SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here, we present that these pyridobenzothiazole derivatives also significantly inhibit SARS-CoV-2 RdRp, as demonstrated using both polymerase- and cell-based antiviral assays.

The key intermediates, [(1R*,2R*,4R*,6R*)-6- (12a) and [(1R*,2R*,4R*,5S*)-5-(hydroxymethyl)- bicyclo[2.2.1]heptan-2-yl]methyl benzoates (12b), were prepared from (1R*,2S*,4R*)- bicyclo[2.2.1]hept-5-en-2-ylmethyl benzoate by hydroboration, oxidation with pyridinium dichromate and subsequent reduction of the thus obtained ketones. The Mitsunobu reaction of12aand12bwith 6-chloropurine afforded 6-chloropurine derivatives, which were converted into others purine analogues. Thymine analogues were prepared from [(1R*,2R*,4S*,6S*)-6- (25a) and [(1R*,2S*,4R*,5S*)-5-aminobicyclo[2.2.1]heptan-2-yl]methanols (25b), which were prepared from alcohols12aand12bin several easy steps.

The non-hydrolyzable alkylcarbonate analogs of O-acetyl-ADP-ribose have been synthesized from the phosphorylated ribose derivatives after coupling with AMP morpholidate promoted by mechanical grinding. The analogs were assessed for their ability to inhibit the human sirtuin homolog SIRT1.

We report on the preparation of novel 1′-homonucleoside derivatives locked in a West conformation by 1′,4′-bridge consisting of annulated benzene or naphthalene ring. The crucial step of the synthesis was Diels–Alder reaction of an appropriate aryne with a suitable furane derivative. Antiviral properties of novel compounds were studied and slight activity against HCV was detected in several compounds.

The search for new drugs against COVID-19 and its causative agent, SARS-CoV-2, is one of the major trends in current medicinal chemistry. Targeting capping machinery could be one of therapeutic concepts based on a unique mechanism of action. Viral RNA cap synthesis involves two methylation steps, the first of which is mediated by the nsp14 protein. Here, we rationally designed and synthesized a series of compounds capable of binding to both the S-adenosyl-L-methionine and the RNA binding site of SARS-CoV-2 nsp14 7-N methyltransferase. These hybrid molecules exerted excellent potency, high selectivity towards various human methyltransferases, they are nontoxic and highly cell permeable. Despite the outstanding activity against the enzyme, our compounds showed poor antiviral performance in vitro. This suggests that the activity of this viral methyltransferase is mainly associated with immune response. Our compounds represent unique tools to further explore the role of the SARS-CoV-2 nsp14 methyltransferase in viral replication.