Patrick A. M. Jansen , 1 , Danique A. van der Krieken 1 , Peter N. M. Botman 2 , Richard H. Blaauw 2 , Lorenzo Cavina 2 , Eline M. Raaijmakers 2 , Erik de Heuvel 2 , Julia Sandrock 2 , Lian J. Pennings 3 , Pedro H. H. Hermkens 4 , Patrick L. J. M. Zeeuwen 1 , Floris P. J. T. Rutjes 5 , Joost Schalkwijk , 1
6 June 2019
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.