Analysis of an ampicillin propyl ester prodrug which inhibits the growth of Escherichia coli.
An ampicillin prodrug was synthesized by utilizing the chemical reaction of ampicillin with diazopropane (CH(3)CH(2)CHN(2)) in an organic solvent. The result is esterification of the carboxylic acid functional group. The ampicillin prodrug is a solid that forms yellow crystals which are soluble in water and LB agarose media. The ampicillin prodrug was stable for more than 10 weeks when stored at < or = 0.0 degrees C. The prodrug has reduced hydrogen-bonding capability compared with the unmodified structure of ampicillin. Evaluation of the logP parameter (the octanol/water partition coefficient) indicates that the ampicillin prodrug (logP=1.773) has increased lipophilic characteristics relative to the unmodified ampicillin structure (logP=1.06). The lipophilic substituent constant for the esterification of the carboxylic acid is 0.713, a positive value which indicates that the substituent has a lipophilic nature. The ampicillin prodrug was solubilized into LB agarose media at a concentration of 0.228 mg/ml, and was found to induce 100% growth inhibition of an ampicillin-susceptible and streptomycin-resistant Escherichia coli strain (designated DH1), and induced greater than 30% growth inhibition of an ampicillin-resistant E. coli strain (designated PKK). Synthesis of this prodrug utilizing a diazoalkane was highly efficient, with no undesirable by-products being formed.
Bartzatt
Ronald
R
University of Nebraska, College of Arts & Sciences, Chemistry Department, Durham Science Center, Omaha, NE 68182, USA. bartzatt@mail.unomaha.edu
Malesa
Cynthia
C
D000667:Ampicillin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000668:Ampicillin Resistance; D001391:Azo Compounds / Q000737:chemistry; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D008958:Models, Molecular; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D013045:Species Specificity
D001391:Azo Compounds; D011355:Prodrugs; D000667:Ampicillin