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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(1 H ,5 H )-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 1 5, 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,  13 C-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.

polycyclic aromatic compounds

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