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1.
Eur J Med Chem ; 186: 111882, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31753514

RESUMO

A series of halogenated (4-methoxyphenyl)-1H-tetrazol-5-amine regioisomers (1a-9a, 1b-9b) were synthesized from their corresponding thiourea analogues (1-9). The synthesis pathway was confirmed by an X-ray crystallographic studies of 1a, 1b and 5a. Title derivatives were tested for their in vitro antitubercular activity against standard, "wild-type" and atypical mycobacteria. The highest therapeutic potential was attributed to isomeric N-(bromophenyl)tetrazoles 8a and 9a. Their growth-inhibitory effect against multidrug-resistant Mycobacterium tuberculosis Spec. 210 was 8-16-fold stronger than that of the first-line tuberculostatics. Other new tetrazole-derived compounds were also more or equally effective towards that pathogen comparing to the established pharmaceuticals. Among non-tuberculous strains, Mycobacterium scrofulaceum was the most susceptible to the presence of the majority of tetrazole derivatives. The synergistic interaction was found between 9a and streptomycin, as well as the additivity of both 8a and 9a in pairs with isoniazid, rifampicin and ethambutol. None of the studied compounds displayed antibacterial or cytotoxic properties against normal and cancer cell lines, which indicated their highly selective antimycobacterial effects.


Assuntos
Aminas/farmacologia , Antituberculosos/farmacologia , Mycobacterium/efeitos dos fármacos , Tetrazóis/farmacologia , Aminas/síntese química , Aminas/química , Antituberculosos/síntese química , Antituberculosos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química
2.
Med Chem ; 16(1): 52-62, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30727906

RESUMO

BACKGROUND: EGFR is a clinically approved drug target in cancer. The first generation tyrosine kinase inhibitors targeting L858R mutated EGFR are routinely used to treat non-small cell lung cancer (NSCLC). However, the presence of a secondary mutation (T790M) tenders these inhibitors ineffective and thus results in the relapse of the disease. OBJECTIVE: New reversible inhibitors are required, which act against T790M/L858R (TMLR) double mutants and overcome resistance. METHOD: In the present study, various Fragment based QSAR (G-QSAR) models along with interaction terms have been studied for amino-pyrimidine derivatives having biological activity against TMLR mutant enzyme. RESULTS: The G-QSAR models developed using partial least squares regression via stepwise forward- backward variable selection technique showed the best results. The model showed a high correlation coefficient (r² = 0.86), cross-validation coefficient (q² = 0.81) and predicted correlation (predicted r² = 0.62), which indicated that the model is robust and predictive. Based on the model, it was revealed that at R1 position increasing saturated carbon (number of -CH atom connected with 3 single bonds i.e. SsssCHcount) and retention index (chi3) is desired for the enhancement of bioactivity. Additionally, at the R2 position, increasing lipophilic character (slogp) and at site R3, the polarizability of compound need to be increased for better inhibitory activity. We further studied the contribution of interactions among significant descriptors in enhancing the activity of the compounds. It revealed that the presence of Sum((R1-SsssCHcount, R2-slogp) and Mult(R1-chi3, R3-polarizabilityAHC) are the most significantly influencing descriptors. We further compared the variation in the most and least active compounds which established that retention of the above properties is essential for imparting significant inhibitory activity to these molecules. CONCLUSION: The study provides site specific information wherein chemical group variation influences the inhibitory potency of TMLR amino-pyrimidine inhibitors, which can be used for designing new molecules with the desired activity.


Assuntos
Aminas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Aminas/síntese química , Aminas/química , Relação Dose-Resposta a Droga , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Quantitativa Estrutura-Atividade
3.
Eur J Med Chem ; 185: 111866, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734023

RESUMO

Introducing pyrimidine bases, the basic components of nucleic acid, to P2 ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitors because of the carbonyl and amino groups promoting the formation of extensive hydrogen bonding interactions. In this work, we provide evidence that inhibitor 10e, with N-2-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide as the P2 ligand and a 4-methoxylphenylsulfonamide as the P2' ligand, displayed remarkable enzyme inhibitory and antiviral activity, with the IC50 2.53 nM in vitro and a promising inhibition ratio with 68% against wild-type HIV-1 in vivo, with low cytotoxicity. This inhibitor also exhibited appreciable antiviral activity against DRV-resistant HIV-1 variants, which was of great value for further study.


Assuntos
Acetamidas/farmacologia , Aminas/farmacologia , Fármacos Anti-HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Aminas/síntese química , Aminas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , HIV-1/enzimologia , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
4.
J Enzyme Inhib Med Chem ; 34(1): 1652-1659, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31530034

RESUMO

Eight genetically distinct carbonic anhydrase (EC 4.2.1.1) enzyme families (α-, ß-, γ- δ-, ζ-, η-, θ- and ι-CAs) were described to date. On the other hand, 16 mammalian α-CA isoforms are known to be involved in many diseases such as glaucoma, edema, epilepsy, obesity, hypoxic tumors, neuropathic pain, arthritis, neurodegeneration, etc. Although CA inhibitors were investigated for the management of a variety of such disorders, the activators just started to be investigated in detail for their in vivo effects. This review summarizes the activation profiles of α-, ß, γ-, δ-, ζ- and η- CAs from various organisms (animals, fungi, protozoan, bacteria and archaea) with the most investigated classes of activators, the amines and the amino acids.


Assuntos
Aminas/farmacologia , Aminoácidos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Aminas/síntese química , Aminas/química , Aminoácidos/síntese química , Aminoácidos/química , Bactérias/enzimologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Entamoeba histolytica/enzimologia , Fungos/enzimologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular
5.
Comput Biol Chem ; 83: 107124, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31563021

RESUMO

We have recently explored novel class of potentially anti-breast cancer active enamidines in which four molecules 4a-c and 4h showed higher anticancer activity compared to standard drug doxorubicin. As a part of extension of this work, we have further evaluated in silico cheminformatic studies on bioactivity prediction of synthesized series of enamidines using mole information. The normal cell line study of four lead compounds 4a-c and 4h against African green monkey kidney vero strain further revealed that the compounds complemented good selectivity in inhibition of cancer cells. The in silico bioactivity and molecular docking studies also revealed that the compounds have significant interactions with the drug targets. The results reveal that enamidine moieties are vital for anti-breast cancer activity as they possess excellent drug-like characteristics, being potentially good inhibitors of cyclin dependent kinases7 (CDK7).


Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , Azidas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Simulação por Computador , Quinases Ciclina-Dependentes/antagonistas & inibidores , Pargilina/análogos & derivados , Inibidores de Proteínas Quinases/farmacologia , Aminas/síntese química , Aminas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Azidas/síntese química , Azidas/química , Sítios de Ligação/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/química , Quinases Ciclina-Dependentes/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Ligações de Hidrogênio , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Pargilina/síntese química , Pargilina/química , Pargilina/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Células Vero
6.
Mater Sci Eng C Mater Biol Appl ; 105: 110055, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546416

RESUMO

Designing of mechanically tough elastomeric materials encompassed with intrinsic surface hydrophobicity, antistatic and antimicrobial attributes is in skyrocketing demands, especially to protect the instruments which are submerged in water. Herein, the authors depicted the fabrication of interpenetrating polymer network-based nanocomposites containing different doses of octadecylamine capped Cu/RGO nanohybrid. The structures and morphologies of the synthesized nanohybrid and the fabricated nanocomposites were characterized by using FTIR, XRD, XPS, TGA, FESEM and TEM analyses. Most interestingly the nanocomposites showed good hydrophobicity (static contact angle: 119.2°-129.3°), low surface resistivity (~107 Ω m) and strong antimicrobial activity towards Gram negative (Pseudomonas aeruginosa and Yersinia pestis) and Gram positive (Bacillus cereus) bacterial strains. The fabricated nanocomposites also exhibited antifungal (Candida albicans) activity. In addition, the fabricated nanocomposites showed excellent mechanical properties including high tensile strength (14.03-20.9 MPa), outstanding flexibility (1887-2470%), excellent toughness (249.89-510.1 MJ.m-3), high scratch resistance (>10 kg) and high thermostability (281-288 °C). Therefore, the fabricated nanocomposites can be used as an effective thin film for many advanced applications.


Assuntos
Aminas , Anti-Infecciosos , Substâncias Antieletricidade Estática , Bactérias/crescimento & desenvolvimento , Candida albicans/crescimento & desenvolvimento , Cobre , Grafite , Nanocompostos , Aminas/química , Aminas/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Substâncias Antieletricidade Estática/química , Substâncias Antieletricidade Estática/farmacologia , Cobre/química , Cobre/farmacologia , Grafite/química , Grafite/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Nanocompostos/química , Nanocompostos/uso terapêutico , Oxirredução
7.
Eur J Med Chem ; 182: 111655, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494468

RESUMO

Stereo- and regioisomers of a series of N,N-bis(alkanol)amine aryl ester derivatives have been prepared and studied as multidrug resistance (MDR) modulators. The new compounds contain a 2-(methyl)propyl chain combined with a 3-, 5- or 7-methylenes long chain and carry different aromatic ester portions. Thus, these compounds have a methyl group on the 3-methylenes chain and represent branched homologues of previously studied derivatives. The introduction of the methyl group gives origin to a stereogenic center and consequently to (R) and (S) enantiomers. In the pirarubicin uptake assay on K562/DOX cell line these compounds showed good activity and efficacy and in many cases enantioselectivity was observed. Docking studies confirmed the influence of the stereocenter on the interaction in the P-gp pocket. The P-gp interaction mechanism and selectivity towards MRP1 and BCRP were also evaluated on MDCK transfected cells overexpressing the three transporters. Almost all these compounds inhibited both P-gp and BCRP, but only derivatives with specific structural characteristics showed MRP1 activity. Moreover, two compounds, (S)-3 and (R)-7, showed the ability to induce collateral sensitivity (CS) against MDR cells. Therefore, these two CS-promoting agents could be considered interesting leads for the development of selective cytotoxic agents for drug-resistant cells.


Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , Desenho de Drogas , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ésteres/farmacologia , Aminas/síntese química , Aminas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/síntese química , Ésteres/química , Humanos , Células K562 , Células Madin Darby de Rim Canino/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
8.
Anticancer Res ; 39(9): 4805-4810, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519582

RESUMO

BACKGROUND/AIM: Ro 90-7501 has been reported as an inhibitor of the amyloid ß42 fibril assembly that is associated with Alzheimer's disease. The present study aimed to elucidate the radiosensitizing effects of Ro 90-7501 and focused on ATM signaling after irradiation. MATERIALS AND METHODS: Clonogenic survival, apoptosis, and cell-cycle assays as well as western blotting were performed in HeLa cells treated with irradiation and Ro 90-7501. Tumor growth delay assay was also performed using BALB/c-nu mice. RESULTS: The combination of irradiation with Ro 90-7501 showed significant radiosensitizing effects in clonogenic survival and tumor growth delay assays. Ro 90-7501 significantly increased apoptosis and impaired cell cycle after irradiation. Western blotting showed that Ro 90-7501 suppressed the phosphorylation of ATM and its downstream proteins, such as H2AX, Chk1, and Chk2, after irradiation. CONCLUSION: Ro 90-7501 inhibits DNA damage response by inhibiting ATM and has significant radiosensitizing effects on cervical cancer cells.


Assuntos
Aminas/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Benzimidazóis/farmacologia , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo
9.
Eur J Med Chem ; 182: 111593, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31446245

RESUMO

A novel series of phenylthiazoles bearing cyclic amines at the phenyl-4 position was prepared with the objective of decreasing lipophilicity and improving the overall physicochemical properties and pharmacokinetic profile of the compounds. Briefly, the piperidine ring (compounds 10 and 12) provided the best ring size in terms of antibacterial activity when tested against 16 multidrug-resistant clinical isolates. Both compounds were superior to vancomycin in the ability to eliminate methicillin-resistant Staphylococcus aureus (MRSA), residing within infected macrophages and to disrupt mature MRSA biofilm. Additionally, compounds 10 and 12 exhibited a fast-bactericidal mode of action in vitro. Furthermore, the new derivatives were 160-times more soluble in water than the previous lead compound 1b. Consequently, compound 10 was orally bioavailable with a highly-acceptable pharmacokinetic profile in vivo that exhibited a half-life of 4 h and achieved a maximum plasma concentration that exceeded the minimum inhibitory concentration (MIC) values against all tested bacterial isolates.


Assuntos
Aminas/farmacologia , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Obesidade/tratamento farmacológico , Tiazóis/farmacologia , Aminas/química , Animais , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Obesidade/microbiologia , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
10.
Eur J Med Chem ; 182: 111613, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31437780

RESUMO

Alzheimer's disease (AD) is associated with multifactorial neuropathological conditions, which include cholinergic deficit, amyloid-beta plaques formation, loss of neuronal plasticity and neuronal death. Treating such multifactorial conditions with a single target directed approach is considered to be inadequate. Accordingly, multi-target directed ligand (MTDL) strategy has been evolved as an auspicious approach for the treatment of AD. In light of that, a library of 2-substituted benzo[d]oxazol-5-amine derivatives (29-39; 86-107) was designed using the scaffold hopping guided MTDLs strategy, synthesized and evaluated through various in-vitro and in-vivo biological studies. The optimal compound 92 exhibited potent inhibitory activities against AChE (IC50 = 0.052 ±â€¯0.010 µM), BuChE (IC50 = 1.085 ±â€¯0.035 µM), and significant amyloid-beta aggregation (20 µM) inhibition. The compound possessed better blood-brain barrier permeability (Pe = 10.80 ±â€¯0.055 × 10-6 cm s-1) in PAMPA assay and neuro protective properties (40 µM) on SH-SY5Y neuroblastoma cell lines. Furthermore, in-vivo behavioural studies were performed on Y-maze test (scopolamine-induced amnesia model) and Morris water maze test (Aß1-42 induced ICV rat model). The compound 92, at a dose of 10 mg/kg oral administration, demonstrated a substantial improvement of the cognitive and special memory impairment. In summary, both in-vitro and in-vivo investigations evidenced that compound 92 was a potential lead for the discovery of safe and effective disease-modifying agents for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminas/farmacologia , Inibidores da Colinesterase/farmacologia , Descoberta de Drogas , Fármacos Neuroprotetores/farmacologia , Oxazóis/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Aminas/síntese química , Aminas/química , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Enguias , Feminino , Cavalos , Humanos , Ligantes , Masculino , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Oxazóis/síntese química , Oxazóis/química , Ratos , Ratos Wistar , Escopolamina , Relação Estrutura-Atividade
11.
J Enzyme Inhib Med Chem ; 34(1): 1178-1185, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31282230

RESUMO

The activation of the ß-class carbonic anhydrases (CAs, EC 4.2.1.1) from the bacteria Brucella suis and Francisella tularensis with amine and amino acids was investigated. BsuCA 1 was sensitive to activation with amino acids and amines, whereas FtuCA was not. The most effective BsuCA 1 activators were L-adrenaline and D-Tyr (KAs of 0.70-0.95 µM). L-His, L-/D-Phe, L-/D-DOPA, L-Trp, L-Tyr, 4-amino-L-Phe, dopamine, 2-pyridyl-methylamine, D-Glu and L-Gln showed activation constants in the range of 0.70-3.21 µM. FtuCA was sensitive to activation with L-Glu (KA of 9.13 µM). Most of the investigated compounds showed a weak activating effect against FtuCA (KAs of 30.5-78.3 µM). Many of the investigated amino acid and amines are present in high concentrations in many tissues in vertebrates, and their role in the pathogenicity of the two bacteria is poorly understood. Our study may bring insights in processes connected with invasion and pathogenic effects of intracellular bacteria.


Assuntos
Aminas/farmacologia , Aminoácidos/farmacologia , Brucella suis/enzimologia , Anidrases Carbônicas/metabolismo , Ativação Enzimática/efeitos dos fármacos , Francisella tularensis/enzimologia , Aminas/química , Aminoácidos/química , Anidrases Carbônicas/genética , Relação Estrutura-Atividade
12.
Mater Sci Eng C Mater Biol Appl ; 103: 109877, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349493

RESUMO

N-halamine compounds have been applied as antibacterial agents owing to the oxidative chlorine. In this work, graphene oxide (GO) as carrier was used to load N-halamine compounds for the sustained-release of chlorine in order to maintain long-term biocidal efficacies. 3­(3'­Acrylic acid propylester)­5,5­dimethylhydantoin (APDMH) was synthesized using 5,5­dimethylhydantoin as a heterocyclic precursor and attached on the surface of GO nanosheets via in-situ polymerization. The modified GO composites were characterized by Fourier transform infrared (FT-IR) spectra, scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and thermogravimetric analysis (TGA). The chlorinated GO nanosheets modified with polymerized APDMH (PAPDMH) were very stable and possessed long-term antibacterial properties. The GO-PAPDMH-Cl composites exhibited good antimicrobial efficacies against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli O157:H7) with log reductions of 7.20 and 7.06 within 30 min of contact time, respectively.


Assuntos
Aminas , Antibacterianos , Escherichia coli O157/crescimento & desenvolvimento , Grafite , Staphylococcus aureus/crescimento & desenvolvimento , Aminas/química , Aminas/farmacocinética , Aminas/farmacologia , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Grafite/química , Grafite/farmacocinética , Grafite/farmacologia
13.
Eur J Med Chem ; 179: 38-55, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31233921

RESUMO

Indoleamine 2, 3-dioxygenase 1 (IDO1) plays a key role in tryptophan catabolism which is an important mechanism in immune tolerance. The small molecule epacadostat is the most advanced IDO1 inhibitor, but its phase III trials as a single agent or in combinations with PD-1 antibody failed to show appreciable objective responses. To gain more insight on the antitumor efficacy of IDO1 inhibitors, we have designed a series of analogues of epacadostat by incorporating a cyclic aminosulfonamide moiety as the sidechain capping functionality. Compound 5a was found to display significant potency against recombinant hIDO1 and hIDO1 expressed HEK293 cancer cells. This compound has improved physico-chemical properties, acceptable PK parameters as well as optimal cardiac safety. Similar to epacadostat, 5a is ineffective as single agent in the CT-26 syngeneic xenograft model, however, the combination of 5a with PD-1 antibody showed both elevated tumor growth inhibition and prolonged median life span.


Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Oxidiazóis/farmacologia , Aminas/síntese química , Aminas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Células HEK293 , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
14.
Int J Oral Sci ; 11(2): 15, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31068570

RESUMO

Tooth decay is prevalent, and secondary caries causes restoration failures, both of which are related to demineralization. There is an urgent need to develop new therapeutic materials with remineralization functions. This article represents the first review on the cutting edge research of poly(amido amine) (PAMAM) in combination with nanoparticles of amorphous calcium phosphate (NACP). PAMAM was excellent nucleation template, and could absorb calcium (Ca) and phosphate (P) ions via its functional groups to activate remineralization. NACP composite and adhesive showed acid-neutralization and Ca and P ion release capabilities. PAMAM+NACP together showed synergistic effects and produced triple benefits: excellent nucleation templates, superior acid-neutralization, and ions release. Therefore, the PAMAM+NACP strategy possessed much greater remineralization capacity than using PAMAM or NACP alone. PAMAM+NACP achieved dentin remineralization even in an acidic solution without any initial Ca and P ions. Besides, the long-term remineralization capability of PAMAM+NACP was established. After prolonged fluid challenge, the immersed PAMAM with the recharged NACP still induced effective dentin mineral regeneration. Furthermore, the hardness of pre-demineralized dentin was increased back to that of healthy dentin, indicating a complete remineralization. Therefore, the novel PAMAM+NACP approach is promising to provide long-term therapeutic effects including tooth remineralization, hardness increase, and caries-inhibition capabilities.


Assuntos
Aminas/farmacologia , Fosfatos de Cálcio/química , Fosfatos de Cálcio/farmacologia , Dentina/química , Nanocompostos/química , Nanopartículas , Remineralização Dentária/métodos , Cálcio , Humanos
15.
Eur J Med Chem ; 176: 11-20, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31091477

RESUMO

A novel series of dihydroquinazolin-2-amine derivatives were synthesized and evaluated for their anti-HIV-1 activity in MT-4 cell cultures. All of the molecules were active against wild-type HIV-1 with EC50 values ranging from 0.61 µM to 0.84 nM. The most potent inhibitor, compound 4b, had an EC50 value of 0.84 nM against HIV-1 strain IIIB, and thus was more active than the reference drugs efavirenz and etravirine. Moreover, most of the compounds maintained high activity (low-micromolar EC50 values) against strains bearing the reverse transcriptase (RT) E138K mutation. Compound 4b had EC50 values of 3.5 nM and 66 nM against non-nucleoside reverse transcriptase inhibitor-resistant strains bearing the RT E138K and RES056 mutations. In enzyme activity assays, compound 4b exhibited an IC50 value of 10 nM against HIV-1 RT. Preliminary SARs and molecular docking studies provide valuable insights for further optimization.


Assuntos
Aminas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Quinazolinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Aminas/síntese química , Aminas/metabolismo , Aminas/toxicidade , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Quinazolinas/síntese química , Quinazolinas/metabolismo , Quinazolinas/toxicidade , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/toxicidade , Relação Estrutura-Atividade
16.
Eur J Pharmacol ; 855: 103-111, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31063768

RESUMO

Many ring-substituted phenethylamines exert psychedelic effects that are thought to be primarily mediated by interactions with serotonergic 5-hydroxytryptamine 2 (5-HT2A) receptors. The 2,5-dimethoxyphenethylamine (2C derivative) core structure with small lipophilic substituents at the 4-position seems to be particularly favorable for psychedelic effects. In contrast, 2C derivatives with bulky lipophilic substituents at the 4-position of the phenyl ring tend to display antagonist behavior at serotonin 5-HT2 receptor sites. To gain a better understanding of agonist and antagonist behavior of substituted phenethylamines, binding affinities and functional activation and inhibition of a series of 4'-aryl substituted 2,5-dimethoxyphenethylamine (2C-BI derivatives) at various monoamine receptors were determined. In addition, the interactions of the compounds with monoamine transporters were assessed. Various 2C-BI derivatives potently bound to human serotonergic and adrenergic receptors and to rat and mouse trace amine-associated receptor 1. Additionally, 2C-BI-8 and 2C-BI-12 activated serotonin 5-HT2A and 5-HT2B receptors at submicromolar concentrations. 2C-BI-1 and 2C-BI-7 were the only 2C-BI derivatives to activate human trace amine-associated receptor 1. 2C-BI-3 and 2C-BI-4 interacted with monoamine transporters but with low overall potency. In conclusion, the tested 2C-BI derivatives displayed diverse pharmacological profiles. The relatively high affinities of various 2C-BI derivatives at the serotonin 5-HT2A receptor indicate a high steric tolerance of the binding pocket. Potent partial activation of the serotonin 5-HT2A receptor by 2C-BI-8 and 2C-BI-12 suggests that these substances may potentially exert psychedelic effects similar to other compounds of the 2C family.


Assuntos
Aminas/química , Aminas/metabolismo , Receptores de Amina Biogênica/metabolismo , Aminas/farmacologia , Animais , Monoaminas Biogênicas/metabolismo , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Células HEK293 , Humanos , Camundongos , Células NIH 3T3 , Ligação Proteica
17.
ACS Appl Mater Interfaces ; 11(19): 17814-17822, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31022343

RESUMO

Pathogenic microbial contamination from microbial adhesion and subsequent formation of the biofilm on surfaces of plastic food packaging materials, especially with robust resistance to antimicrobial agents, is a major reason for the outbreak of foodborne infections. Conventional strategies in controlling the contaminations are significantly limited either by biofouling or by the irreversible consumption of antimicrobial agents. Herein, we report a robust methodology to create rechargeable biocidal poly(vinyl alcohol- co-ethylene) films (SBMA@HAF films) with antifouling function via chemically incorporating both N-halamine (HAF) and zwitterionic moieties [[2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA)]. The promise of the design exhibits three features to defeat bacterial contaminations: (i) zwitterionic moieties can effectively reduce bacterial attachment onto the films, (ii) N-halamine with robust rechargeable biocidal activity can rapidly kill any attached bacteria, and (iii) any inactivated bacterial debris can be easily released to avoid biofilm formation due to the superhydrophilicity of the zwitterions. The resulting SBMA@HAF films exhibit integrated properties of high transparency, robust mechanical property, great hydrophilicity, ease of chlorine recharging (>250 ppm), long-term stability, high biocidal efficacy (>99.9999% via contact killing), and promising antifouling functions, which enable the SBMA@HAF films to serve as a biocidal material in food packaging applications.


Assuntos
Aminas/química , Escherichia coli/efeitos dos fármacos , Embalagem de Alimentos , Aminas/farmacologia , Biofilmes/efeitos dos fármacos , Incrustação Biológica , Cloro/química , Escherichia coli/patogenicidade , Microbiologia de Alimentos , Humanos , Polímeros/química , Propriedades de Superfície/efeitos dos fármacos
18.
Int J Mol Sci ; 20(7)2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30959896

RESUMO

Acid-sensing ion channel 3 (ASIC3) is an important member of the acid-sensing ion channels family, which is widely expressed in the peripheral nervous system and contributes to pain sensation. ASICs are targeted by various drugs and toxins. However, mechanisms and structural determinants of ligands' action on ASIC3 are not completely understood. In the present work we studied ASIC3 modulation by a series of "hydrophobic monoamines" and their guanidine analogs, which were previously characterized to affect other ASIC channels via multiple mechanisms. Electrophysiological analysis of action via whole-cell patch clamp method was performed using rat ASIC3 expressed in Chinese hamster ovary (CHO) cells. We found that the compounds studied inhibited ASIC3 activation by inducing acidic shift of proton sensitivity and slowed channel desensitization, which was accompanied by a decrease of the equilibrium desensitization level. The total effect of the drugs on the sustained ASIC3-mediated currents was the sum of these opposite effects. It is demonstrated that drugs' action on activation and desensitization differed in their structural requirements, kinetics of action, and concentration and state dependencies. Taken together, these findings suggest that effects on activation and desensitization are independent and are likely mediated by drugs binding to distinct sites in ASIC3.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Aminas/química , Aminas/farmacologia , Guanidina/análogos & derivados , Guanidina/farmacologia , Animais , Células CHO , Cricetulus , Eletrofisiologia , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas
19.
Molecules ; 24(8)2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31013675

RESUMO

Two near-infrared fluorescent probes (A and B) containing hemicyanine structures appended to dipicolylamine (DPA), and a dipicolylamine derivative where one pyridine was substituted with pyrazine, respectively, were synthesized and tested for the identification of Zn(II) ions in live cells. In both probes, an acetyl group is attached to the phenolic oxygen atom of the hemicyanine platform to decrease the probe fluorescence background. Probe A displays sensitive fluorescence responses and binds preferentially to Zn(II) ions over other metal ions such as Cd2+ ions with a low detection limit of 0.45 nM. In contrast, the emission spectra of probe B is not significantly affected if Zn(II) ions are added. Probe A possesses excellent membrane permeability and low cytotoxicity, allowing for sensitive imaging of both exogenously supplemented Zn(II) ions in live cells, and endogenously releases Zn(II) ions in cells after treatment of 2,2-dithiodipyridine.


Assuntos
Aminas , Carbocianinas , Corantes Fluorescentes , Ácidos Picolínicos , Zinco/metabolismo , Aminas/química , Aminas/farmacologia , Carbocianinas/química , Carbocianinas/farmacologia , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Células HeLa , Humanos , Microscopia de Fluorescência , Ácidos Picolínicos/química , Ácidos Picolínicos/farmacologia
20.
Eur J Med Chem ; 172: 71-94, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30947123

RESUMO

In this study, a new series of N,N-bis(alkanol)amine aryl ester heterodimers was synthesized and studied. The new compounds were designed based on the structures of our previous arylamine ester derivatives endowed with high P-gp-dependent multidrug resistance reversing activity on a multidrug-resistant leukemia cell line. All new compounds were active in the pirarubicin uptake assay on the doxorubicin-resistant erythroleukemia K562 cells (K562/DOX). Compounds bearing a linker made up of 10 methylenes showed unprecedented high reversal activities regardless of the combination of aromatic moieties. Docking results obtained by an in silico study supported the data obtained by the biological tests and a study devoted to establish the chemical stability in phosphate buffer solution (PBS) and human plasma showed that only a few compounds exhibited a significant degradation in the human plasma matrix. Ten selected non-hydrolysable derivatives were able to inhibit the P-gp-mediated rhodamine-123 efflux on K562/DOX cells, and the evaluation of their apparent permeability and ATP consumption on other cell lines suggested that the compounds can behave as unambiguous or not transported substrates. The activity of these the compounds on the transport proteins breast cancer resistance protein (BCRP) and multidrug resistance associated protein 1 (MRP1) was also analyzed. All tested derivatives displayed a moderate potency on the BCRP overexpressing cells; while only four molecules showed to be effective on MRP1 overexpressing cells, highlighting a clear structural requirement for selectivity. In conclusion, we have identified a new very powerful series of compounds which represent interesting leads for the development of new potent and efficacious P-gp-dependent MDR modulators.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Aminas/farmacologia , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ésteres/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aminas/síntese química , Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Células CACO-2 , Dimerização , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/química , Humanos , Células K562 , Modelos Moleculares , Estrutura Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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