RESUMO
Monobactams play an important role in antibiotic drug discovery. Based on the structural characteristics of aztreonam and its biological targets, six new monobactam derivatives (2a-c and 3a-c) were synthesized and their in vitro antibacterial activities were investigated. Compounds 2a-c showed higher activities against tested gram-negative bacteria than that of parent aztreonam. Monobactam 2c exhibited the most potent activities, with MIC ranging from 0.25 to 2 µg/mL against most bacteria.
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Monobactamas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monobactamas/síntese química , Monobactamas/química , Relação Estrutura-AtividadeRESUMO
A monocyclic ring in their structure characterizes monobactams, a subclass of ß-lactam antibiotics. Many of these compounds have a bactericidal mechanism of action and acts as penicillin and cephalosporins, interfering with bacterial cell wall biosynthesis. The synthesis of novel ß-lactams is an emerging area of organic synthesis research due to the problem of increasing bacterial resistance to existing ß -lactam antibiotics, and, in this way, new compounds have been presented with several structural modifications, aiming to improve biological activities. Among the biological activities studied, the most outstanding are antibacterial, antitubercular, anticholesterolemic, anticancer, antiinflammatory, antiviral, and anti-enzymatic, among others. This review explores the vast number of works related to monocyclic ß-lactams, compounds of great importance in scientific research.
Assuntos
Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Monobactamas/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antituberculosos/síntese química , Antituberculosos/química , Estrutura Molecular , Monobactamas/síntese química , Monobactamas/químicaRESUMO
Based on the structural characteristics of aztreonam (AZN) and its target PBP3, a series of new monobactam derivatives bearing various substituents on oxime residue were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative bacteria. Among them, compounds 8p and 8r displayed moderate potency with MIC values of 0.125-32 µg/mL against most tested Gram-negative strains, comparable to AZN. Meanwhile, the combination of 8p and 8r with avibactam as a ß-lactamases inhibitor, in a ratio of 1:16, showed a promising synergistic effect against both ESBLs- and NDM-1-producing K. pneumoniae, with significantly reduced MIC values up to 8-fold and >256-fold respectively. Furthermore, both of them demonstrated excellent safety profiles both in vitro and in vivo. The results provided powerful information for further structural optimization of monobactam antibiotics to fight ß-lactamase-producing resistant Gram-negative bacteria.
Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Monobactamas/farmacologia , Oximas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monobactamas/síntese química , Monobactamas/química , Oximas/química , Relação Estrutura-AtividadeRESUMO
A series of novel pyridone conjugated monobactams with various substituents at the (4) position were synthesized and evaluated for their antibacterial activities against a panel of multidrug-resistant (MDR) Gram-negative bacteria in vitro. Compounds 46d, 54 and 75e displayed good to moderate activities against P. aeruginosa, among which the activity of 75e against P. aeruginosa was comparable to that of BAL30072 under iron limitation condition. Compounds 35, 46d, 54, 56a, 56c and 56d exhibited good to excellent antibacterial activities against E. coli and K. pneumoniae, which were comparable or superior to that of BAL30072. In vitro liver microsomal stability was further evaluated and the results manifested that Compounds 35, 46d and 54 were metabolically stable in human liver microsomes.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Monobactamas/química , Monobactamas/farmacologia , Antibacterianos/síntese química , Desenho de Fármacos , Resistência a Múltiplos Medicamentos , Farmacorresistência Bacteriana Múltipla , Escherichia coli/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Monobactamas/síntese química , Pseudomonas aeruginosa/efeitos dos fármacos , Piridonas/síntese química , Piridonas/química , Piridonas/farmacologiaRESUMO
Bromine induced lactamization of vinyl acetohydroxamates facilitated syntheses of monocyclic ß-lactams suitable for incorporation of a thiomethyl and extended functionality at the C(4) position. Elaboration of the resulting substituted N-hydroxy-2-azetidinones allowed incorporation of functionalized α-amino substituents appropriate for enhancement of antibiotic activity. Evaluation of antibacterial activity against a panel of Gram-positive and Gram-negative bacteria revealed structure-activity relationships (SAR) and identification of potent new monobactam antibiotics. The corresponding bis-catechol conjugate, 42, has excellent activity against Gram-negative bacteria including carbapenemase and carbacephalosporinase producing strains of Acinetobacter baumannii, which have been listed by the WHO as being of critical concern worldwide.
Assuntos
Bactérias Gram-Negativas/efeitos dos fármacos , Monobactamas/química , beta-Lactamas/química , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/enzimologia , Proteínas de Bactérias , Catecóis/farmacologia , Métodos , Testes de Sensibilidade Microbiana , Monobactamas/síntese química , Relação Estrutura-Atividade , beta-LactamasesRESUMO
The development of biomaterials able to act against a wide range of bacteria, including antibiotic resistant bacteria, is of great importance since bacterial colonization is one of the main causes of implant failure. In this work, we explored the possibility to functionalize hydroxyapatite (HA) nanocrystals with some monocyclic N-thio-substituted ß-lactams. To this aim, a series of non-polar azetidinones have been synthesized and characterized. The amount of azetidinones loaded on HA could be properly controlled on changing the polarity of the loading solution and it can reach values up to 17 wt%. Data on cumulative release in aqueous solution show different trends which can be related to the lipophilicity of the molecules and can be modulated by suitable groups on the azetidinone. The examined ß-lactams-HA composites display good antibacterial activity against reference Gram-positive and Gram-negative bacteria. However, the results of citotoxicity and antibacterial tests indicate that HA loaded with 4-acetoxy-1-(methylthio)-azetidin-2-one displays the best performance. In fact, this material strongly inhibited the bacterial growth of both methicillin resistant and methicillin susceptible clinical isolates of S. aureus from surgical bone biopsies, showing to be a very good candidate as a new functional biomaterial with enhanced antibacterial activity.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Materiais Biocompatíveis/química , Durapatita/química , Monobactamas/química , Monobactamas/farmacologia , Antibacterianos/síntese química , Azetidinas/química , Azetidinas/farmacologia , Bactérias/efeitos dos fármacos , Portadores de Fármacos , Liberação Controlada de Fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monobactamas/síntese química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
A series of monobactam derivatives were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative strains, taking Aztreonam and BAL30072 as the leads. Six conjugates (12a-f) bearing PIH-like siderophore moieties were created to enhance the bactericidal activities against Gram-negative bacteria based on Trojan Horse strategy, and all of them displayed potencies against susceptible Gram-negative strains with MIC ≤ 8 µg/mL. SAR revealed that the polar substituents on the oxime side chain were beneficial for activities against resistant Gram-negative bacteria. Compounds 19c and 33a-b exhibited the promising potencies against ESBLs-producing E. coli and Klebsiella pneumoniae with MICs ranging from 2 µg/mL to 8 µg/mL. These results offered powerful information for further strategic optimization in search of the antibacterial candidates against MDR Gram-negative bacteria.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Monobactamas/química , Monobactamas/farmacologia , Antibacterianos/síntese química , Aztreonam/análogos & derivados , Aztreonam/síntese química , Aztreonam/farmacologia , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Monobactamas/síntese química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologiaRESUMO
An efficient method to synthesize the ß-lactams with high regioselectivity via Pd-catalyzed C(sp(3))-H bond activation and intramolecular amination of simple and readily available aminoquinoline carboxamides was demonstrated. C6F5I plays a significant role in the formation of the C-N bond of the four-membered ring ß-lactams. High yield along with wide substrate scope and functional group tolerance makes this reaction applicable to build natural-product-derived ß-lactams. This method has been applied to the efficient synthesis of the ß-lactamase inhibitor MK-8712.
Assuntos
Amidas/química , Monobactamas/síntese química , Paládio/química , Inibidores de beta-Lactamases , beta-Lactamas/síntese química , Aminação , Aminoquinolinas/química , Catálise , Estrutura Molecular , Monobactamas/química , Monobactamas/farmacologia , beta-Lactamas/químicaRESUMO
A series of N-methylthio-ß-lactams with antibacterial activity were thoroughly evaluated as antioxidants. We found that only the presence of a polyphenolic moiety anchored to the ß-lactam ring ensured an adequate antioxidant potency. New compounds, efficiently combining in one structure antioxidant and antibacterial activity, may provide a promising basis for the development of new leads useful in adverse clinical conditions such as in cystic fibrosis patients, in whom colonization by MRSA and epithelial damage by chronic pulmonary oxidative stress take place.
Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Azetidinas/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Monobactamas/farmacologia , Sulfetos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antioxidantes/síntese química , Antioxidantes/química , Azetidinas/síntese química , Azetidinas/química , Fibrose Cística/microbiologia , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monobactamas/síntese química , Monobactamas/química , Relação Estrutura-Atividade , Sulfetos/síntese química , Sulfetos/químicaRESUMO
Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.
Assuntos
Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Monobactamas/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Proteínas Sanguíneas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Monobactamas/síntese química , Monobactamas/química , Ratos , Relação Estrutura-AtividadeRESUMO
The bridged monobactam ß-lactamase inhibitor MK-8712 (1) effectively inhibits class C ß-lactamases. Side chain N-alkylated and ring-opened analogs of 1 were prepared and evaluated for combination with imipenem to overcome class C ß-lactamase mediated resistance. Although some analogs were more potent inhibitors of AmpC, none exhibited better synergy with imipenem than 1.
Assuntos
Antibacterianos/química , Inibidores Enzimáticos/química , Monobactamas/síntese química , Inibidores de beta-Lactamases , Antibacterianos/síntese química , Antibacterianos/farmacologia , Sítios de Ligação , Simulação por Computador , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Imipenem/farmacologia , Testes de Sensibilidade Microbiana , Monobactamas/farmacologia , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , beta-Lactamases/metabolismoRESUMO
Rhomboids are relatively recently discovered intramembrane serine proteases that are conserved throughout evolution. They have a wide range of biological functions, and there is also much speculation about their potential medical relevance. Although rhomboids are weakly inhibited by some broad-spectrum serine protease inhibitors, no potent and specific inhibitors have been identified for these enzymes, which are mechanistically distinct from and evolutionarily unrelated to the classical soluble serine proteases. Here we report a new biochemical assay for rhomboid function based on the use of quenched fluorescent substrate peptides. We have developed this assay into a high-throughput format and have undertaken an inhibitor and activator screen of approximately 58,000 small molecules. This has led to the identification of a new class of rhomboid inhibitors, a series of monocyclic ß-lactams, which are more potent than any previous inhibitor. They show selectivity, both for rhomboids over the soluble serine protease chymotrypsin and also, importantly, between different rhomboids; they can inhibit mammalian as well as bacterial rhomboids; and they are effective both in vitro and in vivo. These compounds represent important templates for further inhibitor development, which could have an impact both on biological understanding of rhomboid function and potential future drug development.
Assuntos
Ensaios de Triagem em Larga Escala , Proteínas de Membrana/metabolismo , Monobactamas , Proteínas Recombinantes de Fusão/metabolismo , Serina Proteases/metabolismo , Inibidores de Serina Proteinase , Sequência de Aminoácidos , Animais , Células COS , Chlorocebus aethiops , Cromatografia Líquida de Alta Pressão , Clonagem Molecular , Escherichia coli , Corantes Fluorescentes/análise , Expressão Gênica , Cinética , Proteínas de Membrana/genética , Camundongos , Dados de Sequência Molecular , Monobactamas/síntese química , Monobactamas/farmacologia , Relação Quantitativa Estrutura-Atividade , Proteínas Recombinantes de Fusão/genética , Serina Proteases/genética , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologia , Bibliotecas de Moléculas Pequenas/análise , Especificidade da Espécie , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Especificidade por SubstratoRESUMO
A simple and efficient procedure for the stereoselective synthesis of new azetidinone-isothiazolidinones has been developed. New compounds were tested in vitro on a panel of Gram-positive and Gram-negative bacterial pathogens, some of them showing weak antibacterial activity.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Azetidinas/química , Bactérias/efeitos dos fármacos , Monobactamas/síntese química , Monobactamas/farmacologia , Tiazolidinas/química , Amoxicilina/farmacologia , Antibacterianos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monobactamas/química , EstereoisomerismoRESUMO
Solid-phase organic synthesis (SPOS) has become an effective synthetic tool for the preparation of combinatorial libraries of non-oligomeric small molecules. Owing to their high efficacy and extremely safe toxicological profile, beta-lactam antibiotics are the first choice for bacterial infectious diseases. Moreover, beta-lactam compounds have also showed other biological activities that include inhibition of prostate specific antigen, thrombin, human cytomegalovirus protein, human leukocyte elastase and cholesterol absorption. Thus, the application of combinatorial and related methodologies to the chemistry of the beta-lactam ring has been recognized as a very attractive challenge by different research groups around the world. This review covers the solid-phase and combinatorial chemistry related to mono-and multicyclic beta-lactam compounds that has been reported in the literature from 1999 to 2004.
Assuntos
Técnicas de Química Combinatória/métodos , beta-Lactamas/síntese química , Azetidinas/síntese química , Azetidinas/química , Compostos Bicíclicos com Pontes/síntese química , Catálise , Ciclização , Iminas/química , Estrutura Molecular , Monobactamas/síntese química , Resinas Sintéticas/químicaRESUMO
The monobactam sodium 3-benzylcarbamoyl-2-oxo-1-azetidinesulfonate, bearing a retro (vs classical beta-lactam)-amide side chain, has been synthesized and the kinetics of its reaction with typical beta-lactamases studied. The new compound is generally a poorer substrate than the analogous compound with a normal side chain but its formation of a transiently stable complex with a class C beta-lactamase sustains the retro-amide side-chain concept.
Assuntos
Amidas/química , Monobactamas/química , Monobactamas/síntese química , beta-Lactamases/química , Catálise , Enterobacter cloacae/enzimologia , Hidrólise , Cinética , Conformação Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
New cis monocyclic beta-lactams were synthesized by [2+2] Staudinger cycloaddition reactions of the imine (3,4-dimethoxybenzylidene)-(4-methoxyphenyl)-amine and ketenes derived from different acyl chlorides and Et3N. These monocyclic beta-lactams were then cleaved by ceric ammonium nitrate (CAN) to give NH-monocyclic beta-lactams, which in turn were converted to N-sulfonyl monocyclic beta-lactams by treatment with four different sulfonyl chlorides in the presence of Et3N and 4,4-dimethyl-aminopyridine (DMAP).
Assuntos
Antibacterianos/síntese química , Monobactamas/síntese química , Antibacterianos/química , Modelos Biológicos , Conformação Molecular , Monobactamas/químicaRESUMO
Beta-lactam ring-containing compounds such as penicillins, ampicillin, amoxicillin, cephalosporins and carbapenem are among the most famous antibiotics. This article reviews the recent developments in the study of such compounds. The introductory paragraph, which highlights the significance of the subject and cites most of the leading references of the previous century, is followed by an overview of beta-lactams and some novel methodologies for the synthesis of bi-, tri- and polycyclic derivatives. The rest of the sections deal with design, synthesis and biological activity of monobactams and carbapenems. Many of them have potential antibacterial activity, even against some resistant strains, and enzyme inhibitory activity.
Assuntos
Antibacterianos/síntese química , Carbapenêmicos/síntese química , Monobactamas/síntese química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Carbapenêmicos/isolamento & purificação , Carbapenêmicos/farmacologia , Monobactamas/isolamento & purificação , Monobactamas/farmacologiaRESUMO
The syntheses of some new sugar-based monocyclic beta-lactams possessing several other functionalities in addition to the carbohydrate moiety are described. The key step was the Staudinger [2+2] cycloaddition of chiral carbohydrate Schiff base 5 with phthalimidoacetyl chloride to yield the sugar-based monocyclic beta-lactam 6 as a single isomer. Treatment of protected beta-lactams 6 and 8 with methylhydrazine afforded the free amino beta-lactams 9 and 10. Acylation of these free amino beta-lactams with benzoyl, phenoxyacetyl, cinnamoyl and phenylacetyl chloride in the presence of pyridine afforded beta-lactams 11a-d and 12a-d. Some of these novel beta-lactams were found to be active against Staphilococcus citrus, Klebsiella pneumoniae, Escherichia coli and Bacillus subtilis.
Assuntos
Antibacterianos/síntese química , Carboidratos/química , Monobactamas/síntese química , Antibacterianos/química , Antibacterianos/metabolismo , Galactose/química , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Estrutura Molecular , Monobactamas/química , Monobactamas/metabolismoRESUMO
Reaction of the amino acid D-phenylalanine ethyl ester (4) with cinnamaldehyde gave chiral Schiff base 5, which underwent an asymmetric Staudinger [2+2] cycloaddition reaction with phthalimidoacetyl chloride to give the monocyclic beta-lactam 6 as a single stereoisomer. Ozonolysis of 6 followed by reduction with lithium aluminum tri(tert-butoxy) hydride afforded the hydroxymethyl beta-lactam 8. Treatment of 8 with methansulfonyl chloride gave the mesylated monocyclic beta-lactam 9, which was converted to the bicyclic beta-lactam 10 upon treatment with 1,8-diazabicyclo[5,4.0] undec-7-ene (DBU). Deprotection of the phthalimido group in beta-lactams 6 and 10 by methylhydrazine and subsequent acylation of the free amino beta-lactams with different acyl chlorides in the presence of pyridine afforded mono and bicyclic beta-lactams 14a-d and 15a-d respectively. The compounds prepared were tested against Escherichia coli, Staphilococcus citrus, Klebsiella pneumanie and Bacillus subtillis. Some of these compounds showed potential antimicrobial activities.
Assuntos
Antibacterianos , Compostos Bicíclicos com Pontes , Monobactamas , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Estrutura Molecular , Monobactamas/síntese química , Monobactamas/química , Monobactamas/farmacologiaRESUMO
A series of monobactam inhibitors of HCMV (N(o)) protease bearing a heterocycle linked by a methylene group at C-4 is described. Inhibitors containing a heterocycle such as a 2-furyl, 2-thiophenyl, 4-methyl-2-tetrazole and 2-benzothiazole were found to be active in a plaque reduction assay. Furthermore, 2-benzothiazole derivatives were shown to inhibit the HCMV protease activity inside cells by using a cell transfection assay, indicating that their antiviral activity in the plaque reduction assay could be attributed to protease inhibition.