Prodrugs composed of β-lactam antibiotics and β-lactamase inhibitors

Abstract

The presence of $\beta$-lactamases which cleave the $\beta$-lactam ring of penicillins and cephalosporins to biologically inactive compounds has been thought to be the major factor of the bacterial resistance against $\beta$-lactam antibiotics. And another defects of $\beta$-lactam antibiotics were poor acid stability and poor absorption in the gastrointestinal tract because of its high polarity of $\beta$-lactam molecule. Thus, to overcome the problem of bacterial degradation, enhance the absorption of drug and find more convenient route of administration, $\beta$-lactamase inhibitors(CP 45,889,6-$\alpha$-chloropenicillanic acid sulphone) were combined with $\beta$-lactam antibiotics (penicillins, cephalosporins) by forming double ester linkage of formaldehyde hydrate. The carboxy residue at C-3 of $\beta$-lactamase inhibitors was chloromethylated by the reaction with chloromethylchlorosulfate. The chloromethyl-$\beta$-lactamase inhibitor was reacted with sodium iodide in acetone, to obtain iodomethyl-$\beta$-lactamase inhibitor. Then, iodomethyl-$\beta$-lactamase inhibitor was reacted with sodium or potassium salt of penicillins of cephalosporins in dimethylformamide, to give prodrugs composed of $\beta$-lactam antibiotic and $\beta$-lactamase inhibitor. These esters are thought to be well absorbed by gastrointestinal tract and after absorption hydrolyzed with simultaneous liberation of the active components. In vitro antimicrobiological activity of $\beta$-lactam antibiotic-$\beta$-lactamase inhibitor pairs against two $\beta$-lactamase producing strain; Escherichia coli H 294 (pBR322) and Bacillus subilis, was tested almost every case of $\beta$-lactam antibiotics $\beta$-lactamase inhibitor pair showed synergistic effect. To illucidate the possibility of being used as drug of choice, further study about the properties associated with absorption, stability in gastric juice, lability at neutral pH and safty seems to be required.