Antiviral opportunities of Mannich bases derived from triterpenic <i>N</i>‐propargylated indoles

Abstract

Abstract Oleanolic and glycyrrhetic acids alkyne derivatives were synthesized as a result of propargylation of the indole NH‐group condensed with the triterpene A‐ring, the following aminomethylation led to a series of Mannich bases. The synthesized compounds were tested for their potential inhibition of influenza A/PuertoRico/8/34 (H1N1) virus in Madin‐Darby canine kidney (MDCK) cell culture and SARS‐CoV‐2 pseudovirus in baby hamster kidney‐21‐human angiotensin‐converting enzyme 2 (BHK‐21‐hACE2) cells. Mannich bases of oleanolic and glycyrrhetic acids N ‐propargylated indoles 7 , 8 , and 12 were the most efficacious against influenza virus A with IC 50 7–10 μM together with a low toxicity (CC 50 &gt; 145 μM) and high selectivity index SI value 20. Indolo‐oleanolic acid morpholine amide Mannich base holding N ‐methylpiperazine moiety 9 showed anti‐SARS‐CoV‐2 pseudovirus activity with EC 50 value of 14.8 μM. Molecular docking and dynamics modeling investigated the binding mode of the compounds 7 and 12 into the binding pocket of influenza A virus M2 protein and compound 9 into the RBD domain of SARS‐CoV‐2 spike glycoprotein.