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1.
ChemMedChem ; 19(11): e202300545, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38445815

RESUMO

Among the many neglected tropical diseases, leishmaniasis ranks second in mortality rate and prevalence. In a previous study, acridine derivatives were synthesized and tested for their antileishmanial activity against L. chagasi. The most active compound identified in that study (1) showed a single digit IC50 value against the parasite (1.10 µg/mL), but its macromolecular target remained unknown. Aiming to overcome this limitation, this work exploited inverse virtual screening to identify compound 1's putative molecular mechanism of action. In vitro assays confirmed that compound 1 binds to Leishmania chagasi pteridine reductase 1 (LcPTR1), with moderate affinity (Kd=33,1 µM), according to differential scanning fluorimetry assay. Molecular dynamics simulations confirm the stability of LcPTR1-compound 1 complex, supporting a competitive mechanism of action. Therefore, the workflow presented in this work successfully identified PTR1 as a macromolecular target for compound 1, allowing the designing of novel potent antileishmanial compounds.


Assuntos
Acridinas , Inibidores Enzimáticos , Oxirredutases , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismo , Acridinas/química , Acridinas/farmacologia , Acridinas/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Simulação de Dinâmica Molecular , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Compostos de Espiro/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Dose-Resposta a Droga , Leishmania/efeitos dos fármacos , Leishmania/enzimologia , Simulação de Acoplamento Molecular
2.
Eur J Med Chem ; 104: 148-56, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26454648

RESUMO

A series of thiophene-2-thiosemicarbazones derivatives (5-14) was synthesized, characterized and evaluated for their antitumor activity. They were tested in vitro against human tumor cell lines through the colorimetric method. The results revealed that compounds 7 and 9 were the most effective in inhibiting 50% of the cell growth after 48 h of treatment. As compound 7 showed a potent antiproliferative profile, it has been chosen for further studies in 786-0 cell line by flow cytometry. Treatments with compound 7 (50 µM) induced early phosphatidylserine exposure after 18 h of exposure and this process progressed phosphatidylserine exposure with loss of cell membrane integrity after 24 h of treatment, suggesting a time-dependent cell death process. Regarding the cell cycle profile, no changes were observed after treatment with compound 7 (25 µM), suggesting a mechanism of cell death independent on the cell cycle. The in vivo studies show that compound 7 possess low acute toxicity, being the doses of 30-300 mgKg(-1) chosen for studies in Ehrlich solid tumor model in mice. All doses were able to inhibit tumor development being the lowest one the most effective. Our findings highlight thiophene-2-thiosemicarbazones as a promising class of compounds for further studies concerning new anticancer therapies.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carcinoma de Ehrlich/tratamento farmacológico , Tiofenos/farmacologia , Tiossemicarbazonas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carcinoma de Ehrlich/patologia , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Relação Estrutura-Atividade , Tiofenos/administração & dosagem , Tiofenos/síntese química , Tiofenos/química , Tiossemicarbazonas/administração & dosagem , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química
3.
Molecules ; 18(12): 15035-50, 2013 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-24322489

RESUMO

Thiazacridine and imidazacridine derivatives have shown promising results as tumors suppressors in some cancer cell lines. For a better understanding of the mechanism of action of these compounds, binding studies of 5-acridin-9-ylmethylidene-3-amino-2-thioxo-thiazolidin-4-one, 5-acridin-9-ylmethylidene-2-thioxo-thiazolidin-4-one, 5-acridin-9-ylmethylidene-2-thioxo-imidazolidin-4-one and 3-acridin-9-ylmethyl-thiazolidin-2,4-dione with calf thymus DNA (ctDNA) by electronic absorption and fluorescence spectroscopy and circular dichroism spectroscopy were performed. The binding constants ranged from 1.46 × 10(4) to 6.01 × 10(4) M(-1). UV-Vis, fluorescence and circular dichroism measurements indicated that the compounds interact effectively with ctDNA, both by intercalation or external binding. They demonstrated inhibitory activities to human topoisomerase I, except for 5-acridin-9-ylmethylidene-2-thioxo-1,3-thiazolidin-4-one. These results provide insight into the DNA binding mechanism of imidazacridines and thiazacridines.


Assuntos
Acridinas/síntese química , Acridinas/farmacologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacologia , Acridinas/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Dicroísmo Circular , DNA/química , DNA/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Ativação Enzimática/efeitos dos fármacos , Humanos , Estrutura Molecular , Inibidores da Topoisomerase I/metabolismo
4.
Molecules ; 17(3): 2298-315, 2012 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-22367025

RESUMO

Fifty 2-[(arylidene)amino]-4,5-cycloalkyl[b]thiophene-3-carbonitrile derivatives were screened for their in vitro antifungal activities against Candida krusei and Cryptococcus neoformans. Based on experimentally determined minimum inhibitory concentration (MIC) values, we conducted computer-aided drug design studies [molecular modelling, chemometric tools (CPCA, PCA, PLS) and QSAR-3D] that enable the prediction of three-dimensional structural characteristics that influence the antifungal activities of these derivatives. These predictions provide direction with regard to the syntheses of new derivatives with improved biological activities, which can be used as therapeutic alternatives for the treatment of fungal infections.


Assuntos
Antifúngicos/farmacologia , Desenho Assistido por Computador , Desenho de Fármacos , Nitrilas/farmacologia , Tiofenos/farmacologia , Candida/efeitos dos fármacos , Simulação por Computador , Cryptococcus neoformans/efeitos dos fármacos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Modelos Moleculares , Análise de Componente Principal , Relação Quantitativa Estrutura-Atividade , Análise de Regressão , Propriedades de Superfície
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