Gram-positive and gram-negative antibiotic activity of asymmetric and monomeric robenidine analogues

Abstract

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 17 and 20 against VRE with 20 the most active, MIC of 0.5 μg mL-1. Analogues 2, 14, 17, 19 and 20 were equipotent or more potent than the lead 1. Introduction of an indole moiety, 30, resulted in the most MRSA active robenidine analogue, MIC of 1.0 μg mL-1. Imine C=NH isosteres (C=O / C=S) were inactive. Monomeric analogues, 33-35 were 16 - 64 μg mL-1 active against MRSA and VRE. Analogue 36, lacking the terminal hydrazide NH moiety showed modest Gram-negative activity at 64 μg mL-1. 4-t-Butyl 45 was Gram -positive and -negative active at of 16 - 64 μg mL-1. Typically additional aromatic moiety modification was poorly tolerated, except with concomitant introduction of an imine C-alkyl moiety. The activity of these analogues against MRSA and VRE ranged from 8 μg mL-1 with 64 and 68, to inactive (MIC > 128 μg mL-1) with the naphthyl 69 and 70 and the indole 73. Gram-negative activity was most promising with 62 and 68 at 16 μg mL-1 against E. coli. Against Ps. aeruginosa, the highest activity observed was with MIC values of 32 μg mL-1 with 62 and 64. Combined, these findings support the further development of the (E)-2-benzylidenehydrazine-1-carboximidamide scaffold as a promising Gram-positive and Gram-negative antibiotic development.