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1.
Molecules ; 26(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672630

RESUMO

Despite advances achieved over the last decade, infections caused by multi-drug-resistant bacterial strains are increasingly becoming important societal issues that need to be addressed. New approaches have already been developed in order to overcome this problem. Photodynamic antimicrobial chemotherapy (PACT) could provide an alternative to fight infectious bacteria. Many studies have highlighted the value of cationic photosensitizers in order to improve this approach. This study reports the synthesis and the characterization of cationic porphyrins derived from methylimidazolium and phenylimidazolium porphyrins, along with a comparison of their photophysical properties with the well-known N-methylpyridyl (pyridinium) porphyrin family. PACT tests conducted with the tetracationic porphyrins of these three families showed that these new photosensitizers may offer a good alternative to the classical pyridinium porphyrins, especially against S.aureus and E.coli. In addition, they pave the way to new cationic photosensitizers by the means of derivatization through amide bond formation.


Assuntos
Antibacterianos/farmacologia , Imidazóis/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Piridinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Imidazóis/síntese química , Imidazóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Porfirinas/síntese química , Porfirinas/química , Pseudomonas aeruginosa/efeitos dos fármacos , Piridinas/síntese química , Piridinas/química , Staphylococcus aureus/efeitos dos fármacos
2.
J Med Chem ; 64(2): 1180-1196, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33439019

RESUMO

G-protein coupled receptors (GPCRs) exist in an equilibrium of multiple conformational states, including different active states, which depend on the nature of the bound ligand. In consequence, different conformational states can initiate specific signal transduction pathways. The study identified compound 7e, which acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT6R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted receptor conformational changes for 7e and inverse agonist PZ-1444. In cell-based assays, neutral antagonists of the 5-HT6R (7e and CPPQ), but not inverse agonists (SB-258585, intepirdine, PZ-1444), displayed glioprotective properties against 6-hydroxydopamine-induced and doxorubicin-induced cytotoxicity. These suggest that targeting the activated conformational state of the 5-HT6R with neutral antagonists implicates the protecting properties of astrocytes. Additionally, 7e prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HT6R.


Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Humanos , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/prevenção & controle , Masculino , Conformação Molecular , Neuritos/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade
3.
Int J Mol Sci ; 22(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429999

RESUMO

Online Chemical Modeling Environment (OCHEM) was used for QSAR analysis of a set of ionic liquids (ILs) tested against multi-drug resistant (MDR) clinical isolate Acinetobacter baumannii and Staphylococcus aureus strains. The predictive accuracy of regression models has coefficient of determination q2 = 0.66 - 0.79 with cross-validation and independent test sets. The models were used to screen a virtual chemical library of ILs, which was designed with targeted activity against MDR Acinetobacter baumannii and Staphylococcus aureus strains. Seven most promising ILs were selected, synthesized, and tested. Three ILs showed high activity against both these MDR clinical isolates.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Imidazóis/química , Piridinas/química , Acinetobacter baumannii/patogenicidade , Infecções Bacterianas/microbiologia , Resistência a Múltiplos Medicamentos , Humanos , Imidazóis/síntese química , Líquidos Iônicos/síntese química , Líquidos Iônicos/química , Piridinas/síntese química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Relação Estrutura-Atividade
4.
Food Chem ; 334: 127345, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32712485

RESUMO

The development of a novel molecularly imprinted solid-phase extraction (MISPE) method for simultaneous preconcentration of imazapyr (IMP), imazapic (IMZ) and imazethapyr (IMT) with determination by HPLC-PAD (High performance liquid chromatography - photodiode-array detector) is proposed. The polymer synthesis was performed using imazethapyr as template molecule and 1-vinylimidazole as functional monomer. The method is based on preconcentration of 100.0 mL of sample through 200.0 mg of molecularly imprinted poly(vinylimidazole-TRIM) (MIP-1VN) at pH 4.0, followed by elution with 2.0 mL of MeOH:CH2Cl2:HAc (34:62:4, v/v). The range of analytical curve (0.29-200.0, 0.21-200.0 and 0.15-200.0 µg L-1), limits of detection (0.09, 0.06 and 0.04 µg L-1) and preconcentration factors (92, 96 and 98) determined for the herbicides, IMP, IMZ and IMT, respectively, were greatly superior when compared with those ones obtained with commercial adsorbents. The analytical method was successfully applied to spiked surface water and rice samples with good results of recovery values (86-107%).


Assuntos
Herbicidas/análise , Impressão Molecular/métodos , Oryza/química , Extração em Fase Sólida/métodos , Poluentes Químicos da Água/análise , Cromatografia Líquida de Alta Pressão/métodos , Contaminação de Alimentos/análise , Imidazóis/análise , Imidazóis/síntese química , Imidazóis/química , Limite de Detecção , Niacina/análogos & derivados , Niacina/análise , Ácidos Nicotínicos/análise , Ácidos Nicotínicos/química , Polivinil/síntese química , Polivinil/química , Sementes/química , Extração em Fase Sólida/instrumentação
5.
Cancer Sci ; 112(3): 1141-1149, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33377228

RESUMO

PIK3CA is the most frequently mutated oncogene in cervical cancer, and somatic mutations in the PIK3CA gene result in increased activity of PI3K. In cervical cancer, the E545K mutation in PIK3CA leads to elevated cell proliferation and reduced apoptosis. In the present study, we designed and synthesized a novel pyrrole-imidazole polyamide-seco-CBI conjugate, P3AE5K, to target the PIK3CA gene bearing the E545K mutation, rendered possible by nuclear access and the unique sequence specificity of pyrrole-imidazole polyamides. P3AE5K interacted with double-stranded DNA of the coding region containing the E545K mutation. When compared with conventional PI3K inhibitors, P3AE5K demonstrated strong cytotoxicity in E545K-positive cervical cancer cells at lower concentrations. PIK3CA mutant cells exposed to P3AE5K exhibited reduced expression levels of PIK3CA mRNA and protein, and subsequent apoptotic cell death. Moreover, P3AE5K significantly decreased the tumor growth in mouse xenograft models derived from PIK3CA mutant cells. Overall, the present data strongly suggest that the alkylating pyrrole-imidazole polyamide P3AE5K should be a promising new drug candidate targeting a constitutively activating mutation of PIK3CA in cervical cancer.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Mutação com Ganho de Função , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Camundongos , Nylons/síntese química , Nylons/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Pirróis/síntese química , Pirróis/farmacologia , Pirróis/uso terapêutico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Anticancer Res ; 40(9): 4913-4919, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878779

RESUMO

BACKGROUND/AIM: A new class of imidazo[2,1-b][1,3,4]thiadiazole compounds have recently been evaluated as inhibitors of phosphorylation of focal adhesion kinase (FAK) in pancreatic cancer. FAK is overexpressed in mesothelioma and has recently emerged as an interesting target for the treatment of this disease. MATERIALS AND METHODS: Ten imidazo[2,1-b][1,3,4]thiadiazole compounds characterized by indole bicycle and a thiophene ring, were evaluated for their cytotoxic activity in two primary cell cultures of peritoneal mesothelioma, MesoII and STO cells. RESULTS: Compounds 1a and 1b showed promising antitumor activity with IC50 values in the range of 0.59 to 2.81 µM in both cell lines growing as monolayers or as spheroids. Their antiproliferative and antimigratory activity was associated with inhibition of phospho-FAK, as detected by a specific ELISA assay in STO cells. Interestingly, these compounds potentiated the antiproliferative activity of gemcitabine, and these results might be explained by the increase in the mRNA expression of the key gemcitabine transporter human equilibrative nucleoside transporter-1 (hENT-1). CONCLUSION: These promising results support further studies on new imidazo[2,1-b][1,3,4]thiadiazole compounds as well as on the role of both FAK and hENT-1 modulation in order to develop new drug combinations for peritoneal mesothelioma.


Assuntos
Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Transportador Equilibrativo 1 de Nucleosídeo/genética , Quinase 1 de Adesão Focal/metabolismo , Imidazóis/farmacologia , Tiadiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Estrutura Molecular , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/patologia , Fosforilação/efeitos dos fármacos , Tiadiazóis/síntese química , Tiadiazóis/química , Células Tumorais Cultivadas
7.
J Chromatogr A ; 1625: 461331, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32709357

RESUMO

In this work, a novel imidazolium bonding method was proposed for the synthesis of hydrophilic interaction liquid chromatography (HILIC) stationary phases. One obtained stationary phase (SilprAprImCl) was derived from direct reaction between N-(3-aminopropyl)-imidazole and 3-chloropropylated silica gel. Other two materials (SilprAprImBF4 and SilprAprImTf2N) were obtained from SilprAprImCl by ion exchange reaction, respectively. Fourier-transform infrared spectroscopy and elemental analysis afforded the proofs of successful imidazolium immobilization and satisfied bonding efficiency. Various polar compounds such as saccharides, nucleosides, and nucleobases were utilized to evaluate the retention behaviours of these materials in HILIC mode. Different effects from mobile composition, column temperature, imidazolium unite and paired anions (Cl-, BF4-, and Tf2N-) in imidazolium were proved and discussed. Separation mechanism and the role of the imidazolium ions were also investigated in mobile phases with different pH. Moreover, chromatographic stability was evaluated by consecutive injections. Finally, the reliability of these stationary phases was demonstrated by the separation of oligosaccharides in real fructooligosaccharides samples.


Assuntos
Cromatografia Líquida/métodos , Interações Hidrofóbicas e Hidrofílicas , Imidazóis/química , Propanóis/química , Ânions , Concentração de Íons de Hidrogênio , Imidazóis/síntese química , Líquidos Iônicos/química , Nucleosídeos/química , Nucleosídeos/isolamento & purificação , Oligossacarídeos/química , Propanóis/síntese química , Reprodutibilidade dos Testes , Temperatura
8.
Proc Natl Acad Sci U S A ; 117(24): 13267-13274, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32487725

RESUMO

Continuous reaction networks, which do not rely on purification or timely additions of reagents, serve as models for chemical evolution and have been demonstrated for compounds thought to have played important roles for the origins of life such as amino acids, hydroxy acids, and sugars. Step-by-step chemical protocols for ribonucleotide synthesis are known, but demonstrating their synthesis in the context of continuous reaction networks remains a major challenge. Herein, compounds proposed to be important for prebiotic RNA synthesis, including glycolaldehyde, cyanamide, 2-aminooxazole, and 2-aminoimidazole, are generated from a continuous reaction network, starting from an aqueous mixture of NaCl, NH4Cl, phosphate, and HCN as the only carbon source. No well-timed addition of any other reagents is required. The reaction network is driven by a combination of γ radiolysis and dry-down. γ Radiolysis results in a complex mixture of organics, including the glycolaldehyde-derived glyceronitrile and cyanamide. This mixture is then dried down, generating free glycolaldehyde that then reacts with cyanamide/NH3 to furnish a combination of 2-aminooxazole and 2-aminoimidazole. This continuous reaction network models how precursors for generating RNA and other classes of compounds may arise spontaneously from a complex mixture that originates from simple reagents.


Assuntos
Evolução Química , Modelos Químicos , RNA/química , RNA/síntese química , Acetaldeído/análogos & derivados , Acetaldeído/síntese química , Acetaldeído/química , Cianamida/síntese química , Cianamida/química , Raios gama , Imidazóis/síntese química , Imidazóis/química , Origem da Vida , Oxazóis/síntese química , Oxazóis/química , Fotoquímica , Água/química
9.
J Med Chem ; 63(9): 4603-4616, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32223240

RESUMO

Glioblastoma multiforme (GBM) is the deadliest form of brain tumor. It is known for its ability to escape the therapeutic options available to date thanks to the presence of a subset of cells endowed with stem-like properties and ability to resist to cytotoxic treatments. As the cytosolic enzyme aldehyde dehydrogenase 1A3 turns out to be overexpressed in these kinds of cells, playing a key role for their vitality, treatments targeting this enzyme may represent a successful strategy to fight GBM. In this work, we describe a novel class of imidazo[1,2-a]pyridine derivatives as aldehyde dehydrogenase 1A3 inhibitors, reporting the evidence of their significance as novel drug candidates for the treatment of GBM. Besides showing an interesting functional profile, in terms of activity against the target enzyme and selectivity toward highly homologous isoenzymes, representative examples of the series also showed a nanomolar to picomolar efficacy against patient-derived GBM stem-like cells, thus proving the concept that targeting aldehyde dehydrogenase might represent a novel and promising way to combat GBM by striking its ability to divide immortally.


Assuntos
Aldeído Oxirredutases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Piridinas/farmacologia , Aldeído Oxirredutases/química , Aldeído Oxirredutases/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Glioblastoma/tratamento farmacológico , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Piridinas/síntese química , Piridinas/metabolismo , Relação Estrutura-Atividade
10.
Sci Rep ; 10(1): 6534, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32300169

RESUMO

Novel derivatives possessing imidazo[1,2-a]pyrazine and 1H-benzo[d]imidazole scaffolds were synthesized using Suzuki-Miyaura cross-coupling reactions. In vitro anticancer activities against NCI-60 cancer cell panels were tested at 10 µM concentration. The best results were obtained from substitution of two 1-cyclohexyl-1H-benzo[d]imidazole groups present at C-6 and C-8 positions of imidazo[1,2-a]pyrazine (31). Compound 31 was found to be cytotoxic against 51 cell lines and cytostatic against 8 cell lines with broad range of growth inhibitions (-98.48 to 98.86%). GI50 value of compound 31 was found in the range of 0.80-2.87 µM for 59 human cancer cell lines at five-dose concentration levels. DNA binding study of potent compound 31 was suggested that this compound was intercalated into DNA base pairs with binding constant of 1.25 × 104 M-1. Compound 31 showed effective binding with bovine serum albumin (BSA) and presented binding constant value of 3.79 ×104 M-1. Pharmacokinetic studies revealed that all compounds are following Lipinski's rule of five and expected to be orally active.


Assuntos
DNA/metabolismo , Imidazóis/síntese química , Imidazóis/farmacocinética , Soroalbumina Bovina/metabolismo , Animais , Ligação Competitiva , Bovinos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Etídio/metabolismo , Transferência Ressonante de Energia de Fluorescência , Células HEK293 , Humanos , Imidazóis/química , Imidazóis/farmacologia , Simulação de Acoplamento Molecular , Desnaturação de Ácido Nucleico , Ligação Proteica , Espectrometria de Fluorescência , Temperatura
11.
Parasitol Res ; 119(6): 1925-1941, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32279093

RESUMO

Toxoplasmosis is a common parasitic disease caused by Toxoplasma gondii. Limitations of available treatments motivate the search for better therapies for toxoplasmosis. In this study, we synthesized a series of new imidazole derivatives: bis-imidazoles (compounds 1-8), phenyl-substituted 1H-imidazoles (compounds 9-19), and thiopene-imidazoles (compounds 20-26). All these compounds were assessed for in vitro potential to restrict the growth of T. gondii. To explore the structure-activity relationships, molecular analyses and bioactivity prediction studies were performed using a standard molecular model. The in vitro results, in combination with the predictive model, revealed that the imidazole derivatives have excellent selectivity activity against T. gondii versus the host cells. Of the 26 compounds screened, five imidazole derivatives (compounds 10, 11, 18, 20, and 21) shared a specific structural moiety and exhibited significantly high selectivity (> 1176 to > 27,666) towards the parasite versus the host cells. These imidazole derivatives are potential candidates for further studies. We show evidence that supports the antiparasitic action of the imidazole derivatives. The findings are promising in that they reinforce the prospects of imidazole derivatives as alternative and effective antiparasitic therapy as well as providing evidence for a probable biological mechanism.


Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Toxoplasma/efeitos dos fármacos , Animais , Células Cultivadas , Humanos , Imidazóis/síntese química , Modelos Moleculares , Relação Estrutura-Atividade , Toxoplasmose/parasitologia
12.
J Enzyme Inhib Med Chem ; 35(1): 702-712, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32164459

RESUMO

A series of 2,4-disubstituted-5-(6-alkylpyridin-2-yl)-1H-imidazoles, 7a-c, 11a-h, and 16a-h has been synthesised and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Incorporation of a quinoxalin-6-yl moiety and a methylene linker at the 4- and 2-position of the imidazole ring, respectively, and a m-CONH2 substituent in the phenyl ring generated a highly potent and selective ALK5 inhibitor 11e. Docking model of ALK5 in complex with 11e showed that it fitted well in the ATP-binding pocket with favourable interactions.


Assuntos
Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Células CACO-2 , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Relação Estrutura-Atividade
13.
J Med Chem ; 63(7): 3538-3551, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32134266

RESUMO

The overaccumulation of glycogen appears as a hallmark in various glycogen storage diseases (GSDs), including Pompe, Cori, Andersen, and Lafora disease. Accumulating evidence suggests that suppression of glycogen accumulation represents a potential therapeutic approach for treating these GSDs. Using a fluorescence polarization assay designed to screen for inhibitors of the key glycogen synthetic enzyme, glycogen synthase (GS), we identified a substituted imidazole, (rac)-2-methoxy-4-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-phenyl-1H-imidazol-5-yl)phenol (H23), as a first-in-class inhibitor for yeast GS 2 (yGsy2p). Data from X-ray crystallography at 2.85 Å, as well as kinetic data, revealed that H23 bound within the uridine diphosphate glucose binding pocket of yGsy2p. The high conservation of residues between human and yeast GS in direct contact with H23 informed the development of around 500 H23 analogs. These analogs produced a structure-activity relationship profile that led to the identification of a substituted pyrazole, 4-(4-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrogallol, with a 300-fold improved potency against human GS. These substituted pyrazoles possess a promising scaffold for drug development efforts targeting GS activity in GSDs associated with excess glycogen accumulation.


Assuntos
Inibidores Enzimáticos/química , Glicogênio Sintase/antagonistas & inibidores , Imidazóis/química , Pirazóis/química , Animais , Caenorhabditis elegans/enzimologia , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Glicogênio Sintase/química , Glicogênio Sintase/metabolismo , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Cinética , Estrutura Molecular , Ligação Proteica , Pirazóis/síntese química , Pirazóis/metabolismo , Saccharomyces cerevisiae/enzimologia , Relação Estrutura-Atividade
14.
J Med Chem ; 63(6): 3188-3204, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32134652

RESUMO

Autotaxin (ATX, also known as ENPP2) is a predominant lysophosphatidic acid (LPA)-producing enzyme in the body, and LPA regulates various physiological functions, such as angiogenesis and wound healing, as well as pathological functions, including proliferation, metastasis, and fibrosis, via specific LPA receptors. Therefore, the ATX-LPA axis is a promising therapeutic target for dozens of diseases, including cancers, pulmonary and liver fibroses, and neuropathic pain. Previous structural studies revealed that the catalytic domain of ATX has a hydrophobic pocket and a hydrophobic channel; these serve to recognize the substrate, lysophosphatidylcholine (LPC), and deliver generated LPA to LPA receptors on the plasma membrane. Most reported ATX inhibitors bind to either the hydrophobic pocket or the hydrophobic channel. Herein, we present a unique ATX inhibitor that binds mainly to the hydrophobic pocket and also partly to the hydrophobic channel, inhibiting ATX activity with high potency and selectivity in vitro and in vivo. Notably, our inhibitor can rescue the cardia bifida (two hearts) phenotype in ATX-overexpressing zebrafish embryos.


Assuntos
Imidazóis/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Pirimidinas/uso terapêutico , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cristalografia por Raios X , Cardiopatias/prevenção & controle , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imidazóis/síntese química , Imidazóis/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/metabolismo , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo , Relação Estrutura-Atividade , Peixe-Zebra
15.
J Med Chem ; 63(7): 3610-3633, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32150414

RESUMO

Imidazoline I2 receptors (I2-IR), widely distributed in the CNS and altered in patients that suffer from neurodegenerative disorders, are orphans from a structural point of view, and new I2-IR ligands are urgently required for improving their pharmacological characterization. We report the synthesis and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of a new family of bicyclic α-iminophosphonates endowed with relevant affinities for human brain I2-IR. Acute treatment in mice with a selected compound significantly decreased Fas-associated protein with death domain (FADD) in the hippocampus, a key signaling mediator of neuroprotective actions. Additionally, in vivo studies in the familial Alzheimer's disease 5xFAD murine model revealed beneficial effects in behavior and cognition. These results are supported by changes in molecular pathways related to cognitive decline and Alzheimer's disease. Therefore, bicyclic α-iminophosphonates are tools that may open new therapeutic avenues for I2-IR, particularly for unmet neurodegenerative conditions.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Imidazóis/uso terapêutico , Receptores de Imidazolinas/metabolismo , Nootrópicos/uso terapêutico , Organofosfonatos/uso terapêutico , Animais , Chlorocebus aethiops , Reação de Cicloadição , Cães , Feminino , Células HeLa , Hipocampo/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Imidazóis/farmacocinética , Ligantes , Células Madin Darby de Rim Canino , Camundongos , Estrutura Molecular , Nootrópicos/síntese química , Nootrópicos/metabolismo , Nootrópicos/farmacocinética , Organofosfonatos/síntese química , Organofosfonatos/metabolismo , Organofosfonatos/farmacocinética , Relação Quantitativa Estrutura-Atividade , Células Vero
16.
J Med Chem ; 63(6): 3028-3046, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32069401

RESUMO

PI3K-Akt-mTOR signaling pathway has been validated as an effective targeting pathway for cancer therapy. However, no PI3K/mTOR dual inhibitor has been approved by the FDA yet. Therefore, it is still essential to discover a candidate with good efficacy and low toxicity. In our design, a series of imidazo[1,2-a]pyridine derivatives had been synthesized and subjected to activity assessment in vitro and in vivo. 15a was proved to be a potent PI3K/mTOR dual inhibitor with excellent kinase selectivity, modest plasma clearance, and acceptable oral bioavailability. Besides, 15a displayed significant inhibition of tumor growth in HCT116 and HT-29 xenografts without obvious effect on body weight.


Assuntos
Imidazóis/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Desenho de Fármacos , Feminino , Células HCT116 , Células HT29 , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacocinética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/metabolismo
17.
Molecules ; 25(3)2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32024141

RESUMO

The macrocyclic cavitand MeMeCH2 is used as a template for the mechanochemical synthesis of 0.2MeMeCH2@RHO-Zn16(Cl2Im)32 (0.2MeMeCH2@ZIF-71) and RHO-ZnBIm2 (ZIF-11) zeolitic imidazolate frameworks (ZIFs). It is shown that MeMeCH2 significantly accelerates the mechanochemical synthesis, providing high porosity products (BET surface areas of 1140 m2/g and 869 m2/g, respectively). Templation of RHO-topology ZIF frameworks constructed of linkers larger than benzimidazole (HBIm) was unsuccessful. It is also shown that cavitands other than MeMeCH2-namely MeHCH2, MeiBuCH2, HPhCH2, MePhCH2, BrPhCH2, BrC5CH2-can serve as effective templates for the synthesis of x(cavitand)@RHO-ZnIm2 products. The limitations on cavitand size and shape are explored in terms of their effectiveness as templates.


Assuntos
Imidazóis/química , Estruturas Metalorgânicas/química , Zeolitas/química , Fenômenos Químicos , Técnicas de Química Sintética , Imidazóis/síntese química , Estruturas Metalorgânicas/síntese química , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Zeolitas/síntese química
18.
Dalton Trans ; 49(6): 1864-1872, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-31967143

RESUMO

Organometallic complexes have important application in the field of protein staining, with potential for use in proteomic analysis. The rational synthesis of a trinuclear luminescent organometallic complex with two platinum(ii) centres appended to the cyclometalated ligand of the iridium(iii) centre is reported here. Two di-2-picolylamine groups bonded to the cyclometalated phenyl pyridine moiety provide three coordinating sites to each platinum centre. The replacement of chloride in the fourth coordination site of two square planar platinum metal centres with the imidazole nitrogen or sulphur atom of histidine/cysteine is evident from the change in luminescence intensity upon binding these amino acids. The increase in luminescence emission intensity upon binding of histidine to the organometallic complex allowed it to be used as a protein staining agent. Reversibility of staining upon washing with imidazole enhances the possibility of its application in mass spectrometric analysis.


Assuntos
Complexos de Coordenação/química , Irídio/química , Substâncias Luminescentes/química , Proteínas/análise , Complexos de Coordenação/síntese química , Imidazóis/síntese química , Imidazóis/química , Luminescência , Substâncias Luminescentes/síntese química , Modelos Moleculares , Coloração e Rotulagem
19.
J Fluoresc ; 30(2): 259-267, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31989418

RESUMO

A novel naked eye fluorescence sensor (ANI) based on naphthalimide and imidazolium moieties for fluoride detection has been designed and synthesized by multiple step synthesis. The fluorescence response of ANI sensor was significantly quenched in the presence of fluoride ion upon the interaction between an acidic amide proton and acidic C2 proton (-C(2)H-) of imidazolium compound. The binding behavior of ANI and F- ion was extensively explored by using NMR titration. Comparison of binding ability of ANI and AN sensors addressed the dominant electrostatic and hydrogen bonding interaction with F- ion. Consequently, ANI sensor highlights a strong binding with F- ions with a high selectivity over AN. Interestingly, ANI demonstrated a naked-eye response with colorimetric and fluorometric assay.


Assuntos
Corantes Fluorescentes/química , Fluoretos/análise , Imidazóis/química , Naftalenos/química , Cátions/síntese química , Cátions/química , Corantes Fluorescentes/síntese química , Imidazóis/síntese química , Estrutura Molecular , Naftalenos/síntese química , Espectrometria de Fluorescência
20.
J Med Chem ; 63(3): 1233-1244, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31939669

RESUMO

Human hand, foot, and mouth disease (HFMD) is a serious public health threat with high infection rates in children and infants who reside in Asia and the Pacific regions, and no effective drugs are currently available. Enterovirus 71 (EV71) and coxsackievirus A16 are the major etiological pathogens. Based on an essential hydrophobic pocket on the viral capsid protein VP1, we designed and synthesized a series of small molecular weight compounds as inhibitors of EV71. A potential drug candidate named NLD-22 exhibited excellent antiviral activity (with an EC50 of 5.056 nM and a 100% protection rate for mice at a dose of 20 mg/kg) and low toxicity. NLD-22 had a favorable pharmacokinetic profile. High-resolution cryo-electron microscopy structural analysis confirmed NLD-22 bound to the hydrophobic pocket in VP1 to block viral infection. In general, NLD-22 was indicated to be a promising potential drug candidate for the treatment of HFMD.


Assuntos
Antivirais/uso terapêutico , Enterovirus Humano A/efeitos dos fármacos , Doença de Mão, Pé e Boca/tratamento farmacológico , Imidazóis/uso terapêutico , Animais , Antivirais/síntese química , Antivirais/metabolismo , Antivirais/farmacocinética , Sítios de Ligação , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Desenho de Fármacos , Enterovirus Humano A/química , Feminino , Imidazóis/síntese química , Imidazóis/metabolismo , Imidazóis/farmacocinética , Cristalino/patologia , Masculino , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Ligação Proteica , Ratos Sprague-Dawley , Peixe-Zebra
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