Design, synthesis and biological evaluation of novel [5,5]-fused thiazolidine/oxazolidine inhibitors for targeting prolyl oligopeptidase

In the course of developing prolyl oligopeptidase (POP) inhibitors, our group has synthesized different series of inhibitors ranging from chiral bicyclic scaffolds to peptidomimetics, the design of which has been a product of in silico derived high-throughput screening followed by docking-guided optimization. In line with our objective to rigidify a known pseudopeptidic inhibitor, we proposed to develop [5,5]-fused thiazolidine-based inhibitors. This scaffold was previously abandoned due to unforeseen oxidation by cytochrome P450 and subsequent isomerization to yield complex mixtures of metabolites with unknown pharmacodynamic properties. However, the ease of functionalization by which this scaffold could be transformed to mimic the pseudo-peptide and its ideal geometry warranted revisiting. We envision the topology of the bicyclic core can be modified to exhibit either additional steric or electronic constraints, and as such, circumvent our initial dilemma. Herein, we report our findings on an expedited series obtained in fewer than 10 steps, followed by testing in recombinant human POP and living neurons.