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Influence of the γ-carboline and carbazole pharmacophore moieties on anticholinesterase and antiradical activity of multifunctional agents for the treatment of neurodegenerative diseases

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Russian Chemical Bulletin Aims and scope

Abstract

A comparative analysis of the esterase profile and antiradical activity of two groups of hybrid compounds, viz., tetrahydro-γ-carboline conjugates with carbazoles and tetrahydrocarbazoles (I) and carbazole conjugates with carbazoles and tetrahydrocarbazoles (II), was performed. The replacement of the tetrahydro-γ-carboline moiety (conjugates I) by the carbazole group (conjugates II) was shown to significantly reduce the ability of the compounds to inhibit butyrylcholinesterase (BChE) and scavenge free radicals. The tetrahydro-γ-carboline–tetrahydrocarbazole combination is optimal in terms of both high anti-BChE activity and free radical scavenging ability. According to molecular modeling calculations, the stronger binding of tetrahydro-γ-carboline conjugates (I) in the BChE active site compared to carbazole conjugates (II) is attributed to the ability of I to form ionic and π-cation interactions with amino acid residues lining the BChE gorge. Therefore, conjugates of tetrahydro-γ-carboline and tetrahydrocarbazole derivatives are the most promising compounds for the design of new multitarget drugs combining cognitive-stimulating and antioxidant properties.

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Authors and Affiliations

  1. Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severnyi proezd, 142432, Chernogolovka, Moscow Region, Russian Federation

    G. F. Makhaeva, N. P. Boltneva, N. V. Kovaleva, E. V. Rudakova, A. Yu. Aksinenko & V. B. Sokolov

  2. Institute of Problems of Chemical Physics, Russian Academy of Sciences, 1 prosp. Akad. Semenova, 142432, Chernogolovka, Moscow Region, Russian Federation

    N. V. Kovaleva

  3. N. M. Emanuel Institute of Biochemical Physics, Russian Academy of Science, 4 ul. Kosygina, 119334, Moscow, Russian Federation

    S. V. Lushchekina

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  1. G. F. Makhaeva
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  2. N. P. Boltneva
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  3. N. V. Kovaleva
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  6. A. Yu. Aksinenko
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Correspondence to G. F. Makhaeva.

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Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1724–1731, September, 2018.

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Makhaeva, G.F., Boltneva, N.P., Kovaleva, N.V. et al. Influence of the γ-carboline and carbazole pharmacophore moieties on anticholinesterase and antiradical activity of multifunctional agents for the treatment of neurodegenerative diseases. Russ Chem Bull 67, 1724–1731 (2018). https://doi.org/10.1007/s11172-018-2282-5

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