Design, Synthesis and Assay of Novel Methylxanthine–Alkynylmethylamine Derivatives as Acetylcholinesterase Inhibitors

Design, Synthesis and Assay of Novel Methylxanthine–Alkynylmethylamine Derivatives as Acetylcholinesterase Inhibitors Научная публикация

Журнал

Molecules
, E-ISSN: 1420-3049

Вых. Данные

Год: 2022, Том: 27, Номер: 24, Страницы: 8787 Страниц : 1 DOI: 10.3390/molecules27248787

Ключевые слова

methylxanthines; caffeine; theophylline; theobromine; A3-coupling reactions; acetylcholinesterase inhibitor; molecular docking study

Авторы

Reshetnikov Danila V. ¹ , Ivanov Igor D. ² , Baev Dmitry S. ¹ , Rybalova Tatyana V. ¹ , Mozhaitsev Evgenii S. ¹ , Patrushev Sergey S. ¹ , Vavilin Valentin A. ^2,3 , Tolstikova Tatyana G. ¹ , Shults Elvira E. ¹

Организации

1	N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences
2	The Federal Research Center Institute of Molecular Biology and Biophysics
3	Novosibirsk State University

Xanthine derivatives have been a great area of interest for the development of potent bioactive agents. Thirty-eight methylxanthine derivatives as acetylcholinesterase inhibitors (AChE) were designed and synthesized. Suzuki–Miyaura cross-coupling reactions of 8-chlorocaffeine with aryl(hetaryl)boronic acids, the CuAAC reaction of 8-ethynylcaffeine with several azides, and the copper(I) catalyzed one-pot three-component reaction (A3-coupling) of 8-ethynylcaffeine, 1-(prop-2-ynyl)-, or 7-(prop-2-ynyl)-dimethylxanthines with formaldehyde and secondary amines were the main approaches for the synthesis of substituted methylxanthine derivatives (yield 53–96%). The bioactivity of all new compounds was evaluated by Ellman’s method, and the results showed that most of the synthesized compounds displayed good and moderate acetylcholinesterase (AChE) inhibitory activities in vitro. The structure-activity relationships were also discussed. The data revealed that compounds 53, 59, 65, 66, and 69 exhibited the most potent inhibitory activity against AChE with IC50 of 0.25, 0.552, 0.089, 0.746, and 0.121 μM, respectively. The binding conformation and simultaneous interaction modes were further clarified by molecular docking studies.

Reshetnikov D.V. , Ivanov I.D. , Baev D.S. , Rybalova T.V. , Mozhaitsev E.S. , Patrushev S.S. , Vavilin V.A. , Tolstikova T.G. , Shults E.E.
Design, Synthesis and Assay of Novel Methylxanthine–Alkynylmethylamine Derivatives as Acetylcholinesterase Inhibitors
Molecules. 2022. V.27. N24. P.8787. DOI: 10.3390/molecules27248787 WOS РИНЦ

Поступила в редакцию:	2 нояб. 2022 г.
Принята к публикации:	7 дек. 2022 г.
Опубликована online:	11 дек. 2022 г.

Web of science	WOS:000902786100001
РИНЦ	54086345
OpenAlex	W4312210272