Discovery and rational optimization of 2, 2′-((1H-indole-2,3-diyl) bis (thio))diacetamide as novel SARS-CoV-2 RdRp inhibitors

Abstract

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 EC₅₀ values against coronavirus HCoV-OC43 than Remdesivir, highlighting their potential for further development as broad-spectrum antiviral agents.