- Title
- Robenidine analogues as gram-positive antibacterial agents
- Creator
- Abraham, Rebecca J.; Stevens, Andrew J.; O'Handley, Ryan; McCluskey, Adam; Trott, Darren J.; Young, Kelly A.; Russell, Cecilia; Qvist, Anastasia; Khazandi, Manouchehr; Wong, Hui San; Abraham, Sam; Ogunniyi, Abiodun D.; Page, Stephen W.
- Relation
- Journal of Medicinal Chemistry Vol. 59, Issue 5, p. 2126-2138
- Publisher Link
- http://dx.doi.org/10.1021/acs.jmedchem.5b01797
- Publisher
- American Chemical Society
- Resource Type
- journal article
- Date
- 2016
- Description
- 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.
- Subject
- robenidine; animals; anti-bacterial agents; dose-response relationship; escherichia coli; gram-positive bacteria; liposomes; vancomycin-resistant enterococci
- Identifier
- http://hdl.handle.net/1959.13/1347380
- Identifier
- uon:30033
- Identifier
- ISSN:0022-2623
- Language
- eng
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