Synthesis and in Silico Antiviral Activity of Novel Bioactive Thiobarbituric Acid Based Hydrazones and Pyrazoles against SARS-CoV-2 Main Protease (Mpro)

Owing to its broad spectrum biological activity, pyrimidines have been extensively employed as building blocks for synthesizing various drug mimic molecules. In the present work, a novel 2-hydrazineyl-5-(2-phenylhydrazineylidene)pyrimidine-4,6(1H,5H)-dione 3 was prepared and was subsequently reacted with a variety of substituted benzaldehyde derivatives 4a-c, 6, and heteroaryl ketones namely, 2-acetylthiophene 8, acetophenone 10a, 2-acetylpyridine 10b, or 3-acetylindole 12 to give the respective hydrazones 5a-c, 7, 9, 11a,b, or 13. Moreover, the reaction of hydrazine 3 with commercially available active methylene compounds, namely, ethyl benzoylacetate 14, acetylacetone 16, and diethyl malonate 18, afford the respective pyrazole derivatives 15, 17, and 19. All reactions were preceded in good yields and the structures of the synthesized compounds were confirmed by elemental analysis, IR, 1H-NMR, C-13-NMR and mass spectral data. The anti-viral activity of the synthesized derivatives was investigated against SARS-CoV-2 main protease (Mpro) using molecular docking combined with molecular dynamics simulation (MD). The docking scores against (PDB: 6LU7), were calculated via Standard Precision (SP) method of the Glide docking module of Meastro. The docking score of the novel compounds ranged between -7.29 and -6.02 with good affinity toward Mpro. Pyrazolinone 19 demonstrated the lowest docking score (-7.293 kcal/mol) and glide emodel -72.978, showed three hydrogen bond interactions with GLU166, GLY143 and the catalytic dyad CYS145. Thus, compound 19 was chosen for further molecular dynamics simulation study for 20 ns. The results indicated that the protein was almost stabilized with average four to five hydrogen bonds with compound 19 during the simulation period. This means the potential inhibitory activity of the promising pyrazolinone 19 against SARS-CoV-2 Mpro.

Automated summary

In this study, a series of pyrimidine derivatives with broad-spectrum biological activity were synthesized, and their antiviral activity against SARS-CoV-2 main protease (Mpro) was investigated using molecular docking and molecular dynamics simulation. Among them, pyrazolinone 19 exhibited the strongest inhibitory activity with good affinity towards Mpro, making it a potential candidate for antiviral drug development.