Non-Covalent Inhibitors of AmpC ß-Lactamase

Abstract

β-lactamases are the most widespread resistance mechanism to β-lactam antibiotics, such as penicillins and cephalosporins. In response to these enzymes, inhibitors have been introduced. Unfortunately, these inhibitors are also β-lactams, and resistance to them has developed rapidly. Consequently, the present invention provides a novel structure-based approach to inhibitors of these enzymes.

1 . A lactamase inhibitor compound of a formula
   A-SO 2 —NH—R   
     wherein A is a thiophen-2-yl moiety substituted with a carboxylate group and a pharmaceutically-acceptable cation at the 3-position of said thiophenyl moiety and adjacent said SO 2  moiety; and wherein R is selected from phenyl, biphenyl, pyridinyl, pyrazinyl, thiophenyl, pyrrolyl, fluorenyl, benzothiazyl, anthryl, naphthyl, 1,8-diazanaphthyl, 1,4,6,8-tetranaphthyl, 1-azanaphthyl, indenyl, purinyl, indolyl, pyrimidyl, pyridazyl, pyrazopyrimidyl, indazolyl, azaadenyl, adenosyl, 1,2,4-triazinyl, and 1,3,5-triazinyl moieties and, wherein said R moiety comprises a substituent selected from alkyl, cycloalkyl, arylalkyl, nitroalkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, azoalkyl, cyanoallyl, amidoalkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxy, alkoxycarbonyl, hydroxy, amino, alkylamino, cycloalkylamino, arylamino, amidocarbonyl, alkylcarboxamido, arylcarboxamido, carboxy, formyl, alkylcarbonyl, arylcarbonyl, carboxycarbonyl, sulfonyl, alkylsulfonyl, sulfoxy, sulfamoyl, nitrile, azo, alkylazo, arylazo, hydrazinyl, hydrazincarbonyl, nitroso, nitro, cyclicalkenyl, heterocyclicalkenyl and combinations thereof. 
   
   
       2 . The lactamase inhibitor compound of  claim 1  wherein R is phenyl with a 4-chloro substituent.