Discovery of 4,6‐bis(2‐((E)‐benzylidene)hydrazinyl)pyrimidin‐2‐Amine with Antibiotic Activity
Dr. Cecilia C. Russell,
Dr. Andrew Stevens,
Kelly A. Young,
Jennifer R. Baker,
Siobhann N. McCluskey,
Dr. Manouchehr Khazandi,
Hongfei Pi,
Dr. Abiodun Ogunniyi,
Dr. Stephen W. Page,
Prof. Darren J. Trott,
Prof. Adam McCluskey
Affiliations
Dr. Cecilia C. Russell
Chemistry, School of Environmental & Life Sciences The University of Newcastle University Drive Callaghan NSW 2308 Australia
Dr. Andrew Stevens
Chemistry, School of Environmental & Life Sciences The University of Newcastle University Drive Callaghan NSW 2308 Australia
Kelly A. Young
Chemistry, School of Environmental & Life Sciences The University of Newcastle University Drive Callaghan NSW 2308 Australia
Jennifer R. Baker
Chemistry, School of Environmental & Life Sciences The University of Newcastle University Drive Callaghan NSW 2308 Australia
Siobhann N. McCluskey
Chemistry, School of Environmental & Life Sciences The University of Newcastle University Drive Callaghan NSW 2308 Australia
Dr. Manouchehr Khazandi
Australian Centre for Antimicrobial Resistance Ecology School of Animal and Veterinary Sciences University of Adelaide, Roseworthy Campus Mudla Wirra Road Roseworthy 5371 SA Australia
Hongfei Pi
Australian Centre for Antimicrobial Resistance Ecology School of Animal and Veterinary Sciences University of Adelaide, Roseworthy Campus Mudla Wirra Road Roseworthy 5371 SA Australia
Dr. Abiodun Ogunniyi
Australian Centre for Antimicrobial Resistance Ecology School of Animal and Veterinary Sciences University of Adelaide, Roseworthy Campus Mudla Wirra Road Roseworthy 5371 SA Australia
Dr. Stephen W. Page
Neoculi Pty Ltd Burwood 3125 VIC Australia
Prof. Darren J. Trott
Australian Centre for Antimicrobial Resistance Ecology School of Animal and Veterinary Sciences University of Adelaide, Roseworthy Campus Mudla Wirra Road Roseworthy 5371 SA Australia
Prof. Adam McCluskey
Chemistry, School of Environmental & Life Sciences The University of Newcastle University Drive Callaghan NSW 2308 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.
