Discovery of 4,6‐bis(2‐((E)‐benzylidene)hydrazinyl)pyrimidin‐2‐Amine with Antibiotic Activity

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.