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1.
Pharmaceuticals (Basel) ; 17(2)2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38399438

RESUMO

Malaria, Chagas disease, and leishmaniasis are tropical diseases caused by protozoan parasites of the genera Plasmodium, Trypanosoma and Leishmania, respectively. These diseases constitute a major burden on public health in several regions worldwide, mainly affecting low-income populations in economically poor countries. Severe side effects of currently available drug treatments and the emergence of resistant parasites need to be addressed by the development of novel drug candidates. Natural 2,5-Diketopiperazines (2,5-DKPs) constitute N-heterocyclic secondary metabolites with a wide range of biological activities of medicinal interest. Its structural and physicochemical properties make the 2,5-DKP ring a versatile, peptide-like, and stable pharmacophore attractive for synthetic drug design. In the present work, twenty-three novel synthetic 2,5-DKPs, previously synthesized through the versatile Ugi multicomponent reaction, were assayed for their anti-protozoal activities against P. falciparum, T. cruzi, and L. infantum. Some of the 2,5-DKPs have shown promising activities against the target protozoans, with inhibitory concentrations (IC50) ranging from 5.4 to 9.5 µg/mL. The most active compounds also show low cytotoxicity (CC50), affording selectivity indices ≥ 15. Results allowed for observing a clear relationship between the substitution pattern at the aromatic rings of the 2,5-DKPs and their corresponding anti-Plasmodium activity. Finally, calculated drug-like properties of the compounds revealed points for further structure optimization of promising drug candidates.

2.
Bioorg Chem ; 102: 104080, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32683182

RESUMO

Diketopiperazines (DKPs) have been regarded as an important scaffold from the viewpoint of synthesis due to their biological properties for the treatment of several diseases, including cancer. In this work, two novel series of enantiomeric 2,6-DKPs derived from α-amino acids were synthesized through nucleophilic substitution and intramolecular cyclization reactions. All the compounds were docked against histone deacetylase 8 (HDAC8), which is a promising target for the development of anticancer drugs. These compounds bound into the active site of HDAC8 in a similar way to Trichostatin A (TSA), which is an HDAC8 inhibitor. This study showed that the conformation of the 2,6-DKP ring, stereochemistry, and the type of substituent on the chiral center had an important role in the binding modes. The Gibbs free energies and dissociation constants values of HDAC8-ligand complexes showed that compounds (S)-4hBn, (S)-4m, (R)-4h, and (R)-4m were more stable and affine towards HDAC8 than TSA. The inhibitory activities of 4a, (S)-4h, (S)- and (R)-4(g, l, m) were evaluated in vitro on HDAC8. It was found that compounds (R)-4g (IC50 = 21.54 nM) and (R)-4m (IC50 = 10.81 nM) exhibited better inhibitory activities than TSA (IC50 = 28.32 nM). These results suggested that 2,6-DKPs derivatives may be promising anticancer agents for further biological studies.


Assuntos
Dicetopiperazinas/antagonistas & inibidores , Histona Desacetilases/efeitos dos fármacos , Simulação de Acoplamento Molecular/métodos , Proteínas Repressoras/efeitos dos fármacos , Desenho de Fármacos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
3.
Biofouling ; 36(5): 597-609, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32573275

RESUMO

This work investigated chloroform extracts from culture supernatants of two human probiotic bacteria, Lactobacillus casei CRL 431 and Lactobacillus acidophilus CRL 730 for the production of virulence factors and quorum sensing (QS) interference against three Pseudomonas aeruginosa strains. Both extracts inhibited biofilm biomass (up to 50%), biofilm metabolic activity (up to 39%), the production of the enzyme elastase (up to 63%) and pyocyanin (up to 77%), and decreased QS, without presenting any antibacterial acgivity. In addition, the chloroform extracts of both strains disrupted preformed biofilms of the three strains of P. aeruginosa analyzed (up to 40%). GC-MS analysis revealed that the major compounds detected in the bioactive extracts were four diketopiperazines. This study suggests that the metabolites of L. casei and L. acidophilus could be a promising alternative to combat the pathogenicity of P. aeruginosa.


Assuntos
Probióticos , Pseudomonas aeruginosa , Percepção de Quorum/efeitos dos fármacos , Antibacterianos/farmacologia , Biofilmes , Humanos , Virulência , Fatores de Virulência
4.
Electron. j. biotechnol ; Electron. j. biotechnol;40: 40-44, July. 2019. tab, ilus
Artigo em Inglês | LILACS | ID: biblio-1053231

RESUMO

Background: The study of plant-associated microorganisms is very important in the discovery and development of bioactive compounds. Pseudomonas is a diverse genus of Gammaproteobacteria comprising more than 60 species capable of establishing themselves in many habitats, which include leaves and stems of many plants. There are reports of metabolites with diverse biological activity obtained from bacteria of this genus, and some of the metabolites have shown cytotoxic activity against cancer cell lines. Because of the high incidence of cancer, research in recent years has focused on obtaining new sources of active compounds that exhibit interesting pharmacodynamic and pharmacokinetic properties that lead to the development of new therapeutic agents. Results: A bacterial strain was isolated from tumors located in the stem of Pinus patula, and it was identified as Pseudomonas cedrina. Extracts from biomass and broth of P. cedrina were obtained with chloroform:methanol (1:1). Only biomass extracts exhibited antiproliferative activity against human tumor cell lines of cervix (HeLa), lung (A-549), and breast (HBL-100). In addition, a biomass extract from P. cedrina was fractioned by silica gel column chromatography and two diketopiperazines were isolated: cyclo-(L-Prolyl-L-Valine) and cyclo-(L-Leucyl-L-Proline). Conclusions: This is the first report on the association of P. cedrina with the stems of P. patula in Mexico and the antiproliferative activity of extracts from this species of bacteria against human solid tumor cell lines.


Assuntos
Pseudomonas/química , Pinus/microbiologia , Linhagem Celular Tumoral/efeitos dos fármacos , Antineoplásicos/farmacologia , Plantas/microbiologia , Simbiose , Biomassa , Gammaproteobacteria/química , Proliferação de Células/efeitos dos fármacos
5.
Electron. j. biotechnol ; Electron. j. biotechnol;28: 35-40, July. 2017. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-1015831

RESUMO

Background: It has been a very common practice to use probiotics or their metabolites as alternative antimicrobial strategies for the treatment and prevention of infections as rampant and indiscriminate use of antibiotics causes the development of antibiotic-resistant pathogens. The objective of this study was to select a potential antimicrobial probiotic strain of Escherichia coli from the human gastrointestinal tract and investigate the production of diketopiperazines that contribute to the antimicrobial activity. Results: E. coli GutM4 was isolated from the feces of a healthy adult. E. coli GutM4 showed significant antagonistic activity against 10 indicator pathogens, and this activity was no less than that of the reference strain E. coli Nissle 1917 against eight of the indicator pathogens. Moreover, E. coli GutM4 produced antagonistic substances containing trypsin-targeted peptide bonds because the inhibitory effects of E. coli GutM4 supernatant significantly decreased upon treatment with trypsin. Consistent with the antagonistic activity and peptide compounds of E. coli GutM4, 14 2,5-diketopiperazines were isolated from the fermented broth of E. coli GutM4, including 12 cyclo(Pro-Phe), 3 cyclo(Pro-Tyr), and 5 cyclo(4-hydroxyl-Pro-Leu), which are reported to have antipathogenic activity. Conclusion: E. coli GutM4 produces 2,5-diketopiperazines that are partly involved in antagonistic action against human pathogens in vitro.


Assuntos
Humanos , Probióticos/farmacologia , Escherichia coli/metabolismo , Dicetopiperazinas/farmacologia , Peptídeos , Bactérias/efeitos dos fármacos , Técnicas In Vitro , Candida albicans/efeitos dos fármacos , Probióticos/metabolismo , Escherichia coli/isolamento & purificação , Dicetopiperazinas/metabolismo , Fezes/microbiologia , Microbioma Gastrointestinal
6.
Molecules ; 22(6)2017 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-28608830

RESUMO

Diketopiperazines can be generated by non-enzymatic cyclization of linear dipeptides at extreme temperature or pH, and the complex medium used to culture bacteria and fungi including phytone peptone and trypticase peptone, can also produce cyclic peptides by heat sterilization. As a result, it is not always clear if many diketopiperazines reported in the literature are artifacts formed by the different complex media used in microorganism growth. An ideal method for analysis of these compounds should identify whether they are either synthesized de novo from the products of primary metabolism and deliver true diketopiperazines. A simple defined medium (X. fastidiosa medium or XFM) containing a single carbon source and no preformed amino acids has emerged as a method with a particularly high potential for the grown of X. fastidiosa and to produce genuine natural products. In this work, we identified a range of diketopiperazines from X. fastidiosa 9a5c growth in XFM, using Ultra-Fast Liquid Chromatography coupled with mass spectrometry. Diketopiperazines are reported for the first time from X. fastidiosa, which is responsible for citrus variegated chlorosis. We also report here fatty acids from X. fastidiosa, which were not biologically active as diffusible signals, and the role of diketopiperazines in signal transduction still remains unknown.


Assuntos
Dicetopiperazinas/farmacologia , Peptonas/química , Xylella/efeitos dos fármacos , Carbono/química , Caseínas/química , Cromatografia Líquida , Dicetopiperazinas/síntese química , Dicetopiperazinas/química , Peptonas/síntese química , Peptonas/farmacologia , Hidrolisados de Proteína/química , Espectrometria de Massas por Ionização por Electrospray , Xylella/crescimento & desenvolvimento
7.
Bioorg Med Chem Lett ; 26(10): 2438-2441, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27080179

RESUMO

Three new diketopiperazines (1-3), cyclo(l-Pro-d-trans-Hyp) (1), cyclo(l-Pro-d-Glu) (2), and cyclo(d-Pro-d-Glu) (3) and five known diketopiperazines (4-8) were isolated from the endolichenic fungus Colpoma sp. CR1465A identified from the Costa Rican plant Henriettea tuberculosa (Melatomataceae). The structures of the new compounds 1-3 were elucidated using a combination of extensive spectroscopic analyses, including 2D NMR and HR-MS, and their absolute configurations were determined by a combination of NOESY analysis and Marfey's method. Cyclo(l-Pro-d-allo-Thr) (4) was recently isolated from a South China Sea marine sponge Callyspongia sp., but its NMR spectroscopic data were not reported, and cyclo(l-Pro-l-Asp) (5) was previously reported but only as a synthetic product. The NMR data assignments of compounds 4 and 5 are reported for the first time. All of the isolated compounds were tested for antifungal and antimicrobial properties.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Callyspongia/química , Dicetopiperazinas/química , Dicetopiperazinas/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Animais , Antibacterianos/química , Antifúngicos/química , Costa Rica , Avaliação Pré-Clínica de Medicamentos/métodos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana
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