RESUMO
Constitutively erythromycin-resistant apathogens are more difficult to address than inducibly resistant and efflux-resistant strains. Three series of the 4th generation 2-fluoro 9-oxime erythromycin ketolides were synthesized and evaluated. Incorporation of substituted heteroaryl groups (a - m), in contrast to previously reported the unsubstituted heteroaryl groups, proved to the beneficial for enhancement of the activities of the 9-propgargyl ketolide 8 series and the 9-allyl ketolide 14 series. But these aryl groups (a - m) cannot supply the resulting compounds 8 and 14, unlike corresponding the 6-allyl ketolide 20 series, with activity against constitutively resistant Streptococcus pneumoniae. However, hybrids of macrolides and quinolones (8, 14 and 20, Arâ¯=â¯n - t) exhibited not only high activities against susceptible, inducibly erm-mediated resistant, and efflux-mediated resistant strains, but also significantly improved potencies against constitutively resistant Streptococcus pneumoniae and Streptococcus pyogenes. The capacity was highlighted by introduction of newly designed carbamoyl quinolones (q, r, s and t) rather than commonly seen carboxy quinolones (o and p) as the pharmacophores. Structure-activity relationships and molecular modelling indicated that 8r, 14r and 20q may have different binding sites compared to current erythromycins. Moreover, 8r, 14r and 20q have 2.5-3.6 times prolonged half-life and 2.3- to 2.6-fold longer mean residence time in vivo over telithromycin. These findings pave the way for rational design of novel non-telithromycin macrolides that target new binding sites within bacterial ribosomes.
Assuntos
Antibacterianos/farmacologia , Cetolídeos/farmacologia , Oximas/farmacologia , Quinolonas/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Cetolídeos/síntese química , Cetolídeos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oximas/síntese química , Oximas/química , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-AtividadeRESUMO
A series of quinoylalkyl side chains was designed and synthesized, followed by introduction into ketolides by coupling with building block 6 or 32. The corresponding targets 7a-n, 33b, and 33e were tested for their in vitro activities against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed a similar antibacterial spectrum and comparable activity to telithromycin. Among them, two C2-F ketolides, compounds 33b and 33e, displayed excellent activities against macrolide-sensitive and macrolide-resistant pathogens.
Assuntos
Antibacterianos/farmacologia , Haemophilus influenzae/efeitos dos fármacos , Cetolídeos/farmacologia , Quinolinas/farmacologia , Staphylococcus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Azitromicina/farmacologia , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana , Cetolídeos/síntese química , Cetolídeos/química , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
Chemoselective substitutions in the C10-methyl group of erythromycin A ketolides is reported. The C10-methyl group in the clarithromycin derived substrate 10,11-anhydro-O6-methyl-descladinosylerythromycin was activated by conversion into an allyl acetate and thereafter to the corresponding allylic cyanide. Both the allylic acetate and the cyanide reacted with carbonyldiimidazole and ammonia to afford a C11,C12-cyclic carbamate with concurrent elimination of the allylic function to yield a methylene α,ß-unsaturated ketone. Conjugate addition with amines resulted in stereoselective C-N bond formation between the terminal methylene carbon and the amino nitrogen. Carbylation in the methylene group was effected under Stille conditions for cross-coupling with Pd-catalysis. With anion stabilized nucleophiles, such as a sodium salt of a malonate, stereoselectivity was observed in the formation of the 10-substituent. Stereoselective cycloaddition with trimethylsilyldiazomethane afforded a spirane where the C10 carbon of the macrolide skeleton had become a quaternary spirocarbon. Antibacterial in vitro data for a selected group of compounds against strains of respiratory pathogens S. pneumoniae and S. aureus are reported. Most of the compounds tested showed improved activities over CLA as a reference compound against efflux resistant S. pneumoniae as well as against efflux and inducibly resistant strains of S. aureus.
Assuntos
Antibacterianos/síntese química , Claritromicina/síntese química , Cetolídeos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Claritromicina/química , Claritromicina/farmacologia , Cetolídeos/química , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Erythromycin was long viewed as a bacteriostatic agent. The erythromycin derivatives, 9-oxime ketolides have a species-specific bactericidal profile. Among them, the 3'-allyl version of the 9-oxime ketolide 1 (Ar=3-quinolyl; 17a) is bactericidal against Streptococcus pneumoniae and Streptococcus pyogenes. In contrast, the 2-fluoro analogs of 1, 13a (Ar=6-quinolyl), 13b (Ar=3-quinolyl) and 24a (Ar=4-isoquinolyl), show bactericidal activities against S. pneumoniae, Staphylococcus aureus and Moraxella catarrhalis, while the 2-fluoro analogs 13c (Ar=3-aminopyridyl) and 24b (Ar=3-carbamoylpyridyl) are only bactericidal against S. pneumoniae and Haemophilus influenzae. Reduction of the ketolides led to novel epiacylides, the 3-O-epimers of the acylides. Alteration of linker length (30b vs. 30a), 2-fluorination (33 vs. 30a) and incorporation of additional spacers at the 9-oxime or 6-OH (35, 40 vs. 30a) did not restore the epiacylides back to be as active as the acylide 31. Molecular docking suggested that epimerization at the 3-position reshapes the orientation of the 3-O-sidechain and leads to considerably weaker binding with bacterial ribosomes.
Assuntos
Antibacterianos/farmacologia , Cetolídeos/farmacologia , Oximas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Cetolídeos/síntese química , Cetolídeos/química , Simulação de Acoplamento Molecular , Oximas/síntese química , Oximas/química , Ribossomos/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Descoberta de Drogas/métodos , Macrolídeos/síntese química , Macrolídeos/farmacologia , Amino Açúcares/síntese química , Amino Açúcares/química , Amino Açúcares/farmacologia , Antibacterianos/química , Bactérias/efeitos dos fármacos , Humanos , Cetolídeos/síntese química , Cetolídeos/química , Macrolídeos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologiaRESUMO
Without quantum theory any understanding of molecular interactions is incomplete. In principal, chemistry, and even biology, can be fully derived from non-relativistic quantum mechanics. In practice, conventional quantum chemical calculations are computationally too intensive and time consuming to be useful for drug discovery on more than a limited basis. A previously described, original, quantum-based computational process for drug discovery and design bridges this gap between theory and practice, and allows the application of quantum methods to large-scale in silico identification of active compounds. Here, we show the results of this quantum-similarity approach applied to the discovery of novel liver-stage antimalarials. Testing of only five of the model-predicted compounds in vitro and in vivo hepatic stage drug inhibition assays with P. berghei identified four novel chemical structures representing three separate quantum classes of liver-stage antimalarials. All four compounds inhibited liver-stage Plasmodium as a single oral dose in the quantitative PCR mouse liver-stage sporozoites-challenge model. One of the newly identified compounds, cethromycin [ABT-773], a macrolide-quinoline hybrid, is a drug with an extensive (over 5,000 people) safety profile warranting its exploitation as a new weapon for the current effort of malaria eradication. The results of our molecular modeling exceed current state-of-the-art computational methods. Drug discovery through quantum similarity is data-driven, agnostic to any particular target or disease process that can evaluate multiple phenotypic, target-specific, or co-crystal structural data. This allows the incorporation of additional pharmacological requirements, as well as rapid exploration of novel chemical spaces for therapeutic applications.
Assuntos
Antimaláricos/administração & dosagem , Antimaláricos/síntese química , Biologia Computacional/métodos , Reposicionamento de Medicamentos/métodos , Malária/tratamento farmacológico , Administração Oral , Animais , Antimaláricos/química , Cetolídeos/administração & dosagem , Cetolídeos/síntese química , Cetolídeos/química , Malária/parasitologia , Camundongos , Plasmodium berghei/efeitos dos fármacos , Teoria Quântica , Relação Estrutura-AtividadeRESUMO
We present here the novel ketolide RBx 14255, a semisynthetic macrolide derivative obtained by the derivatization of clarithromycin, for its in vitro and in vivo activities against sensitive and macrolide-resistant Streptococcus pneumoniae. RBx 14255 showed excellent in vitro activity against macrolide-resistant S. pneumoniae, including an in-house-generated telithromycin-resistant strain (S. pneumoniae 3390 NDDR). RBx 14255 also showed potent protein synthesis inhibition against telithromycin-resistant S. pneumoniae 3390 NDDR. The binding affinity of RBx 14255 toward ribosomes was found to be more than that for other tested drugs. The in vivo efficacy of RBx 14255 was determined in murine pulmonary infection induced by intranasal inoculation of S. pneumoniae ATCC 6303 and systemic infection with S. pneumoniae 3390 NDDR strains. The 50% effective dose (ED50) of RBx 14255 against S. pneumoniae ATCC 6303 in a murine pulmonary infection model was 3.12 mg/kg of body weight. In addition, RBx 14255 resulted in 100% survival of mice with systemic infection caused by macrolide-resistant S. pneumoniae 3390 NDDR at 100 mg/kg four times daily (QID) and at 50 mg/kg QID. RBx 14255 showed favorable pharmacokinetic properties that were comparable to those of telithromycin.
Assuntos
Antibacterianos/farmacologia , Cetolídeos/farmacologia , Pneumonia Bacteriana/tratamento farmacológico , Inibidores da Síntese de Proteínas/farmacologia , Sepse/tratamento farmacológico , Streptococcus pneumoniae/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Farmacorresistência Bacteriana , Cetolídeos/síntese química , Cetolídeos/farmacocinética , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/mortalidade , Pneumonia Bacteriana/patologia , Inibidores da Síntese de Proteínas/síntese química , Inibidores da Síntese de Proteínas/farmacocinética , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo , Sepse/microbiologia , Sepse/mortalidade , Sepse/patologia , Streptococcus pneumoniae/patogenicidade , Streptococcus pneumoniae/fisiologia , Análise de SobrevidaRESUMO
A practicable method of introducing a side chain to the C-4' position of 5-O-desosamine in the 14-membered ketolides was developed. And using this method, a series of novel modified 5-O-mycaminose ketolides were synthesized. These ketolides containing 5-O-4'-carbamate mycaminose were evaluated for their in vitro antibacterial activities against some respiratory pathogens. 15b and 18e showed comparable activity to telithromycin and clarithromycin.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Cetolídeos/química , Cetolídeos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Antibacterianos/química , Relação Dose-Resposta a Droga , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Cetolídeos/síntese química , Meticilina/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A novel series of 10-hydroxyl ketolide derivatives were synthesized, during which a distinctive intermediate, 3-O-descladinosyl-3-oxo-11-deoxy-10,11-epoxy-6-O-methylerythromycin A, was obtained from 6-O-methylerythromycin A. The structure and stereochemistry of this novel structure were confirmed via NMR and X-ray crystallography. Moreover, antibacterial evaluations were established in order to assess our modifications and acquire a deep understanding of the ketolides' structure-activity relationship (SAR).
Assuntos
Antibacterianos/síntese química , Cetolídeos/química , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Sítios de Ligação , Claritromicina/química , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Cetolídeos/síntese química , Cetolídeos/farmacologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Conformação Molecular , Simulação de Acoplamento Molecular , Peptidil Transferases/química , Peptidil Transferases/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
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 series of 9-O-(3-aryl-2-propargyl)oxime ketolides 8 was synthesized and evaluated for in vitro antibacterial activity. Among 8, 8b-8d, and 8h-8l displayed dramatically improved potency against inducibly MLS(B)-resistant and efflux-resistant pathogens as compared to clarithromycin and azithromycin. Especially, 8i (Ar=4-isoquinolyl) possessed an MIC of 0.064 µg/mL against constitutively MLS(B)-resistant Streptococcus pneumoniae, and MICs of 0.032-0.064 µg/mL against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus hominis. The analog 10 with a propyl linker was less effective than both the corresponding 8 and 9 containing propynyl and propenyl linkers. A docking study was performed to gain insight into the binding mode of series 8 and 9 and to rationalize the disparity found in the SAR of 8 and 9.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Cetolídeos/síntese química , Cetolídeos/farmacologia , Antibacterianos/química , Carbonatos/síntese química , Carbonatos/química , Carbonatos/farmacologia , Ciclização , Cetolídeos/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Simulação de Acoplamento MolecularRESUMO
A series of novel modified 5-O-desosamine-ketolides were synthesized. The 5-O-desosamine fragment was removed from ketolide by an efficient and mild manipulation. 4-O-substituted desosamine was introduced into the ketolide aglycon and various coupling methods were essayed for the glycosylation. Three novel ketolides were tested for in vitro antibacterial activity against a panel of susceptible and resistant pathogens. Compound 26 showed potent activity against all the methicillin-sensitivity and resistant pathogens.
Assuntos
Antibacterianos/farmacologia , Cetolídeos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Fagos de Streptococcus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Cetolídeos/síntese química , Cetolídeos/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
The MIC(90) of RBx 14255, a novel ketolide, against Clostridium difficile was 4 µg/ml (MIC range, 0.125 to 8 µg/ml), and this drug was found to be more potent than comparator drugs. An in vitro time-kill kinetics study of RBx 14255 showed time-dependent bacterial killing for C. difficile. Furthermore, in the hamster model of C. difficile infection, RBx 14255 demonstrated greater efficacy than metronidazole and vancomycin, making it a promising candidate for C. difficile treatment.
Assuntos
Antibacterianos/farmacologia , Clostridioides difficile/efeitos dos fármacos , Enterocolite Pseudomembranosa/tratamento farmacológico , Cetolídeos/farmacologia , Animais , Antibacterianos/síntese química , Clostridioides difficile/crescimento & desenvolvimento , Cricetinae , Farmacorresistência Bacteriana/efeitos dos fármacos , Enterocolite Pseudomembranosa/microbiologia , Enterocolite Pseudomembranosa/mortalidade , Humanos , Cetolídeos/síntese química , Metronidazol/farmacologia , Testes de Sensibilidade Microbiana , Taxa de Sobrevida , Vancomicina/farmacologiaRESUMO
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
Novel sources of antibiotics are required to address the serious problem of antibiotic resistance. Telithromycin (2) is a third-generation macrolide antibiotic prepared from erythromycin (1) and used clinically since 2004. Herein we report the details of our efforts that ultimately led to the total synthesis of (-)-4,8,10-tridesmethyl telithromycin (3) wherein methyl groups have been replaced with hydrogens. The synthesis of desmethyl macrolides has emerged as a novel strategy for preparing bioactive antibiotics.
Assuntos
Antibacterianos/síntese química , Cetolídeos/síntese química , Antibacterianos/farmacologia , Cetolídeos/farmacologia , Espectroscopia de Ressonância MagnéticaRESUMO
A set of 17 novel ketolides bearing an aryltetrazolyl-substituted alkyl side chain were synthesized and evaluated for their antibacterial activities, which the aryltetrazolyl group was selected to replace the hetero-aryl moiety of the side chain in telithromycin for designing new compounds. The synthesis of aryltetrazolyl alkylamines was reported in detail. The antibacterial activities of new ketolides were evaluated against a number of pathogens including macrolide-resistant organisms by using telithromycin as the reference. Many of the evaluated compounds exhibited remarkable activities against both erythromycin-susceptible and erythromycin-resistant organisms such as Staphylococcus aureus (except S. aureus AD-08), Pseudomonas aeruginosa and Escherichia coli. Among these, the compound 11e exhibited excellent antibacterial potency against all the strains in comparison with others.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Cetolídeos/química , Cetolídeos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Cetolídeos/síntese química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura MolecularRESUMO
A novel series of ketolides with 11,12-sulfur contained aryl alkyl side chains were synthesized and evaluated for their antibacterial activity. These ketolides exhibited potent activity against key macrolide sensitive and resistant respiratory pathogens. The newly synthesized 9a, 9e, 9k and 9n showed a similar antimicrobial spectrum and comparable activity to telithromycin, the commercial ketolide antibacterial.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Cetolídeos/química , Cetolídeos/farmacologia , Enxofre/química , Antibacterianos/síntese química , Cetolídeos/síntese química , Testes de Sensibilidade MicrobianaRESUMO
A series of novel 6-O-substituted and 6,12-di-O-substituted 8a-aza-8a-homoerythromycin A and 9a-aza-9a-homoerythromycin A ketolides were synthesized and evaluated for in vitro antibacterial activity against a panel of representative erythromycin-susceptible and erythromycin-resistant test strains. Another series of ketolides based on 14-membered erythromycin oxime scaffold was also synthesized and their antibacterial activity compared to those of 15-membered azahomoerythromycin analogues. In general, structure-activity studies have shown that 14-membered ketolides displayed favorable antibacterial activity in comparison to their corresponding 15-membered analogues within 9a-azahomoerythromycin series. However, within 8a-azahomoerythromycin series, some compounds incorporating a ketolide combined with either quinoline or quinolone pharmacophore substructures showed significantly potent activity against a variety of erythromycin-susceptible and macrolide-lincosamide-streptogramin B (MLS(B))-resistant Gram-positive pathogens as well as fastidious Gram-negative pathogens. The best compounds in this series overcome all types of resistance in relevant clinical Gram-positive pathogens and display hitherto unprecedented in vitro activity against the constitutively MLS(B)-resistant strain of Staphylococcus aureus. In addition, they also represent an improvement over telithromycin (2) and cethromycin (3) against fastidious Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis.
Assuntos
Antibacterianos/química , Farmacorresistência Bacteriana , Eritromicina/análogos & derivados , Cetolídeos/química , Quinolonas/química , Antibacterianos/farmacologia , Resistência a Múltiplos Medicamentos , Haemophilus influenzae/efeitos dos fármacos , Cetolídeos/síntese química , Cetolídeos/farmacologia , Testes de Sensibilidade Microbiana , Moraxella catarrhalis/efeitos dos fármacos , Quinolonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of C-12 pyrazolinyl spiro ketolide derivatives were designed and synthesized. The C-12 modifications involved replacing the natural C-12 methyl group in clarithromycin core with different pyrazolinyl spiros via chemical synthesis. Potential anti-bacterial activities against both erythromycin-susceptible and erythromycin-resistant bacteria were reported.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Cetolídeos/farmacologia , Pirazóis/farmacologia , Compostos de Espiro/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Haemophilus influenzae/efeitos dos fármacos , Cetolídeos/síntese química , Cetolídeos/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Pirazóis/síntese química , Pirazóis/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Staphylococcus/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of novel 6-O-substituted 8a-aza-8a-homoerythromycin A ketolides was synthesized and evaluated for in vitro antibacterial activity. Key strategic elements of the synthesis include the base-induced E-Z isomerization of 3-O-descladinosyl-6-O-allylerythromycin A 9(E)-oxime followed by ring-expanding reaction of the resulting 9(Z)-oxime via Beckmann rearrangement. The ketolides showed potent activity against a variety of erythromycin-susceptible and macrolide-lincosamide-streptogramin B (MLS(B)) resistant Gram-positive and fastidious Gram-negative pathogens. The best compounds in this series overcome all types of resistance in relevant clinical Gram-positive pathogens and display in vitro activity comparable to telithromycin and cethromycin.