Decoupling Neuroprotection from MAO Inhibition via Indane-to-Azaindane Bioisosteric Replacement of Rasagiline

Abstract Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with neuroprotective effects, whose dependence on MAO-B inhibition remains unclear. Here, indane-to-azaindane rasagiline isosteres (rac-2a and rac-2b) were developed to investigate whether neuroprotection can be decoupled from MAO-B inhibition. Direct regioselective oxidation of 4-azaindane catalyzed by Mn(OAc)2/tBuOOH afforded the key 4-azaindan-1-one intermediate (6a). In paraquat-insulted dopaminergic differentiated SH-SY5Y cells, both analogs showed neuroprotection at 10 and 100 μM, with rac-2b outperforming rasagiline. The azaindane analogs displayed markedly reduced MAO-B inhibition and no time-dependent inhibition. These findings demonstrate that rasagiline neuroprotection can be dissociated from MAO-B inhibition, supporting azaindane bioisosterism for exploring MAO-independent neuroprotection.