A compound for targeting and inhibiting ABCB1 (P-gp) and preparation method and application thereof

Abstract

The application discloses a kind of compound for targeting inhibition ABCB1 (P-gp) and preparation method and application, belong to biological medicine technical field.The application designs and synthesizes 6 ABCB1 (P-gp) inhibitors, and biological activity evaluation reveals that these compounds can effectively reverse cell drug resistance caused by high expression of ABCB1 (P-gp), and the toxicity of cell level is lower than the first generation P-gp inhibitor verapamil (Verapamil) and the third generation P-gp inhibitor (WK-X-34), and it has important significance to enhance the curative effect of tumor drug or antibiotic.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a compound that targets and inhibits ABCB1 (P-gp), its preparation method, and its application. Background Technology

[0002] Chemotherapy remains an effective treatment for cancer patients; however, most patients who initially respond to chemotherapy eventually develop resistance. Multidrug resistance (MDR), characterized by cross-resistance to drugs with different molecular structures, intracellular targets, and pharmacological effects, has become one of the main causes of chemotherapy failure in cancer. Various mechanisms have been proposed to explain resistance, including aberrant expression of glutathione peroxidase 4 (GPX4), cytochrome P4501B1 (CYP1B1), and signal transducer and activator of transcription 3 (STAT3). However, overexpression of ATP-binding cassette (ABC) transporters is widely considered a key cause of the MDR phenotype, with P-glycoproteins (P-gp, ABCB1) being the most prominent. Encoded by the MDR1 gene on chromosome 7q21, P-glycoproteins pump broad-spectrum chemotherapeutic drugs (such as paclitaxel, cisplatin, and doxorubicin) out of cancer cells, leading to decreased intracellular drug levels and thus weakening the therapeutic effect. Structurally, P-gp is a 170 kDa plasma membrane glycoprotein composed of 1280 amino acids. It has two pseudo-symmetrical hemispheres, each containing a long transmembrane domain (TMD, six transmembrane segments) and a cytoplasmic nucleotide-binding domain (NBD). The TMD is mainly involved in substrate recognition and transport, while the NBD is responsible for the energy generation step of ATP hydrolysis, inducing a conformational change in the TMD to expel the substrate from the cell.

[0003] P-gp is normally distributed in normal and healthy tissues, including epithelial cells in the small intestine, bile ducts, proximal convoluted tubules of the kidneys, and blood-brain barrier endothelial cells; however, it is overexpressed in a variety of multidrug-resistant malignant cancer cells. Given the importance of the ABCB1 transporter in clinical oncology, P-gp inhibitors or chemosensitizers have been extensively studied as MDR reversals. Over the past thirty years, through extensive efforts, three generations of P-gp inhibitors have been developed: (1) First-generation P-gp inhibitors include verapamil (VRP), cyclosporine A, reserpine, quinidine, and tamoxifen, although their clinical use is limited by low affinity and the high toxicity of the doses required to effectively inhibit P-gp; (2) Structural modifications of first-generation P-gp inhibitors led to the discovery of second-generation P-gp inhibitors, including (R)-verapamil, valspodar (PSC 833), and pyricorda citrate (VX-710), which have significantly higher affinity for P-gp, but they exhibit unpredictable clinical pharmacokinetic interactions; (3) Third-generation P-gp inhibitors (such as tariquidar, zosuquidar, laniquidar, and elacridar) have been obtained through quantitative structure-activity relationship analysis and combinatorial chemistry, which also exhibit high selectivity and potency, but their clinical efficacy remains poor. Due to poor response or unexpected toxic side effects, and to our knowledge, no P-gp inhibitors have been approved for clinical use. Therefore, it is crucial to design and develop novel P-gp inhibitors with improved efficacy and tolerability.

[0004] Taking advantage of the fact that ABCB1(P-gp) is a hydrophobic protein containing a large number of hydrophobic amino acids and has a large binding pocket, we introduced a large hydrophobic functional group to occupy the active pocket of ABCB1(P-gp) to increase hydrophobic interactions and binding affinity, thereby improving the inhibitory activity of ABCB1(P-gp). Summary of the Invention

[0005] To address the problems mentioned above, the present invention aims to provide a compound that targets and inhibits ABCB1 (P-gp), its preparation method, and its application. The compound of the present invention can effectively inhibit ABCB1 (P-gp) protein, thereby reversing drug resistance in tumor cells.

[0006] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0007] This invention provides an adamantane ABCB1 (P-gp) inhibitor of formula (Ⅰ) or a pharmacologically or physiologically acceptable salt thereof:

[0008]

[0009] in:

[0010] Linker is a linking group, representing -alkylene, -alkoxy, -piperazinyl, or -1,2,3-triazolyl, wherein the -alkylene, -alkoxy, or -piperazinyl group is selected from any one or any combination of the following groups, where m and n represent natural numbers from 1 to 20:

[0011] -(CH2) n -or-(CH2) n -C(O)NH(CH2CH2O) m -or-(CH2) n -NHC(O)(CH2) m -or-(CH2CH2O) n -C(O)NH(CH2CH2O) m -or

[0012] Furthermore, the compounds provided by the present invention are, as shown below, stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically or physiologically acceptable salts or prodrugs.

[0013]

[0014] The pharmacologically or physiologically acceptable salts mentioned in this invention refer to the salts formed by the adamantane ABCB1 (P-gp) inhibitors of this invention and pharmacologically or physiologically acceptable acids or bases.

[0015] The present invention also proposes a pharmaceutical composition comprising the aforementioned adamantane ABCB1 (P-gp) inhibitor or its stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0016] The pharmaceutical composition further includes pharmaceutically acceptable carriers, excipients, diluents, excipients, mediators, or combinations thereof.

[0017] The pharmaceutical composition is an injection, an oral preparation, or a mucosal delivery preparation.

[0018] This invention also provides the use of adamantane ABCB1 (P-gp) inhibitors or pharmaceutical compositions comprising such compounds. Specifically:

[0019] The use of the adamantane ABCB1 (P-gp) inhibitor or pharmaceutical composition containing the compound in reversing resistance to antitumor drugs (chemotherapeutic drugs, targeted drugs, and ADC drugs) and antibiotics.

[0020] The aforementioned adamantane-based ABCB1 (P-gp) inhibitor or pharmaceutical composition containing this compound is used in the preparation of a treatment for drug resistance caused by ABCB1 (P-gp) overexpression. Diseases associated with ABCB1 (P-gp) overexpression include tumors and infectious diseases caused by microorganisms.

[0021] The use of the adamantane ABCB1 (P-gp) inhibitor or pharmaceutical composition containing the compound in reversing tumor cell resistance and bacterial resistance.

[0022] The tumor is any one of gastric cancer, breast cancer, lung cancer, ovarian cancer, colonic adenocarcinoma, clear cell renal cell carcinoma, lung adenocarcinoma, prostate cancer, rectal adenocarcinoma, thyroid cancer, and endometrial cancer. Furthermore, the tumor cell drug resistance and bacterial drug resistance are caused by high expression of ABCB1 (P-gp).

[0023] This invention also proposes a synthetic route for adamantane-based ABCB1 (P-gp) inhibitors represented by the general formula, specifically including the following steps:

[0024] The preparation of the tetrahydroisoquinoline skeleton shown in the general formula involves coupling with the adamantane functional group through multiple reaction types, including amide condensation. The synthetic route is as follows:

[0025]

[0026] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

[0027] Compared with first-generation ABCB1 (P-gp) inhibitors, the compounds involved in this invention can significantly reverse tumor cell drug resistance; compared with third-generation ABCB1 (P-gp) inhibitors, they improve the efficiency of reversing tumor cell drug resistance, and their cytotoxicity is also significantly reduced compared with third-generation inhibitors. Attached Figure Description

[0028] Figure 1 Synthetic routes for compounds DJYPGP-1 to DJYPGP-6;

[0029] Figure 2 For preliminary assessment of the compound's cytotoxicity. Detailed Implementation

[0030] The present invention will be further described below with reference to the accompanying drawings to provide a better understanding of the technical solution.

[0031] The technical and scientific terms used in the following embodiments have the same meanings as commonly understood by one of ordinary skill in the art to which this invention pertains. The basic raw materials and reagents are commercially available and have a purity of 97% or higher. The room temperature described in this invention is 25-30°C. This invention provides a general and specific description of the materials and experimental methods used in the experiments.

[0032] Example 1: Synthesis and structural confirmation of adamantane-based ABCB1 (P-gp) inhibitors. The synthetic route for the final products DJYPGP-1 to DJYPGP-6 is as follows: Figure 1 As shown.

[0033] Synthesis of intermediate 3:

[0034] 4-Nitrophenylethyl bromide (1, 5.5 g, 23.94 mmol), 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2, 5.0 g, 21.77 mmol), and potassium carbonate (7.52 g, 54.42 mmol) were dissolved in 100 mL of acetonitrile and heated under reflux for 12 h. After the reaction was complete, the mixture was cooled to room temperature and filtered to obtain a yellow solid precipitate, yielding 5.2 g of intermediate 3, which could be used in the next step without further purification.

[0035] Synthesis of intermediate 4:

[0036] 6,7-Dimethoxy-2-(4-nitrophenylethyl)-1,2,3,4-tetrahydroisoquinoline (3,2.4 g, 7 mmol) was dissolved in EtOH (10 mL). Zinc powder (4.6 g, 70 mmol) and saturated ammonium chloride (10 mL) were then added to this solution. The system was refluxed at 80 °C for 8 hours, and TLC analysis showed complete consumption of reactant 3. At this point, the reaction mixture was alkalized (pH 8) by adding 10% sodium hydroxide aqueous solution. The resulting mixture was filtered through a diatomaceous earth filter and washed with DCM. The organic layer was collected, and the solvent was removed under reduced pressure to give target compound 4 as a light orange solid. Following the preparation method for compound 4, intermediates 6 and PID-2 to 3 were obtained.

[0037] Synthesis of intermediate 5

[0038] 4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)aniline (4,0.92 g, 2 mmol) was added to a solution containing 5 mL of DCM, 2-nitrobenzoyl chloride (444 mg, 2.4 mmol), and triethylamine (1 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was diluted with water, extracted three times with DCM, washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography. Following the preparation method of compound 5, intermediates 7 and PID-1, as well as the final products DJYPGP-4 to 6, were obtained.

[0039] The general method for amide condensation: HATU (1.2 equivalents), DIPEA (6 equivalents), and an amino-containing intermediate (1.2 equivalents) are added to a stirred solution containing a carboxylic acid intermediate (1.2 equivalents) in DCM, and the reaction mixture is stirred at room temperature for 12 hours. The reaction solution is diluted with water, extracted three times with DCM, washed with brine, dried over Na₂SO₄, filtered, and concentrated. The resulting residue is purified by column chromatography. The final products DJYPGP-1 to 3 are synthesized according to this method.

[0040] Synthesis of intermediate 8

[0041] A solution of methyl 4-((2-((4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)phenyl)carbamoyl)phenyl)carbamoyl)benzoate (PID-1, 1.2 g, 2 mmol) in 10 mL of EtOH solution was added to a 20% NaOH aqueous solution. The mixture was stirred at 80 °C for 8 hours. After the reaction was complete, the reaction mixture was acidified to pH 4-5 with 6N HCl, and the solid was collected by filtration. It could be used in the next step without further purification.

[0042] Synthesis of Intermediate 10

[0043] Compound 9 was dissolved in DCM, TFA was added to the reaction mixture, and the system was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue could be used for the next step without further purification.

[0044] The final product characterization data are as follows:

[0045] 2-(2-(adamantane-1-yl)acetamyl)-N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)phenyl)benzamide (DJYPGP-1) 1H NMR (400MHz, CDCl3) δ10.46 (s, 1H), 8.63 (d, J = 3.5Hz, 1H), 8.35 (dt, J = 8.4, 1.8Hz, 1H), 7.53–7.42(m,3H),7.26(ddd,J=8.6,7.5,1.5Hz,1H),7.20–7.14(m,2H),6.92(qd,J=7.5 ,7.0,1.2Hz,1H),6.52(s,1H),6.46(s,1H),3.75(s,3H),3.74(s,3H),3.59(s,2H),2.90 –2.63(m,9H),1.99(s,2H),1.94–1.84(m,3H),1.65–1.57(m,8H),1.52(d,J=3.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ169.38,166.41,146.47,146.15,137.82,136.06,134.64,131.23,128.34,126.19,125.26,125.00,121.74 ,120.61,120.54,120.14,110.26,108.39,59.01,54.85,54.81,54.56,52.36,49.94,41.46,35.68,32.35,32.27,27.59,27.53.

[0046] 2-(3-(2-(adamantane-1-yl)acetamido)propamido)-N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)phenyl)benzamide (DJYPGP-2) 1 H NMR (400MHz, DMSO) δ10.60(s,1H),10.37(s,1H),8.20(d,J=8.3Hz,1H),7.81–7.72(m,2H),7.63(s,1H ),7.61(s,1H),7.51(td,J=8.0,1.5Hz,1H),7.47–7.29(m,1H),7.26–7.22(m,2H),6.66(d,J=2.6Hz,1 H),6.64(s,1H),3.70(d,J=2.6Hz,3H),3.70(s,3H),3.56(s,2H),3.30(t,J=6.2Hz,2H),2.75–2.64(m ,7H),2.47(t,J=6.5Hz,2H),1.78(d,J=15.9Hz,4H),1.57(dd,J=11.6,3.3Hz,4H),1.51–1.43(m,10H).13 C NMR (101MHz, DMSO) δ170.53,169.95,167.27,147.58,147.33,138.35,137.07,136.65,132.08,130.25,129.23,129.11,126.95,126.30,12 3.57,122.04,121.23,112.16,110.36,60.02,55.92,55.89,55.49,5 1.02,50.46,42.47,37.69,36.84,35.54,32.86,32.52,28.69,28.47.

[0047] N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)phenyl)carbamoyl)phenyl)adamantane-1-carboxamide (DJYPGP-3) 1 H NMR (400MHz, CDCl3) δ10.68(s,1H),8.66(s,1H),8.31(dd,J=8.4,1.1Hz,1H),7.60–7.54(m, 2H),7.42(dd,J=7.9,1.6Hz,1H),7.28–7.16(m,3H),6.91(td,J=7.6,1.2Hz,1H),6.53(s,1H) ,6.47(s,1H),3.77(s,3H),3.76(s,3H),3.62(s,2H),2.87(dd,J=10.1,5.9Hz,2H),2.76(dd t,J=16.1,11.1,5.4Hz,6H),2.07–1.99(m,3H),1.90(d,J=3.0Hz,6H),1.68(t,J=3.1Hz,6H). 13 C NMR (101MHz, CDCl3) δ176.53,166.17,146.56,146.23,138.13,135.61,135.02,134.99,130.98,128.31,126.14,124.89,121 .76,121.19,121.07,119.80,110.28,108.40,59.40,58.85,54.89,54.85,54.43,49.86,40.84,38.02,35.44,32.24,27.11.

[0048] 2-(4-(2-(adamantane-1-yl)acetamido)benzamido)-N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)phenyl)benzamide (DJYPGP-4) 1 H NMR (400MHz, DMSO) δ11.67(s,1H),10.52(s,1H),10.11(s,1H),8.48(dd,J=8.3,1.1Hz, 1H),7.92(dd,J=7.9,1.6Hz,1H),7.85(d,J=8.8Hz,2H),7.79–7.71(m,2H),7.70–7.56(m ,3H),7.28(t,J=7.7Hz,3H),6.73(d,J=12.3Hz,2H),3.72(s,3H),3.72(s,3H),2.94(s,2 H),2.86(s,2H),2.10(s,2H),1.97–1.88(m,5H),1.71–1.62(m,10H),1.62–1.56(m,6H). 13 C NMR(101MHz,DMSO)δ170.34,167.87,164.62,148.11,147.66,142.97,139 .22,137.11,135.37,132.75,129.75,129.41,129.34,129.02,128.42,125 .16,123.66,123.06,121.79,121.70,119.17,112.03,110.21,55.96,55. 92,51.31,50.49,48.90,42.46,42.24,36.81,36.75,33.28,28.47,28.41.

[0049] 2-(4-(4-(2-((1S,3S)-adamantane-1-yl)acetyl)piperazin-1-carbonyl)benzamido)-N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)phenyl)benzamide (DJYPGP-5) 1H NMR (400MHz, CDCl3) δ11.82(s,1H),8.63(d,J=8.4Hz,1H),8.48(s,1H),7.98(d,J=7.9Hz,2H),7.59(dd,J=8.0,1.5Hz,1 H),7.51(d,J=8.3Hz,2H),7.43(dd,J=7.5,5.3Hz,3H),7.22(d,J=8.2Hz,2H),7.04–6.97(m,1H),6.54(d,J=2.7Hz,1H), 6.48(d,J=4.3Hz,1H),3.78(d,J=1.8Hz,3H),3.77(s,3H),3.72(s,2H),3.63(d,J=4.1Hz,3H),3.57(d,J=15.3Hz,2H),3 .38(d,J=37.7Hz,3H),2.90(q,J=4.9,4.4Hz,2H),2.82–2.74(m,6H),2.12(s,2H),1.91(s,9H),1.64(d,J=12.5Hz,6H). 13 C NMR (101MHz, CDCl3) δ166.54,163.70,146.64,146.29,138.50,136.15,134.41,131.86,128.97,128.44,126.79,126.50,126.11,125.93,12 4.75,122.26,120.86,120.24,110.28,108.38,58.72,54.91,54.87,5 4.36,49.85,45.01,41.83,35.67,32.73,32.17,28.68,27.61,27.23.

[0050] N1-(2-(2-((1S,3S)-adamantane-1-yl)acetamyl)ethyl)-N4-(2-((4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline)-2(1H)-yl)ethyl)phenyl)carbamoyl)phenyl)terephthalamide (DJYPGP-6) 1H NMR (400MHz, CDCl3) δ11.75(s,1H),8.90(s,1H),8.50(dd,J=8.4,1.1Hz,1H),7.94(d,J=8.4Hz,2H),7.87(d,J=8.5Hz,2H),7.75( q,J=3.5,2.4Hz,1H),7.62–7.56(m,2H),7.53(dd,J=8.0,1.5Hz,1H),7.30(ddd,J=8.6,7.5,1.5Hz,1H),7.21(s,1H),7.19(s,1H), 6.92–6.85(m,1H),6.53(s,1H),6.46(d,J=2.5Hz,1H),6.38(t,J=5.6Hz,1H),3.76(s,3H),3.75(s,3H),3.60(s,2H),3.49–3.43(m ,2H),3.43–3.36(m,2H),2.86(dd,J=10.2,5.8Hz,2H),2.80–2.71(m,6H),1.86(s,2H),1.78(t,J=3.2Hz,3H),1.55–1.38(m,12H). 13 CNMR(101MHz,CDCl3)δ173.43,167.63,167.25,165.11,147.70,147.37,139.14 ,137.17,137.08,135.90,132.56,129.49,127.78,127.71,127.57,126.14,126. 04,125.24,123.41,121.99,121.95,121.17,111.44,109.55,60.06,56.04,56.00,51.67,51.05,42.71,42.12,39.47,36.72,33.41,32.92,28.63,28.54,22.78.

[0051] Example 2: Assay for reversing tumor cell drug resistance

[0052] Antiproliferative activity assays of doxorubicin (DOX) in SW620 cells and drug-resistant SW620 / AD300 cells were performed: The IC50 of doxorubicin with all target compounds (5 μM) in SW620 cells and drug-resistant SW620 / AD300 cells (overexpressing ABCB1 / P-gp) was evaluated using the CCK8 assay. 50 Simply put, cells are packed at 5 × 10⁻⁶ 3Cells were seeded at a density of 10 cells / well in 96-well plates for 24 hours. Then, cells were treated with different concentrations of doxorubicin for 48 hours. The experimental groups received 5 μM of a synthetic ABCB1 (P-gp) inhibitor, as well as the commercially available first-generation P-gp inhibitor verapamil and the third-generation P-gp inhibitor WK-X-34. The negative control group received only the corresponding doxorubicin. Subsequently, 10 μL of CCK8 solution was added to each well, and after 1.5 hours of incubation, the absorbance at 450 nm was measured using a TECAN microplate reader. The absorbance values ​​were converted to inhibition rates, and the IC50 was calculated using Graphpad Prism5. 50 Values. The results are shown in Table 1:

[0053] Table 1 Evaluation of the effect of reversing tumor cell drug resistance

[0054]

[0055]

[0056] Table 1 shows that compound DJYPGP-5 has a significant ability to reverse tumor cell resistance, with a reversal index of 78.6, significantly higher than that of the first-generation P-gp inhibitor verapamil (RF = 10.1). Furthermore, the reversal effect of this compound is also enhanced compared to the third-generation P-gp inhibitor (WK-X-34) (RF = 45.9). More importantly, this compound exhibits lower cytotoxicity than WK-X-34, as the combination of WK-X-34 and doxorubicin significantly reduced the doxorubicin IC50 in wild-type SW620 cells. 50 The compound DJYPGP-5 showed an IC50 value against doxorubicin in wild-type SW620 cells. 50 The relatively small impact of the ClogP value indicates that WK-X-34 has strong cytotoxicity. Furthermore, we can also see that, within a certain range, increasing the ClogP value of the compound helps to improve its ability to reverse ABCB1(P-gp)-mediated drug resistance.

[0057] Example 3: Cytotoxicity Detection

[0058] To further determine the effect of the compound on cytotoxicity, we selected another drug-resistant gastric cancer cell line—MKN45 / R—and used the MTT assay to detect the inhibitory rate of the compound at 5 μM. The basic procedures were similar to those in Example 2, and the results are as follows: Figure 2 As shown, from Figure 2 It can be seen that the cytotoxicity of the synthesized ABCB1(P-gp) inhibitors is lower than that of the positive control compounds verapamil and WK-X-34, especially compounds DJYPGP-1 and DJYPGP-4-6.

Claims

1. A compound which targets the inhibition of ABCB1 (P-gp) characterized in that, The compound is DJYPGP-5, and its structural formula is as follows: 。 2. The method for preparing the compound that targets and inhibits ABCB1 (P-gp) according to claim 1, characterized in that... The synthetic route is as follows: 。 3. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a compound that targets and inhibits ABCB1 (P-gp) as described in claim 1, or a pharmacologically or physiologically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

4. The use of a compound of claim 1 that targets and inhibits ABCB1 (P-gp) or a pharmacologically or physiologically acceptable salt thereof, or the pharmaceutical composition of claim 3, in the preparation of an ABCB1 (P-gp) inhibitor or degrader medicament.

5. The use of a compound of claim 1 that targets and inhibits ABCB1 (P-gp) or a pharmacologically or physiologically acceptable salt thereof, or the pharmaceutical composition of claim 3, as an ABCB1 (P-gp) inhibitor or degrader in the preparation of a medicament for treating ABCB1 (P-gp) resistance-related diseases.

6. The application according to claim 5, characterized in that, The diseases associated with ABCB1 (P-gp) are tumors and microbial infectious diseases.

7. The use of a compound of claim 1 that targets and inhibits ABCB1 (P-gp) or a pharmacologically or physiologically acceptable salt thereof, or the pharmaceutical composition of claim 3, as an ABCB1 (P-gp) inhibitor or degrader in the preparation of drugs that reverse tumor drug resistance or antibacterial drug resistance.

8. In the application according to claim 7, the tumor in the tumor drug refers to any one of gastric cancer, breast cancer, lung cancer, ovarian cancer, colonic adenocarcinoma, renal chromophobe carcinoma, renal clear cell carcinoma, lung adenocarcinoma, prostate cancer, rectal adenocarcinoma, thyroid cancer, and endometrial cancer; the antibacterial drug refers to an antibacterial infection drug, and the bacteria include Gram-positive bacteria and Gram-negative bacteria.

9. The application according to claim 8, characterized in that, The tumor or bacterial infection is caused by drug resistance due to high expression of ABCB1 (P-gp).

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