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 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 EH 1 and in human liposomes for 75.