tetano
Editor, Senior Moderator
Bioorg Med Chem
. 2025 Mar 7:123:118153.
doi: 10.1016/j.bmc.2025.118153. Online ahead of print. Discovery and rational optimization of 2, 2'-((1H-indole-2,3-diyl) bis (thio))diacetamide as novel SARS-CoV-2 RdRp inhibitors
Yu Shi[SUP] 1 [/SUP], Jianyuan Zhao[SUP] 1 [/SUP], Min Li[SUP] 2 [/SUP], Liya Wei[SUP] 2 [/SUP], Qi Shan[SUP] 3 [/SUP], Minghua Wang[SUP] 1 [/SUP], Mei Zhu[SUP] 1 [/SUP], Shan Cen[SUP] 1 [/SUP], Guoning Zhang[SUP] 4 [/SUP], Juxian Wang[SUP] 5 [/SUP], Yucheng Wang[SUP] 6 [/SUP]
Affiliations
The COVID-19 pandemic has significantly strained global health infrastructures while profoundly affecting the socio-economic landscape. RNA-dependent RNA polymerase (RdRp) plays a pivotal role in the replication and transcription of RNA viruses, making it a critical target for antiviral drug development. In this work, we describe the discovery, rational optimization, and synthesis of a novel series of non-nucleoside SARS-CoV-2 RdRp inhibitors featuring a 2,2'-((1H-indole-2,3-diyl)bis (thio))diacetamide core. The inhibitory activity of these compounds was evaluated, with most demonstrating a higher inhibitory effect than Remdesivir. Notably, the most potent candidates suppressed RNA synthesis dose-dependently and exhibited greater resistance to nsp14/nsp10 exonuclease-mediated proofreading compared to Remdesivir. Furthermore, 10b6 and 10b12 showed 1.6- to 2-fold lower EC[SUB]50[/SUB] values against coronavirus HCoV-OC43 than Remdesivir, highlighting their potential for further development as broad-spectrum antiviral agents.
Keywords: 2,2′-((1H-indole-2,3-diyl) bis (thio)) diacetamide derivatives; COVID-19; Non-nucleoside inhibitor; RdRp inhibitor.
. 2025 Mar 7:123:118153.
doi: 10.1016/j.bmc.2025.118153. Online ahead of print. Discovery and rational optimization of 2, 2'-((1H-indole-2,3-diyl) bis (thio))diacetamide as novel SARS-CoV-2 RdRp inhibitors
Yu Shi[SUP] 1 [/SUP], Jianyuan Zhao[SUP] 1 [/SUP], Min Li[SUP] 2 [/SUP], Liya Wei[SUP] 2 [/SUP], Qi Shan[SUP] 3 [/SUP], Minghua Wang[SUP] 1 [/SUP], Mei Zhu[SUP] 1 [/SUP], Shan Cen[SUP] 1 [/SUP], Guoning Zhang[SUP] 4 [/SUP], Juxian Wang[SUP] 5 [/SUP], Yucheng Wang[SUP] 6 [/SUP]
Affiliations
- PMID: 40132469
- DOI: 10.1016/j.bmc.2025.118153
The COVID-19 pandemic has significantly strained global health infrastructures while profoundly affecting the socio-economic landscape. RNA-dependent RNA polymerase (RdRp) plays a pivotal role in the replication and transcription of RNA viruses, making it a critical target for antiviral drug development. In this work, we describe the discovery, rational optimization, and synthesis of a novel series of non-nucleoside SARS-CoV-2 RdRp inhibitors featuring a 2,2'-((1H-indole-2,3-diyl)bis (thio))diacetamide core. The inhibitory activity of these compounds was evaluated, with most demonstrating a higher inhibitory effect than Remdesivir. Notably, the most potent candidates suppressed RNA synthesis dose-dependently and exhibited greater resistance to nsp14/nsp10 exonuclease-mediated proofreading compared to Remdesivir. Furthermore, 10b6 and 10b12 showed 1.6- to 2-fold lower EC[SUB]50[/SUB] values against coronavirus HCoV-OC43 than Remdesivir, highlighting their potential for further development as broad-spectrum antiviral agents.
Keywords: 2,2′-((1H-indole-2,3-diyl) bis (thio)) diacetamide derivatives; COVID-19; Non-nucleoside inhibitor; RdRp inhibitor.