Synthesis of new acetylharmine derivatives and their neurotropic activity

Abstract

Alkaloids containing a β-carboline fragment are of significant interest as potential new physiologically active agents for the treatment of central nervous system disorders. The roots of Peganum harmala L. (family Zygophyllaceae) are a promising and readily available raw material for the production of active pharmaceutical substances. The β-carboline alkaloid harmine is a promising compound for the development of novel, original neurotropic drugs based on these alkaloids. The article considers the ways of synthesizing new compounds based on the alkaloid harmine and, simultaneously, studies the neurotropic activity of new harmine derivatives containing various substituents at the C-8 position. Harmine was selectively acetylated at the 8-position using acetyl chloride and tin tetrachloride, yielding 8-acetylharmine. This intermediate was then used to synthesize a series of novel harmine derivatives, including 8-{Z}-1-{Z}-(1-(arylidene)hydrazono)ethyl and 8-cinnamoyl analogs. The evaluation of the neurotropic action of samples of C-8 harmine derivatives was carried out on models of experimental stress using the “Open Field” and “Elevated Plus Maze” tests. Several compounds exhibited marked antidepressant activity with sedative effects comparable to those of amitriptyline. It was demonstrated that structural modifications at the C-8 position of harmine contribute to the generation of new pharmacophores capable of crossing the blood-brain barrier and modulating behavioral responses. In particular, the compounds 8-acetylharmine (2) and {(Z)-1-[(Z)-(2-arylidene)hydrazono]ethyl}-harmines (4–5), at a dose of 10 mg/kg, demonstrated behavioral features indicative of reduced anxiety levels in animals. These findings highlight the potential of β-carboline-based harmine derivatives for the development of novel neurotropic agents.

Keywords: β-carbolines, harmine, 8-acetylharmine, (Z)-hydrazono-8-acetylharmine, chalcone derivatives of harmine, neurotropic activity.