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Biotechnology and Applied Biochemistry (2002) 36, (89–93) (Printed in Great Britain)

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Analysis of an ampicillin propyl ester prodrug which inhibits the growth of Escherichia coli

Ronald Bartzatt*¹ and Cynthia Malesa†

*University of Nebraska, College of Arts & Sciences, Chemistry Department, Durham Science Center, Omaha, NE 68182, U.S.A., and †University of Nebraska, College of Arts & Sciences, Biology Department, Omaha, NE 68182, U.S.A.

Key words: anti-bacterial, antibiotic, bacteria, diazopropane, penicillin.

Abbreviation used: LSC, lipophilic substituent constant.

¹To whom correspondence should be addressed (e-mail bartzatt@mail.unomaha.edu).

An ampicillin prodrug was synthesized by utilizing the chemical reaction of ampicillin with diazopropane (CH₃CH₂CHN₂) 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 0.0 °C. The prodrug has reduced hydrogen-bonding capability compared with the unmodified structure of ampicillin. Evaluation of the log P parameter (the octanol/water partition coefficient) indicates that the ampicillin prodrug (log P =1.773) has increased lipophilic characteristics relative to the unmodified ampicillin structure (log P = 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.

Received 4 January 2002/28 May 2002; accepted 7 June 2002

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