A Search for Sars‐CoV‐2 Main Protease Inhibitors: Synthesis and Docking Study of Steroidal Dinitriles

Abstract

Coronaviruses are continually evolving, as evidenced by the emergence of three closely related pathogenic variants over the past two decades: SARS (2002), MERS (2012), and SARS‐CoV‐2 (2019); and the appearance of many new SARS‐CoV‐2 strains during the COVID‐19 pandemic. Hence, COVID‐19 has now become a pandemic disease; with a real possibility for the emergence of new deadly SARS‐related coronaviruses. The SARS‐CoV‐2 main protease, Mpro is an attractive drug target for the development of inhibitors against SARS type and other coronaviruses because it is essential for the viral life cycle and highly conserved among a wide range of pathogenic coronaviruses. This motivated the synthesis of novel inhibitors of Mpro, which could be the basis for COVID‐19 drug development. The synthesis of new 5,6 : 16,17‐diseco and 6,7 : 16,17‐disecoandrostane 16,17a‐dinitriles is reported. In silico ADMET analyses suggest that the synthesized compounds possess drug‐like properties with no predicted toxicities. Structural similarity analyses indicates that synthesized B,D‐diseco 16,17a‐dinitrile derivatives have potential as protease inhibitors. Molecular docking simulations suggest that B,D‐diseco 16,17a‐dinitriles could inhibit substrate binding by Mpro. The present study suggests that newly synthesized androstane 5,6 : 16,17‐diseco‐5‐keto‐6‐oic acid and 6,7 : 16,17‐diseco‐6,7‐dioic acid 16,17a‐dinitriles 8 and 11 could represent a starting point for the design of Mpro inhibitors against SARS type coronaviruses.