SAR studies of anti-MRSA non-zwitterionic 3-heteroarylthiocephems

SAR studies in a series of 3-heteroarylthio substituted cephalosporins esta blished that high activity against methicillin-resistant Staphylococcus aur eus (MRSA) can be achieved with various heteroaryl substituents. Early resu lts showed that highly lipophilic 3-heteroarylthio substituents, which were necessary for anti-MRSA activity, caused high affinity of such cephems tow ard serum proteins. Our earlier published efforts described discovery of zw itterionic cephems MC-02,331 and RWJ-54428 (MC-02,479), where serum binding was reduced by employing basic, positively charged functionalities attache d to the 3-heteroarylthio substituent. In order to avoid low solubility pro blems associated with most such zwitterionic cephalosporins a wide variety of non-basic heteroaryl substituents was tested (non-zwitterionic cephems a re more easily formulated as water soluble sodium salts for intravenous adm inistration). Considerable reduction in serum binding was obtained in some analogs while maintaining high anti-MRSA potency.