Evaluation of nitrocatechol bearing cyclic chalcones and related analogues as dual monoamine oxidase and catechol-O-methyltransferase inhibitors
Abstract
Parkinson’s disease (PD) is one of the leading causes of disability in the world. A better understanding of the aetiology of this disorder will lead to better medications, and would improve the quality of life for millions of patients worldwide. By inhibiting the degradation of dopamine in the midbrain, enzyme inhibitors of both catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) are important drugs in the treatment of PD. Dopamine is degraded both peripherally and centrally by COMT to yield 3-O-methyldopa, which can reduce L-dopa absorption at the brain-blood barrier. COMT inhibitors have shown a great promise in reducing akinesia in controlled clinical trials. The MAO-catalysed degradation of dopamine yields reactive oxygen species which may accelerate neuronal degeneration in PD. Thus, MAO-B inhibitors are specifically used for PD pharmacotherapy. MAO-B inhibitors are considered to be safe medication with excellent safety profiles.
By employing the hybrid theory for the design of new drugs, this study used the chalcone structure and the nitrocatechol moiety to design dual inhibitors for COMT and MAO. By using acid catalysed aldol condensation, aith a refluxtime of 24 – 26 hours, a series of nitrocatechol derivatives of chalcone was synthesised in good yields (71–84%). Bicyclic systems were also incorporated into the chalcone structure. An analysis of the structure-activity relationships showed an increase in MAO-B inhibition activity with the inclusion of either a methoxy or hydroxy group on the 5-position of the indanone bicyclic system. Overall the inhibition of MAO-B was moderate, with none of the compounds exhibiting IC50 values in the nanomolar range. The most potent IC50 for MAO-B inhibition was 7.26 μM for compound G, which bears chromanone as the bicyclic system. In contrast to their MAO inhibition potencies, the chalcones were good potency COMT inhibitors with IC50 values in the nanomolar range. The most potent COMT inhibitor was compound C with an IC50 value of 0.163 μM. The potency of this compounds can be attributed to the addition of the nitrocatechol moiety. This study concludes that the indanone bicyclic system substituted with methoxy or hydroxyl groups on the 5-position has potential for the design of dual inhibitors of MAO-B and COMT.
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