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. 2023 Jan 11;28(2):739.
doi: 10.3390/molecules28020739.

Synthesis and Molecular Docking Study of Novel Pyrimidine Derivatives against COVID-19

Zahra M Alamshany  1 , Reham R Khattab  2 , Nasser A Hassan  2 , Ahmed A El-Sayed  2 , Mohamed A Tantawy  3 , Ahmed Mostafa  4 , Allam A Hassan  5
Affiliations

Synthesis and Molecular Docking Study of Novel Pyrimidine Derivatives against COVID-19

Zahra M Alamshany et al. Molecules. .

Abstract

A novel series of pyrido[2,3-d]pyrimidines; pyrido[3,2-e][1,3,4]triazolo; and tetrazolo[1,5-c]pyrimidines were synthesized via different chemical transformations starting from pyrazolo[3,4-b]pyridin-6-yl)-N,N-dimethylcarbamimidic chloride 3b (prepared from the reaction of o-aminonitrile 1b and phosogen iminiumchloride). The structures of the newly synthesized compounds were elucidated based on spectroscopic data and elemental analyses. Designated compounds are subjected for molecular docking by using Auto Dock Vina software in order to evaluate the antiviral potency for the synthesized compounds against SARS-CoV-2 (2019-nCoV) main protease M pro. The antiviral activity against SARS-CoV-2 showed that tested compounds 7c, 7d, and 7e had the most promising antiviral activity with lower IC50 values compared to Lopinavir, "the commonly used protease inhibitor". Both in silico and in vitro results are in agreement.

Keywords: COVID-19; molecular docking; phosgeniminium chloride; pyridopyrimidine derivatives; spectroscopic data.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Examples of marketed pyrazolopyridine drugs.
Figure 2
Figure 2
Pyrazolopyridines with reported antimicrobial, antibacterial and anticancer efficacies as well as DNA-binding affinity.
Scheme 1
Scheme 1
Reagents: (i) PIC (Me2N=C(Cl)2Cl), 6 °C/6h; (ii) (Me2N=C(Cl)2Cl), 25 °C/18h; (iii) H2NNH2•H2O, 25 °C/18h; (iv) H2NNH2•H2O, 5 °C/6h; (v) stirring at 25 °C/18h; Ar = (a) C6H4NO2(4), (b) thien-2-yl.
Scheme 2
Scheme 2
Reagents: (i) RCHO: R= (c) C6H4Cl (4), (d) C6H4Br (4), (e) C6H4Me (4), (f) glucosyl, (g) xylosyl; (ii) FeCl3/EtOH or KI/DMSO; Ar = (a) C6H4NO2 (4).
Scheme 3
Scheme 3
Reagents: (i) RCHO: R = (c) C6H4Cl(4), (d) C6H4Br(4); (ii) FeCl3/EtOH or KI/DMSO; Ar= (b) thien-2-yl.
Scheme 4
Scheme 4
Mechanism Dimroth rearrangement.
Scheme 5
Scheme 5
Reagents: (i) NaNO2/AcOH (ii) CS2; (iii) HC(OEt)3 (iv) Me2N=C(Cl)2Cl; Ar = C6H4NO2 (p).
Figure 3
Figure 3
Cell viability and virus inhibition assays for the novel tested anti-viral drugs in Vero-E6 cells. Various dilutions of the drugs were applied to the 90% confluent cell monolayers and assayed after 72 h with MTT assay.
Figure 4
Figure 4
3D interaction (left), and hydrogen bond formation (right), between reference ligand (RL), and tested compound 7f with 6Y2F protein.
See this image and copyright information in PMC

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