Escaping from Flatland: Antimalarial Activity of sp 3 -Rich Bridged Pyrrolidine Derivatives.

We utilized synthetic photochemistry to generate novel sp ³ -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.
Competing Interests: The authors declare the following competing financial interest(s): B.C. and K.I.B.M. are employees of their respective universities and cofounders and owners of Photodiversity Ltd. J.D. and B.L. are employees of Medicines for Malaria Venture (MMV).
(© 2020 American Chemical Society.)