tetano
Editor, Senior Moderator
J Med Chem
. 2023 Nov 22.
doi: 10.1021/acs.jmedchem.3c01876. Online ahead of print. Design, Synthesis, and Biological Evaluation of Trisubstituted Piperazine Derivatives as Noncovalent Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease Inhibitors with Improved Antiviral Activity and Favorable Druggability
Shenghua Gao[SUP] 1 2 [/SUP], Letian Song[SUP] 1 [/SUP], Katharina Sylvester[SUP] 3 [/SUP], Beatrice Mercorelli[SUP] 4 [/SUP], Arianna Loregian[SUP] 4 [/SUP], Karoly Toth[SUP] 5 [/SUP], Renato H Weiße[SUP] 6 [/SUP], Abibe Useini[SUP] 6 [/SUP], Norbert Sträter[SUP] 6 [/SUP], Mianling Yang[SUP] 1 [/SUP], Bing Ye[SUP] 1 [/SUP], Ann E Tollefson[SUP] 5 [/SUP], Christa E Müller[SUP] 3 [/SUP], Xinyong Liu[SUP] 1 [/SUP], Peng Zhan[SUP] 1 [/SUP]
Affiliations
The ongoing transmission of SARS-CoV-2 necessitates the development of additional potent antiviral agents capable of combating the current highly infectious variants and future coronaviruses. Here, we present the discovery of potent nonpeptide main protease (M[SUP]pro[/SUP]) inhibitors with prominent antiviral activity and improved pharmacokinetic properties. Three series of 1,2,4-trisubstituted piperazine derivatives were designed and synthesized, and the optimal GC-78-HCl demonstrated high enzyme-inhibitory potency (IC[SUB]50[/SUB] = 0.19 μM) and exhibited excellent antiviral activity (EC[SUB]50[/SUB] = 0.40 μM), reaching the same level as Nirmatrelvir (EC[SUB]50[/SUB] = 0.38 μM). Additionally, GC-78-HCl displayed potent antiviral activities against various SARS-CoV-2 variants as well as HCoV-OC43 and HCoV-229E, indicating its potential broad-spectrum anticoronaviral activity. Notably, the pharmacokinetic properties of GC-78-HCl were somewhat enhanced compared to those of the lead compound. Furthermore, the cocrystal and molecular docking elucidated the mechanism of action. In conclusion, we discovered a novel nonpeptidic M[SUP]pro[/SUP] inhibitor with promising antiviral activity and a favorable pharmacokinetic profile.
. 2023 Nov 22.
doi: 10.1021/acs.jmedchem.3c01876. Online ahead of print. Design, Synthesis, and Biological Evaluation of Trisubstituted Piperazine Derivatives as Noncovalent Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease Inhibitors with Improved Antiviral Activity and Favorable Druggability
Shenghua Gao[SUP] 1 2 [/SUP], Letian Song[SUP] 1 [/SUP], Katharina Sylvester[SUP] 3 [/SUP], Beatrice Mercorelli[SUP] 4 [/SUP], Arianna Loregian[SUP] 4 [/SUP], Karoly Toth[SUP] 5 [/SUP], Renato H Weiße[SUP] 6 [/SUP], Abibe Useini[SUP] 6 [/SUP], Norbert Sträter[SUP] 6 [/SUP], Mianling Yang[SUP] 1 [/SUP], Bing Ye[SUP] 1 [/SUP], Ann E Tollefson[SUP] 5 [/SUP], Christa E Müller[SUP] 3 [/SUP], Xinyong Liu[SUP] 1 [/SUP], Peng Zhan[SUP] 1 [/SUP]
Affiliations
- PMID: 37992202
- DOI: 10.1021/acs.jmedchem.3c01876
The ongoing transmission of SARS-CoV-2 necessitates the development of additional potent antiviral agents capable of combating the current highly infectious variants and future coronaviruses. Here, we present the discovery of potent nonpeptide main protease (M[SUP]pro[/SUP]) inhibitors with prominent antiviral activity and improved pharmacokinetic properties. Three series of 1,2,4-trisubstituted piperazine derivatives were designed and synthesized, and the optimal GC-78-HCl demonstrated high enzyme-inhibitory potency (IC[SUB]50[/SUB] = 0.19 μM) and exhibited excellent antiviral activity (EC[SUB]50[/SUB] = 0.40 μM), reaching the same level as Nirmatrelvir (EC[SUB]50[/SUB] = 0.38 μM). Additionally, GC-78-HCl displayed potent antiviral activities against various SARS-CoV-2 variants as well as HCoV-OC43 and HCoV-229E, indicating its potential broad-spectrum anticoronaviral activity. Notably, the pharmacokinetic properties of GC-78-HCl were somewhat enhanced compared to those of the lead compound. Furthermore, the cocrystal and molecular docking elucidated the mechanism of action. In conclusion, we discovered a novel nonpeptidic M[SUP]pro[/SUP] inhibitor with promising antiviral activity and a favorable pharmacokinetic profile.