ABSTRACT
Reductive amination of the C-20 aldehyde group of tylosin and related macrolides yielded a large series of derivatives with potentially useful antibiotic properties. Evaluation of these new compounds was conducted on the basis of: 1) Broad antimicrobial spectrum in vitro, with particular emphasis on inhibition of Pasteurella multocida and Pasteurella haemolytica; 2) in vivo efficacy, especially when given orally, against P. multocida in experimental infections in chicks; and 3) bioavailability after oral administration to laboratory animals. The most useful activity was found within a series of derivatives produced by reductive amination of desmycosin with secondary amines.
Subject(s)
Pasteurella/drug effects , Tylosin/analogs & derivatives , Amination , Animals , Chickens , Mice , Microbial Sensitivity Tests , Molecular Structure , Oxidation-Reduction , Pasteurella Infections/drug therapy , Streptococcal Infections/drug therapy , Streptococcus pyogenes/drug effects , Structure-Activity Relationship , Tylosin/chemical synthesis , Tylosin/pharmacologyABSTRACT
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.
Subject(s)
Leucomycins/chemical synthesis , Administration, Oral , Aldehydes/chemical synthesis , Aldehydes/pharmacokinetics , Aldehydes/pharmacology , Animals , Bacteria, Anaerobic/drug effects , Biological Availability , Chemical Phenomena , Chemistry , Leucomycins/pharmacokinetics , Mice , Microbial Sensitivity Tests , Staphylococcus/drug effects , Streptococcus/drug effects , Structure-Activity RelationshipABSTRACT
A large group of ester derivatives of tylosin-related macrolides was prepared in which the hydroxyl groups at C-3 and C-4'' were acylated by either chemical or biochemical methods. Most of the derivatives exhibited excellent in vitro antimicrobial activity. However, only the 3,4''-diacyl derivatives of tylosin and macrocin showed any significant improvements of in vivo efficacy against experimental infections in rodents.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Leucomycins/chemical synthesis , Streptomyces/metabolism , Acylation , Anti-Bacterial Agents/biosynthesis , Anti-Bacterial Agents/pharmacology , Chemical Phenomena , Chemistry , Leucomycins/biosynthesis , Leucomycins/pharmacology , Structure-Activity RelationshipABSTRACT
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.
