Monoamine oxidases (MAOs) are a family of enzymes that catalyze the oxidative deamination of monoamines. They are found bound on the outer membrane of mitochondria and are present in almost all the body tissues with varying percentage. Two isoforms, MAO-A and MAO-B, where discovered and the important difference is in the shape of their active site, which also impacts their ability to metabolize different substrates. MAOs are important in the breakdown of monoamines ingested by food and also serve to inactivate monoamine neurotransmitters. Because of the latter, they are involved in a number of neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. Several MAO inhibitors have been developed that inhibit one or both of the isoforms for the purpose of treating these diseases.
As part of this master's thesis we synthesized 5-(benzyloxy) indole analogs, as potential MAO-B inhibitors, based on the previously tested compound 1-(4-acetylpiperazin-1-yl)-2- (5-(benzyloxy)-1H-indol-1-yl)ethane-1-one 4, which showed an inhibitory effect on MAO-B. We used two different protocols for the synthesis of our analogs that consisted of reactions N-alkylation, N-acylation, and in some cases ester hydrolysis and removal of Boc protection group. Synthesized analogs differed in substituents attached to the nitrogen of the piperazine ring, or alternatively, the piperazine ring was replaced with a ring without a basic center on position 4.
We evaluated synthesized final compounds with biochemical testing on human MAO-A and MAO-B and determined their inhibitory potencies. We confirmed that our compounds were more potent at inhibiting MAO-B isoform. The basic center was important for inhibition, because comparable derivatives with the piperazine ring had better performance than those without it. The presence of an unsaturated bond in the alkyl chain has also been shown to have a favorable effect on the inhibitory potency; in the case of saturated chains, the prolongation of the chain decreased activity. The most potent inhibitor was 2-(5-(benzyloxy)-1H-indol-1-yl)-1-(4-benzylpiperazin-1-yl) ethane-1-one (compound 12) with IC50 = 1.95 ?M, which was the closest one to the nanomolar concentrations we wanted to achieve.
To conclude, the compound 12 represents an important starting point for further development of new potent MAO-B inhibitors as potential active substances in neurodegenerative conditions.