COVID-19 therapeutics: Small-molecule drug development targeting SARS-CoV-2 main protease

Design, Synthesis, X-ray Crystallography, and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease

“…1 H NMR (CDCl 3 , 400 MHz) δ 8.48 (d, J = 4.1 Hz, 1H), 8.40 (s, 1H), 8.25 (s, 1H), 7.52−7.35 (m, 3H), 7.11 (dd, J = 7.6, 4.9 Hz, 1H), 6.03 (s, 1H), 5.98 (s, 1H), 5.68 (s, 1H), 5.30 (s, 1H), 5.12 (s, 1H), 3.83 (s, 2H), 1.36 (s, 9H). 13 (17). 1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (s, 1H), 8.06 (s, 1H), 7.48 (s, 1H), 7.19 (s, 1H), 7.08 (s, 4H), 6.28 (s, 1H), 5.87 (s, 1H), 5.08− 4.99 (m, 1H), 3.83 (s, 2H), 3.33 (s, 2H), 2.78 (s, 1H), 2.54 (s, 1H), 1.33 (s, 9H).…”

“…A number of inhibitors of SARS-CoV-2 Mpro have been developed, with most of the potent ones being peptidomimetic compounds bearing an electrophilic “warhead” group to covalently bind to Cys145 (Figure ), ,− including FDA-approved drug nirmatrelvir (PF-07321332) . Nevertheless, studies toward finding more chemotypes of Mpro inhibitors are desirable, given Mpro’s essential roles in replication of SARS-CoV-2 and other coronaviruses.…”

On the origins of SARS-CoV-2 main protease inhibitors

“…Many reports have already listed all the, sometimes related, 36 inhibitors reported for their effect on chymotrypsin-like proteases of human rhinovirus, 37–40 enterovirus 71, 41 SARS and MERS coronaviruses 42–46 and then SARS-CoV-2. 2–4,6,17,18,47–70 In the present text, the many publications 26 solely based on in silico docking approaches 71,72 and/or on traditional/ancestral medicine beliefs which only described frequent hitters/pan-assay interference compounds (PAINS) 73–77 were ignored. This choice is a bid to discourage such all too obvious pollution of the scientific literature, 78,79 not to mention the issue of lack of reproducibility of some data from the academia.…”

Synthesis and Evaluation of 9-Aminoacridines with SARS-CoV-2 Antiviral Activity

“…These proteases are essential for viral replication, making them attractive targets for antiviral therapeutics . There are currently a number of M pro inhibitors that have advanced to clinical trials; however, none have yet reached the market …”

“…13 There are currently a number of M pro inhibitors that have advanced to clinical trials; however, none have yet reached the market. 14 A hot topic in the identification for antiviral drug candidates is the repurposing of existing drugs for new targets. 1 The above-mentioned remdesivir was originally developed for the treatment of hepatitis C and was later repositioned for COVID-19.…”