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

Cecilia C Russell; Andrew Stevens; Kelly A Young; Jennifer R Baker; Siobhann N McCluskey; Manouchehr Khazandi; Hongfei Pi; Abiodun Ogunniyi; Stephen W Page; Darren J Trott; Adam McCluskey

doi:10.1002/open.201800241

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

ChemistryOpen. 2019 Jul 4;8(7):896-907. doi: 10.1002/open.201800241. eCollection 2019 Jul.

Affiliations

¹ Chemistry, School of Environmental & Life Sciences The University of Newcastle University Drive Callaghan NSW 2308 Australia.
² Australian Centre for Antimicrobial Resistance Ecology School of Animal and Veterinary Sciences University of Adelaide, Roseworthy Campus Mudla Wirra Road Roseworthy 5371 SA Australia.
³ Neoculi Pty Ltd Burwood 3125 VIC Australia.

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.