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 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.

Olive-Shaped Organic Cages: Synthesis and Remarkable Promotion of Hydrazone Condensation through Encapsulation in Water

“…mp 206–207 °C (amorphous solid). 1 H NMR (DMSO- d 6 , 400 MHz): δ 10.6 (s, 2H), 7.98–8.13 (m, 3H), 7.54 (s, 2H), 7.47 (d, 2H, J = 4.0 Hz), 7.23–7.27 (m, 2H), 7.14 (d, 2H, J = 4.0 Hz), 2.33 (s, 6H) …”

“…mp 229–230 °C (amorphous solid). 1 H NMR (DMSO- d 6 , 400 MHz): δ 10.64 (s, 2H), 8.46 (s, 2H), 7.94 (d, 2H, J = 2 Hz), 7.21–7.29 (m, 6H), 2.41 (s, 6H) …”

Recent advances in indole dimers and hybrids with antibacterial activity against methicillin‐resistant Staphylococcus aureus

“…The indole dimer 20 (MIC: 1.0 and 4.0 µg/ml) showed potential activity against MRSA and VRE, and the SAR indicated that the indole moiety was crucial for the activity, and replacement of the indole skeleton by phenyl or pyridinyl was detrimental to activity. [ 47 ] The naphthalene‐containing indole dimers 21 (MIC: 5.0–522 µg/ml) and 22 (MIC: 11–193 µg/ml) were sensitive to S. aureus and MRSA, and the most active dimer 21a (MIC: 5.0 µg/ml) was comparable to linezolid (MIC: 6.0 µg/ml) and vancomycin (MIC: 3.0 µg/ml) against the two strains, and it was 9.6‐fold more potent than oxacillin (MIC: 48 µg/ml) against MRSA. [ 48 ] In addition, this dimer was nontoxic toward human HEK and SH‐SY5Y cells.…”

Amino Alcohols as Potential Antibiotic and Antifungal Leads

“…As part of a series of studies we have developed a number of classes of biologically active molecules [ 15 , 16 , 17 , 18 , 19 , 20 ]. With our in-house compound library, we sought to examine one of our compound series, that were originally designed to target the aryl hydrocarbon receptor (AhR) ( Figure 1 ) [ 15 , 21 , 22 , 23 ], for activity against methicillin-resistant Staphylococcus aureus (MRSA), E. coli , Klebsiella pneumoniae , Acinetobacter baumannii and Pseudomonas aeruginosa ; and the yeasts Candida albicans and Cryptococcus neoformans .…”