Design, synthesis, docking, and biochemical characterization of non-nucleoside SARS-CoV-2 RdRp inhibitors. (15th February 2023)

• Record Type: Journal Article
• Authors: Brindani, Nicoletta; Munafò, Federico; Menichetti, Andrea; Donati, Elisa; Nigro, Michela; Ottonello, Giuliana; Armirotti, Andrea; De Vivo, Marco
• Is Part Of: Bioorganic & medicinal chemistry. Volume 80(2023)
• Publication Date: 2023-02-15
• Subjects: SARS-CoV-2 -- RdRp inhibitor -- Antiviral -- 1, 4-benzopyrane -- Molecular modeling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2023.117179
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Identification of novel compounds with potential to develop antiviral SARS-CoV-2 drugs. These new compounds are non-nucleoside RdRp inhibitors. 17 1, 4-benzopyrone derivatives synthetized and characterized for their activity. A structure–activity relationship supported by molecular modelling. Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic. The identification of effective antiviral drugs remains an urgent medical need. In this context, here we report 17 new 1, 4-benzopyrone derivatives, which have been designed, synthesized, and characterized for their ability to block the RNA-dependent RNA polymerase (RdRp) enzyme, a promising target for antiviral drug discovery. This compound series represents a good starting point for developing non-nucleoside inhibitors of RdRp. Compounds 4, 5, and 8 were the most promising drug-like candidates with good potency in inhibiting RdRp, improved in vitro pharmacokinetics compared to the initial hits, and no cytotoxicity effects on normal cell (HEK-293). Compound 8 (ARN25592 ) stands out as the most promising inhibitor. Our results indicate that this new chemical class of 1, 4-benzopyrone derivatives deserves further exploration towards novel and potent antiviral drugs for the treatment of SARS-CoV-2 and potentially other viruses.