Design, Synthesis, and Bioactivity of Novel Bifunctional Small Molecules for Alzheimer's disease

Meihao Liang; Lili Gu; Hongjie Zhang; Jingli Min; Zunyuan Wang; Zhen Ma; Chixiao Zhang; Shenxin Zeng; Youlu Pan; Dongmei Yan; Zhengrong Shen; Wenhai Huang

doi:10.1021/acsomega.2c02130

Design, Synthesis, and Bioactivity of Novel Bifunctional Small Molecules for Alzheimer's disease

ACS Omega. 2022 Jul 20;7(30):26308-26315. doi: 10.1021/acsomega.2c02130. eCollection 2022 Aug 2.

Authors

Meihao Liang^{1

2}, Lili Gu², Hongjie Zhang², Jingli Min², Zunyuan Wang², Zhen Ma², Chixiao Zhang², Shenxin Zeng², Youlu Pan², Dongmei Yan², Zhengrong Shen², Wenhai Huang^{1

2}

Affiliations

¹ Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 310013, China.
² Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang 310013, P.R. China.

Abstract

The abnormal phosphorylation of the τ-protein is a typical early pathological feature of Alzheimer's disease (AD). The excessive phosphorylation of the τ-protein in the brain causes the formation of neurofibrillary tangles (NFTs) and increases the neurotoxicity of amyloid-β (Aβ). Thus, targeting the τ-protein is considered a promising strategy for treating AD. Herein, we designed and synthesized a series of molecules containing bifunctional groups to recognize the τ-protein and the E3 ligase. The molecules were examined in vitro, and their effects were tested on PC12 cells. In addition, we further studied the pharmacokinetics of compound I3 in healthy rats. Our data showed that compound I3 could effectively degrade τ-protein, reduce Aβ-induced cytotoxicity, and regulate the uneven distribution of mitochondria, which may open a new therapeutic strategy for the treatment of AD.