Gram-Positive and Gram-Negative Antibiotic Activity of Asymmetric and Monomeric Robenidine Analogues.

Desymmetrisation of robenidine (1: N',2-bis((E)-4-chlorobenzylidene)hydrazine-1-carboximidhydrazide) and the introduction of imine alkyl substituents gave good antibiotic activity. Of note was the increased potency of two analogues against vancomycin-resistant Enterococci (VRE), one of which returned a MIC of 0.5 μg mL-1 . Five analogues were found to be equipotent or more potent than the lead 1. Introduction of an indole moiety resulted in the most active robenidine analogue against methicillin-resistant S. aureus (MRSA), with a MIC of 1.0 μg mL-1 . Imine C=NH isosteres (C=O/C=S) were inactive. Monomeric analogues were 16-64 μg mL-1 active against MRSA and VRE. An analogue that lacks the terminal hydrazide NH moiety showed modest Gram-negative activity at 64 μg mL-1 . A 4-tert-butyl analogue was shown to be active against both Gram-positive and -negative strains at 16-64 μg mL-1 . In general, additional modifications with aromatic moieties was poorly tolerated, except with concomitant introduction of an imine C-alkyl group. The activity of these analogues against MRSA and VRE ranged from 8 μg mL-1 to inactive (MIC>128 μg mL-1 ) with the naphthyl and indole analogues. Gram-negative activity was most promising with two compounds at 16 μg mL-1 against E. coli. Against P. aeruginosa, the highest activity observed was with MIC values of 32 μg mL-1 with another two analogues. Combined, these findings support the further development of the (E)-2-benzylidenehydrazine-1-carboximidamide scaffold as a promising scaffold for the development of antibiotics against Gram-positive and Gram-negative strains.