New patent application published for: System and Method for Inhibiting the Nain Protease (Mpro) of SARS-CoV-2

System and Method for Inhibiting the Nain Protease (Mpro) of SARS-CoV-2

Claims

1. A system for inhibiting the main protease (Mpro) of SARS-CoV-2, comprising a benzimidazole-based compound derived from an amphetamine scaffold.
2. The system of claim 1, wherein the benzimidazole core includes a fluorine atom at the 7-position.
3. The system of claim 2, wherein the benzimidazole scaffold facilitates pi-stacking interactions with His41 in the Mpro active site.
4. The system of claim 3, wherein the chiral side chain includes a modified amphetamine backbone with a chiral carbon bearing a methyl group and an isobutyl group.
5. The system of claim 4, wherein the isobutyl group fills the hydrophobic S2 pocket of Mpro.
6. The system of claim 5, wherein the nitrile warhead forms a covalent bond with the catalytic Cys145 of Mpro.
7. The system of claim 6, wherein the glutamine-mimicking side chain forms hydrogen bonds with Gln189, Glu166, and Thr190 in the Mpro active site.
8. The system of claim 7, wherein the compound is administered in a pharmaceutical composition to treat COVID-19 and related coronavirus infections.
9. The system of claim 8, wherein the pharmaceutical composition is an oral tablet with a dose of 10-100 mg.
10. The system of claim 9, wherein the compound is modified with a histidine-mimicking side chain to target picornavirus 3Cpro.
11. A method for synthesizing a benzimidazole-based compound for inhibiting the main protease (Mpro) of SARS-CoV-2.
12. The method of claim 11, comprising the step of synthesizing 7-fluorobenzimidazole by starting with 2-nitro-4-fluoroaniline and reducing the nitro group to an amine.
13. The method of claim 12, comprising the step of cyclizing with formic acid to yield 7-fluorobenzimidazole.
14. The method of claim 13, comprising the step of performing a Suzuki coupling at C5 using (R)-2-methyl-3-bromopropionitrile.
15. The method of claim 14, comprising the step of adding the isobutyl group to the chiral carbon using isobutylmagnesium bromide.
16. The method of claim 15, comprising the step of synthesizing the glutamine-mimicking side chain starting with serine and protecting the hydroxyl.
17. The method of claim 16, comprising the step of converting the carboxyl to amide and deprotecting the hydroxyl.
18. The method of claim 17, comprising the step of lithiation of C2 of benzimidazole with n-BuLi and quenching with CO2 to form a carboxyl group.
19. The method of claim 18, comprising the step of coupling with H2NCH2CH(OH)CONH2 using EDC/HOBt.
20. The method of claim 19, wherein the final product is 7-fluorobenzimidazole(5)-CH(CH3) (CH2CH(CH3)2)-CH2-CN-CONHCH2CH(OH)CONH2.
21. A method for inhibiting the main protease (Mpro) of SARS-CoV-2, comprising administering a pharmaceutical composition containing a benzimidazole-based compound derived from an amphetamine scaffold to a subject in need thereof.
22. The method of claim 21, wherein the benzimidazole core includes a fluorine atom at the 7-position.
23. The method of claim 22, wherein the benzimidazole scaffold facilitates pi-stacking interactions with His41 in the Mpro active site.
24. The method of claim 23, wherein the chiral side chain includes a modified amphetamine backbone with a chiral carbon bearing a methyl group and an isobutyl group.
25. The method of claim 24, wherein the isobutyl group fills the hydrophobic S2 pocket of Mpro.
26. The method of claim 25, wherein the nitrile warhead forms a covalent bond with the catalytic Cys145 of Mpro.
27. The method of claim 26, wherein the glutamine-mimicking side chain forms hydrogen bonds with Gln189, Glu166, and Thr190 in the Mpro active site.
28. The method of claim 27, wherein the compound is administered in a pharmaceutical composition to treat COVID-19 and related coronavirus infections.
29. The method of claim 28, wherein the pharmaceutical composition is an oral tablet with a dose of 10-100 mg.
30. The method of claim 29, wherein the compound is modified with a histidine-mimicking side chain to target picornavirus 3Cpro.