6-Bromoindolglyoxylamido derivatives as antimicrobial agents and antibiotic enhancers
- Bioorg Med Chem. 2019 May 15;27(10):2090-2099. doi: 10.1016/j.bmc.2019.04.004.
- 1. School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
- 2. Aix Marseille Univ, INSERM, SSA, MCT, Faculté de pharmacie, 27 bd Jean Moulin, 13385 Marseille, France.
- 3. YELEN, 10 bd Tempête, 13820 Ensues la Redonne, France.
- 4. Laboratoire Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS, Muséum National d'Histoire Naturelle, 57 rue Cuvier (C.P. 54), 75005 Paris, France.
- 5. School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: [email protected].
The combination of increased incidence of drug-resistant strains of bacteria and a lack of novel drugs in development creates an urgency for the search for new antimicrobials. Initial screening of compounds from an in-house library identified two 6-bromoindolglyoxylamide polyamine derivatives (3 and 4) that exhibited intrinsic antimicrobial activity towards Gram-positive bacteria, Staphylococcus aureus and S. intermedius with polyamine 3 also displaying in vitro Antibiotic enhancing properties against the resistant Gram-negative bacterium Pseudomonas aeruginosa. A series of 6-bromo derivatives (5-15) were prepared and biologically evaluated, identifying analogues with enhanced Antibacterial activity towards Escherichia coli and with moderate to excellent Antifungal properties. Polyamine 3, which includes a spermine chain, was the most potent of the series - its mechanism of action was attributed to rapid membrane permeabilization and depolarization in both Gram-positive and Gram-negative bacteria.