Design, synthesis, and biological activity studies of novel iron-chelating hybrids targeting pathological pathways associated with Alzheimer’s disease.
Abstract
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease involving neuroinflammation, oxidative stress, and metal dyshomeostasis, supporting the development of multifunctional therapeutic candidates. In this study, we rationally designed, synthesized, and characterized a new series of six phthalimide-acetohydroxamic acid derivatives combining hMAO-B inhibitory and iron-chelating properties. Spectroscopic and fluorescence studies demonstrated their selective interaction with iron ions. Several hybrids exhibited potent and selective inhibition of hMAO-B, with DES 5a and DES 5a’ showing IC50 values in the nanomolar range (28 and 40 nM, respectively). These compounds also displayed myeloperoxidase (MPO) inhibitory activity, supporting their potential to modulate oxidative pathways. In silico ADME prediction revealed favorable drug-like and CNS-related properties, while cytotoxicity evaluation on differentiated SH-SY5Y neuronal cells confirmed satisfactory safety profiles (CC50 > 100 μM for all hybrids), with DES 5a’ identified as the safest compound. This compound also displayed inhibitory activity against Aβ1−42 self-aggregation (38.8 ± 1.5%) at 12.5 μM. Overall, these findings highlight this new class of hybrids as promising multifunctional candidates for further development against AD.
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BibTeX
@article{nguyen2026design,
title = {{Design, synthesis, and biological activity studies of novel iron-chelating hybrids targeting pathological pathways associated with Alzheimer’s disease.}},
author = {Camille Nguyen and Firas El Kadiry and Quentin Muziot and Marc Maresca and Cédric Spitz and Sylvia Pietri},
journal = {European Journal of Medicinal Chemistry Reports},
year = {2026},
month = oct,
doi = {10.1016/j.ejmcr.2026.100377},
url = {https://hal.science/hal-05800675v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Design, synthesis, and biological activity studies of novel iron-chelating hybrids targeting pathological pathways associated with Alzheimer’s disease.
AU - Camille Nguyen
AU - Firas El Kadiry
AU - Quentin Muziot
AU - Marc Maresca
AU - Cédric Spitz
AU - Sylvia Pietri
PY - 2026
DA - 2026/10/14
JO - European Journal of Medicinal Chemistry Reports
DO - 10.1016/j.ejmcr.2026.100377
UR - https://hal.science/hal-05800675v1
AB - Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease involving neuroinflammation, oxidative stress, and metal dyshomeostasis, supporting the development of multifunctional therapeutic candidates. In this study, we rationally designed, synthesized, and characterized a new series of six phthalimide-acetohydroxamic acid derivatives combining hMAO-B inhibitory and iron-chelating properties. Spectroscopic and fluorescence studies demonstrated their selective interaction with iron ions. Several hybrids exhibited potent and selective inhibition of hMAO-B, with DES 5a and DES 5a’ showing IC50 values in the nanomolar range (28 and 40 nM, respectively). These compounds also displayed myeloperoxidase (MPO) inhibitory activity, supporting their potential to modulate oxidative pathways. In silico ADME prediction revealed favorable drug-like and CNS-related properties, while cytotoxicity evaluation on differentiated SH-SY5Y neuronal cells confirmed satisfactory safety profiles (CC50 > 100 μM for all hybrids), with DES 5a’ identified as the safest compound. This compound also displayed inhibitory activity against Aβ1−42 self-aggregation (38.8 ± 1.5%) at 12.5 μM. Overall, these findings highlight this new class of hybrids as promising multifunctional candidates for further development against AD.
SN - 2772-4174
ER -