Synthesis, structural analysis and antibacterial activity of a butyl ester derivative of ampicillin.

Background: Ester groups placed on medicinal agents have been found to increase lipophilicity (more positive log p value). Alterations in a partition coefficient may affect medicinal activity. Formation of an ester group such as -C(O)OCH(2)CH(2)CH(2)CH(3) from a carboxyl group [-C(O)OH] can be efficiently accomplished utilizing diazoalkanes and produces a prodrug-like structure of ampicillin (a bipartate drug carrier). Formation of an ester group may produce beneficial changes in medicinal parameters such as log P, log BB, and molecular polar surface area (TPSA).
Methods: An ester of ampicillin was synthesized by replacing the carboxyl group with a butyl ester group. The ester formed was synthesized utilizing diazobutane, which is a gas at room temperature and reacts with the acidic hydrogen of the carboxylic acid. The ampicillin ester was dissolved into LB agarose media at levels of 0.228 and 0.180 mg/ml, and its antibacterial activity was compared to that of normal ampicillin. Medicinal parameters such as log P, solubility, polar surface area, log BB, molecular dipole, Clog P, intestinal absorption and the 'Rule of 5' were determined.
Results: The ampicillin ester consisted of yellow crystals that were stable for >12 weeks at 0 degrees C. The ester has reduced hydrogen bonding capacity and increased lipophilic character (by log P) compared to the parent structure. Each concentration of the ester tested induced 100% growth inhibition of ampicillin-susceptible but streptomycin-resistant Escherichia coli bacteria, and >30% growth inhibition of an ampicillin-resistant E. COLI. This ester compound of ampicillin showed zero violations of the 'Rule of 5', which indicates good bioavailability and good bioactivity. Intestinal absorption indicated by TPSA value showed moderate absorption activity for both parent and ester compounds. The lipophilic substituent constant for the butyl ester is +0.941, which indicates increased lipophilicity. The ester group improves log BB and dermal permeability of ampicillin.
Conclusion: The butyl ester of ampicillin inhibited the growth of susceptible and resistant E. COLI. Favorable values for parameters such as TPSA, log P, log BB, and zero violations of the 'Rule of 5' suggest good bioavailability and good bioactivity.
(Copyright 2003 S. Karger AG, Basel)