Escaping from Flatland: Antimalarial Activity of sp3-Rich Bridged Pyrrolidine Derivatives

10 Nov 2020

Cox B, Duffy J, Zdorichenko V, Bellanger C, Hurcum J, Laleu B, Booker-Milburn KI, Elliott LD, Robertson-Ralph M, Swain CJ, Bishop SJ, Hallyburton I, Anderson M

ACS Medicinal Chemistry Letters
PMID: 33335673

Doi: 10.1021/acsmedchemlett.0c00486

Photo: BrianAJackson/iStock


We utilized synthetic photochemistry to generate novel sp-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) 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.

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