Synthesis and Some Properties of New 5-Hydroxy-2-[(hetarylthio)methyl]-4H-pyran-4-ones

The reaction of 2-thioxoazines with chlorokojic acid in the presence of KOH in DMF led to the formation of new hybrid molecules containing fragments of kojic acid and azaheterocycle linked by the SCH2 spacer. In silico prediction of bioavailability parameters was carried out, possible protein targets were predicted by the protein ligand docking method.

4-one) is widely used in the pharmaceutical industry, agrochemistry, cosmetology [1][2][3][4][5], and as a ligand for complex compounds [6] and building blocks for construction of biologically active heterocyclic molecules [7][8][9]. Being one of the most studied and available non-toxic tyrosinase inhibitors [10,11], kojic acid as a bioactive molecule is not devoid of disadvantages, among which should be noted the lack of stability during storage and a relatively low inhibitory activity. For this reason, in recent years, the direction of the γ-pyrones chemistry devoted to the preparation of conjugates of kojic acid or other derivatives functionalized at C 6 OH groups has been developed [12][13][14][15][16][17][18]. Among the new effective tyrosinase inhibitors, it is worth noting a number of hybrid molecules combining a kojic acid residue and an aryl/hetaryl moiety -for example, Mannich base 2 [18], 1,2,3-triazole derivatives 3 [19,20], substituted thiophenol 4 [21] or 4-amino-1,2,4-triazoles 5 [22] (Scheme 1). In addition, a number of hybrid structures with a kojic acid motif are known, demonstrating a different spectrum of biological action. Thus, functionalization with a kojic acid was used to create 10 B-labeled derivatives of dodecaboranethiol 6 for boron neutron capture therapy of cancer [23]. Compound ML221 7 is a highly effective antagonist of the APJ apelin receptor with possible use in the therapy of cardiovascular diseases [24] (Scheme 1). Pivalic acid esters 8 have been shown to be effective inhibitors of neutrophil elastase suitable for the treatment of inflammatory lung diseases [25], while piperazine derivatives 9 exhibit antituberculosis [26] and anticancer [27] effects. According to patent data [28], 2-mercaptoimidazoline derivatives 10 exhibit antibacterial activity.
We performed the reaction of some active S-nucleophiles of the azaheterocyclic series with chlorkojic acid 11 (Hlg = Cl). It was found that 2-thioxopyridines 12а, 12b react with chloride 11 in the presence of 1 equiv. of 10% aqueous KOH with the formation of previously unknown hybrid molecules 13а, 13b containing kojic acid and nicotinonitrile fragments (Scheme 2). Under similar conditions, 2-thioxo-1,2dihydroquinoxaline 14 was converted to compound 15 in 28% yield.
The cLog P value for all the studied structures indicates probable good absorption and permeability [68][69][70]. At the same time, for all the compounds, the log S value < -4.0 indicates low solubility (less than 1×10 -4 mol/L). The molecular weights of all the compounds and the TPSA parameter met the criteria for oral bioavailability. The studied compounds show a moderate risk of oncogenic action associated with the presence of a 5-hydroxypyran-4-one fragment. However, the total predicted values of the drug score are rather high. To predict the ADMET parameters (Absorption, Distribution, Metabolism, Excretion, Toxicity) and probable targets, the SwissADME [72] and GUSAR [73] software packages were also used. The results are shown in Table 2. In general, the assessment of acute toxicity Ar = Ph (a), 2,4-Cl 2 C 6 H 3 (b). allows all the studied compounds to be classified as IV and V hazard classes according to the OECD criteria [74]. For these compounds, an inhibitory effect on a wide range of cytochrome P450 isoforms is postulated. Possible protein targets for the obtained compounds were predicted using the new Galaxy Sagittarius protein ligand docking protocol [75] based on the GalaxyWeb web server [76,77]. The 3D joint structures were preoptimized by molecular mechanics in an MM2 force field to optimize geometry and minimize energy. Docking using the GalaxySagittarius protocol was performed in the Binding compatability prediction and Re-ranking using docking modes. Table 3 shows the results of docking for each of compounds 13а, 13b, 15 for 10 target-ligand complexes with the minimum free binding energy ΔG bind and the best estimate of the protein-ligand interaction. Predicted protein targets are specified using ID-identifiers in the Protein Data Bank (PDB) and in the UniProt database. As one can see from the Table 3, common receptors for compounds 13a, 13b, and 15 are RPA (Replication Protein A, PDB ID 4luv) phosphoprotein responsible for DNA replication and repair in eukaryotes, 3-phosphoinositol-dependent protein kinase-1 (PDK1, PDB ID 4rqv), and apoptosis regulator Mcl-1 (PDB ID 6qfq) (Fig. 1). Thus, 5-hydroxy-2-[(hetarylthio)methyl]-4H-pyran-4-ones 13а, 13b, and 15 can be considered as promising objects for screening in order to search for new agents for the treatment and therapy of oncological diseases.
In conclusion, we developed a convenient method for the preparation of previously unknown 5-hydroxy-2-[(hetarylthio)methyl]-4H-pyran-4-ones by the reaction of 2-thioxonicotinonitrile and 2-thioxo-1,2dihydroquinoxaline derivatives with 5-hydroxy-2chloromethyl-4H-pyran-4-one (chlorokojic acid). The results of in silico experiments on the assessment of probable protein targets, toxicity, and bioavailability parameters make it possible to consider the obtained compounds as promising objects for the development of new drugs with antitumor action.
EXPERIMENTAL IR spectra were registered on a Bruker Vertex 70 spectrometer with an ATR attachment. 1 H and 13 C NMR spectra were recorded on a Bruker Avance III HD 400 MHz instrument (400.17 and 100.63 MHz, respectively) in a DMSO-d 6 solution. Chromato-mass spectra were recorded on a Bruker Customer MicrOTOF instrument in the range of m/z 50-1200, the method of ionization was electrospray (ESI). Elemental analysis was performed on an Elementar vario Micro cube instrument. The individuality of the obtained samples was controlled by TLC on Sorbfil-A plates (LLC Imid, Krasnodar), eluent was acetone-hexane mixture (1 : 1) or ethyl acetate, visualized with iodine vapors or UV light.

CONFLICT OF INTEREST
No conflict of interest was declared by the authors.

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