title: Robenidine Analogues as Gram-Positive Antibacterial Agents.
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.
authors.affiliation: School of Animal and Veterinary Sciences, University of Adelaide , Roseworthy Campus, Mudla Wirra Road, Roseworthy, 5371 SA, Australia.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Abraham
authors.affiliation: Chemistry, Centre for Chemical Biology, School of Environmental and Life Sciences, The University of Newcastle , University Drive, Callaghan, 2308 NSW, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Stevens
authors.affiliation: Chemistry, Centre for Chemical Biology, School of Environmental and Life Sciences, The University of Newcastle , University Drive, Callaghan, 2308 NSW, Australia.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Young
authors.affiliation: Chemistry, Centre for Chemical Biology, School of Environmental and Life Sciences, The University of Newcastle , University Drive, Callaghan, 2308 NSW, Australia.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Russell
authors.affiliation: Chemistry, Centre for Chemical Biology, School of Environmental and Life Sciences, The University of Newcastle , University Drive, Callaghan, 2308 NSW, Australia.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Qvist
authors.affiliation: School of Animal and Veterinary Sciences, University of Adelaide , Roseworthy Campus, Mudla Wirra Road, Roseworthy, 5371 SA, Australia.
authors.forename: Manouchehr
authors.initials: M
authors.lastname: Khazandi
authors.affiliation: School of Animal and Veterinary Sciences, University of Adelaide , Roseworthy Campus, Mudla Wirra Road, Roseworthy, 5371 SA, Australia.
authors.forename: Hui San
authors.initials: HS
authors.lastname: Wong
authors.affiliation: School of Animal and Veterinary Sciences, University of Adelaide , Roseworthy Campus, Mudla Wirra Road, Roseworthy, 5371 SA, Australia.|School of Veterinary and Life Sciences, Murdoch University , 90 South Street, Murdoch, 6150 WA, Australia.
authors.forename: Sam
authors.initials: S
authors.lastname: Abraham
authors.affiliation: School of Animal and Veterinary Sciences, University of Adelaide , Roseworthy Campus, Mudla Wirra Road, Roseworthy, 5371 SA, Australia.
authors.forename: Abiodun D
authors.initials: AD
authors.lastname: Ogunniyi
authors.affiliation: Neoculi Pty Ltd , Burwood, 3125 VIC, Australia.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Page
authors.affiliation: School of Animal and Veterinary Sciences, University of Adelaide , Roseworthy Campus, Mudla Wirra Road, Roseworthy, 5371 SA, Australia.
authors.forename: Ryan
authors.initials: R
authors.lastname: O'Handley
authors.affiliation: Chemistry, Centre for Chemical Biology, School of Environmental and Life Sciences, The University of Newcastle , University Drive, Callaghan, 2308 NSW, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
authors.affiliation: School of Animal and Veterinary Sciences, University of Adelaide , Roseworthy Campus, Mudla Wirra Road, Roseworthy, 5371 SA, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Trott
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012370:Robenidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D008081:Liposomes; D012370:Robenidine