CN-122010828-A - PLpro protease small molecule inhibitor and preparation method and application thereof

CN122010828ACN 122010828 ACN122010828 ACN 122010828ACN-122010828-A

Abstract

The invention is suitable for the technical field of biological medicine, and provides a PLpro protease small molecule inhibitor, a preparation method and application thereof, wherein the chemical structural formula is shown as follows: . The invention provides a PLpro protease small molecule inhibitor and a preparation method thereof, and researches and analyzes that the PLpro protease small molecule inhibitor has obvious inhibition effect on novel coronaviruses and has strong activity recovery capability on infected cells.

Inventors

YANG BO
TUO HAO
LIU XUEYAN

Assignees

吉林大学

Dates

Publication Date: 20260512
Application Date: 20260408

Claims (5)

1. A PLpro protease small molecule inhibitor, which is characterized by the following chemical structural formula: 。
2. A method of preparing the PLpro small molecule protease inhibitor according to claim 1, comprising the steps of: (1) Preparation of Compound 1_2a 1.00 equivalents of Compound 1_1a and 1.00 equivalents of Compound 1a were dissolved in a mixture of dioxane and water, 3.00 equivalents of K 2 CO 3 and 0.10 equivalents of Pd (dppf) Cl 2 were added under a nitrogen atmosphere, the mixture was degassed and purged with nitrogen, the mixture was heated and stirred under a nitrogen atmosphere, after the reaction was completed, the reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was washed, dried, filtered and concentrated under reduced pressure to give a residue, which was purified to give Compound 1_2a; the chemical structural formula of the compound 1_1a is as follows: ; The chemical structural formula of the compound 1a is as follows: ; the chemical structural formula of the compound 1_2a is as follows: ; (2) Preparation of Compound 1_3a 1.00 equivalent of Compound 1_2a is dissolved in a mixture of THF and water, 3.00 equivalent of LiOH H 2 O is added, the mixture is heated and stirred, after the reaction is finished, the reaction mixture is poured into H 2 O, the pH is regulated by HCl, then extracted by ethyl acetate, and the organic layer is washed, dried, filtered and concentrated under reduced pressure to obtain Compound 1_3a; the chemical structural formula of the compound 1_3a is as follows: ; (3) Preparation of Compound 1_4a 1.00 equivalent of Compound 1_3a and 1.20 equivalent of Compound 3a were mixed in DMF, 1.50 equivalent of HATU and 3.00 equivalent of DIEA were added, the mixture was stirred for reaction, after the reaction was completed, the reaction mixture was concentrated under vacuum to obtain residue, the residue was purified, and the eluent was concentrated under vacuum to obtain Compound 1_4a; the chemical structural formula of the compound 3a is as follows: ; the chemical structural formula of the compound 1_4a is as follows: ; (4) Preparation of PLpro protease small molecule inhibitors: 1.00 equivalents of compound 1_4a was dissolved in THF and MeOH, N 2 was added, 0.37 equivalent of Pd/C was added, the suspension was degassed under vacuum, then aerated with H 2 , the reaction was stirred under H 2 conditions, after the reaction was completed, the reaction mixture was filtered, the filter residue was washed with MeOH, the filtrate was concentrated under reduced pressure to give a residue, the residue was purified, the eluent was concentrated under vacuum, and the remaining aqueous solution was lyophilized to give the PLpro protease small molecule inhibitor.
3. The method for producing a PLpro small-molecule inhibitor of protease according to claim 2, wherein in step (1), the organic layer is washed and dried with saturated brine, and dried with sodium sulfate.
4. The method of claim 2, wherein in step (2), the pH is adjusted with HCl, specifically 1M HCl to 2; The organic layer is washed and dried by saturated brine and sodium sulfate.
5. Use of a PLpro protease small molecule inhibitor according to claim 1 in the manufacture of an anti-coronavirus medicament.

Description

PLpro protease small molecule inhibitor and preparation method and application thereof Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to a PLpro protease small-molecule inhibitor, a preparation method and application thereof. Background The novel coronavirus (SARS-CoV-2) is the main pathogen causing the novel coronavirus infection (COVID-19), the genome of the single-stranded RNA virus belonging to the genus beta coronavirus encodes a plurality of non-structural proteins, wherein papain (Papain-like protease, PLpro) plays a dual key role in viral replication and immune escape, namely, on one hand, PLpro participates in the cleavage process of viral polyprotein, ensuring the correct assembly and release of virus particles, which is an indispensable link of the viral life cycle, and on the other hand, it can interfere with natural immune response by the ubiquitination of host cell signal proteins, thereby promoting the continuous infection of viruses. Although the existing direct antiviral drugs have a certain clinical progress, challenges such as fluctuation of curative effect, generation of drug resistance and insufficient conservation of targets still exist in the face of constantly occurring variant strains. Therefore, the development of a novel small molecule inhibitor aiming at PLpro which is a highly conserved and functionally critical target is expected to cooperatively inhibit virus replication and enhance host immune response through a dual mechanism, and provides a drug candidate strategy with broad spectrum potential for coping with current and future coronavirus related epidemic situations, thereby having important scientific significance and clinical value. Disclosure of Invention The embodiment of the invention aims to provide a PLpro protease small molecule inhibitor which aims to solve the problems in the background technology. The embodiment of the invention is realized in such a way that a PLpro protease small molecule inhibitor has the chemical structural formula as follows: 。 Another object of the embodiments of the present invention is to provide a preparation method of PLpro protease small molecule inhibitor, which includes the following steps: (1) Preparation of Compound 1_2a 1.00 equivalents of Compound 1_1a and 1.00 equivalents of Compound 1a were dissolved in a mixture of dioxane and water, 3.00 equivalents of K 2CO3 and 0.10 equivalents of Pd (dppf) Cl 2 were added under a nitrogen atmosphere at 25 ℃, after the mixture was degassed and purged with nitrogen, the mixture was heated to 90℃and stirred under a nitrogen atmosphere for 2 hours, after the completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was washed, dried, filtered and concentrated under reduced pressure to give a residue, which was subjected to column chromatography purification to give Compound 1_2a; the chemical structural formula of the compound 1_1a is as follows: ; The chemical structural formula of the compound 1a is as follows: ; the chemical structural formula of the compound 1_2a is as follows: ; (2) Preparation of Compound 1_3a 1.00 equivalents of Compound 1_2a was dissolved in a mixture of THF and water, 3.00 equivalents of LiOH. H 2 O was added at 25 ℃, the mixture was heated to 70 ℃ and stirred at 70 ℃ for 12 hours, after the reaction was completed, the reaction mixture was poured into H 2 O, pH was adjusted with HCl, followed by extraction with ethyl acetate, washing, drying, filtration and concentration under reduced pressure to give Compound 1_3a; the chemical structural formula of the compound 1_3a is as follows: ; (3) Preparation of Compound 1_4a 1.00 equivalents of Compound 1_3a and 1.20 equivalents of Compound 3a were mixed in DMF, 1.50 equivalents of HATU and 3.00 equivalents of DIEA were added, the mixture was stirred at 25℃for 5 hours, after the reaction was completed, the reaction mixture was concentrated in vacuo to give a residue, the residue was purified by HPLC, and the eluate was concentrated in vacuo to give Compound 1_4a; the chemical structural formula of the compound 3a is as follows: ; the chemical structural formula of the compound 1_4a is as follows: ; (4) Preparation of PLpro protease small molecule inhibitors: 1.00 equivalents of compound 1_4a was dissolved in THF and MeOH, N 2 was added at 25 ℃ and 0.37 equivalent of Pd/C was added, the suspension was degassed under vacuum, then aerated with H 2, the reaction stirred for 12 hours under 25 ° C, H 2, after completion of the reaction, the reaction mixture was filtered, the filter residue was washed with MeOH, the filtrate was concentrated under reduced pressure to give a residue, the residue was purified by HPLC, the eluate was concentrated under vacuum, and the remaining aqueous solution was lyophilized to give the PLpro protease small molecule inhibitor. Another object of the embodiment of the invention