Synthesis and Evaluation of Antibacterial Activity of the Dual-Action Agents

: beta-lactamase inhibitors with cytotoxic agents or beta-lactam antibiotics

Abstract

The dual-action mechanisms explored in this thesis are:
(1) the conjugates of a β-lactam antibiotic and a cytotoxic agent, aiming at exploitation of synergistic effect in killing bacteria via blocking metabolism by the antibiotic and damaging bacterial nucleus by the cytotoxic agent
(2) the conjugates of a β-lactam antibiotic and a B-lactamase inhibitor

The first group of the conjugates consist of a β-lactam antibiotic and a cytotoxic agent: antitumour agents temozolomide, mitozolomide and their derivative ethyl 8-carbamoyl-3,4-dihydro-4-oxo-imidazo[5, 1-d]-1,2,3,5-tetrazine-3-acetate, were converted into their corresponded carboxylic acids (2.5, 2.6 and 2.9), then acylated with N-hydroxy-succinimide to give the active esters (2.7, 2.8 and 2.10). Reactions of the active esters (2.7, 2.8 and 2.10) with ampicillin, amoxicillin and cefalexin produced the conjugates of a B-lactam antibiotic with a cytotoxic agent (2.1a-f).

The second group of the conjugates are the integration of a cytotoxic agent with a cephalosporin via its 3-methylene group. Cephalosporines 2-11a-c were synthesised and converted to 3,4-ene precursor (2.14), followed by esterification with 2.5 or 2.6 respectively, then deprotection to give the conjugates (2.2a-f). Antibacterial activity of the conjugates has been tested against a panel of bacteria including several β-lactamase producing strains. The results of first group conjugates demonstrated little synergistic effect against bacteria, while the second group demonstrated some synergistic effect against bacteria.

β-lactamase inhibitors, tazobactam and sulbactam have been synthesised for preparation of the conjugates of a β-lactam antibiotic with a β-lactamase inhibitor. However, a number of attempts have been made to conjugate amoxicillin and tazobactam without success.

Date of Award	2001
Original language	English
Awarding Institution	Aston University