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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.
Org Biomol Chem ; 17(45): 9778-9791, 2019 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-31701105

RESUMO

This study investigates the synthesis of ß-branched amines and ß-branched quaternary ammonium chloride ionic liquids as novel extractants. The synthesis methodology was tailored to facilitate the reaction scale-up and the use of biorenewable starting materials. The developed process is an overall green, easy and straightforward synthesis of ß-branched amines, and ammonium salts, starting from linear aldehydes. In order to evaluate the potential of the synthesised materials in applications, the rheology, density, thermal stability, chemical stability, phase transitions, and mutual solubility with water of the novel extractants was studied.


Assuntos
Líquidos Iônicos/síntese química , Compostos de Amônio Quaternário/síntese química , Aminas/síntese química , Aminas/química , Interações Hidrofóbicas e Hidrofílicas , Líquidos Iônicos/química , Estrutura Molecular , Compostos de Amônio Quaternário/química , Solubilidade , Água/química
5.
Org Biomol Chem ; 17(40): 8982-8986, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31584061

RESUMO

A facile microwave assisted three-component protocol allows the synthesis of chiral aryl-1,2-mercaptoamines in water in a few minutes with high yields, bypassing the use of toxic aziridine intermediates. The chiral 1,2-mercaptoamines were then deracemized through enzymatic resolution of the racemates using monoamine oxidase (MAO-N) biocatalysts.


Assuntos
Aminas/metabolismo , Monoaminoxidase/metabolismo , Água/metabolismo , Aminas/síntese química , Aminas/química , Biocatálise , Micro-Ondas , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/química , Estereoisomerismo , Água/química
6.
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
7.
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
8.
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
9.
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
10.
Drug Deliv ; 26(1): 744-755, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31340676

RESUMO

A drug and gene co-delivery system with chemotherapeutic sensibilization was prepared and used for nasopharyngeal carcinoma therapy. For this purpose, the graphene oxide (GO) was conjugated with the redox hyperbranched poly(amido amine) (HPAA) and then the targeting molecule, transferrin (Tf), was also conjugated. The obtained Tf-HPAA-GO could co-deliver docetaxel (DOC) and MMP-9 shRNA plasmid (pMMP-9) effectively and showed the targeting effect to HNE-1 cells. The co-delivery system showed the effective drug and gene delivery ability with high cytotoxicity and gene transfection efficiency. Besides that, Tf-HPAA-GO/DOC also showed the chemotherapeutic sensibilization effect, the formulation containing HPAA segments showed much higher cytotoxicity than free DOC. Benefiting from the sensibilization effect and DOC/pMMP-9 co-delivery strategy, this Tf-HPAA-GO/DOC/pMMP-9 co-delivery system exhibited the significantly improved therapeutic efficacy to HNE-1 tumor in a combined manner which was confirmed by in vitro and in vivo assays. This strategy provided an easily delivery system combining the drug/gene co-delivery, chemotherapeutic sensibilization, and targeting into one single platform, which showed a promising application in cancer therapy.


Assuntos
Antineoplásicos/administração & dosagem , Docetaxel/administração & dosagem , Grafite/administração & dosagem , Metaloproteinase 9 da Matriz/genética , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Transferrina/administração & dosagem , Células 3T3 , Aminas/síntese química , Aminas/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Terapia Combinada , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Terapia Genética , Glutationa/metabolismo , Grafite/química , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/metabolismo
11.
Chemphyschem ; 20(16): 2110-2121, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31265754

RESUMO

The physicochemical properties and transfection efficacies of two samples of a cationic lipid have been investigated and compared in 2D (monolayers at the air/liquid interface) and 3D (aqueous bulk dispersions) model systems using different techniques. The samples differ only in their chain composition due to the purity of the oleylamine (chain precursor). Lipid 8 (using the oleylamine of technical grade for cost-efficient synthesis) shows lateral phase separation in the Langmuir layers. However, the amount of attached DNA, determined by IRRAS, is for both samples the same. In 3D systems, lipid 8 p forms cubic phases, which disappear after addition of DNA. At physiological temperatures, both lipids (alone and in mixture with cholesterol) assemble to lamellar aggregates and exhibit comparable DNA delivery efficiency. This study demonstrates that non-lamellar structures are not compulsory for high transfection rates. The results legitimate the utilization of oleyl chains of technical grade in the synthesis of cationic transfection lipids.


Assuntos
Aminas/química , DNA/química , Lipídeos/química , Lipossomos/química , Aminas/síntese química , Aminas/normas , Aminas/toxicidade , Animais , Bovinos , Linhagem Celular Tumoral , Colesterol/química , Técnicas de Transferência de Genes/normas , Humanos , Lipídeos/síntese química , Lipídeos/normas , Lipídeos/toxicidade , Lipossomos/normas , Lipossomos/toxicidade , Estrutura Molecular , Transição de Fase , Suínos , Transfecção/normas , Temperatura de Transição
12.
J Chromatogr A ; 1603: 141-149, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31277951

RESUMO

Ethyleneamines have been produced and commercialized for decades in the chemical industry for a diverse range of applications. The presence of amine functional groups provides them opportunity to adsorb onto surfaces which can make them a very challenging sample matrix to analyze using separation techniques. In the present report, a new aqueous SEC-RI method, which enables MWD characterization of higher ethyleneamines, is described. The sample preparation was based on the dilute-and-shoot methodology. A surface-modified SEC column with positively charged groups attached to the stationary phase was used. The mobile phase composition (salt concentration, pH) was optimized to suppress interaction between the ethyleneamines and the packing material. Very symmetrical peak shapes were achieved for low MW monodisperse ethyleneamines despite their high primary amine content. MWD calculations were conducted using conventional narrow standard calibration with partial linear extrapolation of the calibration curve. The narrow standards were of the same chemistry as the samples of interest. Consequently, the standard components display a consistent behaviour towards the column packing as the sample components which makes the present method more robust and the interpretation of the quantitative results more convenient. Effect on the measured MW averages and MW distribution due to various experimental parameters (e.g., system variability, mobile phase preparation, sample concentration) were investigated showing good repeatability (RSD < 2%) for Mn, Mw, and Mz.


Assuntos
Aminas/química , Cromatografia em Gel/métodos , Aminas/síntese química , Calibragem , Peso Molecular , Padrões de Referência , Água/química
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.
Bioconjug Chem ; 30(7): 1969-1978, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31251559

RESUMO

The ortho-hydroxy-protected aryl sulfate (OHPAS) linker is composed of a diaryl sulfate backbone equipped with a latent phenol moiety at the ortho position of one of the aryl units. The Ar-OH released when the ortho phenol undergoes intramolecular cyclization and displaces the second aryl unit can be viewed as a payload. We have shown in the preceding paper that the OHPAS linkers are highly stable chemically and in various plasmas, yet release payloads when exposed to suitable triggering conditions. As an extension of the OHPAS system, we employed a para-hydroxy benzyl (PHB) spacer for coupling to nonphenolic payloads; this tactic again provided a highly stable system capable of smooth release of appended payloads. The PHB modification works beautifully for tertiary amine and N-heterocycle payloads.


Assuntos
Aminas/química , Compostos de Benzil/química , Compostos Heterocíclicos/química , Fenol/química , Sulfatos/química , Álcoois/síntese química , Álcoois/química , Aminas/síntese química , Compostos de Benzil/síntese química , Ciclização , DNA/síntese química , DNA/química , Compostos Heterocíclicos/síntese química , Fenol/síntese química , RNA/síntese química , RNA/química , Sulfatos/síntese química
15.
ACS Appl Mater Interfaces ; 11(26): 23584-23590, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31252498

RESUMO

The increased demand for water highlights the need to utilize reclaimed water of various types. In agriculture, for example, which is considered the largest consumer of freshwater, irrigation with treated wastewater can replace much of the need for freshwater. Wastewater is generally used for irrigation through drippers, releasing small amounts of water to the crops. The contaminants found in treated wastewater increase the accumulation of fouling on the drippers, ultimately culminating in blocking of water exit. Thus, there is a crucial need to develop novel approaches to limit biofilm formation on the dripper. Here, we describe the synthesis of N-halamine-derivatized cross-linked polymethacrylamide nanoparticles (NPs) by copolymerization of the monomer methacrylamide and the cross-linker monomer N, N-methylenebisacrylamide and their subsequent embedding in the polyethylene that is used to fabricate the drippers. The newly designed drip system was activated by chlorinating the incorporated NPs and then was fully characterized. The nanofunctionalized drippers were tested in the field, showing excellent antifouling activity for at least 5 months compared to the control. In addition, the inherent recharging capacity of the antifouling NPs constitutes yet another valuable advantage of the currently reported technology.


Assuntos
Irrigação Agrícola , Aminas/química , Nanopartículas/química , Águas Residuárias/química , Acrilamidas/síntese química , Acrilamidas/química , Aminas/síntese química , Produtos Agrícolas , Reagentes para Ligações Cruzadas/síntese química , Reagentes para Ligações Cruzadas/química , Água Doce/química , Humanos , Eliminação de Resíduos Líquidos
16.
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
17.
Carbohydr Polym ; 216: 113-118, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047047

RESUMO

A controllable drug delivery system demonstrates a promising tool for diverse biomedical applications. In this work, a group of amphiphilic macromolecules was designed and prepared via Schiff base reactions between 2,3-dialdehyde cellulose (DAC) with oleylamine and amino-containing compounds. Benefiting from the self-assemble process of these amphiphilic macromolecules in the poor solvent, a group of novel pH-responsive nanoparticles (NPs) were facilely fabricated by using nanoprecipitation dropping technique. The high amount of aldehyde groups on DAC chains enabled immobilization of tunable amounts of amine compounds (up to 1.67 mmol/g) in the NPs. Furthermore, the Schiff base bonds in NPs allowed the efficient release of the drug in acidic tumor microenvironment by cleaving the Schiff base linkages. This study demonstrates the formation of a group of novel pH-sensitive and drug-loadable NPs, which provide a simple and efficient drug delivery system for the potential application for cancer treatment.


Assuntos
Aminas/química , Celulose/análogos & derivados , Preparações de Ação Retardada/química , Nanopartículas/química , Rodaminas/química , Bases de Schiff/química , Aminas/síntese química , Celulose/síntese química , Celulose/química , Preparações de Ação Retardada/síntese química , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Rodaminas/síntese química , Bases de Schiff/síntese química
18.
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
19.
Mater Sci Eng C Mater Biol Appl ; 100: 724-734, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948110

RESUMO

Cerasomes are hybrid organic-inorganic nanoparticles (NPs) that could be considered as liposomes with rather durable silicon shell. In this study, several cerasome-forming lipoamino acids (CFLA) were synthesized and used as structural blocks for cerasome preparation. Pure cerasomes which contained only CFLA, and mixed cerasomes based on a mixture of CFLA with a disintegrating dipalmitoylphosphatidylcholine (DPPC) lipid were fabricated and characterized in terms of morphology, mean size, ζ-potential, stability at storage. All obtained cerasome samples were found to be much more stable at storage than conventional liposomes (120 and 10 days, respectively). The cerasomes were loaded with doxorubicin (DOX) and tested in vitro using human breast adenocarcinoma MCF-7. Effects of the lipid composition on the physical-chemical properties and cellular uptake of the cerasomes both in 2D (monolayer culture) and 3D (multicellular tumor spheroids) were studied. The biggest accumulation efficiencies as well as the highest cytotoxicity level were found for the mixed cationic cerasomes. These cerasomes could be proposed as promising drug delivery system for cancer treatment.


Assuntos
Aminas/química , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Lipídeos/química , Nanopartículas/química , Silício/química , Aminas/síntese química , Cátions , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Humanos , Concentração Inibidora 50 , Lipídeos/síntese química , Lipossomos , Células MCF-7 , Nanopartículas/ultraestrutura , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia
20.
Org Biomol Chem ; 17(15): 3797-3804, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30916695

RESUMO

Herein, we have presented a facile and efficient method of ring-opening nucleophilic fluorination of aziridines, affording highly regio-selective ß-fluorinated amines. Firstly, the example of ring-opening hydrofluorination of azetidines was reported. Then, the Olah's reagent also provided a promising method for the construction of enantioenriched ß-fluoro-α-amino acid derivatives, which could be used for the preparation of peptide-based bioactive molecules.


Assuntos
Aminas/síntese química , Aminoácidos/química , Azetidinas/química , Aziridinas/química , Aminas/química , Halogenação , Estrutura Molecular , Estereoisomerismo
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