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Type: Journal article
Title: Robenidine analogues as Gram-positive antibacterial agents
Author: Abraham, R.
Stevens, A.
Young, K.
Russell, C.
Qvist, A.
Khazandi, M.
Wong, H.
Abraham, S.
Ogunniyi, A.
Page, S.
O'Handley, R.
McCluskey, A.
Trott, D.
Citation: Journal of Medicinal Chemistry, 2016; 59(5):2126-2138
Publisher: American Chemical Society
Issue Date: 2016
ISSN: 0022-2623
Statement of
Rebecca J. Abraham, Andrew J. Stevens, Kelly A. Young, Cecilia Russell, Anastasia Qvist, Manouchehr Khazandi, Hui San Wong, Sam Abraham, Abiodun D. Ogunniyi, Stephen W. Page, Ryan O, Handley, Adam McCluskey and Darren J. Trott
Abstract: Robenidine, 1 (2,2'-bis[(4-chlorophenyl)methylene]carbonimidic dihydrazide), was active against MRSA and VRE with MIC's of 8.1 and 4.7 μM, respectively. SAR revealed tolerance for 4-Cl isosteres with 4-F (8), 3-F (9), 3-CH3 (22), and 4-C(CH3)3 (27) (23.7-71 μM) and with 3-Cl (3), 4-CH3 (21), and 4-CH(CH3)2 (26) (8.1-13.0 μM). Imine carbon alkylation identified a methyl/ethyl binding pocket that also accommodated a CH2OH moiety (75; 2,2'-bis[1-(4-chlorophenyl)-2-hydroxyethylidene]carbonimidic dihydrazide). Analogues 1, 27 (2,2'-bis{[4-(1,1-dimethylethyl)phenyl]methylene}carbonimidic dihydrazide), and 69 (2,2'-bis[1-(4-chlorophenyl)ethylidene]carbonimidic dihydrazide hydrochloride) were active against 24 clinical MRSA and MSSA isolates. No dose-limiting cytotoxicity at ≥2× MIC or hemolysis at ≥8× MIC was observed. Polymyxin B addition engendered Escherichia coli and Pseudomonas aeruginosa Gram-negative activity MIC's of 4.2-21.6 μM. 1 and 75 displayed excellent microsomal stability, intrinsic clearance, and hepatic extraction ratios with T1/2 > 247 min, CLint < 7 μL/min/mg protein, and EH < 0.22 in both human and mouse liposomes for 1 and in human liposomes for 75.
Keywords: Animals
Pseudomonas aeruginosa
Escherichia coli
Gram-Positive Bacteria
Anti-Bacterial Agents
Microbial Sensitivity Tests
Molecular Structure
Structure-Activity Relationship
Dose-Response Relationship, Drug
Methicillin-Resistant Staphylococcus aureus
Vancomycin-Resistant Enterococci
Rights: © 2016 American Chemical Society
DOI: 10.1021/acs.jmedchem.5b01797
Grant ID:
Appears in Collections:Animal and Veterinary Sciences publications
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