Synthesis and pharmacological evaluation of choroquine derivatives bearing long aminated side chains as antivirus and anti-inflammatory agents

Zilan Song; Yuting Liu; Chenghu Xie; Xiankun Tong; Xue Wang; Yu Zhou; Wangting Gu; Jianping Zuo; Shijun He; Ao Zhang

doi:10.1016/j.bioorg.2021.105346

Synthesis and pharmacological evaluation of choroquine derivatives bearing long aminated side chains as antivirus and anti-inflammatory agents

Bioorg Chem. 2021 Nov:116:105346. doi: 10.1016/j.bioorg.2021.105346. Epub 2021 Sep 11.

Authors

Zilan Song¹, Yuting Liu², Chenghu Xie³, Xiankun Tong², Xue Wang², Yu Zhou², Wangting Gu³, Jianping Zuo⁴, Shijun He⁵, Ao Zhang⁶

Affiliations

¹ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023 China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; Pharm-X Center, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ Pharm-X Center, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: jpzuo@simm.ac.cn.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: heshijun@simm.ac.cn.
⁶ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023 China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; Pharm-X Center, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: ao6919zhang@sjtu.edu.cn.

Abstract

Starting from the antimalarial drugs chloroquine and hydroxychloroquine, we conducted a structural optimization on the side chain of chloroquine by introducing amino substituted longer chains thus leading to a series of novel aminochloroquine derivatives. Anti-infectious effects against SARS-Cov2 spike glycoprotein as well as immunosuppressive and anti-inflammatory activities of the new compounds were evaluated. Distinguished immunosuppressive activities on the responses of T cell, B cell and macrophages upon mitogen and pathogenic signaling were manifested. Compounds 9-11 displayed the most promising inhibitory effects both on cellular proliferation and on the production of multiple pro-inflammatory cytokines, including IL-17, IFN-γ, IL-6, IL-1β and TNF-α, which might be insightful in the pursuit of treatment for immune disorders and inflammatory diseases.

Keywords: Aminochloroquine; Anti-inflammatory; Antivirus; Choroquine; Cytokines.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amines / chemistry
Amines / pharmacology*
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
B-Lymphocytes / immunology
Cell Proliferation / drug effects
Chloroquine / chemical synthesis
Chloroquine / chemistry
Chloroquine / pharmacology*
Cytokines / metabolism
Dose-Response Relationship, Drug
Humans
Macrophages / drug effects
Macrophages / immunology
Microbial Sensitivity Tests
Molecular Structure
SARS-CoV-2 / drug effects*
SARS-CoV-2 / metabolism
Spike Glycoprotein, Coronavirus / antagonists & inhibitors*
Spike Glycoprotein, Coronavirus / metabolism
Structure-Activity Relationship
T-Lymphocytes / drug effects
T-Lymphocytes / immunology

Substances

Amines
Anti-Inflammatory Agents, Non-Steroidal
Antiviral Agents
Cytokines
Spike Glycoprotein, Coronavirus
Chloroquine