Viral mRNA cap methyltransferases (MTases) are emerging targets for the development of broad-spectrum antiviral agents. In this work, we designed potential SARS-CoV-2 MTase Nsp14 and Nsp16 inhibitors by using bioisosteric substitution of the sulfonium and amino acid substructures of the cosubstrate S-adenosylmethionine (SAM), which serves as the methyl donor in the enzymatic reaction. The synthetically accessible target structures were prioritized using molecular docking. Testing of the inhibitory activity of the synthesized compounds showed nanomolar to submicromolar IC 50 values for five compounds. To evaluate selectivity, enzymatic inhibition of the human glycine N -methyltransferase involved in cellular SAM/SAH ratio regulation was also determined, which indicated that the discovered compounds are nonselective inhibitors of the studied MTases with slight selectivity for Nsp16. No cytotoxic effects were observed; however, this is most likely a result of the poor cell permeability of all evaluated compounds.

SARS-CoV-2 nsp14 guanine-N7-methyltransferase plays an important role in the viral RNA translation process by catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to viral mRNA cap. We report a structure-guided design and synthesis of 3-(adenosylthio)benzoic acid derivatives as nsp14 methyltransferase inhibitors resulting in compound 5p with subnanomolar inhibitory activity and improved cell membrane permeability in comparison with the parent inhibitor. Compound 5p acts as a bisubstrate inhibitor targeting both SAM and mRNA-binding pockets of nsp14. While the selectivity of 3-(adenosylthio)benzoic acid derivatives against human glycine N-methyltransferase was not improved, the discovery of phenyl-substituted analogs 5p,t may contribute to further development of SARS-CoV-2 nsp14 bisubstrate inhibitors.

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Inhibition of histone deacetylase activity appears as an original and effective approach for the treatment of cancer. A series of novel quinoline-containing derivatives has been synthesized and found that some of these compounds possess nanomolar histone deacetylase inhibitory activity.Keywords: inhibitors of histone deacetylase, quinoline, Zn 2+ chelating groups.Histone deacetylases (HDAC) are a group of enzymes that catalyze and regulate the process of deacetylation of histones. The process of acetylation-deacetylation of histones is involved in the regulation of chromatin structure and gene expression. Numerous studies have shown that HDAC inhibition leads to the tumor cell differentiation, proliferation, and apoptosis [1, 2]. These findings immensely stimulated a search for substances, both natural and synthetic, which could serve as HDAC inhibitors. As a result of these studies a number of HDAC inhibitors are currently under clinical trials as anticancer agents [3].A widely accepted pharmacophoric description of simple HDAC inhibitors can be conditionally represented by three linearly bonded groups ALX, where A represents a surface recognition zone (CAP), usually an aryl group, which provides potency and selectivity, L is predominantly a hydrophobic linking group, and X represents a moiety that interacts with the catalytic Zn 2+ ion at the HDAC active site, usually a hydroxamic acid group [3].During our recent search for new HDACs inhibitors that would contain a quinoline cycle in the A part of the molecule [4], a new active 2-quinoline derivative 1 (Figure 1) with IC 50 = 4 nM for HeLa extract was found (HeLa extract is a cell type in an immortal cell line that is used in cancer research).A beneficial role of the 2-quinolinyl cycle presence in the A part of the structure 1 on the increase of HDAC inhibitory activity can be clearly demonstrated by comparing the activities of the compounds 13. Thus, the hydroxamate 2 [5] with the phenyl moiety is a more than 200 times weaker HDAC inhibitor in comparison to the quinoline derivative 1. Although a significant increase of the activity can be gained by changing the phenyl group of the structure 2 to the 2-naphthyl group, the naphthyl derivative 3 [6] is still 5 times less active than the compound 1. One can quite easily recognize the above-mentioned pharmacophoric regions ALX in the structures 13.