Escaping from Flatland: Antimalarial Activity of sp<sup>3</sup>-Rich Bridged Pyrrolidine Derivatives
Brian J. Cox, James Duffy, Victor Zdorichenko, Corentin Bellanger, Jessica Hurcum, Benoı̂t Laleu, Kevin I. Booker‐Milburn, Luke D. Elliott, Michael Robertson-Ralph, Christopher J. Swain, Stephen J. Bishop, Irene Hallyburton, Mark Anderson
Abstract
We utilized synthetic photochemistry to generate novel sp3-rich scaffolds and report the design, synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]hexane scaffold. Preliminary antimalarial screening of the library provided promising compounds with activity in the 1–5 μM range with an enhanced hit rate. Further evaluation (solubility, drug metabolism and pharmacokinetics (DMPK), and toxicity) of a selected compound (9) suggested that this series represents an excellent opportunity for further optimization with the framework offering multiple opportunities for the addition of uniquely vectorally positioned extra functionality.