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Synthesis of exo-3-Amino-7-azabicyclo[2.2.1]heptanes as a Class of Malarial Aspartic Protease Inhibitors: Exploration of Two Binding Pockets


  • Dedicated to Professor Alain Krief


The increasing prevalence of drug-resistant strains of malaria-causing Plasmodium parasites necessitates the development of therapeutic agents that inhibit new biochemical targets. We herein describe the design, synthesis, and in vitro evaluation of a class of inhibitors that target the malarial aspartic proteases known as the plasmepsins. The title compounds feature a 7-azanorbornane skeleton that bears an exo-amino function, which was designed to interact with the catalytic dyad of aspartic proteases while providing vectors for the attachment of binding elements that target the flap and S1/S3 binding pockets at the enzyme active site. Their synthesis takes advantage of a solvent-free and highly diastereoselective conjugate addition of amines to bicyclic vinyl sulfones. Structural optimization based on a little-known conformational preference of aryl sulfones produced the most potent inhibitors of this new class. In vitro assays demonstrate that the title compounds are capable of potent (IC50 ≥ 10 nM) inhibition of plasmepsins, while remaining relatively weak inhibitors of the closely related human enzymes cathepsins D and E. The ideal occupation of the flap pocket is crucial for both potency and selectivity over the human proteases. Differently functionalized compounds were synthesized to gain new insights into the molecular recognition properties of this cavity. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)