Discovery of 3-phenyl-1,2,4-oxadiazole derivatives as a new class of SARS-CoV-2 main protease inhibitors

Nihong Guo; Chong Huang; Jingxin Qiao; Yueyue Li; Yifei Wang; Anjie Xia; Guo Zhang; Zhen Fang; Jing You; Linli Li

doi:10.1016/j.bmcl.2023.129238

Discovery of 3-phenyl-1,2,4-oxadiazole derivatives as a new class of SARS-CoV-2 main protease inhibitors

Bioorg Med Chem Lett. 2023 Apr 15:86:129238. doi: 10.1016/j.bmcl.2023.129238. Epub 2023 Mar 15.

Authors

Nihong Guo¹, Chong Huang², Jingxin Qiao², Yueyue Li², Yifei Wang², Anjie Xia², Guo Zhang², Zhen Fang², Jing You², Linli Li³

Affiliations

¹ Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
² State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
³ Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: lilinli@scu.edu.cn.

Abstract

The ongoing COVID-19 pandemic has led to massive infections and deaths and caused tremendous grief among the people. Although vaccines have played an important role in fighting COVID-19, the situation that the protective effect of current vaccines significantly decreases against mutated strains reminds us of the pressing need for developing effective antiviral therapeutics. The main protease (M^pro) is a key enzyme for SARS-CoV-2 viral replication and transcription and an attractive target for drug development. In this research, we report a new series of M^pro inhibitors containing 3-phenyl-1,2,4-oxadiazole. Structure-activity relationship (SAR) studies led to the discovery of the most active compound, 16d, which showed an IC₅₀ value of 5.27 ± 0.26 μM. Collectively, we obtained a new small molecular inhibitor targeting SARS-CoV-2 M^pro, which contains a new scaffold. This compound could be taken as a lead compound for subsequent drug discovery against SARS-CoV-2.

Keywords: 3-phenyl-1,2,4-oxadiazole derivatives; Main protease inhibitor; SARS-CoV-2.

Publication types

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

MeSH terms

Antiviral Agents / pharmacology
COVID-19*
Humans
Molecular Docking Simulation
Pandemics
Protease Inhibitors / pharmacology
SARS-CoV-2

Substances

3C-like proteinase, SARS-CoV-2
Protease Inhibitors
Antiviral Agents