RESUMO
Clarithromycin and congeners are important antibacterial members of the erythromycin A 14-membered macrocyclic lactone family. The macrolide scaffold consists of a multifunctional core that carries both chemically reactive and non-reactive substituents and sites. Two main approaches are used in the preparation of the macrolides. In semisynthesis, the naturally occurring macrocycle serves as a substrate for structural modifications of peripheral substituents. This review is focused on substituents in non-activated positions. In the total synthesis approach, the macrolide antibiotics are constructed by a convergent assembly of building blocks from presynthesized substrates or substrates prepared by biogenetic engineering. The assembled block structures are linear chains that are cyclized by macrolactonization or by metal-promoted cross-coupling reactions to afford the 14-membered macrolactone. Pendant glycoside residues are introduced by stereoselective glycosylation with a donor complex. When available, a short summary of antibacterial MIC data is included in the presentations of the structural modifications discussed.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Eritromicina/química , Eritromicina/farmacologia , Macrolídeos/química , Macrolídeos/farmacologia , Antibacterianos/síntese química , Fenômenos Químicos , Técnicas de Química Sintética , Desenho de Fármacos , Eritromicina/síntese química , Macrolídeos/síntese química , Estrutura MolecularRESUMO
A novel series of 6-O-substituted 8a-aza-8a-homoerythromycin A 3-O-acylides has been discovered with potent activity against key respiratory pathogens, including those inducibly and constitutively resistant to erythromycin. The best compounds in this series 15na and 15nd showed activity comparable to telithromycin, especially against Haemophilus influenzae and constitutively MLSB-resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes. Furthermore, 15na exhibited a number of drug-like attributes including favorable pharmacokinetic properties and in vivo efficacy. For instance, 15na exhibited good oral bioavailability (average F = 42%) and demonstrated in vivo efficacy superior to telithromycin (1) against erythromycin-susceptible S. pneumoniae. As such, 15na has a significant potential for further development of this novel macrolide antibiotics class.
Assuntos
Antibacterianos/química , Farmacorresistência Bacteriana/efeitos dos fármacos , Eritromicina/análogos & derivados , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Disponibilidade Biológica , Eritromicina/síntese química , Eritromicina/química , Eritromicina/farmacocinética , Eritromicina/farmacologia , Humanos , Macrolídeos/farmacologia , Macrolídeos/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Erythromycin B is structurally very similar to erythromycin A, and also shares its clinically important antibacterial activity. Its potential advantage is that it is much more stable to acid. Both compounds are susceptible to 6-9-enol ether formation, involving loss of a proton from C-8. The enol ethers lack antibacterial activity and can give rise to unpleasant gut motilide side-effects. Our previous work on degradation kinetics revealed that the formation of erythromycin B enol ether from erythromycin B is subject to a large deuterium isotope effect. We therefore synthesized 8-d-erythromycin B (in 87% yield) in the hope that acid-catalysed enol ether formation would be reduced, relative to erythromycin B. In a range of microbiological and biochemical assays, deuteriation did not appear to compromise the efficacy of the drug. Degradation studies showed, however, that incorporation of deuterium into erythromycin B reduces (though does not completely suppress) enol ether formation, providing the possibility of using a facile mono-deuteriation to reduce the gut motilide side-effects of the drug.
Assuntos
Álcoois/síntese química , Antibacterianos/química , Eritromicina/análogos & derivados , Éteres/síntese química , Álcoois/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Catálise , Eritromicina/síntese química , Eritromicina/química , Eritromicina/farmacologia , Éteres/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Concentração de Íons de Hidrogênio , Testes de Sensibilidade Microbiana , Conformação Molecular , OxirreduçãoRESUMO
Desmethyl erythronolides have emerged as macrolide targets that may prove effective against resistant bacteria. A five-step sequence to 4,10-didesmethyl (9S)-dihydroerythronolide A (1) from known cyclic bis[allene] 13 is reported. Key structural and mechanistic aspects of the synthesis are discussed along with catalytic allene osmylation. An improved route to 13 is also described.
Assuntos
Alcadienos/química , Antibacterianos/síntese química , Eritromicina/análogos & derivados , Catálise , Eritromicina/síntese química , Estrutura Molecular , EstereoisomerismoRESUMO
A series of novel 11-[3-[(arylcarbamoyl)oxy]propylamino]-11-deoxy-6-O-methyl-3-oxoerythromycin A 11-N,12-O-cyclic carbamate derivatives (6a-h) were designed, synthesized and evaluated for their antibacterial activities in vitro. Most of these compounds had significant antibacterial activity against two groups of pathogens of Methicillin-sensitive Staphylococcus aureus (MIC50=0.031-2 µg ml-1) except 6g and Methicillin-sensitive S. epidermidis (MIC50=0.031-0.5 µg ml-1). MIC90 of 6d against Methicillin-resistant S. epidermidis was at least 16-fold better than that of erythromycin (EMA), azithromycin (AZM) and ABT-773. 6d and 6e had more potent antibacterial activity against S. pneumoniae than EMA, AZM and ABT-773. In particular, compounds 6d and 6e also showed relatively potent activity against Haemophilus influenzae and Streptococcus hemolyticus.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Carbamatos/química , Carbamatos/farmacologia , Eritromicina/análogos & derivados , Azitromicina/farmacologia , Eritromicina/síntese química , Eritromicina/farmacologia , Haemophilus influenzae/efeitos dos fármacos , Cetolídeos/farmacologia , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacosRESUMO
A series of tridecaptin-antibiotic conjugates were synthesized and evaluated for in vitro and in vivo activity against Gram-negative bacteria. Covalently linking unacylated tridecaptin A1 (H-TriA1) to rifampicin, vancomycin, and erythromycin enhanced their activity in vitro but not by the same magnitude as coadministration of the peptide and these antibiotics. The antimicrobial activities of the conjugates were retained in vivo, with the H-TriA1-erythromycin conjugate proving a more effective treatment of Klebseilla pneumoniae infections in mice than erythromycin alone or in combination with H-TriA1.
Assuntos
Antibacterianos/síntese química , Eritromicina/análogos & derivados , Eritromicina/síntese química , Bactérias Gram-Negativas/efeitos dos fármacos , Peptídeos/síntese química , Rifampina/análogos & derivados , Rifampina/síntese química , Vancomicina/análogos & derivados , Vancomicina/síntese química , Acinetobacter baumannii/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Sinergismo Farmacológico , Eritromicina/farmacologia , Escherichia coli/efeitos dos fármacos , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Peptídeos/farmacologia , Rifampina/farmacologia , Vancomicina/farmacologiaRESUMO
Despite the longstanding importance of polyketide natural products in human medicine, nearly all commercial polyketide-based drugs are prepared through fermentation or semi-synthesis. The paucity of manufacturing routes involving de novo chemical synthesis reflects the inability of current methods to concisely address the preparation of these complex structures. Direct alcohol C-H bond functionalization via"C-C bond forming transfer hydrogenation" provides a powerful, new means of constructing type I polyketides that bypasses stoichiometric use of chiral auxiliaries, premetallated C-nucleophiles, and discrete alcohol-to-aldehyde redox reactions. Using this emergent technology, total syntheses of 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, and formal syntheses of rifamycin S and scytophycin C, were accomplished. These syntheses represent the most concise routes reported to any member of the respective natural product families.
Assuntos
Produtos Biológicos/síntese química , Policetídeos/síntese química , Produtos Biológicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Briostatinas/síntese química , Briostatinas/química , Catálise , Eritromicina/análogos & derivados , Eritromicina/síntese química , Eritromicina/química , Humanos , Hidrogenação , Macrolídeos/síntese química , Macrolídeos/química , Estrutura Molecular , Policetídeos/química , Rifamicinas/síntese química , Rifamicinas/química , EstereoisomerismoRESUMO
The 14-membered macrolide 6-deoxyerythronolide B is prepared in 14 steps (longest linear sequence) and 20 total steps. Two different methods for alcohol CH-crotylation via transfer hydrogenation are deployed for the first time in target-oriented synthesis. Enyne metathesis is used to form the 14-membered ring. The present approach represents the most concise construction of any erythronolide reported, to date.
Assuntos
Antibacterianos/síntese química , Eritromicina/análogos & derivados , Álcoois/síntese química , Álcoois/química , Catálise , Eritromicina/síntese química , HidrogenaçãoRESUMO
We report a series of new 9-oxime ether non-ketolides, including 3-hydroxyl, 3-O-acyl and 3-O-alkyl clarithromycin derivatives, and thiophene-containing ketolides 1b-1d. Unlike previously reported ketolide 1a, none of them is comparable to telithromycin. A molecular modeling study was performed to gain insight into the binding mode of alkylides 17-20 with bacterial rRNA and to rationalize the great disparity of their SAR. The 3-O-sidechains of 19 and 20 point to the so-called hydrophilic side of the macrolide ring, as seen in clarithromycin. In contrast, the 3-O-sidechains of 17 and 18 bend to the backside, the so-called hydrophobic side of the macrolide ring. The results clearly indicated the alkylides with improved antibacterial activity might possess a novel binding mode, which is different from clarithromycin and the alkylides with poor activity.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Eritromicina/análogos & derivados , Oximas/síntese química , Oximas/farmacologia , RNA Ribossômico/metabolismo , Antibacterianos/química , Claritromicina/química , Claritromicina/farmacologia , Eritromicina/síntese química , Éter/síntese química , Éter/química , Éter/farmacologia , Cetolídeos/síntese química , Cetolídeos/química , Cetolídeos/farmacologia , Modelos Moleculares , Oximas/química , RNA Bacteriano/metabolismoRESUMO
A novel series of 3-O-carbamoyl erythromycin A derived analogs, labeled carbamolides, with activity versus resistant bacterial isolates of staphylococci (including macrolide and oxazolidinone resistant strains) and streptococci are reported. An (R)-2-aryl substituent on a pyrrolidine carbamate appeared to be critical for achieving potency against resistant strains. Crystal structures showed a distinct aromatic interaction between the (R)-2-aryl (3-pyridyl for 4d) substituent on the pyrrolidine and G2484 (G2505, Escherichia coli) of the Deinococcus radiodurans 50S ribosome (3.2Å resolution).
Assuntos
Antibacterianos/química , Eritromicina/análogos & derivados , Compostos de Metilureia/química , Staphylococcus/isolamento & purificação , Streptococcus/isolamento & purificação , Antibacterianos/síntese química , Sítios de Ligação , Cristalografia por Raios X , Deinococcus/metabolismo , Farmacorresistência Bacteriana , Eritromicina/síntese química , Escherichia coli/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Terciária de Proteína , Pirrolidinas/química , Subunidades Ribossômicas Maiores de Bactérias/química , Subunidades Ribossômicas Maiores de Bactérias/metabolismo , Staphylococcus/efeitos dos fármacos , Streptococcus/efeitos dos fármacosRESUMO
Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the development of new macrolide derivatives with activities against resistant pathogens is urgently needed. A series of novel 6-O-(heteroaryl-isoxazolyl)propynyl 2-fluoro ketolides has been synthesized from erythromycin A. These compounds have shown very promising in vitro and in vivo antibacterial activities against key respiratory pathogens including erythromycin-susceptible/resistant strains.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Haemophilus influenzae/efeitos dos fármacos , Cetolídeos/química , Cetolídeos/farmacologia , Infecções Respiratórias/microbiologia , Staphylococcus/efeitos dos fármacos , Antibacterianos/síntese química , Cristalografia por Raios X , Farmacorresistência Bacteriana , Eritromicina/análogos & derivados , Eritromicina/síntese química , Eritromicina/farmacologia , Infecções por Haemophilus/tratamento farmacológico , Halogenação , Humanos , Cetolídeos/síntese química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Infecções Respiratórias/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológicoRESUMO
Malaria remains one of the most widespread human infectious diseases, and its eradication will largely depend on antimalarial drug discovery. Here, we present a novel approach to the development of the azalide class of antimalarials by describing the design, synthesis, and characterization of novel 2'-O-substituted-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A derivatives consisting of different quinoline moieties covalently liked to a 15-membered azalide scaffold at position 2'. By multistep straightforward synthesis, 19 new, stable, and soluble compounds were created and biologically profiled. Most active compounds from the 4-amino-7-chloroquinoline series showed high selectivity for P. falciparum parasites, and in vitro antimalarial activity improved 1000-fold over azithromycin. Antimalarial potency was equivalent to chloroquine against the sensitive strain (3D7A) and up to 48-fold enhanced over chloroquine against the chloroquine-resistant strain (W2). Concurrently, the antibacterial activity of the compounds was eliminated, thus facilitating the development of malaria-specific macrolide agents.
Assuntos
Antimaláricos/síntese química , Compostos Aza/síntese química , Eritromicina/análogos & derivados , Eritromicina/síntese química , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/síntese química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antimaláricos/farmacologia , Compostos Aza/farmacologia , Linhagem Celular Tumoral , Cloroquina/farmacologia , Resistência a Medicamentos , Eritromicina/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Quinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15-membered azalides with amide and amine functionalities via simple and inexpensive chemical procedures using easily available building blocks. These compounds exhibited marked advances over azithromycin in vitro in terms of potency against Plasmodium falciparum (over 100-fold) and high selectivity for the parasite and were characterized by moderate oral bioavailability in vivo. Two amines and one amide derivative showed improved in vivo potency in comparison to azithromycin when tested in a mouse efficacy model. Results obtained for compound 6u, including improved in vitro potency, good pharmacokinetic parameters, and in vivo efficacy higher than azithromycin and comparable to chloroquine, warrant its further development for malaria treatment and prophylaxis.
Assuntos
Aminoquinolinas/síntese química , Antimaláricos/síntese química , Eritromicina/análogos & derivados , Macrolídeos/síntese química , Amidas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Aminas/síntese química , Aminas/farmacocinética , Aminas/farmacologia , Aminoquinolinas/farmacocinética , Aminoquinolinas/farmacologia , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Azitromicina/farmacologia , Linhagem Celular Tumoral , Resistência a Medicamentos , Eritromicina/síntese química , Eritromicina/farmacocinética , Eritromicina/farmacologia , Humanos , Macrolídeos/farmacocinética , Macrolídeos/farmacologia , Malária/tratamento farmacológico , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Testes de Sensibilidade Parasitária , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
The complexity and low tractability of antibiotic macrolides pose serious challenges to addressing the problem of resistance through semi- or total synthesis. Here we describe a new strategy involving the preparation of a complex yet tractable macrocycle and the transformation of this macrocycle into a range of erythronolide congeners. These compounds represent valuable sectors of erythromycinoid structure space and constitute intermediates with the potential to provide further purchase in this space. The routes are short. The erythronolides were prepared in three or fewer steps from the macrocycle, which was prepared in a longest linear sequence of 11 steps.
Assuntos
Alcadienos/química , Eritromicina/síntese química , Eritromicina/análogos & derivados , Eritromicina/química , Conformação Molecular , EstereoisomerismoRESUMO
Herein, we report the design and synthesis of the novel 12-membered non-antibiotic macrolide (8R,9S)-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM900), which was found to be a potent anti-inflammatory and/or immunomodulatory agent, capable of promoting monocyte to macrophage differentiation. This molecule shows improved acid stability, does not exhibit any anti-bacterial activity and has relatively low cytotoxicity against THP-1 cells. In addition, one of its analogues, (8R,9S)-4â³,13-O-diacetyl-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM911), was found to be twice as effective as EM900.
Assuntos
Anti-Inflamatórios/síntese química , Desenho de Fármacos , Eritromicina/análogos & derivados , Eritromicina/química , Fatores Imunológicos/farmacologia , Imunomodulação/efeitos dos fármacos , Macrolídeos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Eritromicina/síntese química , Eritromicina/farmacologia , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Macrolídeos/síntese química , Macrolídeos/química , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura MolecularRESUMO
As a well-established class, macrolide antibiotics continue to enjoy a remarkable interest within pharmaceutical industry. Several stunning breakthroughs in semi-synthetic study of erythromycin A (EMA) contribute to the important role played by the macrolide class in search for new anti-infectious agents. Earlier structural modifications of EMA to address the issue of acid instability resulted in the first breakthrough in search for anti-infectious agents derived from EMA. Clarithromycin (CAM) and azithromycin (AZM) are two representative antibacterials commercialized during this period. Afterwards, continued research on the modifications of EMA to combat bacterial resistance culminated in the second breakthrough in this field. Telithromycin and cethromycin are two innovative antibacterials discovered in this period for treating community-acquired pneumonia (CAP). Recently, further structural modifications of EMA generate promising antibacterials endlessly, which will hopefully arouse another breakthrough in the near future. In this review, we will give an account of these breakthroughs and discuss the future directions of semi-synthetic research on EMA. In particular, the design and synthesis of some distinguished or promising antibacterials derived from EMA will be highlighted.
Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Descoberta de Drogas/métodos , Eritromicina/análogos & derivados , Eritromicina/farmacologia , Animais , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/síntese química , Bactérias/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Eritromicina/efeitos adversos , Eritromicina/síntese química , HumanosRESUMO
The intent of the study was to prepare and characterize crystalline form of 2'-O-{3-[(7-chloro-4-quinolinyl)amino]propyl}-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (1), a novel 15-membered azalide derivative with antimalarial activity. The crystalline material was prepared by crystallization from acetonitrile reproducible in high yield and purity. Single crystal X-ray studies, X-ray powder diffractometry, differential scanning calorimetry, thermogravimetric analysis, moisture adsorption, Karl Fischer titration, gas chromatography, scanning electron microscopy, optical microscopy, solubility, and solid-state and solution stability were conducted to investigate physicochemical properties of the existing crystalline form. Crystalline 1 is not hygroscopic, does not contain solvents, is physicochemically stable in solid state for up to 4 weeks, and is highly soluble at pH values below 6 and in biorelevant media (simulated gastric fluid, fed simulated intestinal fluid, and fasted simulated intestinal fluid). Solution stability studies (buffers and biorelevant media) indicated that this compound is stable in solutions at pH values 5-6, and that stability is influenced by pH and temperature.
Assuntos
Antimaláricos/química , Eritromicina/química , Adsorção , Antimaláricos/síntese química , Soluções Tampão , Varredura Diferencial de Calorimetria , Química Farmacêutica , Cromatografia Gasosa , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Estabilidade de Medicamentos , Eritromicina/análogos & derivados , Eritromicina/síntese química , Suco Gástrico/química , Concentração de Íons de Hidrogênio , Secreções Intestinais/química , Microscopia Eletrônica de Varredura , Estrutura Molecular , Difração de Pó , Solubilidade , Propriedades de Superfície , Tecnologia Farmacêutica/métodos , Termogravimetria , Temperatura de Transição , Água/químicaRESUMO
A series of derivatives of the amine of 9-dihydro-9-O-ethylamino-N-desmethyl-N-isopropyl erythromycin A derivatives were synthesized as motilin agonists. The compounds were developed for potency without showing antibacterial activity and inhibition of the hERG potassium channel. The formamide of the amide series was found to show the optimal combination of properties relative to carbamates, ureas, thioureas, and amines. This prompted an investigation of heterocyclic isosteres for the amide. In this series the triazole had the optimal combination of properties. From the study, two compounds met the criteria for detailed pharmacokinetic studies.