Penicillins ester prodrugs

Of interest is also that the rate of liberation of penicillin G from the prodrug was much faster than the breakdown of the former by opening of its /3-lactam ring. Furthermore, no breakdown of the pro-moiety A-(hydroxy-methyl)-A-[(ethoxycarbonyl)methyl]benzamide (8.58) to liberate formaldehyde was detected over the timescale of ester hydrolysis. 

Pivaloyloxymethyl (Pom) esters are useful as prodrugs of penicillin and other 0-lactam antibiotics owing to their easy hydrolysis in vivo by ubiquitous non-specific esterases. Mascaretti and co-workers showed that Pom esters can also by cleaved under mild conditions with 2 equivalents of bis(tri-/i-butyltin)oxide as shown in Scheme 6.32. The intermediate tributylstannyl esters are readily hydrolysed on treatment with water to release the carboxylic acid. Functional groups such as aldehydes, thioacetals, amides, vinyl bromides, and nitro compounds are compatible.22... 

SUltamieillin [ban, inn, usan] is a semisynthetic (penicillin) ANTIBIOTIC, a prodrug of ampicillin and sulbactam, joined by a double ester, where the latter is an enzyme inhibitor that is resistant to P-lactamase and inhibits this penicillindegrading enzyme. It can be used clinically as an ANTIBACTERIAL to treat certain infections. 

The phenylacetyl N-protecting group can be removed using penicillin G acylase under mild conditions which preserve sensitive peptide bonds, C-terminal esters and phosphate groups. A novel phosphate prodrug system 46 for amines, amino acids and peptides has been reported. 

These three compounds are all prodrugs of ampicillin. In all three examples, the esters used to mask the carboxylic acid group seem rather elaborate and one may ask why a simple methyl ester is not used. The answer is that methyl esters of penicillins are not metabolized in man. Perhaps the bulkiness of the penicillin skeleton being so close to the ester functional group prevents the esterases from binding the penicillin. 

On the other hand, formation of a prodrug such as a phosphate ester may increase hydrophilicity, thus enhancing solubility. For example, the solubility and dissolution rate of the 77-hydroxymethyl derivative of lomefloxacin is higher than those of the parent compound, and it can be converted readily back to the original molecule. Commonly used prodrugs are procaine penicillin metronidazole phosphate and chloramphenicol sodium succinate. 

Price also stated that one of the significant new advances in penicillin research was the use of esters to enhance the oral absorption of ampi-cillin. This area of research has resulted in a number of ampicillin prodrugs, several of which are available clinically in Europe. Bacampicillin was recently approved for clinical use in the United States. This tech-... 

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