SAR study of niclosamide derivatives for neuroprotective function in SH-SY5Y neuroblastoma

Authors

Shizue Mito, The University of Texas Rio Grande ValleyFollow
Benxu Cheng, The University of Texas Rio Grande Valley
Benjamin A. Garcia, The University of Texas Rio Grande Valley
Xin Yee Ooi, The University of Texas Rio Grande Valley
Daniela Gonzalez, The University of Texas Rio Grande Valley
Tess C. Ruiz, The University of Texas Rio Grande Valley
Francisco X. Elisarraras, The University of Texas Rio Grande Valley

Document Type

Article

Publication Date

11-2023

Abstract

Neurodegenerative disease is a debilitating and incurable condition that affects millions of people around the world. The loss of functions or malfunctions of neural cells are the causes of mortality. A proteosome inhibitor, MG132, is well known to cause neurodegeneration in vitro when model neuronal-derived cell lines are exposed to it. Niclosamide, an anthelmintic drug, which has been used to treat tapeworm infections for more than 50 years, has recently attracted renewed attention in drug repurposing because it has been found to be a good candidate in many drug development screenings. We recently found that all markers of MG132-induced neuronal cell toxicity, including the accumulation of ubiquitinated proteins, were prevented by the presence of niclosamide. In addition, niclosamide was shown to enhance autophagy induced by MG132. There results suggested that niclosamide could act as a neuroprotective agent. In the present study, niclosamide derivatives were synthesized, and the structure-activity relationship (SAR) were determined with respect to protein ubiquitination induced by MG132 and effect on cell survival signaling pathways for neuroprotective function. Our results indicate that phenol OH plays a significant role in neuroprotective activity while the niclosamide derivatives without Cl (5- or 2'-Cl) showed almost the same neuroprotective effect. 4'-NO2 can be replaced by N3 or CF3 whereas NH2 significantly decreased activity. These findings provide guidance for the development of new niclosamide analogues against neurodegenerative diseases including Parkinson's disease.

Comments

Original published version available at https://doi.org/10.1016/j.bmcl.2023.129498

Recommended Citation

Mito, S., Cheng, B., Garcia, B. A., Yee Ooi, X., Gonzalez, D., Ruiz, T. C., Elisarraras, F. X., & Tsin, A. (2023). SAR study of niclosamide derivatives for neuroprotective function in SH-SY5Y neuroblastoma. Bioorganic & medicinal chemistry letters, 96, 129498. https://doi.org/10.1016/j.bmcl.2023.129498

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.

Publication Title

Bioorganic and Medicinal Chemistry Letters

DOI

10.1016/j.bmcl.2023.129498

Academic Level

faculty

Mentor/PI Department

Medical Education