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

Russell, Cecilia C.; Stevens, Andrew; McCluskey, Adam; Pi, Hongfei; Khazandi, Manouchehr; Ogunniyi, Abiodun D.; Young, Kelly A.; Baker, Jennifer R.; McCluskey, Siobhann N.; Page, Stephen W.; Trott, Darren J.

Title: Gram-Positive and Gram-Negative Antibiotic Activity of Asymmetric and Monomeric Robenidine Analogues
Creator: Russell, Cecilia C.; Stevens, Andrew; McCluskey, Adam; Pi, Hongfei; Khazandi, Manouchehr; Ogunniyi, Abiodun D.; Young, Kelly A.; Baker, Jennifer R.; McCluskey, Siobhann N.; Page, Stephen W.; Trott, Darren J.
Relation: ChemMedChem Vol. 13, Issue 23, p. 2573-2580
Publisher Link: http://dx.doi.org/10.1002/cmdc.201800463
Publisher: Wiley-VCH Verlag GmbH & Co. KGaA
Resource Type: journal article
Date: 2018
Description: 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.
Subject: antibiotics; drug repurposing; MRSA; robenidine; VRE; SDG 3; Sustainable Development Goals
Identifier: http://hdl.handle.net/1959.13/1454274
Identifier: uon:44889
Identifier: ISSN:1860-7179
Language: eng
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