Design, synthesis and biological evaluation of peptidomimetic benzothiazolyl ketones as 3CLpro inhibitors against SARS-CoV-2

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

“…The simpler azabicyclo[2.2.1]heptane ring system has also been introduced in the structure of such inhibitors. 310 Further insights were provided in the course of an extensive study of boceprevir analogues which reported some key elements to achieve an antiviral effect in cellulo . 311 Moreover, the same research group recently reported the azaspiro[4.4]nonane derivative MPI-60 ( 82 ), which displays promising antiviral properties 312 and a structure of SARS-CoV-2 M pro bound to this compound was obtained ().…”

Recent Advances in SARS-CoV-2 Main Protease Inhibitors: From Nirmatrelvir to Future Perspectives

“…CoV-2 M pro inhibitors, which were designed starting from Nirmatrelvir [63]. They firstly introduced the [2.2.1]azabicylic ring at the P2 position and the benzothiazolyl warhead at the C-terminus; then, they began to explore different substitutions at P3.…”

“…Compound 48 exhibited an interesting inhibitory activity against SARS-CoV-2 M pro (IC 50 = 1.65 µM), a good antiviral activity against SARS-CoV-2-infected VeroE6 cells (EC 50 = 0.18 µM) and low cytotoxicity. Most importantly, the PK properties and target selectivity of compound 48 were superior to those of other derivatives [63]. In the already mentioned work of Kneller et al, besides the development of nitrilebased compounds, the authors designed a novel SARS-CoV-2 M pro inhibitor bearing a benzothiazolyl ketone warhead [35].…”

“…Other quinazolin-4-one-based non-covalent inhibitors of SARS-CoV-2 M pro are compounds 160 and 161 (Figure 79A), proposed by Zhang et al [116], which were developed starting from the lead Baicalein (159 in Figure 79A) by replacing its chromen-4-one ring and varying the substitution pattern in C2 and N3 positions. The most interesting compound (160) contains a phenyl group both at the C2 and N3 position and posseses higher activity as compared to Baicalein [63]. Furthermore, 160 and 161 showed optimal selectivity against other human proteases and low cytotoxicity [116].…”