Indoles and 1-(3-(benzyloxy)benzyl)piperazines: Reversible and selective monoamine oxidase B inhibitors identified by screening an in-house compound library

The therapeutic indications for monoamine oxidases A and B (MAO-A and MAO-B) inhibitors that have emerged from biological studies on animal and cellular models of neurological and oncological diseases have focused drug discovery projects upon identifying reversible MAO inhibitors. Screening of our in-house academic compound library identified two hit compounds that inhibit MAO-B with IC50 values in micromolar range. Two series of indole (23 analogues) and 3-(benzyloxy)benzyl)piperazine (16 analogues) MAO-B inhibitors were derived from hits, and screened for their structure-activity relationships. Both series yielded low micromolar selective inhibitors of human MAO-B, namely indole 2 (IC50 = 12.63 +/- 1.21 mu M) and piperazine 39 (IC50 = 19.25 +/- 4.89 mu M), which is comparable to selective MAO-B inhibitor isatin (IC50 = 6.10 +/- 2.81 mu M), yet less potent in comparison to safinamide (IC50 = 0.029 +/- 0.002 mu M). Selective MAO-B inhibitors 2, 14, 38 and 39 exhibited favourable permeation of the blood-brain barrier and low cytotoxicity in the human neuroblastoma cell line SHSY5Y.

Automated summary

The therapeutic indications for monoamine oxidases A and B (MAO-A and MAO-B) inhibitors have led to the discovery of reversible MAO inhibitors based on biological studies. Two hit compounds were identified as MAO-B inhibitors from screening of a compound library, and derived two series of inhibitors. These selective MAO-B inhibitors showed favorable blood-brain barrier permeation and low cytotoxicity.