farmacologia , Desenho de Drogas , Enterovirus Humano A/efeitos dos fármacos , Naftiridinas/química , Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Antivirais/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Células Cultivadas , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftiridinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Solubilidade , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 175: 309-329, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096153

RESUMO

Compounds simultaneously inhibiting two targets that are involved in the progression of the same complex disease may exhibit additive or even synergistic therapeutic effects. Here we unveil 2,4,5-trisubstituted imidazoles as dual inhibitors of p38α mitogen-activated protein kinase and glycogen synthase kinase 3ß (GSK3ß). Both enzymes are potential therapeutic targets for neurodegenerative disorders, like Alzheimer's disease. A set of 39 compounds was synthesized and evaluated in kinase activity assays for their ability to inhibit both target kinases. Among the synthesized compounds, potent dual-target-directed inhibitors showing IC50 values down to the low double-digit nanomolar range, were identified. One of the best balanced dual inhibitors presented in here is N-(4-(2-ethyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide (20c) (p38α, IC50 = 16 nM; GSK3ß, IC50 = 35 nM) featuring an excellent metabolic stability and an appreciable isoform selectivity over the closely related GSK3α. Our findings were rationalized by computational docking studies based on previously published X-ray structures.


Assuntos
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Sequência de Aminoácidos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Humanos , Imidazóis/química , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Piridinas/química , Homologia de Sequência de Aminoácidos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
18.
Nat Commun ; 10(1): 1747, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988305

RESUMO

Side chains cover protein surfaces and are fundamental to processes as diverse as substrate recognition, protein folding and enzyme catalysis. However, characterisation of side-chain motions has so far been restricted to small proteins and methyl-bearing side chains. Here we present a class of methods, based on 13C-detected NMR spectroscopy, to more generally quantify motions and interactions of side chains in medium-to-large proteins. A single, uniformly isotopically labelled sample is sufficient to characterise the side chains of six different amino acid types. Side-chain conformational dynamics on the millisecond time-scale can be quantified by incorporating chemical exchange saturation transfer (CEST) into the presented methods, whilst long-range 13C-13C scalar couplings reporting on nanosecond to millisecond motions can be quantified in proteins as large as 80 kDa. The presented class of methods promises characterisation of side-chain behaviour at a level that has so far been reserved for the protein backbone.


Assuntos
Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Proteínas/química , Modelos Moleculares , Conformação Proteica , Dobramento de Proteína , Análise de Sequência de Proteína
19.
Chem Commun (Camb) ; 55(32): 4687-4690, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30938741

RESUMO

DNP solid state NMR spectroscopy allows non-targeted analysis of wild spider silk in unprecedented detail at natural abundance, revealing hitherto unreported features across several species. A >50-fold signal enhancement for each silk, enables the detection of novel H-bonding networks and arginine conformations, and the post-translational modified amino acid, hydroxyproline.


Assuntos
Fibroínas/química , Aranhas/química , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ligações de Hidrogênio , Hidroxiprolina/química , Isótopos de Nitrogênio , Conformação Proteica em Folha beta
20.
Molecules ; 24(8)2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31003403

RESUMO

A phytochemical investigation of the foliose lichen Parmotrema tsavoense (Krog and Swinscow) Krog and Swinscow (Parmeliaceae) resulted in the isolation of a new trichlorinated xanthone, isodemethylchodatin. The structure elucidation of this new norlichexanthone derivative proved tricky owing to proton deficiency, and to the lack of NMR data of closely related analogues. The structure of this compound was determined based on an integrated interpretation of 13C-NMR chemical shifts, MS spectra, and DP4-based computational chemistry was also performed to provide an independent and unambiguous validation of the determined structure. Isodemethylchodatin represents the first chlorinated lichexanthone/norlichexanthone derivative bearing a methoxy group at C-5.


Assuntos
Hidrogênio/química , Líquens/química , Xantonas/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Espectroscopia de Prótons por Ressonância Magnética , Estereoisomerismo
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