Design, synthesis, and biological evaluation of naphthalimide derivatives as dual monoamine oxidase-B and amyloid-β aggregation inhibitors for Alzheimer's disease.
4 affiliations
- 1Drug Design and Synthesis Lab., Department of Chemistry, Jamia Millia Islamia New Delhi-110025 India [email protected] +0091-11-26985507 +0091-9910200655.
- 2Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro Via E. Orabona 4 70125 Bari Italy [email protected].
- 3Department of Medicine and Surgery, LUM University Giuseppe Degennaro Torre Rossi 70010 Casamassima Italy.
- 4Department of Molecular Medicine, Jamia Hamdard New Delhi 110062 India.
Abstract
Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder with multifactorial pathogenesis. Amyloid beta (Aβ) and monoamine oxidase (MAO) are among the key therapeutic targets for its treatment. In this investigation, a series of 18 new naphthalimide-based derivatives were synthesized and assessed for multitarget activity against hAChE, esBuChE, MAO-A, MAO-B, Aβ, and paired helical fragment 6 (PHF6) aggregation. The screened compounds predominantly exhibited dual inhibition of MAO-B and Aβ aggregation to counteract oxidative stress and plaque formation. Among the tested compounds, P12 and P17 were found to have remarkable inhibition against Aβ, with 83% and 91% inhibition, respectively, compared to the reference compound quercetin (75% inhibition). The compound P10 was the most effective MAO-B inhibitor, with an IC₅₀ value of 3.09 ± 0.10 µM. Cytotoxicity studies in SH-SY5Y cells confirmed that compounds were non-toxic up to 25 µM. Additionally, the neuroprotection assays revealed that P10 was capable of reducing oxidative stress effectively against H₂O₂-induced toxicity, while P12 showed superior protection against Aβ-induced neurotoxicity in SH-SY5Y cells. Furthermore, in silico investigations provided structural insights into the predicted ligand-target interaction modes and dynamic behavior of the selected compounds with MAO-B and monomeric Aβ1-42. Consequently, all these findings underscore that naphthalimide derivatives are promising dual inhibitors of amyloid-β aggregation and MAO-B and have potential for further development as MTDLs for AD.
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BibTeX
@article{praveen2026design,
title = {{Design, synthesis, and biological evaluation of naphthalimide derivatives as dual monoamine oxidase-B and amyloid-β aggregation inhibitors for Alzheimer's disease.}},
author = {Rukshar Praveen and Alessandro Gadaleta and Gabriella La Spada and Daniela Valeria Miniero and Aquib Reza and Tohasib Yusub Chaudhari and Abdur Rahman and Marco Catto and Nasimul Hoda},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra07131g},
url = {https://europepmc.org/article/MED/42840889},
note = {CC BY},
}
RIS
TY - JOUR
TI - Design, synthesis, and biological evaluation of naphthalimide derivatives as dual monoamine oxidase-B and amyloid-β aggregation inhibitors for Alzheimer's disease.
AU - Rukshar Praveen
AU - Alessandro Gadaleta
AU - Gabriella La Spada
AU - Daniela Valeria Miniero
AU - Aquib Reza
AU - Tohasib Yusub Chaudhari
AU - Abdur Rahman
AU - Marco Catto
AU - Nasimul Hoda
PY - 2026
DA - 2026/10/06
JO - RSC advances
DO - 10.1039/d6ra07131g
UR - https://europepmc.org/article/MED/42840889
AB - Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder with multifactorial pathogenesis. Amyloid beta (Aβ) and monoamine oxidase (MAO) are among the key therapeutic targets for its treatment. In this investigation, a series of 18 new naphthalimide-based derivatives were synthesized and assessed for multitarget activity against hAChE, esBuChE, MAO-A, MAO-B, Aβ, and paired helical fragment 6 (PHF6) aggregation. The screened compounds predominantly exhibited dual inhibition of MAO-B and Aβ aggregation to counteract oxidative stress and plaque formation. Among the tested compounds, P12 and P17 were found to have remarkable inhibition against Aβ, with 83% and 91% inhibition, respectively, compared to the reference compound quercetin (75% inhibition). The compound P10 was the most effective MAO-B inhibitor, with an IC₅₀ value of 3.09 ± 0.10 µM. Cytotoxicity studies in SH-SY5Y cells confirmed that compounds were non-toxic up to 25 µM. Additionally, the neuroprotection assays revealed that P10 was capable of reducing oxidative stress effectively against H₂O₂-induced toxicity, while P12 showed superior protection against Aβ-induced neurotoxicity in SH-SY5Y cells. Furthermore, in silico investigations provided structural insights into the predicted ligand-target interaction modes and dynamic behavior of the selected compounds with MAO-B and monomeric Aβ1-42. Consequently, all these findings underscore that naphthalimide derivatives are promising dual inhibitors of amyloid-β aggregation and MAO-B and have potential for further development as MTDLs for AD.
SN - 2046-2069
ER -