Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
ChemistryOpen ; 9(4): 442-444, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32269899

RESUMO

A convenient and improved method for the synthesis of beta acids or lupulones, which are known to possess e. g. anti-cancer, anti-inflammatory, anti-oxidative and antimicrobial activity, has been developed successfully. Further derivatization of these complex structures to the corresponding dihydrochromen-7-ones, including the natural product machuone, was realized to simplify their analysis and to confirm their molecular structure. In addition to practical and safe laboratory procedures, the advantages associated with this new approach involve the use of water as a solvent and the direct crystallization of lupunones from acetonitrile, rendering our strategy more efficient and benign as compared to available methods.


Assuntos
Cromonas/síntese química , Floroglucinol/química , Terpenos/síntese química , Catálise , Humulus/química , Estrutura Molecular , Oxirredução , Extratos Vegetais/química , Prenilação , Solventes/química
2.
Chem Asian J ; 15(1): 51-55, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31686429

RESUMO

Monocyclic ß-lactams revive the research field on antibiotics, which are threatened by the emergence of resistant bacteria. A six-step synthetic route was developed, providing easy access to new 3-amino-1-carboxymethyl-4-phenyl-ß-lactams, of which the penicillin-binding protein (PBP) inhibitory potency was demonstrated biochemically.


Assuntos
Aminoácidos/farmacologia , Antibacterianos/farmacologia , Dipeptídeos/farmacologia , Iminas/farmacologia , Lactamas/farmacologia , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Aminoácidos/química , Antibacterianos/síntese química , Antibacterianos/química , Dipeptídeos/síntese química , Dipeptídeos/química , Iminas/química , Lactamas/síntese química , Lactamas/química , Estrutura Molecular , Proteínas de Ligação às Penicilinas/metabolismo
3.
Chemistry ; 25(70): 16128-16140, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31596974

RESUMO

Innovative monocyclic ß-lactam entities create opportunities in the battle against resistant bacteria because of their PBP acylation potential, intrinsically high ß-lactamase stability and compact scaffold. α-Benzylidene-substituted 3-amino-1-carboxymethyl-ß-lactams were recently shown to be potent PBP inhibitors and constitute eligible anchor points for synthetic elaboration of the chemical space around the central ß-lactam ring. The present study discloses a 12-step synthesis of ten α-arylmethylidenecarboxylates using a microwave-assisted Wittig olefination as the crucial reaction step. The library was designed aiming at enhanced ß-lactam electrophilicity and extended electron flow after enzymatic attack. Additionally, increased ß-lactamase stability and intermolecular target interaction were envisioned by tackling both the substitution pattern of the aromatic ring and the ß-lactam C4-position. The significance of α-unsaturation was validated and the R39/PBP3 inhibitory potency shown to be augmented the most through decoration of the aromatic ring with electron-withdrawing groups. Furthermore, ring cleavage by representative ß-lactamases was ruled out, providing new insights in the SAR landscape of monocyclic ß-lactams as eligible PBP or ß-lactamase inhibitors.

4.
ACS Omega ; 3(11): 15235-15245, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30556000

RESUMO

Glycosylation significantly alters the biological and physicochemical properties of small molecules. ß-Lactam alcohols comprise eligible substrates for such a transformation based on their distinct relevance in the chemical and medicinal community. In this framework, the unprecedented enzymatic glycosylation of the rigid and highly strained four-membered ß-lactam azaheterocycle was studied. For this purpose, cis-3-hydroxy-ß-lactams were efficiently prepared in three steps by means of a classical organic synthesis approach, while a biocatalytic step was implemented for the selective formation of the corresponding 3-O-α- and -ß-glucosides, hence overcoming the complexities typically encountered in synthetic glycochemistry and contributing to the increasing demand for sustainable processes in the framework of green chemistry. Two carbohydrate-active enzymes were selected based on their broad acceptor specificity and subsequently applied for the α- or ß-selective formation of ß-lactam-sugar adducts, using sucrose as a glucosyl donor.

5.
Chemistry ; 24(57): 15254-15266, 2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-29882610

RESUMO

As a complement to the renowned bicyclic ß-lactam antibiotics, monocyclic analogues provide a breath of fresh air in the battle against resistant bacteria. In that framework, the present study discloses the in silico design and unprecedented ten-step synthesis of eleven nocardicin-like enantiomerically pure 2-{3-[2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-2-oxoazetidin-1-yl}acetic acids starting from serine as a readily accessible precursor. The capability of this novel class of monocyclic 3-amino-ß-lactams to inhibit penicillin-binding proteins (PBPs) of various (resistant) bacteria was assessed, revealing the potential of α-benzylidenecarboxylates as interesting leads in the pursuit of novel PBP inhibitors. No deactivation by representative enzymes belonging to the four ß-lactamase classes was observed, while weak inhibition of class C ß-lactamase P99 was demonstrated.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Enterococcus faecium/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , beta-Lactamas/química , beta-Lactamas/farmacologia , Aminação , Antibacterianos/síntese química , Infecções Bacterianas/tratamento farmacológico , Simulação por Computador , Desenho Assistido por Computador , Desenho de Fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Enterococcus faecium/metabolismo , Escherichia coli/metabolismo , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Proteínas de Ligação às Penicilinas/metabolismo , beta-Lactamas/síntese química
6.
Appl Microbiol Biotechnol ; 102(7): 3183-3191, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29470619

RESUMO

In the carbohydrate-active enzyme database, GH13_18 is a family of retaining glycoside phosphorylases that act on α-glucosides. In this work, we explored the functional diversity of this family by comparing distinctive sequence motifs in different branches of its phylogenetic tree. A glycoside phosphorylase from Marinobacter adhaerens HP15 that was predicted to have a novel function was expressed and characterised. The enzyme was found to catalyse the reversible phosphorolysis of 2-O-α-D-glucosylglycerol with retention of the anomeric configuration, a specificity that has never been described before. Homology modelling, docking and mutagenesis were performed to pinpoint particular acceptor site residues (Tyr194, Ala333, Gln336) involved in the binding of glycerol. The new enzyme specificity provides additional insights into bacterial metabolic routes, being the first report of a phosphorolytic route for glucosylglycerol in a glucosylglycerol-producing organism. Furthermore, glucosylglycerol phosphorylase might be an attractive biocatalyst for the production of the osmolyte glucosylglycerol, which is currently produced on industrial scale by exploiting a side activity of the closely related sucrose phosphorylase. Family GH13_18 has clearly proven to be more diverse than was initially assumed, and the analysis of specificity-determining sequence motifs has shown to be a straightforward and fruitful tool for enzyme discovery.


Assuntos
Variação Genética , Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/metabolismo , Marinobacter/enzimologia , Marinobacter/genética , Fosforilases/genética , Motivos de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Glucosídeos/metabolismo , Glicosídeo Hidrolases/química , Fosforilases/química , Especificidade por Substrato
7.
Med Res Rev ; 38(2): 426-503, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28815732

RESUMO

Due to the widespread emergence of resistant bacterial strains, an urgent need for the development of new antibacterial agents with novel modes of action has emerged. The discovery of naturally occurring monocyclic ß-lactams in the late 1970s, mainly active against aerobic Gram-negative bacteria, has introduced a new approach in the design and development of novel antibacterial ß-lactam agents. The main goal was the derivatization of the azetidin-2-one core in order to improve their antibacterial potency, broaden their spectrum of activity, and enhance their ß-lactamase stability. In that respect, our review covers the updates in the field of monocyclic ß-lactam antibiotics during the last three decades, taking into account an extensive collection of references. An overview of the relationships between the structural features of these monocyclic ß-lactams, classified according to their N-substituent, and the associated antibacterial or ß-lactamase inhibitory activities is provided. The different paragraphs disclose a number of well-established classes of compounds, such as monobactams, monosulfactams, monocarbams, monophosphams, nocardicins, as well as other known representative classes. Moreover, this review draws attention to some less common but, nevertheless, possibly important types of monocyclic ß-lactams and concludes by highlighting the recent developments on siderophore-conjugated classes of monocyclic ß-lactams.


Assuntos
Antibacterianos/farmacologia , Monobactamas/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo , Antibacterianos/química , Monobactamas/química , Sideróforos/química , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/química
8.
Org Biomol Chem ; 13(9): 2716-25, 2015 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-25598487

RESUMO

Trans- and cis-2-aryl-3-(2-cyanoethyl)aziridines, prepared via alkylation of the corresponding 2-aryl-3-(tosyloxymethyl)aziridines with the sodium salt of trimethylsilylacetonitrile, were transformed into variable mixtures of 4-[aryl(alkylamino)methyl]butyrolactones and 5-[aryl(hydroxy)methyl]pyrrolidin-2-ones via KOH-mediated hydrolysis of the cyano group, followed by ring expansion. In addition, next to this chemical approach, enzymatic hydrolysis of the former aziridinyl nitriles by means of a nitrilase was performed as well, interestingly providing a selective route towards the above-mentioned functionalized γ-lactams.


Assuntos
Aminoidrolases/metabolismo , Aziridinas/síntese química , Aziridinas/metabolismo , Lactamas/metabolismo , Lactonas/metabolismo , Aminoidrolases/química , Aziridinas/química , Hidrólise , Lactamas/síntese química , Lactamas/química , Lactonas/síntese química , Lactonas/química , Estrutura Molecular , Estereoisomerismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA