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Discovery and optimization of olanzapine derivatives as new ferroptosis inhibitors. | LitMetric

Discovery and optimization of olanzapine derivatives as new ferroptosis inhibitors.

Bioorg Chem

Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China. Electronic address:

Published: April 2023

AI Article Synopsis

Article Abstract

Ferroptosis is a new type of cell death associated with many human diseases. It is a new strategy to discover ferroptosis inhibitors for the treatment of ferroptosis-related diseases. Here the FDA-approved drug library containing 1160 molecules was screened for ferroptosis inhibitors in RSL3-induced HT22 mouse hippocampal neuronal cells. As a result, olanzapine showed potent ferroptosis inhibitory activity (EC = 1.18 μM). Structural optimization and the structure-activity relationships (SARs) analysis led to the synthesis of 41 new derivatives (4-44) and one known compound 45. Comparing with olanzapine, its derivative 36 showed nearly sixteen-folds improved ferroptosis inhibition and low cytotoxicity (EC = 0.074 μM, CC = 18.8 μM). Further mechanistic studies revealed that compound 36 specifically inhibited ferroptosis by its antioxidative ability. This work demonstrates that olanzapine protected RSL3-induced ferroptosis in HT22 cell, and its derivative 36 having nanomolar ferroptosis inhibitory activity merit to be developed for drugs against ferroptosis-related neurological diseases.

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Source
http://dx.doi.org/10.1016/j.bioorg.2023.106393DOI Listing

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