Robenidine Analogues as Gram-Positive Antibacterial Agents

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 mu M, 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 mu M) and with 3-Cl (3), 4-CH3 (21), and 4-CH(CH3)(2) (26) (8.1-13.0 mu M). 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 >= 2x MIC or hemolysis at >= 8x MIC was observed. Polymyxin B addition engendered Escherichia coli and Pseudomonas aeruginosa Gram-negative activity MIC's of 4.2-21.6 mu M. 1 and 75 displayed excellent microsomal stability, intrinsic clearance, and hepatic extraction ratios with T-1/2 > 247 min, CLint < 7 mu L/min/mg protein, and E-H < 0.22 in both human and mouse liposomes for 1 and in human liposomes for 75.