TY - JOUR

T1 - Design, Synthesis and Assay of Novel Methylxanthine-Alkynylmethylamine Derivatives as Acetylcholinesterase Inhibitors

AU - Reshetnikov, Danila V

AU - Ivanov, Igor D

AU - Baev, Dmitry S

AU - Rybalova, Tatyana V

AU - Mozhaitsev, Evgenii S

AU - Patrushev, Sergey S

AU - Vavilin, Valentin A

AU - Tolstikova, Tatyana G

AU - Shults, Elvira E

N1 - This research was funded by the Russian Science Foundation Research, grant number 18-13-00361.

PY - 2022/12/11

Y1 - 2022/12/11

N2 - 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.

AB - 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.

KW - Cholinesterase Inhibitors/chemistry

KW - Acetylcholinesterase/metabolism

KW - Molecular Docking Simulation

KW - Xanthines/pharmacology

KW - Structure-Activity Relationship

KW - Molecular Structure

KW - theophylline

KW - theobromine

KW - acetylcholinesterase inhibitor

KW - A3-coupling reactions

KW - caffeine

KW - molecular docking study

KW - methylxanthines

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85144551684&origin=inward&txGid=62d01171c55cc799dd37ef9a61c0c2db

UR - https://www.mendeley.com/catalogue/057e1ec5-47c0-3460-8ce4-aeee69838707/

U2 - 10.3390/molecules27248787

DO - 10.3390/molecules27248787

M3 - Article

C2 - 36557921

VL - 27

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 24

M1 - 8787

ER -