Quinoline and Quinazoline Derivatives Inhibit Viral RNA Synthesis by SARS-CoV-2 RdRp

Abstract

Coronavirus disease 2019 (COVID-19) is a fatal respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The identification of potential drugs is urgently needed to control the pandemic. RNA dependent RNA polymerase (RdRp) is a conserved protein within RNA viruses and plays a crucial role in the viral life cycle, thus making it an attractive target for development of antiviral drugs. In this study, 101 quinoline and quinazoline derivatives were screened against SARS-CoV-2 RdRp using a cell-based assay. Three compounds I-13e , I-13h , and I-13i exhibit remarkable potency in inhibiting RNA synthesis driven by SARS-CoV-2 RdRp and relatively low cytotoxicity. Among these three compounds, I-13e showed the strongest inhibition upon RNA synthesis driven by SARS-CoV-2 RdRp, the resistance to viral exoribonuclease activity and the inhibitory effect on the replication of CoV, thus holding potential of being drug candidate for treatment of SARS-CoV-2.

2-((1H-indol-3-yl)thio)-N-phenyl-acetamides: SARS-CoV-2 RNA-dependent RNA polymerase inhibitors

“…Among them, 6-72-2a surprisingly showed similar inhibition effect as Remdesivir ( Table S1 ). The lipophilic Boc-group may contribute to the activity and a similar result was discovered in our another research, in which the stability of the Boc-group was also demonstrated ( Zhao et al, 2021b ). The structures of these five compounds also suggest that chemical structure of 2-((1H-indol-3-yl)thio) acetamide is pivotal element for its capability against RdRp ( Fig.…”

Quercetin and luteolin are single-digit micromolar inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase

“…Molnupinavir is an orally available and efficacious ribonucleoside analog inhibitor of influenza viruses and, similarly to remdesivir, it has been repurposed against SARS-CoV-2 18 . However, the RdRp complex of coronavirus can excise erroneous mutagenic nucleotides incorporated into viral RNA, thus creating resistance to nucleotide analog drugs 19 , 20 . Consequently, non-nucleoside inhibitors could have more desirable mechanisms of action that would limit the development of resistance.…”

An update on inhibitors targeting RNA-dependent RNA polymerase for COVID-19 treatment: Promises and challenges

“…Three quinoline derivatives (I-13e, I-13h, and I-13i) ( Fig. 9 A) , which are previously reported to have significant activity against the influenza A virus RdRp, exhibit remarkable potency in inhibiting RNA synthesis by targeting SARS-CoV-2 RdRp and relatively low cytotoxicity in a cell-based assay, with therapeutic index (TI) (CC 50 /EC 50 ) values of 65, 34, and 20, respectively [118] . Among these three compounds, I-13e showed the most potent inhibition of RNA synthesis and bypasses viral exonuclease activity concerns common with nucleotide inhibitors, thus holding the potential of being a drug candidate for the treatment of SARS CoV-2.…”