DISCOVERY OF MC-02,331, A NEW CEPHALOSPORIN EXHIBITING POTENT ACTIVITY AGAINST METHICILLIN-RESISTANT STAPHYLOCOCCUS-AUREUS

A systematic approach toward building activity against methicillin-res istant staphylococci into the cephalosporin class of beta-lactam antib iotics is described. Initial work focused on finding the optimal linka ge between the cephem nucleus and a biphenyl pharmacophore, which esta blished that a thio linkage,afforded potent activity in vitro. Efforts to optimize this activity by altering substitution on the pharmacopho re afforded iodophenylthio analog MC-02,002, which although highly pot ent against MRSA, was also highly bound to serum proteins. Further wor k to decrease serum protein binding showed that replacement of the iod o substituent by the positively-charged isothiouronium group afforded potent activity and reduced serum binding, but insufficient aqueous so lubility. Solubility was enhanced by incorporation of a second positiv ely-charged group into the 7-acyl substituent. Such derivatives (MC-02 ,171 and MC-02,306) lacked sufficient stability to staphylococcal beta -lactamase enzymes. The second positive charge was incorporated into t he cephem 3-substituent in order to utilize the beta-lactamase-stable aminothiazolyl(oximino)acetyl class of 7-substituents. These efforts c ulminated with the discovery of bis(isothiouroniummethyl)phenylthio an alog MC-02,331, whose profile is acceptable with respect to potency ag ainst MRSA, serum binding, aqueous solubility, and beta-lactamase stab ility.