Abstract
Robenidine (E)-N'-((E)-1-(4-chlorophenyl)ethylidene)-2-(1-(4-chlorophenyl)ethylidene)hydrazine-1-carboximidhydrazide displays methicillin-resistant Staphyoccoccus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) MICs of 2 μg mL(-1). Herein we describe the structure-activity relationship development of a novel series of guanidine to 2-aminopyrimidine isosteres that ameliorate the low levels of mammalian cytotoxicity in the lead compound while retaining good antibiotic activity. Removal of the 2-NH(2) pyrimidine moiety renders these analogues inactive. Introduction of a central 2-NH(2) triazine moiety saw a 10-fold activity reduction. Phenyl to cyclohexyl isosteres were inactive. The 4-BrPh and 4-CH(3)Ph with MIC values of 2 and 4 μg mL(-1), against MRSA and VRE respectively, are promising candidates for future development.