Multistep Synthesis of Analogues of Remdesivir: Incorporating Heterocycles at the C-1' Position

Studies suggest that the 1'β-CN moiety in remdesivir sterically clashes with the Ser861 residue of the RNA-dependent-RNA polymerase (RdRp), causing a delayed chain termination in the RNA replication process. Replacing C1'β-CN with 5-membered heterocycles such as tetrazoles, oxadiazoles, and triazoles can augment the inhibitory activity and pharmacokinetic profile of C-nucleotides. Synthesis of tetrazole-, triazole-, and oxadiazole-integrated C1' analogues of remdesivir was attempted using general synthetic routes. The final compounds 26, 28, and 29 did not inhibit viral replication; however, the synthetic intermediates, i.e., 27 and 50, exhibited an IC90 = 14.1 μM each. The trifluoromethyl-substituted 1,2,4-oxadiazole 59 showed an IC90 of 33.5 μM. This work adds to the growing evidence of the beneficial medicinal impact of C1,1'-disubstituted C-nucleotides.