An investigation of the monoamine oxidase inhibition properties of pyrrolo[3,4‐f]indole‐5,7‐dione and indole‐5,6‐dicarbonitrile derivatives

Abstract

Hit, Lead & Candidate Discovery In recent studies, we have shown that pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives act as good potency in vitro inhibitors of the monoamine oxidase (MAO) enzymes. To expand on these series and to further derive structure-activity relationships (SARs) for MAO inhibition, in the present study we synthesized additional homologs and related analogs of these chemical classes. Analyzes of the MAO inhibition properties of the synthesized compounds show that among the pyrrolo[3,4-f]indole-5,7-dione derivatives good potency MAO inhibitors exist as exemplified by 10, which possesses IC values for the inhibition of MAO-A and MAO-B of 0.023 and 0.178 µM, respectively. Among thirteen pyrrolo[3,4-f]indole-5,7-diones, nine compounds exhibit IC values for the inhibition of an MAO isoform in the submicromolar range. It may be concluded that active MAO inhibitors, such as 10 represent suitable leads for the development of drugs for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression. MAO inhibitors are also of interest for the treatment of prostate cancer, certain types of cardiomyopathies and Alzheimer's disease.

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

“…New synthetic approaches for the synthesis of 3‐chloro‐, 3‐bromoindole‐5,6‐dicarbonitriles, 3‐chloro‐, 3‐bromopyrrolo[3,4‐ f ]indole‐5,7‐diones, and the corresponding 1‐hydroxy derivatives (Chirkova, ; Chirkova & Filimonov, ) have been developed and are reported in literature (Chirkova et al, ; Chirkova, Kabanova, et al, ; Chirkova, Kabanova, Filimonov, Abramov, et al, ; Chirkova, Kabanova, Filimonov, Samet, et al, ). These syntheses are based on the chlorination or bromination of 2‐aryl‐1‐hydroxyindole‐5,6‐dicarbonitriles ( 13 ) or corresponding pyrrolo[3,4‐ f ]indole‐5,7‐diones ( 16 ) with N ‐chloro‐, N ‐bromosuccinimide (Schemes ).…”

“…Methylated compounds 6c , 8a – b , 9g – h , 11d – f , and 12e – g were obtained by treating the corresponding NH ‐indoles with methyl iodide in the presence of K 2 CO 3 , which gave the target compounds in yields of up to 78% (Schemes ). It should be noted that, in contrast to 1‐methoxypyrrolo[3,4‐ f ]indole‐5,7‐diones (Chirkova, Kabanova, Filimonov, Abramov, et al, ), it was not possible to selectively obtain the monomethylated products by akylation with methyl iodide, since both NH groups are equally reactive towards alkylation. Conditions for the regioselective synthesis of 6‐ N ‐methylpyrrolo[3,4‐ f ]indole‐5,7‐diones therefore could not be established.…”

“…Compounds 7a-b, 8a-b, and 15 were synthesized according the literature protocol (Chirkova, Chernov, et al, 2017), while 9i-l and 10a-d were synthesized as described previously (Chirkova, Kabanova, Filimonov, Samet, et al, 2018). Compounds 13 (Filimonov et al, 2012), 14 (Chirkova et al, 2015), 16, 9m (Chirkova et al, 2016), and 17 (Chirkova, Kabanova, Filimonov, Abramov, et al, 2018) were synthesized as described previously. The physical characterizations of the compounds cited below are given in Supporting Information.…”

“…The refinement was carried out with the SHELXTL program (Sheldrick, 2015). indole-5,7-diones, and the corresponding 1-hydroxy derivatives (Chirkova, 2017; have been developed and are reported in literature (Chirkova et al, 2015;Chirkova, Kabanova, et al, 2017;Chirkova, Kabanova, Filimonov, Abramov, et al, 2018;Chirkova, Kabanova, Filimonov, Samet, et al, 2018). These syntheses are based on the chlorination or bromination of 2-aryl-1-hydroxyindole-5,6-dicarbonitriles (13) It should be noted that the dibromo-N-oxides which formed as intermediates are more labile than the corresponding dichloro-Noxides, and were thus readily transformed to the corresponding 3-bromo-1-hydroxyindoles 14 and 17 by simply boiling in isopropyl alcohol.…”

“…Considering the therapeutic importance of MAO, the discovery and design of high potency inhibitors are pursued by many research groups in both academia and pharmaceutical industry (Carradori, Secci, & Petzer, 2018). We have previously reported on the human MAO inhibition properties of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives (Chirkova et al, 2015(Chirkova et al, , 2016Chirkova, Kabanova, Filimonov, Abramov, et al, 2018). Good MAO inhibition potencies were recorded for some of these derivatives, as exemplified by compounds 1-3 ( Figure 1).…”