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

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-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.

Keywords: Aminopyrimidines; antibacterial activity; drugs discovery; robenidine.

Figure 1

Guanidine based lead, 1, with MIC values of 2 μg mL⁻¹ against both MRSA and VRE.

Scheme 1

Reagents and Conditions: i) EtOH, reflux, 16 h.

Figure 2

A. Superimposition of 1 and 4; and B. Superimposition of 1 and 7, showing the introduction of the exocyclic NH₂ moiety capable of the similar H‐bonding interactions as the central guanidine NH of 1.