An inhibitor against sars-cov-2 virus omicron variant

Abstract

The application provides an anti-SARS-CoV-2 virus Omicron mutant inhibitor, characterized in that the structure is shown in the following general formula: the compound has the effect of inhibiting the infection activity of SARS-CoV-2 virus Omicron mutant BA.2 and BF.7.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, and more specifically, to an inhibitor of the SARS-CoV-2 virus omecron mutant. Background Technology

[0002] The development of antiviral drugs is a continuous global need. The severe acute respiratory syndrome caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which broke out in 2020, is now known as COVID-19 (Coronavirus Disease 2019, or novel coronavirus pneumonia). This global pandemic has caused severe damage to the economy and society and seriously threatens human life. The SARS-CoV-2 virus is a positive-sense single-stranded RNA virus, 29.9 kb in length, composed of four structural proteins (S, E, M, and N) and 16 non-structural proteins (NSP1-16) [AC Brant, W. Tian, ​​V. Majerciak, W. Yang, ZM Zheng, SARS-CoV-2: from its discovery to genome structure, transcription, and replication, Cell Biosci 2021, 11, 136.]. The viral vector binds to the spike protein (S protein) on its membrane surface and angiotensin-converting enzyme 2 (ACE2) on the host cell surface, triggering a conformational change in the S protein subunit. This leads to the fusion of the viral envelope and cell membrane, releasing the viral nucleocapsid into the host cell. Once released into the cell, the viral genomic DNA / RNA serves as a template to guide the synthesis of viral proteins. These precursor proteins are synthesized via the main protease (M... pro Also known as 3CL pro The virus is broken down into multiple components, such as RNA-dependent RNA polymerase (RdRp) and helicase, and assembled into a massive replication and transcription machinery to initiate viral replication. During this process, the S protein receptor-binding subunit mediates viral recognition with cell receptors, the transmembrane subunit mediates membrane fusion, the host cell receptor ACE2, the host cell protease that cleaves precursor proteins, and the viral 3CL... proRdRp and other similar targets are common antiviral targets [Y. Zhao, S. Deng, Y. Bai, J. Guo, G. Kai, X. Huang, X. Jia, Promising natural products against SARS-CoV-2: Structure, function, and clinicaltrials, Phytother Res 2022, 36, 3833-3858.].

[0003] Research and development efforts to combat COVID-19 are in full swing, with major treatment measures falling into three categories: vaccines, biological macromolecules (such as immunoglobulins and monoclonal antibodies), and small molecule chemical drugs (such as protease inhibitors and polymerase inhibitors). Among these, small molecule antiviral drugs have advantages such as easy absorption, convenient administration, and ease of large-scale industrial production, making them a hot research area. Currently, the main targets of marketed small molecule drugs against SARS-CoV-2 are RdRp and 3CL. pro[Xu Xiangrong, Yao Lei, Research progress on small molecule compounds against novel coronavirus, China Pharmaceutical Industry, 2022, 31, 1-8.; Zheng Mengzhu, Li Mingxue, Wu Canrong, Yang Yueying, Wang Yali, Gu Xiaoxia, Xiang Ke, Xu Yang, Chen Lixia, Zhang Yonghui, Research progress on drugs against novel coronavirus, Journal of Huazhong University of Science and Technology (Medical Edition), 2020, 49, 11-14.]. Drugs targeting RdRp include Remdesivir, Molnupiravir, and Favipiravi, all of which are prodrugs of nucleoside analogs. Remdesivir was the first drug to treat COVID-19, approved by the FDA in October 2020. Early use can reduce the risk of severe COVID-19 by up to 87% [RL Gottlieb, CE Vaca, R. Paredes, J. Mera, BJWebb, G. Perez, G. Oguchi, P. Ryan, BU Nielsen, M. Brown, A. Hidalgo, Y. Sachdeva, S. Mittal, O. Osiyemi, J. Skarbinski, et al., Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients, N Engl J Med 2022, 386, 305-315.]. Monapir is an oral antiviral drug approved by the FDA in December 2021 for the treatment of mild to moderate patients at risk of progression. Early use can reduce the risk of hospitalization / death [H. Goswami, A. Alsumali, Y. Jiang, M. Schindler, ER Duke, J. Cohen, A. Briggs, A. Puenpatom, Cost-Effectiveness Analysis of Molnupiravir Versus Best Supportive Care for the Treatment of Outpatient COVID-19 in Adults in the US, Pharmacoeconomics 2022, 40, 699-714.].Favipiravir, an anti-influenza drug launched in 2014, has been recommended by countries such as Japan and Russia for the treatment of mild to moderate COVID-19 patients [B. Abdulrahman, A. Mady, MA Odat, AA Tayar, MA Rana, A.Alharthy, A. Alhazmi, AS Abdelmoaty, MM Hafeez, A. Kuhail, AM Noor, M. Haddad, A. Mady, N. Ali, H. Mhawish, et al., Favipiravir Efficacy And Safety For The Treatment Of Severe Coronavirus Disease 2019: A Retrospective Study, J Ayub Med Coll Abbottabad 2022, 34, 397-402.]. It targets 3CL. pro Inhibitors include parvir (Pfizer) and Xocova. Parvir is a combination of nematrelvir and ritonavir developed by Pfizer, effective in adult patients with mild to moderate COVID-19, reducing the risk of hospitalization / death by up to 89% [ME Charness, K. Gupta, G. Stack, J. Strymish, E. Adams, DC Lindy, H. Mohri, DD Ho, Rebound of SARS-CoV-2 Infection after Nirmatrelvir-Ritonavir Treatment, NEngl J Med 2022, 387, 1045-1047.]. Xocova (ensitrelvir, S-217622) from Shionogi Pharmaceuticals of Japan is the second 3CL inhibitor globally. pro The inhibitor was launched in Japan in November 2022.

[0004] The SARS-CoV-2 virus mutates rapidly, and five mutant strains have been identified so far: Alpha, Beta, Gamma, Delta, and Omicron, each with its own typical mutation sites. Some existing drugs have limited or no efficacy against mutant viruses; for example, favipiravir and remdesivir have shown unsatisfactory clinical results in treating SARS-CoV-2 mutant strains. The WHO has reported Omicron mutant strains including BA.1, BA.2, BA.4, BA.5, BF.7, and BQ.1. Screening small molecule drugs against new mutant strains is an ongoing need in the development of anti-COVID-19 drugs to address the potential risk of ineffectiveness of existing drugs. Summary of the Invention

[0005] This invention aims to overcome the above-mentioned defects by using a self-built marine compound library to screen small molecules with anti-SARS-CoV-2 virus activity. A class of compounds with significant activity was discovered. Based on this, further structural modifications of this family of compounds were carried out, especially the introduction of fluorine and alkoxy groups to improve efficacy, stability and bioavailability. Small molecule compounds with activity against the mutants were screened using the mainstream mutants BA.2 and BF.7 of the Omeprone virus strain.

[0006] This invention provides an inhibitor against the SARS-CoV-2 virus omeprone mutant, characterized by the following general formula:

[0007]

[0008] Wherein, R1 is selected from alkyl groups, and one or more hydrogen atoms on the alkyl group are alkyl derivatives substituted with hydroxyl groups;

[0009] R2 can be any or more, selected from electron-donating or electron-withdrawing groups, such as hydroxyl, alkoxy, halogen, etc. When there is more than one, it can be selected from the same or different substituents.

[0010] R3 is selected from hydroxyl or ester groups;

[0011] R4 is selected from hydroxyl or ester groups.

[0012] Furthermore, the present invention provides an inhibitor against the SARS-CoV-2 virus omeprone mutant, characterized in that:

[0013] The ester groups in R3 and R4 are selected from groups represented by the following general formula:

[0014] ;

[0015] R5 is selected from alkyl groups.

[0016] Furthermore, the present invention provides an inhibitor against the SARS-CoV-2 virus omeprone mutant, characterized in that:

[0017] The ester groups in R3 and R4 are selected from groups represented by the following general formula:

[0018] ;

[0019] R6 is selected from alkyl and alkenyl groups.

[0020] Furthermore, the present invention provides an inhibitor against the SARS-CoV-2 virus omeprone mutant, characterized in that:

[0021] In R4, R6 of the ester group is selected from branched alkyl groups.

[0022] Furthermore, the present invention provides an inhibitor against the SARS-CoV-2 virus omeprone mutant, characterized in that:

[0023] The alkyl groups mentioned above are alkyl groups with no more than 10 carbon atoms;

[0024] The alkenyl groups mentioned above are alkenyl groups with no more than 10 carbon atoms;

[0025] The alkoxy group mentioned above is an alkoxy group with no more than 10 carbon atoms.

[0026] Furthermore, the present invention provides an inhibitor against the SARS-CoV-2 virus Omeprón mutant, characterized by: compounds A1-A6, B1-B9, C1-C8, and D1-D8 as shown in the examples.

[0027] Furthermore, the present invention provides an inhibitor against the SARS-CoV-2 virus Omeprone mutant, characterized in that the specific preparation process is as follows: after inoculating Streptomyces onto a seed culture medium, it is inoculated onto a fermentation culture medium to obtain a fermentation product. After 48 hours of inoculation, a precursor is added and the culture is continued. After fermentation is completed, the fermentation product extracted by ultrasound is concentrated under reduced pressure to obtain a crude extract.

[0028] Furthermore, the present invention provides an inhibitor against the SARS-CoV-2 virus omeprone mutant, characterized in that:

[0029] The above substrates are selected from 3-aminobenzoic acid or its derivatives;

[0030] Among them, the above-mentioned derivatives refer to those in which one or more hydrogen atoms on the phenyl group of 3-aminobenzoic acid are replaced by halogens, alkoxy groups, or hydroxyl groups.

[0031] Furthermore, the present invention provides an inhibitor against the SARS-CoV-2 virus Omeprón mutant, characterized in that it is used to prepare a drug for inhibiting the infectivity of SARS-CoV-2 virus Omeprón mutants BA.2 and BF.7. Attached Figure Description

[0032] Figure 1 The infection rate of the compound at a concentration of 0.625 M against the SARS-CoV-2 omega-2 mutant BA.2

[0033] Figure 2 The infection rate of the compound at a concentration of 0.625 M against the SARS-CoV-2 omega-7 mutant strain BF.7 Detailed Implementation

[0034] This invention is capable of various modifications and embodiments, and therefore specific embodiments are illustrated and described in the accompanying drawings. However, this is not intended to limit the invention to specific implementations, but should be understood to include all modifications, equivalents, and even substitutions that fall within the spirit and scope of this invention.

[0035] Example 1

[0036] Experimental methods in the following examples, unless otherwise specified, are generally performed under standard conditions or as recommended by the manufacturer. Unless otherwise noted, all reagents used in the embodiments of this invention are available from the selling company.

[0037] The Streptomyces flaveolus strain used in this invention was purchased from the German Microbial Culture Collection Center, accession number: DSM 9954.

[0038] The method for preparing the compound includes the following steps:

[0039] Strains △mycB1-B4 were inoculated into seed culture medium at 28 ℃ and 220 rpm for 2 days. Then, at a ratio of 5%, they were inoculated into fermentation medium and cultured at 28 ℃ and 220 rpm for 7 days to obtain the fermentation product. At 48 hours post-inoculation, the precursor (25 mM DMSO / H2O 1:1 sterile solution) was added at a volume of 1 mL / flask (1 L Erlenmeyer flask containing 200 mL of fermentation medium), and the mixture was cultured for another 5 days. After fermentation, the fermentation product was extracted with ethyl acetate using a 1:1 ultrasonic extraction method, repeated four times, and concentrated under reduced pressure to obtain a crude extract.

[0040] Following the above procedure, four types of substrates were fed, resulting in the preparation of a total of 31 products (ansatrienin A1-A6, B1-B9, C1-C8, and D1-D8).

[0041] (a) Feeding and product separation of 3-amino-5-fluorobenzoic acid

[0042] Six new compounds, named ansatrienin A1-A6, were isolated from the fermentation products of strain △mycB1-B4 fed with 3-amino-5-fluorobenzoic acid, as follows:

[0043]

[0044] Table 1. Compounds A1-A6 13 C NMR data

[0045]

[0046] a In CD3OD, 600 MHz for 1 H and 150 MHz for 13 C.

[0047] Table 2. Compounds A1-A3 1 H NMR data

[0048]

[0049] a In CDCl3, 600 MHz for 1 H NMR and 150 MHz for 13 C NMR.

[0050] Table 3. Compounds A4-A6 1 H NMR data

[0051]

[0052] a In CDCl3, 600 MHz for 1 H NMR and 150 MHz for 13 C NMR.

[0053] (II) Feeding and product separation of 3-amino-4-fluorobenzoic acid

[0054] Nine new compounds, named ansatrienin B1-B10, were isolated from the feed fermentation products of 3-amino-4-fluorobenzoic acid, as follows:

[0055]

[0056] Table 4. Compounds B1-B5 13C NMR data

[0057]

[0058] a In CDCl3, 600 MHz for 1 H and 150 MHz for 13 C.

[0059] Table 5. Compounds B6-B9 13 C NMR data

[0060]

[0061] a In CDCl3, 600 MHz for 1 H and 150 MHz for 13 C.

[0062] Table 6. Compounds B1-B3 1 H NMR data

[0063]

[0064] a In CDCl3, 600 MHz for 1 H NMR and 150 MHz for 13 C NMR.

[0065] Table 7. Compounds B4-B6 1 H NMR data

[0066]

[0067] a In CDCl3, 600 MHz for 1 H NMR and 150 MHz for 13 C NMR.

[0068] Table 8. Compounds B7-B9 1 H NMR data

[0069]

[0070] a In CDCl3, 600 MHz for 1 H NMR and 150 MHz for 13 C NMR.

[0071] (III) Feeding and product separation of 3-amino-5-methoxybenzoic acid

[0072] Eight new compounds, named ansatrienin C1-C8, were isolated from the feed fermentation products of 3-amino-5-methoxybenzoic acid.

[0073]

[0074]

[0075] Table 9. Compounds C1-C4 13 C NMR data

[0076]

[0077] a In CDCl3, 600 MHz for 1 H and 150 MHz for 13 C.

[0078] Table 10. Compounds C5-C8 13 C NMR data

[0079]

[0080] a In CDCl3, 600 MHz for 1 H and 150 MHz for 13 C.

[0081] Table 11 Compounds C1-C3 1 H NMR data

[0082]

[0083] a In CDCl3, 600 MHz for 1 H NMR and 150 MHz for 13 C NMR.

[0084] Table 12 Compounds C4-C6 1 H NMR data

[0085]

[0086] a In CDCl3, 600 MHz for 1 H and 150 MHz for13 C.

[0087] Table 13 Compounds C7 and C8 1 H NMR data

[0088]

[0089] a In CDCl3, 600 MHz for 1 H NMR and 150 MHz for 13 C NMR.

[0090] (iv) Feeding and product separation of 3-aminobenzoic acid

[0091] Eight new compounds, named ansatrienin D1-D8, were isolated from the feed fermentation products of 3-aminobenzoic acid.

[0092]

[0093]

[0094] Table 14. Compounds D1-D4 13 C NMR data

[0095]

[0096] a In CDCl3, 600 MHz for 1 H and 150 MHz for 13 C.

[0097] Table 15. Compounds D5-D8 13 C NMR data

[0098]

[0099] a In CDCl3, 600 MHz for 1 H and 150 MHz for 13 C.

[0100] Table 16. Compounds D1-D3 1 H NMR data

[0101]

[0102] a In CDCl3, 600 MHz for 1H and 150 MHz for 13 C.

[0103] Table 17 Compounds D4-D6 1 H NMR data

[0104]

[0105] a In CDCl3, 600 MHz for 1 H and 150 MHz for 13 C.

[0106] Table 18. Compounds D7 and D8 1 H NMR data

[0107]

[0108] a In CDCl3, 600 MHz for 1 H and 150 MHz for 13 C.

[0109] Example 2

[0110] The in vitro activity of the above-mentioned compounds against the SARS-CoV-2 virus Omega-2 mutant strains BA.2 and BF.7 was determined.

[0111] I. Viruses, drugs, reagents and other materials

[0112] 1. Virus: The SARS-CoV-2 virus Omega-2 mutants BA.2 and BF.7 were isolated and cultured from nasopharyngeal swab samples of COVID-19 patients by the Department of Biomedical Protection, Naval Medical University. All experimental procedures involving viral infection were performed in the P3 laboratory of Naval Medical University.

[0113] 2. Compounds: The compounds are those in Example 1, provided by the Department of Natural Products, Department of Pharmacy, Naval Medical University.

[0114] 3. African green monkey kidney cells Vero E6, human liver cancer cell line Huh7, and human cervical cancer cell line Hela-hACE2 (expressing an ACE2 gene variant) were purchased from the Shanghai Institute of Cell Biology, Chinese Academy of Sciences, and are preserved by the Department of Biomedical Protection, Naval Medical University of the Chinese People's Liberation Army.

[0115] 4. The DMEM cell culture medium was a product of Hyclone, USA. When using it, 10% fetal bovine serum, non-essential amino acids, ampicillin and streptomycin (100 U / ml each) were added. All culture medium additives were products of Thermo Fisher, USA.

[0116] 5. Cell digestion solution containing 0.25% trypsin, prepared with phosphate buffer.

[0117] 6. The CCK8 cell viability and proliferation assay kit was a product of MedChemExpress, Inc., USA.

[0118] 7. Rabbit anti-SARS-CoV-2 nucleocapsid protein polyclonal antibody was purchased from Beijing Sino Biological Co., Ltd. (Sino Biological # 40143-T62).

[0119] 8. The Alexa Fluor 488-labeled anti-mouse IgG is a product of Thermo Fisher Scientific, Inc.

[0120] II. Experimental Methods and Results:

[0121] (a) The toxicity of compounds to cells

[0122] Cultured human hepatocellular carcinoma line Huh7 and African green monkey kidney cells Vero E6 were seeded into 96-well plates at 10,000 cells per well with 100 μL of culture medium. After 12 hours, the original culture medium was aspirated, and 100 μL of serially diluted complete DMEM medium containing the compound was added to each well, with final concentrations of 2.5, 5, 10, 20, 40, and 80 μM. Each concentration was repeated in triplicate. The 80 μM drug solution in DMSO served as a control without the drug. The plates were incubated at 37°C in a 5% CO2 incubator. After 48 hours, 10 μL of CCK8 cell viability and proliferation assay reagent was added to each well, and the plates were incubated at 37°C in a 5% CO2 incubator. After 30 minutes, the absorbance at 450 nm was measured using a multi-mode microplate reader. The cytotoxicity of the drug was evaluated based on the difference in absorbance at 450 nm between the drug-treated wells and the solvent-treated wells.

[0123] The results showed that when the concentration was equal to or below 80 μM, there was no significant difference between the two cell types treated with the test compound and the cells treated with DMSO solvent.

[0124] (II) Activity of the compound against SARS-CoV-2 Omeprone virus mutants BA.2 and BF.7

[0125] 1. Activity assay of the compounds against SARS-CoV-2 virus omega-7 mutant strains BA.2 and BF.7 in a cell infection model

[0126] Human cervical cancer cells Hela-hACE2, passaged and cultured, were seeded into 96-well plates at 10,000 cells per well with 100 μL of culture medium and cultured for 12 hours. Then, 50 μL of complete DMEM culture medium containing 1000 PFU of SARS-CoV-2 was added to each well; simultaneously, 50 μL of the compound (diluted with DMEM culture medium) was added to each well at sequentially 2-fold dilutions from a maximum concentration of 20 μM to a minimum concentration of 0.0625 μM. Remdesivir was used as a positive control, and an equal volume of DMSO was used as a negative control. Each concentration was repeated in triplicate, with an equal volume of DMSO as a control without the drug. The plates were incubated at 37°C in a 5% CO2 incubator.

[0127] Twenty hours later, the viral infection status of the cells was detected using immunofluorescence. The specific procedure was as follows: The culture medium in the culture plate was aspirated, and 100 μL of methanol was added to each well. The culture plate was placed at -20°C. After 20 minutes, the culture plate was removed, the methanol was aspirated, and each well was washed once with phosphate-buffered saline (PBS). Then, 100 μL of PBS containing 3% bovine serum albumin (BSA) (hereinafter referred to as 3% BSA-PBS) was added, and the plate was placed on a horizontal shaker and gently shaken at room temperature for 1 hour. The 3% BSA-PBS in the culture plate was aspirated, and 100 μL of 1% BSA-PBS containing anti-SARS-CoV-2 polyclonal antibody (antibody diluted 500-fold) was added to each well. The plate was gently shaken at room temperature for 1 hour. The anti-SARS-CoV-2 polyclonal antibody working solution in the culture plate was aspirated, and each well was washed three times with PBS. Then, 100 μL of Alexa Fluor was added. 488-labeled anti-mouse IgG was incubated in 1% BSA-PBS (fluorescein antibody diluted 1500-fold) at room temperature in the dark with gentle shaking for 1 hour. The fluorescein antibody working solution was aspirated from the culture plate. 100 μL of DAPI nuclear staining solution was added to each well, and the plate was incubated at room temperature in the dark with gentle shaking for 10 minutes. The DAPI nuclear staining solution was aspirated from the culture plate. Each well was washed three times with PBS. The fluorescence distribution of cells in each well was photographed using a BioTek Cytation 5 Imaging Reader. Four fields of view were photographed for each well. The relative percentage of green fluorescent positive cells to the solvent-treated wells was analyzed and calculated, i.e., the virus infection rate, and the infection rate of various compounds at a concentration of 0.625 μM. Based on the percentage of positive cells in wells treated with different concentration gradients of drugs, the infection rate (%) of the drugs against SARS-CoV-2 mutants BA.2 and BF.7 was calculated as: 1 - (number of positive cells in drug-treated wells / number of positive cells in solvent-treated wells) * 100%. The IC50 was calculated based on the infection rate at each concentration. 50 value.

[0128] The infection rate of the compound at a concentration of 0.625 μM against the SARS-CoV-2 omeprazole mutant BA.2 was as follows: Figure 1 As shown in the table below, the IC50 values ​​(μM) of the SARS-CoV-2 omeprazole mutant BA.2 are shown; the results show that the compound can effectively inhibit the infection of Hela-hACE2 cells by the SARS-CoV-2 omeprazole mutant BA.2.

[0129]

[0130] The infection rate of the compound at a concentration of 0.625 μM against the SARS-CoV-2 omeprazole mutant strain BF.7 was as follows: Figure 2As shown in the table below, the IC50 values ​​of the compound against the SARS-CoV-2 omeprazole mutant strain BF.7 are shown in the table below; the results show that the IC50 values ​​of the compound against the SARS-CoV-2 omeprazole mutant strain BF.7 are as follows;

[0131]

[0132] The above experimental results all indicate that the compound has significant inhibitory activity against the infection of SARS-CoV-2 virus omega-3 mutants BA.2 and BF.7, and can be used to prepare drugs against the infection of SARS-CoV-2 virus omega-3 mutants BA.2 and BF.7. Preliminary structure-activity relationship analysis revealed that most compounds in ansatrienin A1-A6 and B1-B9 exhibited enhanced activity against SARS-CoV-2 virus omega-2 mutants BA.2 and BF.7. Furthermore, the introduction of fluorine atoms (including 22-F and 21-F) enhanced their stability and bioavailability, increasing their potential for drug development. The introduction of methoxy groups in ansatrienin C1-C8 stabilized the stability of these compounds, avoiding the structural instability caused by p-phenol (quinone) in ansatrienin A and B. The lack of hydroxyl, fluorine, or methoxy substitutions on the benzene rings of ansatrienin D1-D8 significantly reduced their activity against SARS-CoV-2 virus omega-2 mutants BA.2 and BF.7, suggesting that functional groups on the benzene ring are crucial for the activity.

[0133] While the foregoing has focused on embodiments, these are merely illustrative and do not limit the invention. Those skilled in the art will understand that various modifications and applications not illustrated above can be made without departing from the essential characteristics of these embodiments. For example, the constituent elements specifically shown in the embodiments can be implemented through modifications. Furthermore, various differences related to such modifications and applications should be interpreted as being included within the scope of the invention as defined in the appended claims.

Claims

1. An inhibitor against the SARS-CoV-2 virus omircron mutant, characterized in that, Selected from compounds with the following structures: ； ； ； ； ； 。 2. The inhibitor against the SARS-CoV-2 virus omeprón mutant as described in claim 1, characterized in that, The specific preparation process is as follows: after inoculating Streptomyces △mycB1-B4 onto a seed culture medium, it is inoculated onto a fermentation culture medium to obtain a fermentation product. After 48 hours of inoculation, a precursor is added and the culture is continued. After fermentation is completed, the fermentation product is extracted with ethyl acetate by ultrasonic extraction and then concentrated under reduced pressure to obtain a crude extract. The Streptomyces strain mentioned is Streptomyces flaveolus, purchased from the German Culture Collection Center for Microbial Cultures, accession number: DSM 9954; The strain was fed with 3-amino-5-fluorobenzoic acid, and A1-A4 and A6 were isolated from the feeding fermentation product. The strain was fed with 3-amino-4-fluorobenzoic acid, and B1-B10 were isolated from the feeding fermentation product. The strain was fed with 3-amino-5-methoxybenzoic acid, and C1-C8 were isolated from the feeding fermentation product; The strain was fed with 3-aminobenzoic acid, and D1-D8 were isolated from the feeding fermentation product.

3. The use of the SARS-CoV-2 virus Omeprón mutant inhibitor as described in claim 1 in the preparation of a drug for inhibiting the infectivity of SARS-CoV-2 virus Omeprón mutants BA.2 and BF.7.

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