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1.
Pharmaceuticals (Basel) ; 16(9)2023 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-37765065

RESUMO

Infectious diseases encompass a range of conditions stemming from parasites [...].

3.
Pharmaceuticals (Basel) ; 14(12)2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34959707

RESUMO

Epigenetic modifiers acting through polypharmacology mechanisms are promising compounds with which to treat several infectious diseases. Histone deacetylase (HDAC) enzymes, mainly class I, and extra-terminal bromodomains (BET) are involved in viral replication and the host response. In the present study, 10 compounds were designed, assisted by molecular docking, to act against HDAC class I and bromodomain-4 (BRD4). All the compounds were synthesized and characterized by analytical methods. Enzymatic assays were performed using HDAC-1, -4, and -11 and BRD4. Compounds (2-10) inhibited both HDAC class I, mainly HDAC-1 and -2, and reduced BRD4 activity. For HDAC-1, the inhibitory effect ranged from 8 to 95%, and for HDAC-2, these values ranged from 10 to 91%. Compounds (2-10) decreased the BRD4 activity by up to 25%. The multi-target effects of these compounds show desirable properties that could help to combat viral infections by acting through epigenetic mechanisms.

4.
J Med Chem ; 60(20): 8647-8660, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-28968083

RESUMO

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 µM against active and nonreplicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective, leading to a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the development of a novel chemical class of antitubercular drugs.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Óxidos/química , Análise Espectral/métodos
5.
Nutrients ; 9(11)2017 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-29077030

RESUMO

The chemopreventive and anticancer effects of resveratrol (RSV) are widely reported in the literature. Specifically, mechanisms involving epigenetic regulation are promising targets to regulate tumor development. Bromodomains act as epigenetic readers by recognizing lysine acetylation on histone tails and boosting gene expression in order to regulate tissue-specific transcription. In this work, we showed that RSV is a pan-BET inhibitor. Using Differential Scanning Fluorimetry (DSF), we showed that RSV at 100 µM increased the melting temperature (∆Tm) of BET bromodomains by around 2.0 °C. The micromolar dissociation constant (Kd) range was characterized using Isothermal Titration Calorimetry (ITC). The RSV Kd value accounted to 6.6 µM in case of BRD4(1). Molecular docking proposed the binding mode of RSV against BRD4(1) mimicking the acetyl-lysine interactions. All these results suggest that RSV can also recognize epigenetic readers domains by interacting with BET bromodomains.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Dieta , Epigênese Genética , Lisina/metabolismo , Proteínas Nucleares/metabolismo , Proteínas/antagonistas & inibidores , Estilbenos/farmacologia , Fatores de Transcrição/metabolismo , Acetilação , Proteínas de Ciclo Celular , Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Humanos , Cinética , Simulação de Acoplamento Molecular , Neoplasias/metabolismo , Fitoterapia , Extratos Vegetais/farmacologia , Resveratrol
6.
Pharmaceuticals (Basel) ; 10(2)2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28587160

RESUMO

Tuberculosis (TB), a disease caused mainly by the Mycobacterium tuberculosis (Mtb), is according to the World Health Organization (WHO) the infectious disease responsible for the highest number of deaths worldwide. The increased number of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, and the ineffectiveness of the current treatment against latent tuberculosis are challenges to be overcome in the coming years. The scenario of drug discovery becomes alarming when it is considered that the number of new drugs does not increase proportionally to the emergence of drug resistance. In this review, we will demonstrate the current advances in antitubercular drug discovery, focusing on the research of compounds with potent antituberculosis activity against MDR-TB strains. Herein, active compounds against MDR-TB with minimum inhibitory concentrations (MICs) less than 11 µM and low toxicity published in the last 4 years in the databases PubMed, Web of Science and Scopus will be presented and discussed.

7.
Nutrients ; 8(11)2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27834913

RESUMO

Resveratrol and curcumin are natural products with important therapeutic properties useful to treat several human diseases, including cancer. In the last years, the number of studies describing the effect of both polyphenols against cancer has increased; however, the mechanism of action in all of those cases is not completely comprehended. The unspecific effect and the ability to interfere in assays by both polyphenols make this challenge even more difficult. Herein, we analyzed the anticancer activity of resveratrol and curcumin reported in the literature in the last 11 years, in order to unravel the molecular mechanism of action of both compounds. Molecular targets and cellular pathways will be described. Furthermore, we also discussed the ability of these natural products act as chemopreventive and its use in association with other anticancer drugs.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Curcumina/farmacologia , Neoplasias/tratamento farmacológico , Estilbenos/farmacologia , Animais , Humanos , Resveratrol
8.
Rev. ciênc. farm ; 12: 39-46, 1990. tab, ilus
Artigo em Português | LILACS | ID: lil-167853

RESUMO

Estudamos o aparecimento de agressividade, caracterizada pelo comportamento muricida, em ratos com lesäo eletrolítica bilateral do hipotálamo anterior, pré-tratados com morfina. Observamos a presença desta agressäo com morfina nas doses de 10,20 e 40mg/kg, chegando a atingir um nível de 79 por cento dos animais. Constatamos que este efeito é resultado da associaçäo da lesäo e morfina, uma vez que a lesäo ou a morfina apenas, näo produz agressividade. O comportamento muricida foi bloqueado pelo Nalaxone, indicando que este efeito é próprio do opióide


Assuntos
Animais , Masculino , Camundongos , Ratos , Agressão , Hipotálamo Anterior/lesões , Morfina/farmacologia , Ratos Endogâmicos
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