Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 54
Filtrar
1.
Bioorg Med Chem ; 16(7): 3985-4002, 2008 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-18258437

RESUMEN

Design and synthesis of 16-membered macrolides modified at the C-12 and 13 positions are described. The compounds we report here have an arylalkylamino group attached to the C-12 position of the macrolactone. Both types of derivatives, 12,13-cyclic carbamates and non-carbamate analogues, were synthesized via 12-amino-13-hydroxy intermediates derived from 12,13-epoxide that was prepared by selective epoxidation at the C-12 and C-13 positions. 4'-Hydroxyl analogues were also prepared by acidic hydrolysis of a neutral sugar. These compounds were evaluated for in vitro antibacterial activity against respiratory tract pathogens. Some of these analogues exhibited an improved activity compared with the corresponding parent compound.


Asunto(s)
Antibacterianos/farmacología , Carbamatos/síntesis química , Carbamatos/farmacología , Leucomicinas/síntesis química , Leucomicinas/farmacología , Miocamicina/síntesis química , Miocamicina/farmacología , Alquilación , Aminación , Antibacterianos/síntesis química , Antibacterianos/química , Carbamatos/química , Hidroxilación , Cetólidos/química , Leucomicinas/química , Viabilidad Microbiana/efectos de los fármacos , Miocamicina/química , Estructura Molecular
2.
J Antibiot (Tokyo) ; 70(8): 878-887, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28559578

RESUMEN

Tylosin is a 16-membered macrolide broad-spectrum antibiotic that has an important role in veterinary medicine, active against Gram-positive and a restricted range of Gram-negative bacteria. We synthesized 15 types of tylosin-related derivatives by chemical modification and evaluated them against mastitis pathogens. Among them, 20-deoxy-20-{N-methyl-N-[1-(3-quinolyl)-1H-1,2,3-triazol-4-yl]methylamino}-5-O-mycaminosyltylonolide 2f and 20-deoxy-20-{N-benzyl-N-[1-(3-quinolyl)-1H-1,2,3-triazol-4-yl]methylamino}-5-O-mycaminosyltylonolide 2k were found to not only expand their antibacterial impact to include Gram-negative bacteria, such as Escherichia coli and Klebsiella pneumoniae, but also to retain or increase antibacterial activity against Gram-positive bacteria, such as Staphylococcus aureus and Streptococcus uberis in comparison with the parent tylosin.


Asunto(s)
Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Leucomicinas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Leucomicinas/síntesis química , Leucomicinas/química , Tilosina/farmacología
3.
J Med Chem ; 36(14): 1956-63, 1993 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-8336335

RESUMEN

A practical synthesis of CBI (2) was developed and applied to the synthesis of benzannelated analogs of CC-1065, including CBI-PDE-I-dimer (13) and CBI-bis-indole [(+)-A'BC]. The CBI-PDE-I-dimer was shown to have similar DNA sequence selectivity and structural effects on DNA as (+)-CC-1065. Of particular importance was the observed duplex winding effect that has been associated with the pyrrolidine ring of the nonalkylated subunits of (+)-CC-1065 and possibly correlated with its delayed toxicity effects. The effect of CBI-PDE-I-dimer was also compared to (+)-CC-1065 in the inhibition of duplex unwinding by helicase II and nick sealing by T4 ligase and found to be quantitatively similar. The in vitro and in vivo potencies of the CBI compounds corresponded very closely to the corresponding CPI derivatives. Finally, CBI-PDE-I-dimer was like (+)-CC-1065 in causing delayed toxicity in mice.


Asunto(s)
Antibióticos Antineoplásicos/síntesis química , Indoles , Leucomicinas/síntesis química , Leucomicinas/toxicidad , Animales , Secuencia de Bases , ADN Ligasas/efectos de los fármacos , Duocarmicinas , Femenino , Leucomicinas/química , Leucemia L1210/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Datos de Secuencia Molecular , Relación Estructura-Actividad
4.
J Med Chem ; 25(3): 271-5, 1982 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-7040661

RESUMEN

The reductive amination of an aldehyde group on the aglycon moiety of leucomycins A3 and A5 and tylosin with sodium cyanoborohydride in the presence of NH(CH3)2 or NH2CH3 afforded the corresponding amine derivative. The use of NH3 as an amine source in the reduction of leucomycin A3 and tylosin afforded a novel dimeric derivative, 18,18'-dideoxo-18,18'-iminodileucomycin A3 and 20,20'-dideoxo-20,20'-iminoditylosin, respectively. The structures of the dimers were elucidated by field desorption mass spectral analysis. The dimeric derivative of tylosin possesses considerable antibacterial activity. The binding activity of the dimer of Escherichia coli ribosome was approximately the same as for tylosin.


Asunto(s)
Leucomicinas/síntesis química , Bacterias/efectos de los fármacos , Fenómenos Químicos , Química , Escherichia coli/efectos de los fármacos , Leucomicinas/farmacología , Pruebas de Sensibilidad Microbiana , Ribosomas/metabolismo , Relación Estructura-Actividad
5.
J Med Chem ; 31(3): 590-603, 1988 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-3346875

RESUMEN

The synthesis, physicochemical properties, and biological activities of a series of novel spiro cyclopropyl compounds, modeled on the potent antitumor antibiotic CC-1065 (1), are described. Many of these synthetic analogues are significantly more effective than 1 against murine tumors. In particular, compound 27 exhibits high activity and potency. Structure-activity analysis supports a molecular mechanism for biological action involving hydrophobic interaction of the drug with DNA and acid-catalyzed alkylation of DNA.


Asunto(s)
Antibióticos Antineoplásicos/metabolismo , ADN/metabolismo , Indoles , Leucomicinas/metabolismo , Animales , Antibióticos Antineoplásicos/síntesis química , Fenómenos Químicos , Química Física , Dicroismo Circular , Duocarmicinas , Femenino , Leucomicinas/síntesis química , Leucomicinas/farmacología , Leucemia L1210/tratamiento farmacológico , Leucemia P388/tratamiento farmacológico , Ratones , Ratones Endogámicos DBA , Solubilidad
6.
J Med Chem ; 46(4): 634-7, 2003 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-12570384

RESUMEN

CC-1065 analogues bearing different DNA-binding subunits were synthesized. A terminal C5-NO2 and -F moiety at the DNA-binding subunit increased the drug's potency and antitumor efficacy. A C5-OCH3 reduced the potency and antitumor efficacy. Compound (+/-)-7, bearing a trans double bond, had increased antitumor efficacy. A preliminary toxicity study indicated that terminal C5-OCH3 and -acetamido moieties at the DNA-binding subunit caused delayed death in mice.


Asunto(s)
Antineoplásicos/síntesis química , ADN/química , Indoles/síntesis química , Leucomicinas/síntesis química , Animales , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Ensayos de Selección de Medicamentos Antitumorales , Duocarmicinas , Indoles/farmacología , Indoles/toxicidad , Leucomicinas/química , Leucomicinas/farmacología , Leucemia L1210/tratamiento farmacológico , Ratones , Estereoisomerismo , Relación Estructura-Actividad , Tasa de Supervivencia , Pruebas de Toxicidad Aguda
7.
J Med Chem ; 31(8): 1631-41, 1988 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-3398001

RESUMEN

Modification of the aldehyde group in tylosin and related macrolide antibiotics dramatically enhanced the oral efficacy of the derivatives against experimental infections caused by susceptible bacteria in laboratory animals. A large number and wide variety of aldehyde-modified macrolide derivatives were prepared, utilizing the Mitsunobu reaction and other chemical transformations. Evaluation of in vitro and in vivo antimicrobial activity indicated that derivatives of demycarosyltylosin (desmycosin) combined the broadest spectrum of antimicrobial activity with the best efficacy and bioavailability after oral administration.


Asunto(s)
Leucomicinas/síntesis química , Administración Oral , Aldehídos/síntesis química , Aldehídos/farmacocinética , Aldehídos/farmacología , Animales , Bacterias Anaerobias/efectos de los fármacos , Disponibilidad Biológica , Fenómenos Químicos , Química , Leucomicinas/farmacocinética , Ratones , Pruebas de Sensibilidad Microbiana , Staphylococcus/efectos de los fármacos , Streptococcus/efectos de los fármacos , Relación Estructura-Actividad
8.
J Med Chem ; 20(5): 732-6, 1977 May.
Artículo en Inglés | MEDLINE | ID: mdl-404425

RESUMEN

The synthesis, antimicrobial activity, and binding to ribosomes of leucomycin and leucomycin derivatives are described. In general, the binding of the leucomycins and the leucomycin derivatives to ribosomes correlated with their antimicrobial activity. Some 2'-O-acyl derivatives apparently underwent gradual hydrolysis during antimicrobial assays, for their binding to ribosomes was poor compared to their relatively good antimicrobial activies. Correlation between antimicrobial activity and binding to ribosomes, their molecular site of action, provides some insight into the nature of the active molecular moieties.


Asunto(s)
Antibacterianos/síntesis química , Escherichia coli/metabolismo , Leucomicinas/síntesis química , Ribosomas/metabolismo , Bacillus subtilis/efectos de los fármacos , Depresión Química , Eritromicina/metabolismo , Escherichia coli/ultraestructura , Klebsiella pneumoniae/efectos de los fármacos , Leucomicinas/metabolismo , Leucomicinas/farmacología , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad
9.
J Med Chem ; 40(6): 1041-5, 1997 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-9083494

RESUMEN

Reductive amination of repromicin with polyfunctional amines has led to new macrolide antibacterial agents, some of which are highly potent against the Gram-negative pathogen Pasteurella multocida both in vitro and in a mouse infection model. A key element in this discovery was the recognition that among certain known macrolides increasing lipophilicity results in diminished in vivo activity. One repromicin derivative, 20-[N-[3-(dimethylamino)-propyl]-N-L-alanylamino]-20-deoxorepro micin (35), was selected for advanced evaluation. At 5 mg/kg, a single subcutaneous dose was found to control induced pasteurellosis in swine and induced respiratory disease in cattle.


Asunto(s)
Antibacterianos/farmacología , Macrólidos , Pasteurella multocida/efectos de los fármacos , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/uso terapéutico , Cromatografía Líquida de Alta Presión , Leucomicinas/síntesis química , Leucomicinas/química , Leucomicinas/aislamiento & purificación , Leucomicinas/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Infecciones por Pasteurella/tratamiento farmacológico , Infecciones por Pasteurella/veterinaria , Tilosina/análogos & derivados , Tilosina/farmacología
10.
J Antibiot (Tokyo) ; 34(12): 1577-80, 1981 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-7333970

RESUMEN

9-epi-Leucomycin A5 has been obtained from leucomycin A5 (I) by the following reaction sequence. Leucomycin A5 (I) was treated with Collins reagent (CrO3-pyridine) in the presence of water (13%) to provide 9-dehydroleucomycin A5 (II) in 95% yield. The formyl group was internally protected by the reaction of II with acetic anhydride-K2CO3 to afford 18,2'-di-O-acetyl-9-dehydroleucomycin A5-3,18-hemiacetal (III). Sodium borohydride reaction of II provided a 1 : 1 mixture of natural I and its 9-epimer, 9-epi-leucomycin A5 (IV), which were separated by silica gel chromatography. It was observed that the antimicrobial activities of both enantiomers were virtually identical with some tests strains but that of IV is reduced in comparison with I in some bacteria such as Staphylococcus epidermidis sp-al-1 and Streptococcus pyogenes N. Y. 5.


Asunto(s)
Leucomicinas/síntesis química , Bacterias/efectos de los fármacos , Leucomicinas/farmacología
11.
J Antibiot (Tokyo) ; 37(7): 750-9, 1984 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-6469869

RESUMEN

Among the derivatives protected with t-butyldimethylsilylether of spiramycin I, 2'-O-acetylspiramycin I 3,18-(O-t-butyldimethylsilyl)acetal was found to be a suitable intermediate for 4''-modification of spiramycin I. Seven 4''-sulfonates and four 4''-alkylethers were synthesized, which were more active against bacteria in vitro than spiramycin I. 4''-Substituted derivatives with relatively small sulfonyl and alkyl groups were comparable in therapeutic effect to spiramycin I.


Asunto(s)
Leucomicinas/síntesis química , Animales , Espectroscopía de Resonancia Magnética , Ratones , Pruebas de Sensibilidad Microbiana , Ribosomas/metabolismo
12.
J Antibiot (Tokyo) ; 34(9): 1137-51, 1981 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-7328055

RESUMEN

Derivatives of josamycin and isojosamycin modified at C-9 and C-13 have been prepared by reaction sequences involving treatment of josamycin with alcohols, phenol or 1-methyl-1H-tetrazol-5-ylthiol in acidic media. Several tetrahydro derivatives of josamycin and isojosamycin have also been prepared by reaction sequences involving catalytic hydrogenation. From the 1H NMR studies, it was found that the conformation of the macro-lactone portion of 13-O-methylisojosamycin dimethylacetal, a key intermediate, is flexible and changeable with variation of the solvent.


Asunto(s)
Antibacterianos/síntesis química , Leucomicinas/síntesis química , Fenómenos Químicos , Química , Espectroscopía de Resonancia Magnética
13.
J Antibiot (Tokyo) ; 38(4): 477-84, 1985 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-4008340

RESUMEN

23-Amino-4',23-dideoxymycaminosyl tylonolide diethyl acetal (5) has been prepared from 4',23-dideoxy-23-iodomycaminosyl tylonolide diethyl acetal (3) by treatment with sodium azide followed by selective reduction of the resulting azide (4). 23-Acylamino-23-deoxy (6 approximately 8) and 23-deoxy-23-urethane-type compounds (12 approximately 15) were further prepared. Treatment of the 23-alkylamino-4',23-dideoxymycaminosyl tylonolides (9, 10) with chloroformates gave 23-N-alkyl-23-deoxy-23-urethane-type compounds (16 approximately 21, 29, 30). 23-N-Alkyl-23-deoxy-23-(2-hydroxyethalamino and 2-methoxyethylamino)-4',23-dideoxymycaminosyl tylonolides (22 approximately 25, 27, 28) were prepared from 3 and the corresponding amines. Antibacterial activities and toxicities (for 23 and 27) of these compounds are described. toxicities (for 23 and 27) of these compounds are described.


Asunto(s)
Bacterias/efectos de los fármacos , Leucomicinas/síntesis química , Leucomicinas/farmacología , Relación Estructura-Actividad
14.
J Antibiot (Tokyo) ; 37(7): 738-49, 1984 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-6469868

RESUMEN

4'-Deoxy derivatives of neospiramycin I and their 12-(Z)-isomers were synthesized by reductive dechlorination via 4'-epi-chloro derivatives. The 12-(Z)-derivatives were more active against bacteria in vitro than the corresponding 12-(E)-derivatives in spite of their low affinities to ribosomes.


Asunto(s)
Antibacterianos/síntesis química , Leucomicinas/síntesis química , Espiramicina/análogos & derivados , Cromatografía Líquida de Alta Presión , Isomerismo , Leucomicinas/farmacología , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana
15.
J Antibiot (Tokyo) ; 37(7): 760-72, 1984 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-6469870

RESUMEN

3'',4''-Diacylates and 3,3'',4''-triacylates of spiramycin I were synthesized and evaluated by the four parameters, MIC against bacteria, affinity to ribosomes, retention time in HPLC and therapeutic effect. Among them, 3,3'',4''-tri-O-propionyl and 3,4''-di-O-acetyl-3''-O-butyryl-spiramycin I were the most active in vivo, which were superior to acetylspiramycin.


Asunto(s)
Leucomicinas/síntesis química , Animales , Cromatografía Líquida de Alta Presión , Espectroscopía de Resonancia Magnética , Ratones , Pruebas de Sensibilidad Microbiana , Ribosomas/metabolismo
16.
J Antibiot (Tokyo) ; 39(8): 1108-22, 1986 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-3759662

RESUMEN

A large number and wide variety of acyl derivatives of the tylosin-related macrolides 23-demycinosyltylosin (DMT), 23-demycinosyloxytylosin (DMOT) and 5-O-mycaminosyltylonolide (OMT) were synthesized and evaluated. This encompassed conversion of the hydroxyl groups at 2',4' and 23 of the appropriate macrolides to the corresponding esters, in which a variety of different substitution patterns were examined. A wide range of acyl substituents was investigated, particularly for 23-O-acyl derivatives of OMT, since these were substantially more active in vitro than OMT itself. However, the acyl derivatives which were prepared demonstrated no substantial improvement in oral efficacy or bioavailability over the parent macrolides.


Asunto(s)
Leucomicinas/síntesis química , Acilación , Animales , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Leucomicinas/sangre , Leucomicinas/farmacología , Ratones , Relación Estructura-Actividad
17.
J Antibiot (Tokyo) ; 38(10): 1350-8, 1985 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-4066488

RESUMEN

3,3''-Di-O-acyl-4''-O-sulfonyl and 3,3''-di-O-acyl-4''-O-alkyl derivatives of spiramycin I were synthesized and evaluated by four parameters, antibacterial activity, affinity to ribosomes, lypophilicity and therapeutic effects. Among them, 3,3''-di-O-acetyl-4''-O-mesyl and 3,3''-di-O-acetyl-4''-O-methylspiramycin I having relatively small substituents at 4''-position were the most effective in mouse protection tests, and the results were comparable to acetylspiramycin.


Asunto(s)
Bacterias/efectos de los fármacos , Leucomicinas/síntesis química , Animales , Leucomicinas/farmacología , Ratones , Ribosomas/metabolismo , Solubilidad , Relación Estructura-Actividad
18.
J Antibiot (Tokyo) ; 41(11): 1617-28, 1988 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-3198495

RESUMEN

Eleven 4''-O-acyltylosin derivatives were synthesized and subjected to a two-step screening system consisting of antimicrobial activity and esterase stability assays. The new derivatives were all active against macrolide-resistant Staphylococci and mycoplasmas, but only 4''-O-(4-methoxy)phenylacetyltylosin and 4''-O-(4-acetyl)phenylacetyltylosin showed better resistance to mouse liver esterase than 4''-O-phenylacetyltylosin (reference compound C).


Asunto(s)
Leucomicinas/síntesis química , Animales , Bacterias/efectos de los fármacos , Esterasas/farmacología , Leucomicinas/metabolismo , Leucomicinas/farmacología , Ratones , Relación Estructura-Actividad
19.
J Antibiot (Tokyo) ; 29(5): 536-48, 1976 May.
Artículo en Inglés | MEDLINE | ID: mdl-956042

RESUMEN

9,3''-Diacetylmidecamycin (12) was synthesized from 4''-depropionyl-9,2',4''-triacetylmidecamycin (8) by heating the latter with propionic anhydride in pyridine followed by removal of 2'-acetyl group, with or without 18-enolpropionyl group. Direct acetylation of midecamycin (1) led to the formation of the 3'',4''-positional isomer (6). The structure of 12 was determined by mass, NMR and chemical degradation. The location of 3''-acetyl group was shown by the stereospecific 3 leads to 1 acetyl migration catalyzed by a base of 3-O-acetyl-4-O-propionyl-L-mycarose (13), and comparison of NMR and mass fragmentation with the 3,4-positional isomer (15). The latter's structure was independently supported by the nuclear Overhauser effect between methyl and propionyl group at C-3. The intramolecular 4 leads to 3 acyl shift that was taken place in the forced acylation of the mycarose moiety was found to be affected by the anomeric configuration, nature of aglycones and reaction temperature. Reverse 3 leads to 4 acyl migration occurred in acidic hydrolysis.


Asunto(s)
Antibacterianos , Leucomicinas , Acetilación , Antibacterianos/análogos & derivados , Fenómenos Químicos , Química , Hidrólisis , Leucomicinas/análogos & derivados , Leucomicinas/análisis , Leucomicinas/síntesis química
20.
J Antibiot (Tokyo) ; 37(9): 1007-15, 1984 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-6501102

RESUMEN

Thioether derivatives of tylosin and demycarosyltylosin were synthesized by Michael-type addition of thiol to C-11 of the enone moiety on the aglycone. Some of tylosin derivatives were effective to macrolide resistant Staphylococcus aureus, and their in vivo activities were same or superior than that of tylosin.


Asunto(s)
Antibacterianos/síntesis química , Leucomicinas/síntesis química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Tilosina
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA