Robenidine analogues as gram-positive antibacterial agents

Robenidine, <b>1</b> (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 (<b>8</b>), 3-F (<b>9</b>), 3-CH₃ (<b>22</b>), and 4-C(CH₃)₃ (<b>27</b>) (23.7–71 μM) and with 3-Cl (<b>3</b>), 4-CH₃ (<b>21</b>), and 4-CH(CH₃)₂ (<b>26</b>) (8.1–13.0 μM). Imine carbon alkylation identified a methyl/ethyl binding pocket that also accommodated a CH₂OH moiety (<b>75</b>; 2,2′-bis[1-(4-chlorophenyl)-2-hydroxyethylidene]carbonimidic dihydrazide). Analogues <b>1, 27</b> (2,2′-bis{[4-(1,1-dimethylethyl)phenyl]methylene}carbonimidic dihydrazide), and <b>69</b> (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. <b>1</b> and <b>75</b> displayed excellent microsomal stability, intrinsic clearance, and hepatic extraction ratios with T_1/2 > 247 min, CL_int < 7 μL/min/mg protein, and E_H < 0.22 in both human and mouse liposomes for <b>1</b> and in human liposomes for <b>75