RESUMO
A series of tricyclic ß-lactams were synthesized and evaluated for in vitro antibacterial activities against carbapenem-resistant Enterobacterales (CREs). Starting from a reported tricyclic ß-lactam that combined the cephalosporin skeleton having a γ-lactone ring with a carboxylic acid group, which was reported as a unique partial structure of Lactivicin, we identified the compound which shows potent antibacterial activities against all tested CREs by introducing sulfoxide. In addition, the sulfoxide-introduced tricyclic ß-lactam also shows a strong therapeutic efficacy in the neutropenic mouse lung infection model. These results indicate that the tricyclic ß-lactam skeleton will show sufficient therapeutic performance in clinical use and therefore can serve as a scaffold in the search for new antibacterial agents against CREs.
Assuntos
Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Enterobacteriaceae/efeitos dos fármacos , beta-Lactamas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Carbapenêmicos/síntese química , Carbapenêmicos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , beta-Lactamas/síntese química , beta-Lactamas/químicaRESUMO
We present further study of a subset of carbapenems, arising from a previously reported machine learning approach, with regard to their mouse pharmacokinetic profiling and subsequent study in a mouse model of sub-acute Mycobacterium tuberculosis infection. Pharmacokinetic metrics for such small molecules were compared to those for meropenem and biapenem, resulting in the selection of two carbapenems to be assessed for their ability to reduce M. tuberculosis bacterial loads in the lungs of infected mice. The original syntheses of these two carbapenems were optimized to provide multigram quantities of each compound. One of the two experimental carbapenems, JSF-2204, exhibited efficacy equivalent to that of meropenem, while both were inferior to rifampin. The lessons learned in this study point toward the need to further enhance the pharmacokinetic profiles of experimental carbapenems to positively impact in vivo efficacy performance.
Assuntos
Antituberculosos/farmacocinética , Carbapenêmicos/farmacocinética , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/síntese química , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Carbapenêmicos/síntese química , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Feminino , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/efeitos dos fármacosRESUMO
A formal synthesis of Thienamycin from ethyl (E)-crotonate and a cyclic five-membered nitrone derived from 2-deoxy-d-ribose is described. The synthesis involves 1,3-dipolar cycloaddition, cleavage of the N-O bond in the adduct, and intramolecular N-acylation to afford a bicyclic carbapenam skeleton. Subsequent transformations of the five-membered ring substituents provide the title compound.
Assuntos
Antibacterianos/síntese química , Carbapenêmicos/síntese química , Tienamicinas/síntese química , Antibacterianos/química , Carbapenêmicos/química , Tienamicinas/químicaRESUMO
1,3-Dipolar cycloadditions of 2-deoxy-D-ribose-derived L-threo five-membered cyclic nitrone to α,ß-unsaturated γ- and δ-lactones were investigated. Cycloadducts obtained from δ-lactones, after NO bond cleavage, opening of the lactone ring, and protection of hydroxyl groups were subjected to ß-lactam ring formation by using Mukaiyama's salt. Cycloadducts from γ-lactones subjected to the same reaction sequence undergo ß-elimination of a water molecule to provide pyrrolidine-substituted unsaturated γ-lactones.
Assuntos
Lactonas/química , Óxidos de Nitrogênio/química , beta-Lactamas/síntese química , Carbapenêmicos/síntese química , Carbapenêmicos/química , Reação de Cicloadição , Desoxirribose/química , Estrutura Molecular , Estereoisomerismo , beta-Lactamas/químicaRESUMO
Combinations of ß-lactams of the carbapenem class, such as meropenem, with clavulanate, a ß-lactamase inhibitor, are being evaluated for the treatment of drug-resistant tuberculosis. However, carbapenems approved for human use have never been optimized for inactivation of the unusual ß-lactam targets of Mycobacterium tuberculosis or for escaping to hydrolysis by broad-spectrum ß-lactamase BlaC. Here, we report three routes of synthesis for modification of the two side chains carried by the ß-lactam and the five-membered rings of the carbapenem core. In particular, we show that the azide-alkyne Huisgen cycloaddition reaction catalyzed by copper(I) is fully compatible with the highly unstable ß-lactam ring of carbapenems and that the triazole ring generated by this reaction is well tolerated for inactivation of the L,D-transpeptidase LdtMt1 target. Several of our new carbapenems are superior to meropenem both with respect to the efficiency of in vitro inactivation of LdtMt1 and reduced hydrolysis by BlaC.
Assuntos
Carbapenêmicos/síntese química , Carbapenêmicos/farmacologia , Peptidil Transferases/antagonistas & inibidores , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Humanos , Hidrólise , Cinética , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Peptidil Transferases/metabolismo , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Inibidores de beta-Lactamases/síntese químicaRESUMO
A novel, practical and stereoselective synthesis of (3R,4R)-4-acetoxy-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone, a key intermediate in the preparation of ß-lactam antibiotics is reported. The crucial step of the synthesis is based on the Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade between silyl protected (R)-3-butyn-2-ol and the nitrone derived from benzyl hydroxylamine and benzyl glyoxylate. The obtained adduct is subjected to debenzylation with sodium, or lithium in liquid ammonia followed by oxidation with lead tetraacetate to afford the final product.
Assuntos
Antibacterianos/síntese química , Carbapenêmicos/síntese química , Lactamas/síntese química , beta-Lactamas/síntese química , Amônia/química , Antibacterianos/química , Carbapenêmicos/química , Lactamas/química , Lítio/química , Compostos Organometálicos/química , Oxirredução , Sódio/química , Estereoisomerismo , beta-Lactamas/químicaRESUMO
To improve the oral absorption of meropenem (MEPM), we synthesized and evaluated a series of its double-promoiety prodrugs, in which lipophilic promoieties were introduced into carboxyl and pyrrolidinyl groups. Among these prodrugs, pivaloyloxymethyl (1R,5S,6S)-2-[(3S,5S)-5-(N,N-dimethylcarbamoyl)-1-(isobutyryloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (4) and 1-ethylpropyloxycarbonyloxymethyl (1R,5S,6S)-2-[(3S,5S)-5-(N,N-dimethylcarbamoyl)-1-(isobutyryloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (8) were chosen for further evaluation. Compounds 4 and 8 were well absorbed after oral administration to rats and beagles (bioavailability 18.2-38.4%), and expected to show potent therapeutic efficacy in patients infected with various pathogens, such as penicillin-resistant S. pneumoniae and ß-lactamase-negative ampicillin-resistant H. influenzae.
Assuntos
Carbapenêmicos/química , Pró-Fármacos/síntese química , Pirrolidinas/síntese química , Tienamicinas/metabolismo , Administração Oral , Animais , Antibacterianos/metabolismo , Carbapenêmicos/síntese química , Carbapenêmicos/farmacocinética , Masculino , Meropeném , Pró-Fármacos/farmacocinética , Pirrolidinas/farmacocinética , RatosRESUMO
The present work examines the relationship between the molecular structure and chiroptical properties of carbapenams through use of electronic circular dichroism spectroscopy (ECD). The applicability of the helicity rule that correlates the molecular structures of various ß-lactam analogues and their ECD spectra is examined against a set of differently substituted carbapenams. It is demonstrated that the studied compounds conform to the rule. The rule can be also applied to the carbapenams with an additional chromophoric unit interfering with the amide chromophore. For the representative carbapenams, the experimental curves are compared to the ECD spectra computed using time-dependent density functional theory (TDDFT) in order to validate the experimental data. The study reveals a high effectiveness of the ECD spectroscopy for the configurational assignment at the bridgehead carbon atom and demonstrates a strong dependence of the molecular conformation on substitution of the five-membered ring and side-chain flexibility of investigated carbapenams.
Assuntos
Carbapenêmicos/química , Dicroísmo Circular , Fenômenos Ópticos , Teoria Quântica , Carbapenêmicos/síntese química , Modelos Moleculares , Conformação Molecular , Reprodutibilidade dos Testes , EstereoisomerismoRESUMO
Trimethylsilyl triflate promotes Ferrier-Petasis rearrangement of 4-(vinyloxy)-, 4-(propenyloxy)-, and 4-(isopropenyloxy)azetidin-2-ones to corresponding 4-(carbonylmethyl)azetidin-2-ones. The latter compounds may serve as attractive intermediates in the synthesis of carbapenem antibiotics. To illustrate the potential of this reaction, selected rearrangement products have been transformed into carbapenams.
Assuntos
Azetidinas/química , Carbapenêmicos/síntese química , Cefalosporinas/síntese química , Carbapenêmicos/química , Cefalosporinas/química , Conformação Molecular , EstereoisomerismoRESUMO
The double-edged sword of antibiotic use in the fight against disease has saved countless lives at the cost of an escalation in pathogenic bacteria with increased resistance to multiple antibiotic classes. Reduction of resistance is a complicated multi-step endeavor that requires a sustained international effort of reduced utilization, infection control and development of effective and economical antimicrobial agents. The carbapenems are beta-lactam antibiotics that are stable to most beta-lactamases. They have potent bactericidal activity against a wide range of Gram-positive and Gram-negative aerobic bacteria as well as against anaerobic bacteria, while being safe, efficacious and tolerable. The use of carbapenems in hospitals has therefore been restricted to the empirical treatment of critical patients with a variety of serious infections, e.g., nosocomial pneumonia, septicemia, meningitis and cystic fibrosis. This article reviews patents claiming carbapenem antibacterial agents published from 2004-2008.
Assuntos
Antibacterianos/síntese química , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Carbapenêmicos/síntese química , Carbapenêmicos/uso terapêutico , Animais , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Infecções Bacterianas/microbiologia , Carbapenêmicos/efeitos adversos , Carbapenêmicos/farmacocinética , Descoberta de Drogas , Farmacorresistência Bacteriana Múltipla , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Patentes como Assunto , Relação Estrutura-Atividade , Resultado do TratamentoRESUMO
A library of 30 beta-lactams has been prepared from (3R,4R)-3-[(R)-1'-(tbutyldimethylsilyloxy)-ethyl]-4-acetoxy-2-azetidinone, and the corresponding deacetoxy derivative, by sequential N- and O-functionalizations with various omega-alkenoyl and omega-arylalkanoyl chains. All compounds were selective inhibitors of hFAAH versus hMGL, and IC(50) values in the nanomolar range (5-14 nM) were recorded for the best representatives. From time-dependent preincubation and rapid dilution studies, and from docking analyses in a homology model of the target enzyme, a reversible mechanism of inhibition of hFAAH is proposed.
Assuntos
Amidoidrolases/antagonistas & inibidores , Carbapenêmicos/química , Carbapenêmicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Amidoidrolases/química , Amidoidrolases/metabolismo , Carbapenêmicos/síntese química , Carbapenêmicos/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , Monoacilglicerol Lipases/química , Monoacilglicerol Lipases/metabolismoRESUMO
The synthesis of a new series of 1beta-methylcarbapenems having cyclic sulfonamide moieties is described. Their in-vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of a substituent on the pyrrolidine ring was investigated. One particular compound IIIe having a [1,2,5]thiadiazolidin 1,1-dioxide moiety showed the most potent antibacterial activity.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Carbapenêmicos/síntese química , Viabilidade Microbiana/efeitos dos fármacos , Sulfonamidas/síntese química , Antibacterianos/química , Avaliação Pré-Clínica de Medicamentos , Imipenem/farmacologia , Meropeném , Estrutura Molecular , Relação Estrutura-Atividade , Tienamicinas/farmacologiaRESUMO
Efficient syntheses of N-acetyl thienamycin and epithienamycin A in their readily deprotected form are reported where three contiguous stereocenters are established in a single catalytic asymmetric azetidinone-forming reaction. These examples are a template for synthesizing C-5/C-6 cis or trans carbapenems with independent control of the C-8 stereocenter. A library of oxidatively and sterochemically defined azetidinone precursors to a variety of naturally occurring carbapenems and potential biosynthetic intermediates has been prepared to facilitate studies of carbapenem antibiotic biosynthesis.
Assuntos
Antibacterianos/síntese química , Carbapenêmicos/síntese química , Antibacterianos/química , Carbapenêmicos/química , Catálise , Técnicas de Química Combinatória , Estrutura Molecular , EstereoisomerismoRESUMO
A new series of 1beta-methyl carbapenems possessing a 6,7-disubstituted imidazo[5,1-b]thiazol-2-yl group directly attached to the C-2 position of the carbapenem nucleus was prepared, and their activities against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. First, a benzyl moiety was introduced at the C-6 position of imidazo[5,1-b]thiazole attached to the carbapenem. These benzylated molecules showed potent anti-MRSA activity, but poor water solubility. In order to overcome this drawback, we designed and synthesized di- and tricationic carbapenems and finally discovered a novel carbapenem (15i), which exhibited excellent anti-MRSA activity and good water solubility.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Carbapenêmicos/síntese química , Carbapenêmicos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/química , Carbapenêmicos/química , Cátions , Testes de Sensibilidade Microbiana , SolubilidadeRESUMO
The synthesis of a new series of 1beta-methylcarbapenems having pyrrolidine and piperidine moieties is described. Their in-vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the pyrrolidine ring was investigated. A particular compound III b having an oxime-pyrrolidine moiety showed the most potent antibacterial activity.
Assuntos
Antibacterianos/síntese química , Carbapenêmicos/síntese química , Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Piperidinas , Pirrolidinas , Relação Estrutura-AtividadeRESUMO
A facile approach to carbapenams via Kinugasa reaction between terminal copper acetylides and nonracemic cyclic nitrones derived from malic and tartaric acid is reported. The stereochemical preferences observed in these reactions are explained. The reaction provides an entry to the carbapenams basic skeleton.
Assuntos
Alcinos/química , Carbapenêmicos/síntese química , Óxidos N-Cíclicos/química , Carbapenêmicos/química , Cobre/química , Iodetos/química , Conformação Molecular , EstereoisomerismoRESUMO
An efficient approach for synthesizing a series of 2-sulfide carbapenems has been developed using two successive Cu(I)-catalyzed cross-couplings in a single pot. The method involves highly selective intramolecular coupling of lactam and dihaloalkene using 2,2'-bipyridine as a ligand, followed by intermolecular C-S formation in the presence of another ligand (1,10-phenanthroline, PPh 3) and mercaptan.
Assuntos
Carbapenêmicos/síntese química , Cobre/química , Reagentes de Ligações Cruzadas/química , Alcenos/química , Carbapenêmicos/química , Catálise , Estrutura Molecular , Enxofre/química , Compostos de Vinila/químicaRESUMO
The synthesis of a new series of 1beta-methylcarbapenems having spiro[2,4]heptane moieties is described. Their in-vitro antibacterial activities against both gram-positive and gram-negative bacteria were tested and the effect of substituents on the pyrrolidine ring was investigated. Most compounds were shown to be more active than the compared meropenem and imipenem against Escherichia coli. One particular compound, IIIb, having hydroxy a moiety showed the most potent antibacterial activity.
Assuntos
Antibacterianos/síntese química , Carbapenêmicos/síntese química , Compostos de Espiro/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Carbapenêmicos/química , Carbapenêmicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A new series of 1beta-methyl carbapenems possessing a 6,7-disubstituted imidazo[5,1-b]thiazol-2-yl group directly attached to the C-2 position of the carbapenem nucleus was prepared, and the activities of these compounds against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. To study the effect of basic moieties on anti-MRSA activity, we introduced an amino, or imino, or amidino group at the 6-position of imidazo[5,1-b]thiazole in place of the carbamoylmethyl moiety of CP5068. Anti-MRSA activities of almost all basic group-substituted carbapenems were improved, though some of the compounds showed stronger acute toxicity in mice than IPM. In order to decrease the toxicity without decreasing the activity, we introduced various additional functionalities around the basic moiety. Finally, we obtained CP5484, which has excellent anti-MRSA activity and low acute toxicity.
Assuntos
Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Resistência a Meticilina , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/toxicidade , Carbapenêmicos/síntese química , Carbapenêmicos/toxicidade , Imidazóis/química , Cinética , Testes de Sensibilidade Microbiana , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
The synthesis of a new series of 1beta-methylcarbapenems having cyclic sulfonamide moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituent on the pyrrolidine ring was investigated. A particular compound (IIIi) having 2-methyl-[1,2,6]thiadiazinan-1,1-dioxide moiety showed the most potent antibacterial activity.