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‐NH₂ pyrimidine moiety renders these analogues inactive. Introduction of a central 2‐NH₂ triazine moiety saw a 10‐fold activity reduction. Phenyl to cyclohexyl isosteres were inactive. The 4‐BrPh and 4‐CH₃Ph with MIC values of 2 and 4 μg mL⁻¹, against MRSA and VRE respectively, are promising candidates for future development.