New poly heterocyclic compounds based on pyrimidine-2-thiones: synthesis, evaluation of putative antiviral agents, DFT calculation, and molecular modeling

Owing to the enormous increase in viral infections in recent years, novel antiviral candidates are both eagerly awaited and unquestionably essential for the treatment of a variety of deadly and incapacitating viral disorders. As a part of our program in this area, a new series of thiazolopyrimidine, pyrimidothiazine, [1,2,4]triazolopyrimidine and N-substituted pyrimidinethione 6–17 have been synthesized in good yields (82–91%) through a facile method using new pyrimidinethione 4 as a building block and several reagents as halo acids/ketones or hydrazonyl halids in one framework. By using several spectroscopic methods, including IR, 1H NMR, 13C NMR, elemental analysis, and DFT calculations, the chemical structures of the novel derivatives were confirmed. The synthetic compounds' cytotoxicity and in vitro antiviral efficacy were examined against HSV-1. Results demonstrated that compounds 6, 7b, 14b,c, and 17 have been found to have significant antiviral activity against HSV-1. Additionally, after examining compounds (6 and 7b)' mechanisms of action, we discovered that compound 6 had a virucidal effect and a mild effect on replication at higher concentrations, whereas compound 7b had activity in all three modes of action, with the virucidal effect being the most potent, followed by the replication effect, and then adsorption. In order to comprehend these results, we investigated the thermal and electrical stability of the generated compounds, where their chemical and thermal properties, dipole moment, subtraction of the highest occupied molecular orbital from the lowest unoccupied molecular orbital (HOMO-LUMO gap), and molecular electrostatic potential were computed. We also, examined the binding mechanism, binding affinity, and non-bonding contacts of the generated derivatives using molecular docking against the Herpes simplex virus type-1 thymidine kinase (PDB ID: 2KI5). A hypothetical pharmacophore model was made using the Molecular Operating Environment (MOE) tool and 10 compounds with structural resemblances to those synthesized with known antiviral activity. The current work recommends compounds 6 and 7b as potential lead structures for future research and development of novel anti-HSV-1 medicines.