TY - JOUR

T1 - A versatile synthetic approach to various 5-alkynyl modified isatin derivatives

T2 - Cytotoxicity, acetylcholinesterase inhibition activity and molecular modeling study

AU - Cheremnykh, Kirill P

AU - Ivanov, Igor D

AU - Hamad, Mohammad S

AU - Khlebnikov, Andrey I

AU - Savelyev, Victor A

AU - Pokrovsky, Mikhail A

AU - Pokrovsky, Andrey G

AU - Shults, Elvira E

N1 - This research was supported by the Russian Science Foundation: grant No. 23-73-00077 (synthesis and spectroscopic studies) and grant No. FGMU-2025-0004 (biological experiments). A versatile synthetic approach to various 5-alkynyl modified isatin derivatives: Cytotoxicity, acetylcholinesterase inhibition activity and molecular modeling study / K. P. Cheremnykh, I. D. Ivanov, M. S. Hamad, A. I. Khlebnikov, V. A. Savelyev, M. A. Pokrovsky, A. G. Pokrovsky., E. E. Shults // Bioorganic Chemistry. - Т. 165. - С. 109038

PY - 2025/10

Y1 - 2025/10

N2 - Isatin derivatives have been of great interest in drug development research. 5-Alkynyl substituted isatin derivatives with anticancer potential and acetylcholinesterase inhibition (AChE) activity are designed and synthesized. The copper(I) catalyzed one-pot three-component reaction (AChauhan et al. (2021)3-coupling) of new 3-(1,3-dioxolane)-5-(ethynyl)isatins with formaldehyde and secondary amines or the Sonogashira cross-coupling reaction of C-3 protected iodoisatins with fluoro-N-(prop-2-ynyl)benzamide and prop-2-ynyl 4-fluorobenzoate were the main approaches for the synthesis of 5-(3-X-prop-1-yn-1-yl) substituted isatin derivatives (yield 53-87 %). 1-Benzyl-5-(prop-1-yn-1-yl)indoline-2,3-diones are smoothly formed by refluxing of 3-(1,3-dioxolane)-5-(propynyl)isatins in hydrochloric acid/MeOH (1:9, v/v). Results of in vitro biological assays (MTT-test) revealed that new 3-(1,3-dioxolane)-5-(3-X-prop-1-yn-1-yl)-1-benzylisatin derivatives are exhibited remarkable cytotoxicity against human cervical (C 33 A and CaSki), breast (MCF-7), prostate (DU-145) and glioblastoma (SNB-19 and T98G) cancer cell lines within low micromolar GI50 values. Additionally, all new compounds demonstrated relatively low cytotoxicity against the normal epithelial VERO cells (GI50 > 70 μM), indicating good selectivity. Moreover, the appropriate isatin derivatives displayed good and moderate acetylcholinesterase inhibition activity in vitro (Ellman' s method) with IC50 up to 1.0-3.7 μM comparable to that for clinically used galantamine. Based on the results of in silico experiments the isatin derivatives bearing 5-(prop-1-yn-1-yl) substituents are promising for further search of acetylcholinesterase inhibitors in this series of compounds.

AB - Isatin derivatives have been of great interest in drug development research. 5-Alkynyl substituted isatin derivatives with anticancer potential and acetylcholinesterase inhibition (AChE) activity are designed and synthesized. The copper(I) catalyzed one-pot three-component reaction (AChauhan et al. (2021)3-coupling) of new 3-(1,3-dioxolane)-5-(ethynyl)isatins with formaldehyde and secondary amines or the Sonogashira cross-coupling reaction of C-3 protected iodoisatins with fluoro-N-(prop-2-ynyl)benzamide and prop-2-ynyl 4-fluorobenzoate were the main approaches for the synthesis of 5-(3-X-prop-1-yn-1-yl) substituted isatin derivatives (yield 53-87 %). 1-Benzyl-5-(prop-1-yn-1-yl)indoline-2,3-diones are smoothly formed by refluxing of 3-(1,3-dioxolane)-5-(propynyl)isatins in hydrochloric acid/MeOH (1:9, v/v). Results of in vitro biological assays (MTT-test) revealed that new 3-(1,3-dioxolane)-5-(3-X-prop-1-yn-1-yl)-1-benzylisatin derivatives are exhibited remarkable cytotoxicity against human cervical (C 33 A and CaSki), breast (MCF-7), prostate (DU-145) and glioblastoma (SNB-19 and T98G) cancer cell lines within low micromolar GI50 values. Additionally, all new compounds demonstrated relatively low cytotoxicity against the normal epithelial VERO cells (GI50 > 70 μM), indicating good selectivity. Moreover, the appropriate isatin derivatives displayed good and moderate acetylcholinesterase inhibition activity in vitro (Ellman' s method) with IC50 up to 1.0-3.7 μM comparable to that for clinically used galantamine. Based on the results of in silico experiments the isatin derivatives bearing 5-(prop-1-yn-1-yl) substituents are promising for further search of acetylcholinesterase inhibitors in this series of compounds.

KW - A3-coupling reactions

KW - Acetylcholinesterase inhibitors

KW - Cytotoxicity

KW - Indole-1H-2,3-dione

KW - Isatin

KW - Molecular docking study

KW - Sonogashira reaction

KW - Acetylcholinesterase/metabolism

KW - Humans

KW - Models, Molecular

KW - Cholinesterase Inhibitors/pharmacology

KW - Structure-Activity Relationship

KW - Alkynes/chemistry

KW - Dose-Response Relationship, Drug

KW - Antineoplastic Agents/pharmacology

KW - Animals

KW - Cell Line, Tumor

KW - Molecular Docking Simulation

KW - Molecular Structure

KW - Cell Proliferation/drug effects

KW - Isatin/pharmacology

KW - Drug Screening Assays, Antitumor

UR - https://pubmed.ncbi.nlm.nih.gov/41037862/

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=105017784843&origin=inward

UR - https://www.mendeley.com/catalogue/005bff2e-8430-33f8-9ec7-308eb3b518e4/

U2 - 10.1016/j.bioorg.2025.109038

DO - 10.1016/j.bioorg.2025.109038

M3 - Article

C2 - 41037862

VL - 165

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

SN - 0045-2068

M1 - 109038

ER -