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. 2020 Sep 16;25(18):4238.
doi: 10.3390/molecules25184238.

Methylation of Methyl 4-Hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate: Synthetic, Crystallographic, and Molecular Docking Studies

Sergiy M Kovalenko  1   2   3 , Oleksandr G Drushlyak  4 , Svitlana V Shishkina  1   3   5 , Irina S Konovalova  5 , Illia O Mariutsa  4 , Natalya D Bunyatyan  3   6 , Dmitry V Kravchenko  7 , Vladimir V Ivanov  1 , Alexandre V Ivachtchenko  2 , Thierry Langer  8
Affiliations

Methylation of Methyl 4-Hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate: Synthetic, Crystallographic, and Molecular Docking Studies

Sergiy M Kovalenko et al. Molecules. .

Abstract

Consecutive alkylation of 4-hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate by CH3I has been investigated to establish regioselectivity of the reaction for reliable design and synthesis of combinatorial libraries. In the first stage, the product of S-methylation-methyl 4-hydroxy-2-(methylthio)quinoline-3-carboxylate was obtained. The subsequent alkylation with CH3I led to the formation of both O- and N-methylation products mixture-methyl 4-methoxy-2-(methylthio)quinoline-3-carboxylate and methyl 1-methyl-2-(methylthio)-4-oxo-1,4-dihydroquinoline-3-carboxylate with a predominance of O-methylated product. The structure of synthesized compounds was confirmed by means of elemental analysis, 1H-NMR, 13C-NMR, LC/MS, and single-crystal X-ray diffraction. The quantum chemical calculations of geometry and electron structure of methyl 4-hydroxy-2-(methylthio)quinoline-3-carboxylate's anion were carried out. According to molecular docking simulations, the studied compounds can be considered as potent inhibitors of Hepatitis B Virus replication. Experimental in vitro biological studies confirmed that studied compounds demonstrated high inhibition of HBV replication in 10 µM concentration.

Keywords: X-ray analysis; alkylation; hepatitis B virus; hydrogen bond; molecular docking simulations; quinoline.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Heteroaryl dihydropyrimidines as the HBV inhibitors.
Scheme 1
Scheme 1
The reaction of methyl 2-isothiocyanatobenzoate 1 with dimethyl malonate.
Scheme 2
Scheme 2
Consequent alkylation of 4-hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate 2 with CH3I.
Scheme 3
Scheme 3
Synthesis of 4-hydroxy-2-(methylthio)quinoline-3-carboxylic acid 6.
Scheme 4
Scheme 4
Alkylation of 4-hydroxy-2-thioxo-1,2-dihydroquinoline-3-carboxylate anion 3 by CH3I.
Figure 2
Figure 2
Visualization of the total electrostatic potential map of anion 3 (red regions corresponds to negative charge).
Figure 3
Figure 3
The Csp2–Csp2–Csp2=O and N–Csp2–S–Csp3 torsion angles used for SC1 and SC2 scanning during the study of potential energy surface (PES) in conformational analysis of 3-(methoxycarbonyl)-2-(methylthio)-1,2-dihydroquinolin-4-olate anion; PES as a function of energy and two scanned torsion angles SC1 and SC2.
Figure 4
Figure 4
The most stable conformers of 3-(methoxycarbonyl)-2-(methylthio)-1,2-dihydroquinolin- 4-olate anion according to the conformational study.
Figure 5
Figure 5
Molecular structure of compound 3 according to X-ray diffraction data. Thermal displacement ellipsoids are shown at the 50% probability level.
Figure 6
Figure 6
Centrosymmetric dimer of molecules 3 in the crystal phase. Hydrogen bonds are shown by dashed blue lines.
Figure 7
Figure 7
Molecular structure of compound 4 according to X-ray diffraction data. Thermal displacement ellipsoids are shown at the 50% probability level.
Figure 8
Figure 8
Molecular structure of compound 5 according to X-ray diffraction data. Thermal displacement ellipsoids are shown at the 50% probability level.
Figure 9
Figure 9
Centrosymmetric dimer of molecules 5 in the crystal phase. Hydrogen bonds are shown by dashed blue lines.
Figure 10
Figure 10
Packing of molecules 5 in the crystal. The projection along the [1 0 0] crystallographic direction is presented.
Figure 11
Figure 11
The molecular systems (2–6) under consideration for the docking procedure.
Figure 12
Figure 12
Complexes with highest affinity score presented according to Table 2.
Figure 12
Figure 12
Complexes with highest affinity score presented according to Table 2.
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