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Robenidine analogues as gram-positive antibacterial agents

Abraham, R.J., Stevens, A.J., Young, K.A., Russell, C., Qvist, A., Khazandi, M., Wong, H.S., Abraham, S., Ogunniyi, A.D., Page, S.W., O’Handley, R., McCluskey, A. and Trott, D.J. (2016) Robenidine analogues as gram-positive antibacterial agents. Journal of Medicinal Chemistry, 59 (5). pp. 2126-2138.

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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.

Publication Type: Journal Article
Murdoch Affiliation: School of Veterinary and Life Sciences
Publisher: American Chemical Society
Copyright: © 2016 American Chemical Society
Grant Number:
  • ARC/LP110200770
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