Synthesis of acetamide derivatives of octahydrochromene with arylpiperazine moiety, perspective inhibitors of the Tdp1 enzyme

Lidia Vasilchenko; Nikolay Li-Zhulanov; Konstantin Volcho; Alexandra Zakharenko; Olga Lavrik; Nariman Salakhutdinov

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Synthesis of acetamide derivatives of octahydrochromene with arylpiperazine moiety, perspective inhibitors of the Tdp1 enzyme

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Nariman Salakhutdinov

¹ Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russia
² Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, Russia

Academic Editor: Maria Emília Sousa

Published: 01 November 2023 by MDPI in 9th International Electronic Conference on Medicinal Chemistry session New Small molecules as drug candidates

https://doi.org/10.3390/ECMC2023-15657 (registering DOI)

Abstract:

Earlier in our laboratory, amide derivatives of octahydrochromene were obtained by a three-component Prince-Ritter reaction. These compounds exhibited inhibiting activity against the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1) in the low micromolar range [1]. Based on molecular modeling results, it was proposed that acetamide derivatives of octahydrochromene 3, which contain an arylpiperazine moiety, may exhibit inhibitory activity against Tdp1.

The purpose of this work is the synthesis of chiral acetamide derivatives of octahydrochromene with an arylpiperazine moiety, starting from 2-chloroacetamide, p-tolyloctahydrochromene 1, and substituted arylpiperazines 2.

The alkylation reaction was carried out in acetonitrile by boiling in the presence of К₂СО₃, after purification by column chromatography the yields of the target compounds ranged from 11 to 89%.

Compound 3а didn’t exhibit inhibitory activity against Tdp1, (IC₅₀> 50µM), while compounds 3b-d showed inhibitory activity ranged from 19.3 to 10.3 µМ.

Keywords: tyrosyl-DNA phosphodiesterase 1 inhibitors ; octahydro-2H-chromene; alkylation reaction

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