Novel Abietane Type Sugar Triazole Hybrids and Amides against SARS-CoV-2 Spike Glycoprotein and Influenza A Virus

Abstract

Abietane type diterpenic (dehydroabietic, 2,3-dihydroquinopimaric and maleopimaric) acids were converted by the acid chloride method into a series of aliphatic and heterocyclic amine spacered conjugates. A number of structurally novel derivatives holding 1,2,3-triazole moieties were designed and synthesized by treating of the propargylated amides and esters with a sugar azides using the Cu(I)-catalyzed click chemistry approach. The synthesized N-containing diterpene derivatives were tested for their potential inhibition of influenza A/PuertoRico/8/34 (H1N1) virus in MDCK cell culture and SARS-CoV-2 pseudovirus in BHK-21-hACE2 cells. Among tested forty-five compounds ten derivatives were the most efficacious against influenza virus A with IC₅₀ 0.7–63.4 μM together with high selectivity index SI value from 11 from 94. Dihydroquinopimaric acid N-ethylpiperazine-amide and dehydroabietic acid 1,2,3-triazoles spacered with glucose and lactose showed anti-SARS-CoV-2 pseudovirus activity with EC₅₀ values of 1.79–25.46 μM. Molecular docking and dynamics modeling investigated the binding mode of the lead compounds into the binding pocket of influenza A virus M2 protein and the RBD domain of SARS-CoV-2 spike glycoprotein.