Lipidic peptides. XI. Quantitative structure-activity relationships of a series of lipidic amino acid conjugates of β-lactam antibiotics

Abstract

A series of lipidic amino acid conjugates of β-lactam antibiotics were synthesized and the in vitro and in vivo activity was determined against a variety of Gram-positive and -negative bacteria. The chemical structures of the compounds were characterized by indicator variables showing the presence or absence of a substituent at a certain position, and by their lipophilicity as the calculated logarithmic value of octanol/water partition coefficient (clog P). Stepwise linear regression analysis was applied for revealing quantitative structure-activity relationships (QSAR). The in vitro activities of the compounds did not correlate with in vivo activities indicating the influence of absorption processes. The in vivo oral and subcutaneous activities were influenced by the lipophilicity of the compounds. The optimum clog P values for high in vivo oral and subcutaneous activity were around 6 and 8, respectively. The presence of the long lipidic side chain at position 1 decreased the activity against E. coli and Pseudomonas aeruginosa. Loss of activity against the non-β-lactamase-producing S. aureus was observed for compounds with a lipidic side chain at position 2.