Recently, natural and synthetic nitrogenous heterocyclic
antivirals topped the scene as first choices for the treatment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infections and their accompanying disease, the
coronavirus disease 2019 (COVID-19). Meanwhile, the mysterious evolution of a new strain of SARS-CoV-2, the Omicron variant and its sublineages, caused a new defiance in the continual
COVID-19 battle. Hitting the two principal coronaviral-2 multiplication
enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5'
exoribonuclease (ExoN) synchronously using the same
ligand is a highly effective novel dual pathway to hinder SARS-CoV-2 reproduction and stop
COVID-19 progression irrespective of the SARS-CoV-2 variant type since RdRps and ExoNs are widely conserved among all SARS-CoV-2 strains. Herein, the present computational/
biological study screened our previous small libraries of nitrogenous
heterocyclic compounds, searching for the most ideal
drug candidates predictably able to efficiently act through this double approach. Theoretical filtration gave rise to three promising
antioxidant nitrogenous
heterocyclic compounds of the
1,3,4-thiadiazole type, which are CoViTris2022, Taroxaz-26, and ChloViD2022. Further experimental evaluation proved for the first time, utilizing the in vitro anti-RdRp/ExoN and anti-SARS-CoV-2 bioassays, that ChloViD2022, CoViTris2022, and Taroxaz-26 could effectively inhibit the replication of the new virulent strains of SARS-CoV-2 with extremely minute in vitro anti-RdRp and anti-SARS-CoV-2 EC50 values of 0.17 and 0.41 μM for ChloViD2022, 0.21 and 0.69 μM for CoViTris2022, and 0.23 and 0.73 μM for Taroxaz-26, respectively, transcending the anti-COVID-19
drug molnupiravir. The preliminary in silico outcomes greatly supported these biochemical results, proposing that the three molecules potently strike the key catalytic pockets of the SARS-CoV-2 (Omicron variant) RdRp's and ExoN's vital active sites. Moreover, the idealistic pharmacophoric hallmarks of CoViTris2022, Taroxaz-26, and ChloViD2022 molecules relatively make them typical dual-action inhibitors of SARS-CoV-2 replication and proofreading, with their highly flexible structures open for various kinds of chemical derivatization. To cut it short, the present pivotal findings of this comprehensive work disclosed the promising repositioning potentials of the three 2-aminothiadiazoles, CoViTris2022, Taroxaz-26, and ChloViD2022, to successfully interfere with the crucial
biological interactions of the coronaviral-2 polymerase/
exoribonuclease with the four principal
RNA nucleotides, and, as a result, cure
COVID-19 infection, encouraging us to rapidly start the three drugs' broad preclinical/clinical anti-COVID-19 evaluations. Dual SARS-CoV-2 polymerase (RdRp) and
exoribonuclease (ExoN) inhibition via
nucleoside mimicry is a very effective novel approach for
COVID-19 infection therapy. Hydroxylated nitrogenous
heterocyclic compounds are currently considered first choices in
COVID-19 therapy. Extensive computational investigations disclosed three synthetic 5-substituted-2-amino-1,3,4-thiadiazoles, CoViTris2022, Taroxaz-26, and ChloViD2022, with ideal anti-RdRp/ExoN features. ChloViD2022 was ranked the top among the three
NAs, with biochemical anti-RdRp EC50 value of 0.17 μM. ChloViD2022 accordingly displayed excellent anti-SARS-CoV-2 EC50 value of 0.41 μM against the Omicron variant.