Bioorganic & Medicinal Chemistry Letters, 2020,35, 127781.
Development of sulfahydantoin derivatives as β-lactamase inhibitors
Pierre-Alexandre Paquet-CÔtÉ, Lorea Alejaldre, Camille Lapointe Verreault, Sophie M. C. Gobeil, Rosalie Lamoureux, Laurie BÉdard, Charles-Olivier Normandeau, ClaudÈle Lemay-St-Denis, Joelle N. Pelletier, Normand Voyer.
Abstract
Sulfahydantoin-based molecules may provide a means to counteract antibiotic resistance, which is on the rise. These molecules may act as inhibitors of β-lactamase enzymes, which are key in some resistance mechanisms. In this paper, we report on the synthesis of 6 novel sulfahydantoin derivatives by the key reaction of chlorosulfonyl isocyanate to form α-amino acid derived sulfamides, and their cyclization into sulfahydantoins. The synthesis is rapid and provides the target compounds in 8 steps. We investigated their potential as β-lactamase inhibitors using two common Class A β-lactamases, TEM-1 and the prevalent extended-spectrum TEM-15. Two compounds, 3 and 6, show substantial inhibition of the β-lactamases with IC50 values between 130 and 510 μM and inferred Ki values between 32 and 55 μM.