Tylosin derivatives antimicrobial activity

Several 16-membered macrolides form metabolites which retain antimicrobial activity. As discussed above, 3"-esters such as rokitamycin and miokamycin produce prolonged concentrations of antibiotic in vivo due to the facile 3"- to 4"-0-acyl migration that follows enzymatic removal of the original 4 -ester [34, 269, 270], Following a different approach to overcome the lability of 4"-esters, specific 4"-0-acyl derivatives of tylosin were selected from the series of esters (15) based upon their greater stability toward liver enzymes [80], Although esterases play the most prominent role in metabolism of 16-membered macrolides, other mechanisms such as oxidative hydroxylation, A-demethylation, reduction, and hydrolysis of sugars have been reported for various compounds [91, 96, 115, 259, 270-272]. 

Reductive amination of the aldehyde group to aminomethyl derivatives has provided another route to potentially useful compounds. An initial report described the synthesis of primary amino derivatives of tylosin and leucomycin along with dimeric structures of each [140]. A group of derivatives of tylosin and demycarosyltylosin (desmycosin) were subsequently synthesized and shown to retain antimicrobial activity [141]. From a more extensive series of compounds prepared by reductive amination of tylosin and related macrolides, 20-deoxo-20-(3,5-dimethylpiperidinyl)desmycosin was selected for further development in veterinary medicine [142]. This compound, under the generic name of tilmicosin (see Fig. 7), is being evaluated for treatment of pneumonia in cattle and pigs [143, 144, 145]. 

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