Synthesis and evaluation of enzyme inhibition by novel TT01001 derivatives as monoamine oxidase B inhibitors

Monoamine oxidase (MAO) B is a promising target for treating stroke reperfusion injury, Parkinson’s disease as well as other neurodegenerative diseases. Pharmacological inhibitors of this enzyme have demonstrated the ability to modulate critical neurotransmitter levels, decrease damaging reactive oxygen species and neuroinflammation, and improve mitochondrial dysfunction. We identified TT01001 from a pilot screen which showed good potency for inhibiting MAO-B, with a half-maximal inhibitory concentration below 10 μM. In this study, we explored quantitative-structure activity relationships (QSAR) of 60 derivatives of TT01001 evaluated for MAO-B. Approximately half of these 60 compounds showed IC₅₀ values superior to that of TT01001 (10). Two of the compounds, 37 and 57, displayed improved MAO-B potency and selectivity from MAO-A, with IC₅₀ values of 270 and 460 nM respectively. The mode of inhibition of was determined to be both competitive and reversible, and both compounds exhibited moderate ability to passively diffuse across biological membranes. These compounds can be offered as-is for subsequent drug development processes, or they can be derivatized further using the structure–activity relationship information found herein.