Open AccessDiscovery of 4,6‐bis(2‐(( E )‐benzylidene)hydrazinyl)pyrimidin‐2‐Amine with Antibiotic Activity
Author(s) -
Russell Cecilia C.,
Stevens Andrew,
Young Kelly A.,
Baker Jennifer R.,
McCluskey Siobhann N.,
Khazandi Manouchehr,
Pi Hongfei,
Ogunniyi Abiodun,
Page Stephen W.,
Trott Darren J.,
McCluskey Adam
Publication year - 2019
Publication title -
chemistryopen
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.644
H-Index - 29
ISSN - 2191-1363
DOI - 10.1002/open.201800241
Subject(s) - moiety , chemistry , guanidine , cytotoxicity , antibiotics , pyrimidine , triazine , amine gas treating , combinatorial chemistry , hydrazine (antidepressant) , antibacterial activity , stereochemistry , vancomycin , staphylococcus aureus , bacteria , biochemistry , organic chemistry , biology , in vitro , genetics
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.