RESUMEN
We report here on the structure-activity relationships of hybrids combining 3-descladinosyl clarithromycin with quinolones linked by extended diamine connectors. Several hybrids, exemplified by 23Bc, 23Be, 23Bf, 26Be, and 30Bc, not only restored potency against inducibly resistant pathogens but also exhibited significantly enhanced activities against constitutively resistant strains of Staphylococcus pneumoniae and Staphylococcus pyogenes, which express high-level resistance independent of clarithromycin or erythromycin induction. Additionally, the novel hybrids showed susceptibility against Gram-negative Haemophilus influenzae. Notably, hybrid 23Be demonstrated dual modes of action by inhibiting both protein synthesis and DNA replication in vitro and in vivo. Given these promising characteristics, 23Be emerges as a potential candidate for the treatment of community-acquired bacterial pneumonia.
Asunto(s)
Antibacterianos , Claritromicina , Diseño de Fármacos , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Claritromicina/farmacología , Claritromicina/química , Claritromicina/síntesis química , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Estructura Molecular , Diaminas/química , Diaminas/farmacología , Diaminas/síntesis química , Haemophilus influenzae/efectos de los fármacos , Oximas/química , Oximas/farmacología , Oximas/síntesis química , Relación Dosis-Respuesta a Droga , Humanos , Animales , Streptococcus pyogenes/efectos de los fármacos , Farmacorresistencia Bacteriana/efectos de los fármacosRESUMEN
A novel series of 3-O-descladinosyl-3-keto-clarithromycin derivatives, including 11-O-carbamoyl-3-O-descladinosyl-3-keto-clarithromycin derivatives and 2',9(S)-diaryl-3-O-descladinosyl-3-keto-clarithromycin derivatives, were designed, synthesized and evaluated for their in vitro antibacterial activity. Among them, some derivatives were found to have activity against resistant bacteria strains. In particular, compound 9b showed not only the most significantly improved activity (16 µg/mL) against S. aureus ATCC43300 and S. aureus ATCC31007, which was >16-fold more active than that of CAM and AZM, but also the best activity against S. pneumoniae B1 and S. pyogenes R1, with MIC values of 32 and 32 µg/mL. In addition, compounds 9a, 9c, 9d and 9g exhibited the most effective activity against S. pneumoniae AB11 with MIC values of 32 or 64 µg/mL as well. Unfortunately, 2',9(S)-diaryl-3-O-descladinosyl-3-keto-clarithromycin derivatives failed to exhibit better antibacterial activity than references. It can be seen that the combined modification of the C-3 and C-11 positions of clarithromycin is beneficial to improve activity against resistant bacteria, while the single modification of the C-2'' position is very detrimental to antibacterial activity.
Asunto(s)
Antibacterianos/farmacología , Claritromicina/farmacología , Staphylococcus/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Claritromicina/síntesis química , Claritromicina/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Bacterial infections are still the main significant problem of public health in the world, and their elimination will greatly rely on the discovery of antibacterial drugs. In the processes of our searching for novel macrolide derivatives with excellent activity against sensitive and resistant bacteria, three series of novel N11-, C12- and C13-substituted 15-membered homo-aza-clarithromycin derivatives were designed and synthesized as Series A, B and C by creatively opening the lactone ring of clarithromycin (CAM), introducing various 4-substituted phenyl-1H-1,2,3-triazole side chains at the N11, C12 or C13 position of CAM and macrolactonization. The results from their in vitro antibacterial activity demonstrated that compounds 20c, 20d and 20f displayed not only the most potent activity against S. aureus ATCC25923 with the MIC values of 0.5, 0.5 and 0.5 µg/mL, but also greatly improved activity against B. subtilis ATCC9372 with the MIC values of less than or equal to 0.25, 0.25 and 0.25 µg/mL, respectively. In particular, compound 11g exhibited the strongest antibacterial effectiveness against all the tested resistant bacterial strains and had well balanced activity with the MIC values of 4-8 µg/mL. Further study on minimum bactericidal concentration and kinetics confirmed that compound 11g possessed a bacteriostatic effect on bacterial proliferation. Moreover, the results of molecular docking revealed an potential additional binding force between compound 11g and U790 in addition to the normal binding force of macrolide skeleton, which may explain why this compound performed the most potent activity against resistant bacteria. The results of cytotoxic assay indicated that compounds 20c, 20d and 20f were non-toxic to human breast cancer MCF-7 cells at its effective antibacterial concentration.
Asunto(s)
Antibacterianos/farmacología , Compuestos Aza/farmacología , Bacillus subtilis/efectos de los fármacos , Claritromicina/farmacología , Diseño de Fármacos , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Compuestos Aza/síntesis química , Compuestos Aza/química , Claritromicina/síntesis química , Claritromicina/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Macrolides are widely prescribed in clinic to treat various respiratory tract infections. However, due to their inappropriate use, the prevalence of macrolide-resistant strains among clinical isolates has become a concern for public health. Therefore, novel macrolides skeleton structures against resistant pathogens are badly needed. Thus, three series of novel 15-membered 11a-azahomoclarithromycin derivatives (series A-C) with the 1, 2, 3-triazole side chain were designed and synthesized through creatively opening the ring of clarithromycin (CAM), expanding the ring properly and introducing a suitable side chain of 1, 2, 3-triazole at the C12 and C13 positions, and evaluated for their antibacterial activity. The antibacterial results indicated that compounds 38b, 38l and 38v possessed strong antibacterial activity against Staphylococcus aureus ATCC25923 (0.25⯵g/mL) and Bacillus subtilis ATCC9372 (0.25⯵g/mL). Furthermore, compounds 9e and 38g were found to exhibit promising potent activity (8⯵g/mL) against Streptococcus pneumonia AB11 expressing the ermB and mefA genes. In addition, the determination of minimum bactericidal concentration (MBC) indicated that the most promising compounds 38b, 38l, 38v, 9e and 38g were excellent bacteriostatic agents. The bactericidal curve showed that 9e exhibited antibacterial activity through bacteriostatic mechanism. Finally, 38b, 38l and 38v were confirmed to be non-toxic to MCF-7 breast cancer cells up to a concentration of 32⯵g/mL in preliminary cytotoxicity assay. In summary, 38b, 38l, 38v, 9e and 38g can be served as lead compounds to provide a new perspective for further structural optimization.
Asunto(s)
Antibacterianos/farmacología , Compuestos Aza/farmacología , Claritromicina/farmacología , Diseño de Fármacos , Triazoles/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Compuestos Aza/síntesis química , Compuestos Aza/química , Bacillus subtilis/efectos de los fármacos , Claritromicina/síntesis química , Claritromicina/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/genética , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
In general, potent non-ketolide versions of erythromycin possessed conformationally constricted two- or three-atom-length sidechains at 3-OH. Novel 14-membered non-ketolides possessing long spacers beyond three-atom length were evaluated for antibacterial activity. The most potent one is 34a, featuring a five-atom-length flexible linker from of a pyridine ring to the aglycone. Conversion of the pyridine of 34a to other aryl groups, changing the linker's length of 34a to longer or shorter ones, and variation of the linker flexibility to a rigid olefin or alkyne led to decreased antibacterial activity. The hybrids of macrolides and quinolones 28b, 31 and 34b possessing various sidechains, unlike their 15-membered counterparts, were ineffective compared to 34a. Similar to the marketed ketolide telithromycin, the non-ketolide 34a proved to be a time-dependent bactericidal agent, but it exhibited superior in vivo pharmacokinetic properties such as longer half-life, higher plasma concentration, lower clearance and shorter time to reach the highest drug concentration relative to telithromycin. Molecular docking suggested 34a might π - π interact with the bacterial ribosomal RNA base G2505Ec. This study suggested that the bacteriostatic agent erythromycin can be structurally modified to afford a new bactericidal chemotype that targets the ribosome and is superior to ciprofloxacin with regard to its minimum bactericidal concentration.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Claritromicina/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Claritromicina/síntesis química , Claritromicina/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of novel 4â³-O-desosaminyl clarithromycin derivatives with 11, 12-arylalkyl side chains was synthesized by coupling 6-deoxy-desosamine donors (18, 19) with 4â³-OH of compounds 5a-c. The activities of the target compounds were tested against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed activities against macrolide sensitive and resistant pathogens, and compounds 21d and 21e displayed significant improvement of activities against resistant pathogens.
Asunto(s)
Amino Azúcares/química , Antibacterianos/síntesis química , Claritromicina/análogos & derivados , Claritromicina/síntesis química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Claritromicina/farmacología , Farmacorresistencia Bacteriana , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A novel series of 3-O-arylalkylcarbamoyl-3-O-descladinosyl-9-O-(2-chlorobenzyl)oxime clarithromycin derivatives, were designed, synthesized and evaluated for their in vitro antibacterial activity. These derivatives were found to have strong activity against susceptible and resistant bacteria strains. Among them, compounds 7a and 7q showed the most potent activity (0.125⯵g/mL) against erythromycin-resistant S. pneumoniae expressing the mefA gene. Moreover, compounds 7f, 7i, 7p and 7z displayed remarkably improved activity (4⯵g/mL) against penicillin-resistant S. aureus ATCC31007, and compounds 7a, 7b, 7f, 7p and 7z showed improved activity (8⯵g/mL) against erythromycin-resistant S. pyogenes. In particular, compound 7z exhibited potent and balanced activity against the tested drug-susceptible and -resistant bacterial strains.
Asunto(s)
Antibacterianos/farmacología , Claritromicina/farmacología , Oximas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Bacillus subtilis/efectos de los fármacos , Claritromicina/síntesis química , Claritromicina/química , Diseño de Fármacos , Escherichia coli/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Oximas/síntesis química , Oximas/química , Pseudomonas aeruginosa/efectos de los fármacos , Ribosomas/química , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pyogenes/efectos de los fármacosRESUMEN
A series of novel 11-O-carbamoyl clarithromycin ketolides were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed improved activity compared with references against erythromycin-resistant S. pneumoniae A22072 expressing the mef gene, S. pneumoniae B1 expressing the erm gene and S. pneumoniae AB11 expressing the mef and erm genes. In particular, compounds 9, 18, 19 and 22 showed the most potent activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of 0.5µg/mL. Furthermore, compounds 11, 18, 19, 24 and 29 were also found to exhibit favorable antibacterial activity against erythromycin-susceptible S. pyogenes with the MIC values of 0.125-1µg/mL, and moderate activity against erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372.
Asunto(s)
Antibacterianos/síntesis química , Claritromicina/síntesis química , Cetólidos/química , Antibacterianos/química , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Claritromicina/análogos & derivados , Claritromicina/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Eritromicina/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismo , Pruebas de Sensibilidad Microbiana , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pyogenes/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antibacterianos/síntesis química , Claritromicina/síntesis química , Cetólidos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Espectroscopía de Resonancia Magnética con Carbono-13 , Claritromicina/química , Claritromicina/farmacología , Cetólidos/química , Pruebas de Sensibilidad Microbiana , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Masa por Ionización de Electrospray , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The gastroduodenal diseases caused by Helicobacter pylori were commonly treated with antibiotic clarithromycin as a standard regimen. According to the poorly water-soluble of clarithromycin, the nanocrystal formulation was prepared. The aim of this study was to investigate an enhancement effect of clarithromycin nanocrystals produced by precipitation-lyophilization-homogenization (PLH) method on the saturation solubility, dissolution velocity, antibiotic activity, permeability through the gastric mucus and cellular permeability. Poloxamer 407 and sodium lauryl sulfate (SLS) were chosen as combined stabilizers in the nanocrystal system. The obtained clarithromycin nanocrystals were identified as cubic particles by SEM with a bulk population of approximately 400nm existed in crystalline and/or partial amorphous form as investigated by DSC and XRPD. The saturation solubility of the clarithromycin nanocrystals was increased by 1.5- and 6-folds higher than clarithromycin powder in buffer pH 5.0 and 6.8, respectively. The dissolution profiles of clarithromycin nanocrystals at pH 5.0 and 6.8 were significantly different from clarithromycin powder and the marketed product (f1 value >15 and f2 value <50). All dissolution parameters (relative dissolution rate, percent dissolution efficiency and mean dissolution time) showed that clarithromycin nanocrystals had higher dissolution rate when compared with the clarithromycin powder, the lyophilized coarse suspension and the marketed product. The bioassay study by diffusion agar method showed a maintained antibiotic activity of clarithromycin nanocrystals solubilized in buffer solution which was greater potency than the lyophilized coarse suspension and the clarithromycin powder. Additionally, the nanocrystals possessed higher permeability through gastric mucus and cellular monolayer of Caco-2 and NCI-N87 cells as compared to the lyophilized coarse suspension and the clarithromycin powder. The results indicated that, the developed clarithromycin nanocrystals were a potential delivery system that exerts more effectiveness in H. pylori eradication.
Asunto(s)
Antibacterianos/síntesis química , Precipitación Química , Química Farmacéutica/métodos , Claritromicina/síntesis química , Nanopartículas/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Claritromicina/metabolismo , Claritromicina/farmacología , Relación Dosis-Respuesta a Droga , Liofilización/métodos , Humanos , Nanopartículas/metabolismo , SolubilidadRESUMEN
A series of new 4â³-O-desosaminyl clarithromycin derivatives were designed and synthesized. The efficient synthesis routes of 6-deoxy-desosamine donors 8 and 11 were developed and the methodology of glycosylation of clarithromycin 4â³-OH with desosamine was studied. The activities of the target compounds were tested against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed activities against macrolide sensitive pathogens, and compounds 19 and 22 displayed significant improvement of activities against sensitive pathogens and two strains of MRSE, which verified the importance of desosamine in the interaction of macrolide and its receptor, and offered valuable information of the SAR of macrolide 4â³-OH derivatives.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Claritromicina/análogos & derivados , Claritromicina/síntesis química , Claritromicina/farmacología , Glicosilación , Macrólidos/síntesis química , Macrólidos/farmacología , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
Novel 4â³-O-benzimidazolyl clarithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activities. These benzimidazolyl derivatives exhibited excellent activity against erythromycin-susceptible strains better than the references, and some of them showed greatly improved activity against erythromycin-resistant strains. Compounds 16 and 17, which have the terminal 2-(4-methylphenyl)benzimidazolyl and 2-(2-methoxyphenyl)benzimidazolyl groups on the C-4â³ bishydrazide side chains, were the most active against erythromycin-resistant Staphylococcus pneumoniae expressing the erm gene and the mef gene. In addition, compound 17 exhibited the highest activity against erythromycin-susceptible S. pneumoniae ATCC49619 and Staphylococcus aureus ATCC25923 as well. It is worth noting that the 4â³-O-(2-aryl)benzimidazolyl derivatives show higher activity against erythromycin-susceptible and erythromycin-resistant strains than the 4â³-O-(2-alkyl)benzimidazolyl derivatives.
Asunto(s)
Antibacterianos/síntesis química , Bencimidazoles/síntesis química , Claritromicina/síntesis química , Hidrazinas/química , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Bencimidazoles/farmacología , Claritromicina/análogos & derivados , Claritromicina/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , Eritromicina/farmacología , Expresión Génica , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismo , Staphylococcus aureus/genética , Staphylococcus aureus/crecimiento & desarrollo , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/crecimiento & desarrollo , Relación Estructura-ActividadRESUMEN
Novel clarithromycin derivatives with C-4â³ elongated arylalkyl groups were designed, synthesized and evaluated to probe the effect of different lengths of their C-4â³ side chains on the activity against resistant bacterial strains. These derivatives had excellent activity against erythromycin-susceptible Streptococcus pneumoniae, Streptococcus aureus or Streptococcus pyogenes and some of them exhibited greatly improved activity against erythromycin-resistant strains. Compounds 18 and 16, which had the C-4â³ elongated arylalkyl groups with eight atoms from the 4â³-oxygen atom to the terminal benzene ring, were the most effective against S. pneumoniae expressing the erm gene and the erm and mef genes. In contrast, the most potent compounds 3, 5, 9, 17 and 18 against S. pneumoniae expressing the mef gene had C-4â³ elongated arylalkyl groups with three to eight atoms between the 4â³-oxygen atom and the terminal aromatic ring.
Asunto(s)
Antibacterianos/farmacología , Claritromicina/farmacología , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pyogenes/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Claritromicina/síntesis química , Claritromicina/química , Diseño de Fármacos , Farmacorresistencia Bacteriana , Macrólidos/farmacología , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel series of acylides, 3-O-carbamoyl derivatives of 6,11-di-O-methylerythromycin A, were synthesized and evaluated for their antibacterial activity. These compounds have significant antibacterial activity against gram-positive pathogens, including erythromycin-resistant but methicillin-susceptible Staphylococcus aureus, erythromycin-resistant and methicillin-resistant S. aureus, erythromycin-resistant Streptococcus pneumoniae, and gram-negative pathogens, such as Haemophilus influenzae. Among the derivatives tested, compounds 4p, 4r, 4w, 4x and 4z were found to have potent activity against most susceptible and resistant bacteria. Compound 4p exhibited excellent antibacterial activity in comparison to the others.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Claritromicina/análogos & derivados , Antibacterianos/química , Claritromicina/síntesis química , Claritromicina/química , Claritromicina/farmacología , Descubrimiento de Drogas , Pruebas de Sensibilidad MicrobianaRESUMEN
Resistance to macrolides and beta-lactams has increased sharply amongst key respiratory pathogens, leading to major concern. A novel series of acylides was designed to overcome this resistance and was evaluated for in vitro and in vivo activity. This series of acylides was designed starting from clarithromycin by changing the substitution on the desosamine nitrogen, followed by conversion to 3-O-acyl and 11,12-carbamate. Minimum inhibitory concentrations (MICs) of acylides were determined against susceptible as well as macrolide-lincosamide-streptogramin B (MLS(B))--and penicillin-resistant Streptococcus pneumoniae, Streptococcus pyogenes and Moraxella catarrhalis by the agar dilution method. Microbroth MICs for Haemophilus influenzae were determined according to Clinical and Laboratory Standards Institute guidelines. In vivo efficacy was determined by target organ load reduction against S. pneumoniae 3579 (ermB). The bactericidal potential of promising acylides was also determined. MICs of these compounds against S. pneumoniae, S. pyogenes, H. influenzae and M. catarrhalis were in the range of 0.06-2, 0.125-1, 1-16 and 0.015-0.5 microg/mL, respectively, irrespective of their resistance pattern. Mycoplasma pneumoniae and Legionella pneumophila showed MIC ranges of 0.004-0.125 microg/mL and 0.004-0.03 microg/mL, respectively. The acylides also showed better activity against telithromycin-resistant S. pneumoniae strains. Compounds with a 4-furan-2-yl-1H-imidazolyl side chain on the carbamate (RBx 10000296) showed a target organ load reduction of >3 log(10) colony-forming units/mL and concentration-dependent bactericidal potential against S. pneumoniae 994 mefA and H. influenzae strains. This novel and potent series of acylides active against antibiotic-resistant respiratory pathogens should be further investigated.
Asunto(s)
Antibacterianos/farmacología , Claritromicina/análogos & derivados , Infecciones Comunitarias Adquiridas/microbiología , Haemophilus influenzae/efectos de los fármacos , Moraxella catarrhalis/efectos de los fármacos , Neumonía Bacteriana/microbiología , Streptococcus pneumoniae/efectos de los fármacos , Administración Oral , Animales , Antibacterianos/síntesis química , Antibacterianos/uso terapéutico , Claritromicina/síntesis química , Claritromicina/farmacología , Claritromicina/uso terapéutico , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Neumonía Neumocócica/tratamiento farmacológico , Factores de TiempoRESUMEN
A series of novel 3-O-(3-aryl-E-2-propenyl)clarithromycin derivatives 8 and 3-O-(3-aryl-2-propargyl)clarithromycin derivatives 11 were designed, synthesized, and evaluated for their in vitro antibacterial activities. Compared with 8c and 11c (Ar was 5-pyrimidyl), 3-O-(3-(5'-pyrimidyl)-Z-1-propenyl) counterpart 6c displayed 4- to 64-fold more potent activities against erythromycin-susceptible Staphylococcus aureus and Streptococcus pneumoniae. Moreover, the activities of 6c, 8c, and 11c against erythromycin-resistant S. aureus and S. pneumoniae were in general 4-fold higher than those of the reference compound, clarithromycin and azithromycin.
Asunto(s)
Antibacterianos/síntesis química , Claritromicina/análogos & derivados , Antibacterianos/química , Antibacterianos/farmacología , Claritromicina/síntesis química , Claritromicina/farmacología , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Two series of novel 3-O-carbamoyl derivatives of clarithromycin and 11,12-cyclic carbonate azithromycin were designed, synthesized and evaluated for their in vitro antibacterial activities. Compounds 4j and 4k were the most potent activity against erythromycin-susceptible Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae, which were comparable to those of clarithromycin and azithromycin. Compounds 4d, 4h and 4i showed potent activity against erythromycin-resistant S. pneumoniae encoded by the mef gene and compounds 4h and 4i displayed greatly improved activity against erythromycin-resistant S. pneumoniae encoded by the erm gene. Compound 7c exhibited improved activity against erythromycin-resistant S. pneumoniae encoded by the erm and mef genes.
Asunto(s)
Antibacterianos , Azitromicina/síntesis química , Azitromicina/farmacología , Claritromicina/síntesis química , Claritromicina/farmacología , Streptococcus pneumoniae/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/farmacología , Azitromicina/análogos & derivados , Claritromicina/análogos & derivados , Evaluación Preclínica de Medicamentos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Streptococcus pneumoniae/clasificaciónRESUMEN
In an effort to find new antibiotics, a novel series of 14-membered macrolides with imidazo[4,5-b]pyridinyl sulfur contained alkyl side chains has been synthesized based on commercially available clarithromycin. Chemical transformation of hydroxy group at position C-3 afforded range of ketolides and acylides. Compared to telithromycin, compound 15a demonstrated improved in vitro activity against erythromycin-susceptible and -resistant strains.
Asunto(s)
Antibacterianos/farmacología , Claritromicina/síntesis química , Imidazoles/farmacología , Macrólidos/química , Sulfuros/farmacología , Azufre/química , Antibacterianos/síntesis química , Química Farmacéutica/métodos , Claritromicina/farmacología , Diseño de Fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Eritromicina/síntesis química , Eritromicina/farmacología , Humanos , Imidazoles/síntesis química , Cetólidos/síntesis química , Cetólidos/química , Cetólidos/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Staphylococcus aureus/metabolismo , Streptococcus pneumoniae/metabolismo , Sulfuros/síntesis químicaRESUMEN
A new approach to 4''-substituted derivatives of erythromycin and clarithromycin was developed by converting them into corresponding 4''-malonic monoesters. Subsequent carbodiimide coupling with alcohols and amines provided new macrolide derivatives that are capable of binding to 50S ribosomal subunits and inhibiting protein synthesis in cell-free system.
Asunto(s)
Claritromicina/síntesis química , Eritromicina/síntesis química , Ribosomas/metabolismo , Sistema Libre de Células , Claritromicina/análogos & derivados , Claritromicina/metabolismo , Eritromicina/análogos & derivados , Eritromicina/metabolismo , Inhibidores de la Síntesis de la Proteína/síntesis química , Inhibidores de la Síntesis de la Proteína/metabolismo , ARN Ribosómico 23S/metabolismo , Ribosomas/efectos de los fármacosRESUMEN
Clarithromycin (6-O-methylerythromycin A) is a 14-membered macrolide antibiotic which is active in vitro against clinically important gram-positive and gram-negative bacteria. The selectivity of the methylation of the C-6 OH group is studied on erythromycin A derivatives. To understand the effect of the solvent on the methylation process, detailed molecular dynamics (MD) simulations are performed in pure DMSO, pure THF and DMSO:THF (1:1) mixture by using the anions at the C-6, C-11 and C-12 positions of 2',4"-[O-bis(TMS)]erythromycin A 9-[O-(dimethylthexylsilyl)oxime] under the assumption that the anions are stable on the sub-nanosecond time scale. The conformations of the anions are not affected by the presence of the solvent mixture. The radial distribution functions are computed for the distribution of different solvent molecules around the 'O-' of the anions. At distances shorter than 5 A, DMSO molecules are found to cluster around the C-11 anion, whereas the anion at the C-12 position is surrounded by the THF molecules. The anion at the C-6 position is not blocked by the solvent molecules. The results are consistent with the experimental finding that the methylation yield at the latter position is increased in the presence of a DMSO:THF (1:1) solvent mixture. Thus, the effect of the solvent in enhancing the yield during the synthesis is not by changing the conformational properties of the anions, but rather by creating a suitable environment for methylation at the C-6 position.