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 . 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 . Imine C=NH isosteres (C=O/C=S) were inactive. Monomeric analogues were 16-64 μg mL active against MRSA and VRE. An analogue that lacks the terminal hydrazide NH moiety showed modest Gram-negative activity at 64 μg mL . A 4-tert-butyl analogue was shown to be active against both Gram-positive and -negative strains at 16-64 μg mL . 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 to inactive (MIC>128 μg mL ) with the naphthyl and indole analogues. Gram-negative activity was most promising with two compounds at 16 μg mL against E. coli. Against P. aeruginosa, the highest activity observed was with MIC values of 32 μg mL 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.