2. Academic Validation
  3. Robenidine Analogues as Gram-Positive Antibacterial Agents

Robenidine Analogues as Gram-Positive Antibacterial Agents

  • J Med Chem. 2016 Mar 10;59(5):2126-38. doi: 10.1021/acs.jmedchem.5b01797.
Rebecca J Abraham 1,  Andrew J Stevens 2,  Kelly A Young 2,  Cecilia Russell 2,  Anastasia Qvist 2,  Manouchehr Khazandi 1,  Hui San Wong 1,  Sam Abraham 1 3,  Abiodun D Ogunniyi 1,  Stephen W Page 4,  Ryan O'Handley 1,  Adam McCluskey 2,  Darren J Trott 1
Affiliations

Affiliations

  • 1 School of Animal and Veterinary Sciences, University of Adelaide , Roseworthy Campus, Mudla Wirra Road, Roseworthy, 5371 SA, Australia.
  • 2 Chemistry, Centre for Chemical Biology, School of Environmental and Life Sciences, The University of Newcastle , University Drive, Callaghan, 2308 NSW, Australia.
  • 3 School of Veterinary and Life Sciences, Murdoch University , 90 South Street, Murdoch, 6150 WA, Australia.
  • 4 Neoculi Pty Ltd , Burwood, 3125 VIC, Australia.
PMID: 26765953 DOI: 10.1021/acs.jmedchem.5b01797
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.

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