Design and Synthesis of Antiviral Molnupiravir Analogues

Abstract:

Viral infectious diseases have been proved to be a major threat to our public health, including the ongoing COVID-19 pandemic. Two pillars of fighting viral infectious diseases are vaccines and antiviral drugs. Despite the immense achievements of our COVID-19 vaccines, yet the pace of antiviral drug development is dreadfully slow. Besides Remdesivir, only two more compounds (currently under development by Pfizer and Merck, respectively) are showing significant progress in treating COVID infections. The presented study is the first to pursue a series of chemically modified compounds designed based on the antiviral drug Molnupiravir (EIDD-2801) developed by Merck. The compound has finished the phase II/III clinical trials with a promising positive result and granted an emergency use authorization by the U.S. FDA. The newly designed targets adopted the carbocyclic sugar framework to improve the antiviral activity by increasing the cyto-stability compared to the parent compound. Carbocyclic nucleosides are also known for their prominent board-spectrum antiviral activities with distinct drug action mechanisms. Their antiviral activity stems from inhibiting a host enzyme Adenosylhomocysteine (AdoHcy) hydrolase, then consequentially stop the “capping” progress, a key step in forming the mature viral mRNA. The designed compounds combine the features of Molnupiravir (nucleobase) with the carbocyclic rings to pursue a class of dual antiviral mechanism drug candidates. Potential pro-drug structures are also included to test the pharma kinetic properties. The proposed synthesis strategy successfully achieves the key intermediate via a Mitsunobu coupling reaction. Optimization of the reaction conditions for the critical synthesis steps is detailed in the following discussion.