Discovery of MC-02, 331, a New Cephalosporin Exhibiting Potent Activity Against Methicillin-resistant Staphylococcus aureus

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A systematic approach toward building activity against methicillin-resistant staphylococci into the cephalosporin class of β-lactam antibiotics is described. Initial work focused on finding the optimal linkage between the cephem nucleus and a biphenyl pharmacophore, which established that a thio linkage afforded potent activity in vitro. Efforts to optimize this activity by altering substitution on the pharmacophore afforded iodophenylthio analog MC-02, 002, which although highly potent against MRSA, was also highly bound to serum proteins. Further work to decrease serum protein binding showed that replacement of the iodo substituent by the positively-charged isothiouronium group afforded potent activity and reduced serum binding, but insufficient aqueous solubility. Solubility was enhanced by incorporation of a second positively-charged group into the 7-acyl substituent. Such derivatives (MC-02, 171 and MC-02, 306) lacked sufficient stability to staphylococcal β-lactamase enzymes. The second positive charge was incorporated into the cephem 3-substituent in order to utilize the β-lactamase-stable aminothiazolyl-(oximino)acetyl class of 7-substituents. These efforts culminated with the discovery of bis(isothiouroniummethyl)phenylthio analog MC-02, 331, whose profile is acceptable with respect to potency against MRSA, serum binding, aqueous solubility, and β-lactamase stability.