Monoamine oxidase (MAO) is a flavoenzyme that catalyzes the oxidative deamination of monoamines. There are two known isoforms of the enzyme, namely MAO-A and MAO-B. Both are present in most tissues albeit in different proportions. The two are mainly distinguished by the shape of their active sites and consequently by substrate specificity. Their main function is inactivation of monoamine neurotransmitters, but they also play a crucial role in the breakdown of dietary monoamines. Selective inhibitors of MAO-A are primarily used in the treatment of depression and anxiety disorders, whereas MAO-B inhibitors have a therapeutic role in the treatment of Parkinson’s disease, either as monotherapy or as an add-on treatment. Recently, scientific studies of MAO inhibitors have been primarily focused on their inherent neuroprotective properties.
In the experimental part of this Master’s thesis we designed and synthesized 1-(3-benzyloxy)benzyl)piperazine structural analogues based on a commercially acquired 1-benzhydryl-4-(3-(benzyloxy)benzyl)piperazine, which inhibited human (h)MAO-B in a previously performed test with an IC50 value of 34,8 μM. We kept the (benzyloxy)benzyl fragment untouched in all of the analogues and inserted changes to the structures by attaching different substituents to the nitrogen of the piperazine ring, or alternatively, by virtue of a bioisosteric replacement of the piperazine ring. Most of the analogue compound synthesis was carried using N-alkylation or reductive amination reactions. We managed to successfully resynthesize our hit compound and further 16 more analogues, all of which were biochemically assayed on recombinant hMAO-A and hMAO-B enzymes and assigned an IC50 value or the residual activity of the enzyme RA (%). None of the synthesized compounds managed to obtain an IC50 activity in the desired nanomolar concentrations, yet we can still be pleased with the results, since 11 of them inhibited hMAO-B with IC50 values between ranging from 19 to 71 μM. With the lone exception of compound 10, all of the derivatives where more potent inhibitors of MAO-B. Interestingly, after resynthesis, the hit proved to be completely inactive. With the use of relatively simple and short synthesis protocols, we managed to prepare selective hMAO-B inhibitors, which can serve as a basis for the further optimization of hMAO-B inhibitors.
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