The synthesis and evaluation of benzosuberone derivatives as inhibitors of monoamine oxidase

Abstract

Monoamine oxidase (MAO) is responsible for the catabolism of neurotransmitters such as serotonin and dopamine in the central nervous system and peripheral tissues. MAO inhibitors such as selegiline play a vital part in the treatment of neurodegenerative diseases including Parkinson’s disease (PD) and Alzheimer’s disease. Inhibition of MAO-B elevates dopamine levels in the striatum and provides symptomatic relief for patients with PD. MAO-B inhibitors can be used as monotherapy or in combination with L-dopa to provide symptomatic relief. 1-Benzosuberone and structural derivatives thereof have not yet been evaluated as potential MAO inhibitors. 1-Benzosuberone, however, is structurally similar to rasagiline, a well-known MAO-B inhibitor. 1-Benzosuberone also is structurally similar to α-tetralone, which is a moderately potent reversible inhibitor of MAO-B. In this study, 1-benzosuberone was used as lead compound for the design of new MAO inhibitors. 1-Benzosuberone derivatives were thus synthesised and the structures of the compounds that were successfully synthesised were verified by NMR and MS. The purities of the compounds were determined by HPLC. Although difficulties were encountered during synthesis, four 1-benzosuberone derivatives were successfully synthesised. Recombinant human MAO-A and MAO-B were used as enzyme sources to determine the MAO inhibition potencies of 1-benzosuberone and the synthesised derivatives. The inhibition potencies were expressed as the IC50 values. The results showed that three 1-benzosuberone derivatives display moderately potent inhibition of MAO-B. 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-5-yl acetate is the most potent MAO-B inhibitor with an IC50 value of 8.31 μM. Weak or no inhibition of MAO-A was observed for the derivatives. 1-Benzosuberone showed no MAO-A inhibition and only weak inhibition of MAO-B. The reversibility of MAO inhibition was investigated by dialysis. The reversibility studies showed that the three most active 1-benzosuberone derivatives are reversible MAO-B inhibitors and that 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl acetate potentially exhibit tight binding to MAO-B. Lineweaver-Burk plots were constructed to investigate the mode of MAO-B inhibition of the three most active derivatives. The results showed that the 1-benzosuberone derivatives are competitive inhibitors of MAO-B and the Ki values were determined, which ranged from 8.40 to 17.7 μM. Docking studies were carried out to determine potential binding orientations and interactions of the 1-benzosuberone derivatives to the MAO enzymes. Although the docking yielded no conclusive conclusions, some insight into the binding orientations and interactions that are possible for the 1-benzosuberone derivatives were gained. To conclude, 1-benzosuberone derivatives with moderately potent and specific MAO-B inhibition activities were discovered in this study. These 1-benzosuberone derivatives are reversible and competitive inhibitors of MAO-B and may represent new lead compounds for the future design of MAO-B inhibitors to be used in the treatment of PD.