Design, Synthesis, and Biological Evaluation of Novel Multitarget 7-Alcoxyamino-3-(1,2,3-triazole)-coumarins as Potent Acetylcholinesterase Inhibitors

Nadur, Nathalia F.; Ferreira, Larissa de A. P.; Franco, Daiana P.; de Azevedo, Luciana L.; Caruso, Lucas; Honório, Thiago da S.; Furtado, Priscila de S.; Simon, Alice; Cabral, Lucio M.; Werner, Tobias; Stark, Holger; Kümmerle, Arthur E.

doi:10.3390/ph18091398

Open AccessArticle

Design, Synthesis, and Biological Evaluation of Novel Multitarget 7-Alcoxyamino-3-(1,2,3-triazole)-coumarins as Potent Acetylcholinesterase Inhibitors

by

Nathalia F. Nadur

¹

,

Larissa de A. P. Ferreira

¹,

Daiana P. Franco

¹,

Luciana L. de Azevedo

¹,

Lucas Caruso

¹

,

Thiago da S. Honório

²

,

Priscila de S. Furtado

²,

Alice Simon

²

,

Lucio M. Cabral

²,

Tobias Werner

³

,

Holger Stark

³

and

Arthur E. Kümmerle

^1,*

¹

Laboratory of Molecular Diversity and Medicinal Chemistry (LaDMol-QM), Graduate Program in Chemistry (PPGQ), Institute of Chemistry, Federal Rural University of Rio de Janeiro, Rio de Janeiro 23897-000, Brazil

²

Cell Culture Laboratory (LabCel), Department of Drugs and Pharmaceutics, Faculty of Pharmacy, Federal Rural University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil

³

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Duesseldorf, Germany

^*

Author to whom correspondence should be addressed.

Pharmaceuticals 2025, 18(9), 1398; https://doi.org/10.3390/ph18091398

Submission received: 12 August 2025 / Revised: 10 September 2025 / Accepted: 12 September 2025 / Published: 17 September 2025

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Professor Carlos Alberto Manssour Fraga: Medicinal Chemistry’s Efforts to Discover Novel Bioactive Molecules for Complex Diseases)

Download

Browse Figures

Versions Notes

Abstract

Background: Multitarget-directed ligands (MTDLs), particularly those combining cholinesterase inhibition with additional mechanisms, are promising candidates for Alzheimer’s disease (AD) therapy. Based on our previous identification of a dual-active coumarin derivative, we designed a new series of 7-alkoxyamino-3-(1,2,3-triazole)-coumarins. Methods: These compounds were synthesized by a new Sonogashira protocol and evaluated for AChE and BChE inhibition, enzymatic kinetics, molecular docking, neurotoxicity in SH-SY5Y cells, neuroprotection against H₂O₂-induced oxidative stress, and additional interactions with H₃R and MAOs. Results: All derivatives inhibited AChE with IC₅₀ values of 4–104 nM, displaying high selectivity over BChE (up to 686-fold). Kinetic and docking studies indicated mixed-type inhibition involving both CAS and PAS. The most potent compounds (1h, 1j, 1k, 1q) were non-neurotoxic up to 50 µM, while 1h and 1k also showed neuroprotective effects at 12.5 µM. Selected derivatives (1b, 1h, 1q) demonstrated multitarget potential, including H₃R affinity (K_i as low as 32 nM for 1b) and MAO inhibition (IC₅₀ of 1688 nM for 1q). Conclusions: This series of coumarin–triazole derivatives combines potent and selective AChE inhibition with neuroprotective and multitarget activities, highlighting their promise as candidates for AD therapy.

Keywords: Alzheimer disease; cholinesterase inhibitors; multitarget-directed ligands; click chemistry; H₃R ligands

Graphical Abstract

Share and Cite

MDPI and ACS Style

Nadur, N.F.; Ferreira, L.d.A.P.; Franco, D.P.; de Azevedo, L.L.; Caruso, L.; Honório, T.d.S.; Furtado, P.d.S.; Simon, A.; Cabral, L.M.; Werner, T.; et al. Design, Synthesis, and Biological Evaluation of Novel Multitarget 7-Alcoxyamino-3-(1,2,3-triazole)-coumarins as Potent Acetylcholinesterase Inhibitors. Pharmaceuticals 2025, 18, 1398. https://doi.org/10.3390/ph18091398

AMA Style

Nadur NF, Ferreira LdAP, Franco DP, de Azevedo LL, Caruso L, Honório TdS, Furtado PdS, Simon A, Cabral LM, Werner T, et al. Design, Synthesis, and Biological Evaluation of Novel Multitarget 7-Alcoxyamino-3-(1,2,3-triazole)-coumarins as Potent Acetylcholinesterase Inhibitors. Pharmaceuticals. 2025; 18(9):1398. https://doi.org/10.3390/ph18091398

Chicago/Turabian Style

Nadur, Nathalia F., Larissa de A. P. Ferreira, Daiana P. Franco, Luciana L. de Azevedo, Lucas Caruso, Thiago da S. Honório, Priscila de S. Furtado, Alice Simon, Lucio M. Cabral, Tobias Werner, and et al. 2025. "Design, Synthesis, and Biological Evaluation of Novel Multitarget 7-Alcoxyamino-3-(1,2,3-triazole)-coumarins as Potent Acetylcholinesterase Inhibitors" Pharmaceuticals 18, no. 9: 1398. https://doi.org/10.3390/ph18091398

APA Style

Nadur, N. F., Ferreira, L. d. A. P., Franco, D. P., de Azevedo, L. L., Caruso, L., Honório, T. d. S., Furtado, P. d. S., Simon, A., Cabral, L. M., Werner, T., Stark, H., & Kümmerle, A. E. (2025). Design, Synthesis, and Biological Evaluation of Novel Multitarget 7-Alcoxyamino-3-(1,2,3-triazole)-coumarins as Potent Acetylcholinesterase Inhibitors. Pharmaceuticals, 18(9), 1398. https://doi.org/10.3390/ph18091398

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Menu

Design, Synthesis, and Biological Evaluation of Novel Multitarget 7-Alcoxyamino-3-(1,2,3-triazole)-coumarins as Potent Acetylcholinesterase Inhibitors

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI