Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease

Xiaokang Li; Jian Lu; Yixiang Xu; Jiaying Wang; Xiaoxia Qiu; Lei Fan; Baoli Li; Wenwen Liu; Fei Mao; Jin Zhu; Xu Shen; Jian Li

doi:10.1016/j.apsb.2019.07.006

Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease

Acta Pharm Sin B. 2020 Apr;10(4):646-666. doi: 10.1016/j.apsb.2019.07.006. Epub 2019 Jul 29.

Authors

Xiaokang Li¹, Jian Lu², Yixiang Xu¹, Jiaying Wang², Xiaoxia Qiu¹, Lei Fan³, Baoli Li¹, Wenwen Liu¹, Fei Mao¹, Jin Zhu¹, Xu Shen², Jian Li¹

Affiliations

¹ State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
² School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing 210023, China.
³ Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Abstract

Drug repurposing is an efficient strategy for new drug discovery. Our latest study found that nitazoxanide (NTZ), an approved anti-parasite drug, was an autophagy activator and could alleviate the symptom of Alzheimer's disease (AD). In order to further improve the efficacy and discover new chemical entities, a series of NTZ-based derivatives were designed, synthesized, and evaluated as autophagy activator against AD. All compounds were screened by the inhibition of phosphorylation of p70S6K, which was the direct substrate of mammalian target of rapamycin (mTOR) and its phosphorylation level could reflect the mTOR-dependent autophagy level. Among these analogs, compound 22 exhibited excellent potency in promoting β-amyloid (Aβ) clearance, inhibiting tau phosphorylation, as well as stimulating autophagy both in vitro and in vivo. What's more, 22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice. These results demonstrated that 22 was a potential candidate for the treatment of AD.

Keywords: AChEIs, acetylcholinesterase inhibitors; AD, Alzheimer's disease; APP, amyloid precursor protein; Alzheimer's disease; Autophagy; Aβ, β-amyloid; BBB, blood–brain barrier; CNS, central nervous system; MWM, Morris Water Maze; NCEs, new chemical entities; NFTs, neurofibrillary tangles; NMDA, N-methyl-d-aspartate; NTZ, nitazoxanide; Nitazoxanide; PAMPA, parallel artificial membrane permeation assay; PBL, porcine brain lipid; SPs, senile plaques; Tau protein; WORT, wortmannin; mTOR, mammalian target of rapamycin; β-amyloid.