Search

The design and synthesis of antiviral compounds were guided by computationally predicted data against highly conserved non-structural proteins (Nsps) of the SARS-CoV-2 coronavirus. Chromenephenylmethanone-1 (CPM-1), a novel biphenylpyran (BPP), was selected from a unique natural product library based on in silico docking scores to coronavirus Nsps with high specificity to the methyltransferase protein (2'- O -MTase, Nsp10-16), which is responsible for viral mRNA maturation and host innate immune response evasion. To target the 2'- O -MTase, CPM-1, along with intermediate BPP regioisomers, tetrahydrophenylmethanones (TPMs), were synthesized and structurally validated via nuclear magnetic resonance (NMR) data and DP4+ structure probability analyses. To investigate the activity of these BPPs, the following in vitro assays were conducted: SARS-CoV-2 inhibition, biochemical target validation, mutagenicity, and cytotoxicity. CPM-1 possessed notable activity against SARS-CoV-2 with 98.9% inhibition at 10 µM and an EC 50 of 7.65 µM, as well as inhibition of SARS-CoV-2's 2'- O -MTase (expressed and purified) with an IC 50 of 1.5 ± 0.2 µM. In addition, CPM-1 revealed no cytotoxicity (CC 50 of >100 µM) or mutagenicity (no frameshift or base-pair mutations). This study demonstrates the potential of computational modeling for the discovery of natural product prototypes followed by the design and synthesis of drug leads to inhibit the SARS-CoV-2 2'- O -MTase.

A series of hitherto unknown (1,4-disubstituted-1,2,3-triazol)-( E )-2-methyl-but-2-enyl nucleosides phosphonate prodrugs bearing 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as the key synthetic step. All novel compounds were evaluated for their antiviral activities against HBV, HIV and SARS-CoV-2. Among these molecules, only compound 15j , a hexadecyloxypropyl (HDP)/( isopropyloxycarbonyl -oxymethyl)-ester (POC) prodrug, showed activity against HBV in Huh7 cell cultures with 62% inhibition at 10 μM, without significant cytotoxicity (IC 50 = 66.4 μM in HepG2 cells, IC 50 = 43.1 μM in HepG2 cells) at 10 μM.