Dihydroartemisinin-Ursodeoxycholic Bile Acid Hybrids in the Fight against SARS-CoV-2

Abstract

Here, we propose the molecular hybridization of dihydroartemisinin (DHA) and ursodeoxycholic bile acid (UDCA), approved drugs, for the preparation of antiviral agents against SARS-CoV-2. DHA and UDCA were selected on the basis of their recently demonstrated in vitro activity against SARS-CoV-2. A selection of DHA-UDCA-based hybrids obtained by varying the nature of the linkage and the bile acid conjugation point as well as unconjugated DHA and UDCA were tested in vitro for cytotoxicity and anti-SARS-CoV-2 activity on Vero E6 and Calu-3 human lung cells. The hybrid DHA-t-UDCMe, obtained by conjugation via click chemistry on a gram scale, was identified as a potential candidate for SARS-CoV-2 infection treatment due to significant reduction of viral replication, possibly involving ACE2 downregulation, no cytotoxicity, and chemical stability.

Enzymatic Synthesis of New Acetoacetate–Ursodeoxycholic Acid Hybrids as Potential Therapeutic Agents and Useful Synthetic Scaffolds as Well

“…Furthermore, they also have the common ability to cross the blood–brain barrier [ 8 , 19 ]. Quite curiously, during our recent research focused on KB activities as well as on the synthesis of KB derivatives, we found very little information about the combined activities of UDCA and KBs [ 20 ] and, in spite of the large number of BA conjugates reported in the literature [ 21 , 22 , 23 , 24 , 25 , 26 ], no article has reported the synthesis of covalent UDCA-KB conjugates (this is the same for the other BAs). In order to close this gap, in this work, we describe the enzymatic synthesis of new acetoacetic esters of UDCA.…”