Optimization of pyrrolo[3,4‐f]indole‐5,7‐dione and indole‐5,6‐dicarbonitrile derivatives as inhibitors of monoamine oxidase

Abstract

In recent studies, we have investigated the monoamine oxidase (MAO) inhibition properties of pyrrolo[3,4‐f]indole‐5,7‐dione and indole‐5,6‐dicarbonitrile derivatives. Since numerous high potency MAO inhibitors are present among these chemical classes, the present study synthesizes 44 additional derivatives in an attempt to further derive structure‐activity relationships (SARs) and to establish optimal substitution patterns for MAO inhibition. The results show that, with the exception of one compound, all indole‐5,6‐dicarbonitrile derivatives (10) exhibit submicromolar IC50 values for the inhibition of MAO, with the most potent MAO‐A inhibitor exhibiting an IC50 value of 0.006 μM while the most potent MAO‐B inhibitor exhibits an IC50 value of 0.058 μM. Interestingly, an N‐oxide derivative (4c) also proved to be a potent and nonspecific MAO inhibitor. With the exception of one compound, all of the pyrrolo[3,4‐f]indole‐5,7‐diones (28) also exhibit submicromolar IC50 values for the inhibition of an MAO isoform. The most potent inhibitor exhibit an IC50 value of 0.011 μM for MAO‐A. This study proposes that high potency MAO inhibitors such as those investigated here, may act as lead compounds for the development of treatments for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression.