Abstract
The emergence of multidrug resistant bacteria has prioritized the development of new antibiotics. N-substituted pantothenamides, analogs of the natural compound pantetheine, were reported to target bacterial coenzyme A biosynthesis, but these compounds have never reached the clinic due to their instability in biological fluids. Plasma-stable pantothenamide analogs could overcome these issues. We first synthesized a number of bioisosteres of the prototypic pantothenamide N7-Pan. A compound with an inverted amide bond (CXP18.6-012) was found to provide plasma-stability with minimal loss of activity compared to the parent compound N7-Pan. Next, we synthesized inverted pantothenamides with a large variety of side chains. Among these we identified a number of novel stable inverted pantothenamides with selective activity against Gram-positive bacteria such as staphylococci and streptococci, at low micromolar concentrations. These data provide future direction for the development of pantothenamides with clinical potential.
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Details
1 Radboud University Medical Center, Department of Dermatology, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382)
2 Chiralix, Nijmegen, The Netherlands (GRID:grid.10417.33)
3 Radboud University Medical Center, Department of Medical Microbiology, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382)
4 Hermkens Pharma Consultancy, Oss, The Netherlands (GRID:grid.10417.33)
5 Radboud University, Institute for Molecules and Materials, Nijmegen, The Netherlands (GRID:grid.5590.9) (ISNI:0000000122931605)