Terphenyl compound and application thereof as marine antifouling agent

Abstract

The invention discloses a terphenyl compound and application of the terphenyl compound as a marine antifouling agent. Specifically, the invention relates to a compound shown as a formula (I) and / or a pharmaceutically acceptable salt thereof as an active ingredient. The invention also discloses an application of the compound in preparation of a marine organism fouling resistant coating.

Description

Technical Field

[0001] The present invention belongs to the field of biology, and particularly relates to the application of a class of terphenyl compounds as marine antifouling agents. Background Art

[0002] Alien species invasion refers to the process in which biological species migrate from their original habitats to new ecological environments through natural or human-mediated means. These alien species settle, reproduce, and spread in the local ecosystem, ultimately severely affecting the local ecological environment and damaging local biodiversity. Marine fouling refers to the phenomenon in which a large number of marine organisms colonize and accumulate on substrates immersed in seawater, such as ship bottoms, docks, buoys, and artificial facilities. The fouling organisms attached to the substrate surface include marine microfouling organisms (fouling bacteria, fungi, and benthic diatoms) and marine macrofouling organisms (marine macroalgae, seaweeds, barnacles, mussels, and bryozoans, etc.). Alien species invasion leads to marine fouling, and marine fouling provides conditions for alien species invasion. The interaction between alien species invasion and marine fouling exacerbates marine ecological problems.

[0003] The attachment of marine fouling organisms reduces the navigation speed of shipping and vessels, increases fuel consumption and fuel costs, and has a negative impact on aquaculture systems. The economic losses caused by biological fouling worldwide reach up to hundreds of billions of US dollars annually.

[0004] To reduce the impact of marine biological pollution on marine economic activities and the ecological environment, researchers have developed various forms of marine antifouling technologies to reduce the harm of marine biological pollution. Since the International Maritime Organization (IMO) banned tributyltin (TBT) in 2008, dozens of alternative antifouling agents have been used. Unfortunately, these alternative antifouling agents contain multiple toxic components, accumulate to high levels in coastal waters, contaminate the food chain, cause serious environmental pollution, and threaten human health. Therefore, there is an urgent need to find low-toxic and highly effective antifouling agents. Summary of the Invention

[0005] The following only summarizes some aspects of the present invention and is not limited thereto. These aspects and other parts are more fully described later. All references in this specification are incorporated herein by reference in their entirety. When there are differences between the disclosure of this specification and the cited literature, the disclosure of this specification shall prevail.

[0006] The present invention provides a class of terphenyl compounds for use in the preparation of marine antifouling agents. Specifically, the present invention relates to compounds of formula I or pharmaceutically acceptable salts thereof or solvates of salts thereof. The present invention also discloses the use of such compounds in the preparation of anti-marine biological fouling coatings. The compounds of the present invention have excellent inhibitory activity in preventing and controlling marine fouling and have good application prospects.

[0007] Specifically:

[0008] The present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof or a solvate of the salt, characterized in that the compound has the following structure:

[0009]

[0010] Wherein, R 1 , R 2 , R 3 are each independently optionally H, and R 1 , R 2 and R 3 cannot be H simultaneously;

[0011] X 1 , X 2 , X 3 are each independently optionally H, Cl, Br; specifically,

[0012]

[0013]

[0014] In another embodiment of the present invention, a class of compounds is provided as a marine antifouling agent, characterized in that it comprises a compound of formula I 1–23 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0015] The term "pharmaceutically acceptable salt" in the present invention refers to a non-toxic addition salt of an inorganic or organic acid and / or base; see "Salt selection for basic drugs", Int. J. Pharm. 1986, 33, 201–217. Detailed implementation mode

[0016] For the convenience of further understanding of the present invention, the following examples provide more detailed descriptions thereof; however, these examples are only for better understanding of the invention and are not used to limit the scope or implementation principles of the present invention, and the implementation modes of the present invention are not limited to the following content.

[0017] Example 1: 2',5'-dimethoxy-3'-((2-methylallyl)oxy)-[1,1':4',1”-terphenyl]-4,4”-diol (Compound 1)

[0018]

[0019] Dissolve compound terphenyllin (hereinafter referred to as "Compound A") (200.0 mg, 0.59 mmol) in anhydrous acetone (40 mL), add 3-bromo-2-methylpropene reagent (2.5 eq), anhydrous potassium carbonate (3 eq); stir the reaction solution at 50 °C; after the reaction is completed by TLC detection, quench the reaction with water, extract the reaction solution three times with ethyl acetate, combine the organic phases and concentrate under reduced pressure until dry; obtain a white powder by normal-phase silica gel column chromatography with a yield of 30%.

[0020] 1 H NMR (400 MHz, acetone-d 6 ) δ 8.58 (s, 1H), 8.40 (s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 6.74 (s, 1H), 4.83 (s, 1H), 4.75 (s, 1H), 4.16 (s, 2H), 3.72 (s, 3H), 3.56 (s, 3H), 1.54 (s, 3H); 13 C NMR (100 MHz, acetone-d 6 ) δ 159.8 (C), 158.4 (C), 154.2 (C), 151.7 (C), 145.7 (C), 143.0 (C), 135.2, 132.8 (CH×2), 131.1 (CH×2), 130.4, 125.8, 125.3, 115.9 (CH×2), 115.2 (CH×2), 112.6, 108.8 (CH), 77.3 (CH 2 ), 60.9 (CH 3 ), 56.3 (CH 3 ), 19.6 (CH 3 ). (-)-HR-ESI-MS m / z 391.1552 [M-H] - , (calcd for C 24 H 23 O 5 - , 391.1551).

[0021] Example 2: 3',6'-dimethoxy-4-((2-methylallyl)oxy)-[1,1':4',1”-terphenyl]-2',4”-diol (Compound 2)

[0022]

[0023] A white powder was obtained according to the preparation method of Example 1; the yield was 28%; 1 H NMR(400MHz,acetone-d 6 )δ8.53(s,1H),7.63(s,1H),7.52(d,J=8.6Hz,2H),7.34(d,J=8.8Hz,2H),6.96(d,J=8.8Hz,2H),6.94(d,J=8.6Hz,2H),6.49(s,1H),5.13(s,1H),4.98(s,1H),4.52(s,2H),3.72(s,3H),3.38(s,3H),1.85(s,3H); 13 C NMR(100MHz,acetone-d 6 )δ158.5(C),157.9(C),154.5(C),149.1(C),142.5(C),140.2(C),133.6,133.0(CH×2),130.8(CH×2),130.4,127.5,117.4,116.1(CH×2),114.6(CH×2),112.5,104.2(CH),72.1(CH 2 ),60.7(CH 3 ),56.1(CH 3 ),19.5(CH 3 ).(+)-HR-ESI-MS m / z 393.1686[M+H] + ,(calcd for C 24 H 25 O 5 + ,393.1697).

[0024] Example 3: 3',6'-dimethoxy-4”-((2-methylallyl)oxy)-[1,1':4',1”-terphenyl]-2',4-diol (Compound 3)

[0025]

[0026] A white powder was obtained according to the preparation method of Example 1; the yield was 42%; 1 H NMR(400MHz,acetone-d 6)δ 7.60 (d, J = 8.6 Hz, 2H), 7.59 (s, 1H), 7.26 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.50 (s, 1H), 5.14 (s, 1H), 4.99 (s, 1H), 4.55 (s, 2H), 3.71 (s, 3H), 3.39 (s, 3H), 1.85 (s, 3H); 13 C NMR (100 MHz, acetone-d 6 )δ 159.1 (C), 156.9 (C), 154.6, (C) 149.0 (C), 142.2 (C), 140.1 (C), 133.1, 132.9 (CH×2), 131.8, 130.7 (CH×2), 125.9, 117.9, 115.4 (CH×2), 115.2 (CH×2), 112.6, 104.2 (CH), 72.1 (CH 2 ), 60.7 (CH 3 ), 56.1 (CH 3 ), 19.5 (CH 3 ). (+)-HR-ESI-MS m / z 393.1683 [M+H] + , (calcd for C 24 H 25 O 5 + , 393.1697).

[0027] Example 4: 3',4”-dihydroxy-2',5'-dimethoxy-[1,1':4',1”-terphenyl]-4-ylmethacrylate (Compound 11)

[0028]

[0029] Compound A (100 mg, 0.30 mmol) was dissolved in anhydrous dichloromethane (20 mL), and methacrylic anhydride (2 eq), DMAP (4 eq) and EDC·HCl (4 eq) were added. The reaction mixture was stirred at 45 °C; after the reaction was completed by TLC detection, it was quenched with saturated NaHCO 3 solution; extracted three times with ethyl acetate, the combined organic phases were concentrated under reduced pressure and evaporated to dryness; after normal-phase silica gel column chromatography, it was purified by semi-preparative HPLC to obtain a white powder with a yield of 35%;

[0030] 1 H NMR (400 MHz, acetone-d 6)δ8.26(s,1H),7.72(d,J=8.7Hz,2H),7.65(s,1H),7.28(d,J=8.7Hz,2H),7.26(d,J=8.7Hz,2H),6.86(d,J=8.7Hz,2H),6.57(s,1H),6.34(s,1H),5.86–5.87(m,1H),3.74(s,3H),3.41(s,3H),2.83(s,3H); 13 C NMR(100MHz,acetone-d 6 )δ166.2(C),157.1(C),154.7(C),151.4(C),149.3(C),140.4(C),137.0,136.9,133.0(CH×2),132.7,130.7(CH×2),127.5,125.9,125.8,122.5(CH×2),115.3(CH×2),104.4(CH),61.0(CH 3 ),56.2(CH 3 ),18.5(CH 3 ).(+)-HR-ESI-MS m / z407.1485[M+H] + ,(calcd for C 24 H 23 O 6 + ,407.1489).

[0031] Example 5: 4-(allyloxy)-5'-chloro-3',6'-dimethoxy-[1,1':4',1”-terphenyl]-2',4”-diol (Compound 16)

[0032]

[0033] Compound A (200.0 mg, 0.59 mmol) was dissolved in anhydrous acetone (40 mL), and 3-bromopropene reagent (2.5 eq) and anhydrous potassium carbonate (3 eq) were added; the reaction solution was stirred at 50 °C; after the reaction was completed as detected by TLC, the reaction was quenched by adding water, and the reaction solution was extracted three times with ethyl acetate. The combined organic phases were concentrated under reduced pressure and evaporated to dryness; the corresponding terphenyl compound was obtained by normal-phase silica gel column chromatography. The obtained compound was dissolved in chloroform (10 mL), dimethyl sulfoxide (0.2 eq) and NCS (1.5 eq) were added, and the reaction solution was stirred at 35 °C or 10 - 15 °C; after the reaction was completed as detected by TLC, 15.0 mL of 5% NH 4The reaction was quenched with an aqueous solution of Cl and extracted three times with dichloromethane. The combined organic phases were concentrated under reduced pressure until dry; a white powder was obtained after normal-phase silica gel column chromatography; the yield was 30%;

[0034] 1 H NMR(400MHz,acetone-d 6 )δ8.60(s,1H),7.93(s,1H),7.41(d,J=8.7Hz,2H),7.24(d,J=8.5Hz,2H),7.02(d,J=8.7Hz,2H),6.96(d,J=8.5Hz,2H),6.96(d,J=8.6Hz,2H),6.12(m,1H),5.46(dq,J=17.2,1.6Hz,1H),5.27(dd,J=10.4,1.6Hz,1H),4.63(dt,J=5.2,1.5Hz,2H),3.39(s,3H),3.31(s,3H). 13 C NMR(100MHz,acetone-d 6 )δ158.9(C),158.0(C),151.5(C),148.0(C),143.6(C),134.8,134.5,132.6(CH×2),132.3(CH×2),126.9,126.6,123.9,118.5,117.4,115.7(CH×2),114.8(CH×2),69.3(CH 2 ),60.8(CH 3 ),60.4(CH 3 ).(-)-HR-ESI-MS m / z 411.1011[M-H] - ,(calcd for C 23 H 20 O 5 Cl - ,411.1005)。

[0035] Example 6: 4-(allyloxy)-5'-chloro-3',6'-dimethoxy-[1,1':4',1”-terphenyl]-2',4”-diol (Compound 20)

[0036]

[0037] Compound A (200.0 mg, 0.59 mmol) was dissolved in anhydrous acetone (40 mL), and 3-bromopropene reagent (2.5 eq) and anhydrous potassium carbonate (3 eq) were added. The reaction mixture was stirred at 50 °C. After the reaction was completed as detected by TLC, the reaction was quenched by adding water, and the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were concentrated under reduced pressure and evaporated to dryness. The corresponding terphenyl compound was obtained by normal-phase silica gel column chromatography. The obtained compound was dissolved in chloroform (10 mL), and dimethyl sulfoxide (0.2 eq) and NBS (1.5 eq) were added. The reaction mixture was stirred at 35 °C or 10 - 15 °C. After the reaction was completed as detected by TLC, the reaction was quenched by adding 15.0 mL of 5% NH 4 Cl aqueous solution, and the mixture was extracted three times with dichloromethane. The combined organic phases were concentrated under reduced pressure and evaporated to dryness. After normal-phase silica gel column chromatography, a white powder was obtained; the yield was 33%;

[0038] 1 H NMR (400 MHz, acetone-d 6 ) δ8.88 (s, 1H), 7.79 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.8, 2.0 Hz, 1H), 7.08 - 7.01 (overlapped, 3H), 6.52 (s, 1H), 6.12 (m, 1H), 5.46 (dq, J = 17.2, 1.6 Hz, 1H), 5.28 (dq, J = 10.4, 1.6 Hz, 1H), 4.64 (dt, J = 5.2, 1.5 Hz, 2H), 3.74 (s, 3H), 3.38 (s, 3H); 13 C NMR (100 MHz, acetone-d 6 ) δ159.1 (C), 155.2 (C), 154.5 (C), 149.2 (C), 140.2 (C), 136.1, 134.8, 132.4 (CH×2), 131.6, 130.8 (CH×2), 117.5, 115.4 (CH×2), 104.2 (CH), 69.3 (CH 2 ), 60.8 (CH 3 ), 56.2 (CH 3 ). (-)-HR-ESI-MS m / z 455.0510 [M - H] - , (calcd for C 23 H 20 O 5 Br - , 455.0489).

[0039] Example 7 4”-(allyloxy)-3,5'-dibromo-3',6'-dimethoxy-[1,1':4',1”-terphenyl]-2',4-diol (Compound 21)

[0040]

[0041] A white powder was obtained by referring to the preparation method of Example 6, with a yield of 23%; (+)-HR-ESI-MS m / z 534.9720 [M+H] + ,(calcd for C 23 H 21 O 5 Br 2 + ,534.9750).

[0042] Example 8 4,4″-bis(allyloxy)-5′-bromo-3′,6′-dimethoxy-[1,1′:4′,1″-terphenyl]-2′-ol (Compound 22)

[0043]

[0044] A white powder was obtained by referring to the preparation method of Example 6, with a yield of 35%; (-)-HR-ESI-MS m / z 495.0814 [M-H] - ,(calcd for C 26 H 24 O 5 Br - ,495.0813).

[0045] Example 9 2′,4,4″-tris(allyloxy)-5′-bromo-3′,6′-dimethoxy-1,1′:4′,1″-terphenyl (Compound 23)

[0046]

[0047] A white powder was obtained by referring to the preparation method of Example 6, with a yield of 15%; (+)-HR-ESI-MS m / z 537.1256 [M+H] + ,(calcd for C 29 H 30 O 5 Br + ,537.1271).

[0048] Example 10 Test for the Activity of Inhibiting the Attachment of Marine Diatoms

[0049] (1) Test diatoms: Navicula exigua, N. Leavissima, Amphora ovalis, Skeletonema costatum, and Nitzschia closterium f. minutissima

[0050] (2) Add F / 2 reagent to sterilized seawater, filter the diatom mother liquor into a conical flask containing sterilized seawater (150 mL seawater / bottle), seal it after thorough mixing, and transfer it to a constant temperature incubator for cultivation; when the diatom density reaches 10 5 -10 6 cells / mL, the diatom attachment test can be carried out.

[0051] (3) Sample preparation: Prepare a mother liquor of the compound of the present invention at 1 mg / mL, completely dissolve and mix it using a vortex oscillator, and set aside; according to the size of the wells in a 24-well plate (diameter 1.5 cm), etch circular glass slides with a diameter of 1 cm using a laser etching machine.

[0052] (4) Activity screening: Place the washed glass discs with a diameter similar to the test well diameter of a Costar 24-well microplate into each test well, and accurately add the filtered algal solution and the compound of the present invention thereto using a pipette; set up a positive control group (Econea) and a negative control group in the experiment, and set two parallel wells for all test groups, and cultivate for 24 hours.

[0053] (5) Result processing and analysis: After cultivation, gently pick up the glass discs in the Costar 24-well microplate in the experiment using forceps and rinse the surface with deionized water to remove the diatoms that are not firmly adhered, place them on a glass slide, cover with a coverslip, and observe the experimental results using a fluorescence microscope; use the Image-Pro Plus 6.0 counting software to record the number of diatoms attached in the photo and perform data processing.

[0054] Inhibition rate % = (Number of diatoms attached in the negative group - Number of diatoms attached in the experimental group) / Number of diatoms attached in the negative group × 100%

[0055] Test results:

[0056] Table 2 Inhibitory activities of some compounds of the present invention against marine diatoms at 10 μg / mL

[0057]

[0058]

[0059] In the table, "++++" indicates that the inhibition rate is greater than 90%; "+++" indicates that the inhibition rate is between 70% - 90%; "++" indicates that the inhibition rate is between 50% - 70%; "+" indicates that the inhibition rate is less than 50%.

[0060] Note: The compound A of the present invention was tested in parallel as a control.

[0061] Conclusion: Through the activity tests on five species of marine diatoms, it can be found that the compounds of the present invention exhibit strong growth inhibition activity against diatoms, and the activities of some compounds of the present invention are comparable to those of the positive drug to a certain extent. At the same time, the activity results show that the compounds of the present invention have stronger activity in inhibiting the growth of marine diatoms than compound A. Therefore, the compounds of the present invention have great application prospects in inhibiting the growth of marine diatoms.

[0062] Example 11 Test for inhibiting the secretion activity of mussel byssus

[0063] (1) Preparation of test samples: After the purple mussels (Mytilus eduli, collected from Fengjiahe Wharf, Jimo District, Qingdao City, Shandong Province) used in the experiment were salvaged and brought back to the laboratory, the purple mussels were separated one by one and cleaned; select purple mussels with a shell length of 0.5 - 1 cm, and cut off the external byssus threads with surgical scissors so that the mussels cannot attach naturally, and place them in a glass tank (400mm×250mm×300mm) filled with filtered natural seawater for adaptive cultivation. 50% of the fresh seawater in the breeding tank is replaced every day, the temperature is controlled at about 24°C, and oxygen is continuously introduced; after 1 - 2 days, the mussels adhere to the bottom of the glass tank and can be used for the experiment.

[0064] (2) Sample preparation: Set up a sample group, a blank group, a DMSO solvent group, and a positive group. The initial screening concentration of the compound of the present invention to be tested is set at 10 μg / mL.

[0065] (3) Activity screening: Conduct the experiment in a sterile 6-well plate. Five parallels are set for all condition groups, and a total of 10 mL of solution is added to each well. Use a pipette to add filtered natural seawater and the compound of the present invention to be tested to it and mix well; then place 2 - 3 mussels with good growth status that have been cultivated and domesticated under laboratory conditions in each well. Transfer the 6-well plate to a dark place and observe the status of the mussels every 6 hours. After culturing for 24 hours, record the number of dead mussels, growth status, and the number of byssus of the mussels under different conditions.

[0066] (4) Data processing: The byssus adhered to the inner wall of the 6-well plate by mussels will form a white dot. The secretion of byssus can be judged according to the number of white dots. Use a magnifying glass to observe the number of byssus secreted by mussels under different conditions and calculate the inhibition rate; Inhibition rate % = (Number of byssus secreted by mussels in the negative group - Number of byssus secreted by mussels in the experimental group) / Number of byssus secreted by mussels in the negative group × 100%.

[0067] Results: At 10 μg / mL, Compound 1 can completely inhibit the secretion of byssus by mussels, which is comparable to the positive control Econea.

[0068] In summary, the compounds of the present invention have outstanding effects in preventing and controlling marine fouling, and have further research value and broad development prospects.

[0069] Finally, it should be noted that there are other ways to implement the present invention; correspondingly, the embodiments of the present invention are illustrative, but not limited to the content described in the present invention, and may also be modifications made within the scope of the present invention or equivalent content added in the claims; all publications or patents cited in the present invention will be used as references of the present invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof or a solvate of the salt, characterized in that The compound has the following structure: Wherein, R1, R2, and R3 are each independently and optionally H, And R1, R2 and R3 cannot be H at the same time; X1, X2, X3 are each independently and optionally H, Cl, Br; specifically, 2. An antifouling agent capable of inhibiting the attachment and / or fouling of marine organisms to the surface of underwater structures, characterized in that It contains the compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1 as an effective ingredient.

3. Use of the compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a marine antifouling agent.

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