LAUSR

Repurposing of known drugs and compounds as anticoronavirus disease 2019 (anti-COVID-19) agents through biological reevaluation of their activities, specially the antisevere acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) activities, is a new viable trend in drug discoveries for the pandemic COVID-19 in 2020. Comprehensive inhibition of the coronaviral or coronaviral-2 enzymes and proteins (i.e., multitarget inhibition) can be considered one of the most powerful promising strategies for developing highly potent remedies for COVID-19. However, almost all the reported inhibitors of the different life cycle stages of SARS-CoV-2 lack the extreme potencies against the major and fateful SARS-CoV-2 enzymes (e.g., RNA-dependant RNA polymerase 'RdRp', papain-like protease 'PLpro', and main protease 'Mpro'). Herein, I repurposed and introduced two antioxidant polyphenolic 1,3,4-oxadiazole compounds, previously synthesized by me, 1,2,3-tris[5-(3,4,5-trihydroxyphenyl)-1,3,4-oxadiazol-2-yl]propan-2-ol (named CoViTris2020) and 5-[5-(7-chloro-4-hydroxyquinolin-3-yl)-1,3,4-oxadiazol-2-yl]benzene-1,2,3-triol (named ChloViD2020), as the first multitarget SARS-CoV-2 inhibitors with extremely higher potencies (reach about 65, 171, and 303.5 times, for CoViTris2020, and 20, 52.5, and 93 times, for ChloViD2020, more potent than remdesivir, ivermectin, and favipiravir, respectively). These two unique 2,5-disubstituted-1,3,4-oxadiazole derivatives were computationally studied (through molecular docking in almost all SARS-CoV-2 proteins and one human protein) and biologically evaluated (through one of the most credible in vitro anti-COVID-19 assays) for their anti-COVID-19 activities. The results of the computational docking showed that CoViTris2020 and ChloViD2020 amazingly exhibited very high inhibitory binding affinities with most docked SARS-CoV-2/human proteins (e.g., they exhibited extremely lower binding energies of -12.00 and -9.60 kcal/mol, respectively, with RdRp-RNA). The results of the biological assay showed that CoViTris2020 and ChloViD2020 interestingly exhibited very high and extremely significant anti-COVID-19 activities (anti-SARS-CoV-2 EC50 = 0.31 and 1.01 μM, respectively), and, in addition, they could be also very promising parent lead compounds for the design and synthesis of new anti-COVID-19 agents (through structural modifications and further computational studies). Further investigations for the development of CoViTris2020 and ChloViD2020 as anti-COVID-19 drugs, through in vivo biological evaluations and clinical trials research, are needed. In brief, the rise of CoViTris2020 and ChloViD2020 as the first two members of the new and promising class of anti-COVID-19 polyphenolic 2,5-disubstituted-1,3,4-oxadiazole derivatives would surprisingly make a therapeutic revolution in the treatment of SARS-CoV-2 infection and its accompanied COVID-19.