This research concentrates on the optimization of a series of novel dipeptidyl allyl sulfones as clan CA cysteine protease inhibitors.  The primary target is cruzain, an essential metabolic protease of the parasitic vector of Chagas' disease, T. cruzi. The structure of the inhibitors consists of a R1-Phe-R2-AS-Ph scaffold (AS = allyl sulfone). First vinyl sulfone analogs were synthesized followed by isomerisation to allyl sulfones using n-butyl lithium and t-butyl hydroperoxide. The successful formation and stereochemistry of the allyl sulfone moiety was heavily impacted by sterics, temperature, and base strength. The inhibitors were assayed with three clan CA cysteine proteases (cruzain, cathepsin B, and calpain I) as well as one serine protease (trypsin). The most potent inhibitor, (E)-Mu-Phe-Hfe-AS-Ph, displayed 10-fold selectivity for cruzain with a kobs/[I] of 6,080 � 1,390 M-1s-1.

Evaluation of a series of peptidyl allyl sulfones as clan CA cysteine protease inhibitors

243rd National Meeting (2012)

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