CN114773261A - Disulfide bond compound, preparation method thereof and application thereof in antibiosis - Google Patents

Disulfide bond compound, preparation method thereof and application thereof in antibiosis Download PDF

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CN114773261A
CN114773261A CN202210530660.5A CN202210530660A CN114773261A CN 114773261 A CN114773261 A CN 114773261A CN 202210530660 A CN202210530660 A CN 202210530660A CN 114773261 A CN114773261 A CN 114773261A
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compound
preparation
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disulfide
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CN114773261B (en
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刘映前
李卫国
王璟汝
零春华
张智军
安俊霞
马越
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Guangxi Tianyuan Biochemical Co Ltd
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Abstract

The invention relates to the field of pharmaceutical chemistry, and discloses a disulfide bond compound, a preparation method thereof and application thereof in antibiosis. The compound shows potential inhibition activity on sclerotinia sclerotiorum, rhizoctonia solani, botrytis cinerea, fusarium graminearum, pyricularia grisea, phytophthora capsici, aspergillus flavus, penicillium expansum, brown rot of stone fruit, rhizopus stolonifer, rice bacterial blight, citrus canker, potato phytophthora parasitica, escherichia coli, staphylococcus aureus, candida albicans, bacillus cereus, listeria monocytogenes and salmonella enteritidis, and part of the compound has higher inhibition activity. The disulfide bond compound is simple to prepare, the raw materials are cheap and easy to obtain, and the disulfide bond compound can be developed into a novel bacteriostatic agent which is green, pollution-free and sustainable in development.

Description

Disulfide bond compound, preparation method thereof and application thereof in antibiosis
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a disulfide bond compound, a preparation method thereof and application thereof in antibiosis.
Background
The microorganisms generally include microorganisms having a cell structure such as bacteria, fungi, actinomycetes, etc., and organisms having no intact cell structure such as viruses, mycoplasma, chlamydia, etc. Most microorganisms are harmless to the human body, but some microorganisms can cause various human and animal and plant diseases. For example, phytopathogens are major causes of crop losses and cause huge economic losses, and escherichia coli and staphylococcus aureus can cause various diseases such as gastrointestinal tract infection and urinary tract infection in humans and animals. Currently, the diseases caused by these microorganisms are mainly chemical bactericides. However, due to the shortage of chemical agents and the increase of microbial resistance caused by the abuse of traditional bactericides, the development and innovation of other high-efficiency bactericides are urgently needed.
Bulbus Allii is bulb of Bulbus Allii of Allium of Liliaceae, and has antibacterial and antiinflammatory effects. Alliin and allicin are important bioactive substances in garlic. Research shows that alliin has the biological activities of eliminating free radicals, reducing blood sugar, inhibiting bacteria, protecting liver and the like, can also inhibit the growth of mould in food, and prolongs the preservative and fresh-keeping period of the food. Alliin can generate garlicin under the catalysis of alliinase, and the garlicin has obvious inhibition effect on escherichia coli, staphylococcus aureus, typhoid bacillus and the like, and is widely used in the fields of food and medicine. Disulfide bonds (S-S bonds) are an important chemical functional group in allicin and are also present in various natural small molecule compounds and in the structure of biological proteins. According to literature reports, some small molecule compounds containing disulfide bonds show biological activities such as antibiosis, antitumor and the like, and have low toxicity in vivo, so that the disulfide bonds are introduced into a medicine structure to achieve a better sterilization effect.
Disclosure of Invention
In order to solve the problems, the invention provides a disulfide bond compound and a preparation method thereof, and the disulfide bond compound has higher inhibitory activity on various bacteria and is expected to be developed into a novel bacteriostatic agent which is green, pollution-free and sustainable in development.
In order to achieve the purpose, the scheme provided by the invention is as follows:
a disulfide bond compound characterized by: the compound is a disulfide bond heterocyclic compound and has the following general formula:
Figure BDA0003646332670000011
the specific general structure is respectively as follows:
Figure BDA0003646332670000012
Figure BDA0003646332670000021
specifically, R' in the general formulas (I) to (VI) is one of hydrogen, methyl, methoxy, fluorine and chlorine.
Specifically, R' in the general formulas (I) to (VI) is one of an aliphatic chain, a benzene ring or other heterocyclic groups.
The invention also provides a preparation method of the disulfide bond compounds, and the compounds in the general formulas (I) to (VI) are prepared according to the formulas (I) to (VI):
the following formula:
Figure BDA0003646332670000022
the formula (II):
Figure BDA0003646332670000023
formula III:
Figure BDA0003646332670000024
the formula IV:
Figure BDA0003646332670000025
a fifth expression:
Figure BDA0003646332670000026
the formula is:
Figure BDA0003646332670000027
specifically, when R' in the compound of formula III contains a benzene ring, the compound is prepared according to the following formula:
Figure BDA0003646332670000028
wherein R' in the formula is an aliphatic chain.
The invention provides the application of the disulfide bond compound in preparing antibacterial drugs.
Furthermore, the invention provides application of the disulfide bond compounds in preparing medicaments for preventing and treating sclerotinia sclerotiorum, rhizoctonia solani, botrytis cinerea, fusarium graminearum, rice blast and phytophthora capsici.
Furthermore, the invention provides application of the disulfide bond compound in preparing medicaments for preventing and treating aspergillus flavus, penicillium expansum, brownspot of stone fruit and rhizopus stolonifer.
Furthermore, the invention provides application of the disulfide bond compound in preparing medicines for preventing and treating rice bacterial blight, citrus canker pathogen, potato phytophthora parasitica, escherichia coli, staphylococcus aureus, bacillus cereus, listeria monocytogenes and salmonella enteritidis.
The invention has the following beneficial effects:
1. the disulfide bond compound can be represented by 6 general formulas, a pure product can be obtained after extraction, recrystallization and multiple silica gel column chromatographic separation, and the structures of 32 compounds are determined by spectrum techniques such as mass spectrum, nuclear magnetic resonance and the like (specifically shown in examples 1-32).
2. The results of activity screening show that the disulfide bond compounds of the invention have a certain degree of inhibition effect on sclerotinia sclerotiorum, rhizoctonia solani, botrytis cinerea, fusarium graminearum, rice blast, phytophthora capsici, aspergillus flavus, penicillium expansum, brownrot of karyophyllum, rhizopus stolonifer, fusarium solani, citrus canker, phytophthora parasitica, escherichia coli, staphylococcus aureus, candida albicans, bacillus cereus, listeria monocytogenes and salmonella enteritidis.
3. The disulfide bond compounds have certain bactericidal activity, and can be developed into novel green, pollution-free and sustainable-development bacteriostatic agents. The compound S7 has good antifungal and antibacterial activities, has a broad spectrum, has activity obviously superior to positive control drugs such as azoxystrobin, copper thielavone and norfloxacin, and is expected to be developed into a novel efficient antibacterial drug.
Detailed Description
The invention is further described with reference to the following examples:
example 1 Synthesis of Compound S1
(1) The structural formula of compound S1 is as follows:
Figure BDA0003646332670000031
(2) the synthesis reaction formula of compound S1 is as follows:
Figure BDA0003646332670000041
(3) the preparation method of compound S1 is as follows:
2-mercaptopyridine (1mmol) and n-butylmercaptan (1.5mmol) were dissolved in 10mL of Dichloromethane (DCM) at 0 ℃.1mmol of dichlorodicyanobenzoquinone (DDQ) was then added slowly in portions to the solution and the reaction mixture was stirred in an ice bath for 1 h. The progress of the reaction was monitored by thin layer chromatography. After completion, the solvent was removed by rotary evaporation and the crude compound was purified by column chromatography (ethyl acetate: petroleum ether, 1: 50) to afford the desired product S1.
(4) As a result:
compound S1 was obtained as a colorless oily liquid, yield: 82%;1H NMR(400MHz,Chloroform-d)δ:8.52-8.40(m,1H),7.80-7.55(m,2H),7.06-7.12(m,1H),2.79(t,J＝7.4Hz,2H),1.76-1.57(m,2H),1.41(h,J＝7.4Hz,2H),0.89(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ:160.88,149.67,137.05,120.57,119.67,38.88,31.13,21.77,13.74.MS-ESI m/z:C9H13NS2[M+H]+:200.3300。
example 2 Synthesis of Compound S2
(1) The structural formula of compound S2 is as follows:
Figure BDA0003646332670000042
(2) the preparation method of compound S2 is as follows:
the preparation method differs from example 1 in that: only n-propanethiol was used in place of n-butanethiol in example 1, and the procedure was otherwise as in example 1.
(3) As a result:
compound S2 was obtained as a colorless oily liquid, yield: 85 percent;1H NMR(400MHz,Chloroform-d)δ:8.47-8.42(m,1H),7.75-7.70(m,1H),7.66-7.60(m,1H),7.08-7.03(m,1H),2.76(t,J＝7.3Hz,2H),1.71(h,J＝7.3Hz,2H),0.98(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ:160.85,149.65,137.03,120.55,119.65,41.09,22.42,13.21.MS-ESI m/z:C8H11NS2[M+H]+:186.3030。
example 3 Synthesis of Compound S3
(1) The structural formula of compound S3 is as follows:
Figure BDA0003646332670000043
(2) the preparation method of the compound S3 is as follows:
the preparation method differs from example 1 in that: the same procedure as in example 1 was repeated except that 2-mercaptopyridine used in example 1 was replaced with only 2-mercaptopyrimidine and that n-butylmercaptan used in example 1 was replaced with n-propylmercaptan.
(3) As a result:
the compound S3 was obtained as a colorless oilLiquid, yield: 77%;1H NMR(400MHz,Chloroform-d)δ:8.60(d,J＝4.8Hz,2H),7.07(t,J＝4.8Hz,1H),2.83(t,J＝7.3Hz,2H),1.73(h,J＝7.3Hz,2H),0.99(t,J＝7.3Hz,3H).13C NMR(100MHz,Chloroform-d)δ:172.16,157.92,117.89,40.68,22.21,13.22.MS-ESI m/z:C7H10N2S2[M+H]+:187.2910。
example 4 Synthesis of Compound S4
(1) The structural formula of compound S4 is as follows:
Figure BDA0003646332670000051
(2) the preparation method of the compound S4 is as follows:
the preparation method differs from example 1 in that: the same procedure as in example 1 was repeated except that allyl mercaptan was used instead of n-butylmercaptan in example 1.
(3) As a result:
compound S4 was obtained as a brown oily liquid, yield: 34 percent;1H NMR(400MHz,Chloroform-d)δ:8.50-8.40(m,1H),7.71-7.56(m,2H),7.14-7.00(m,1H),5.92-5.71(m,1H),5.25-5.13(m,1H),5.12-5.02(m,1H),3.41(d,J＝7.3Hz,2H).13C NMR(100MHz,Chloroform-d)δ:160.28,149.54,136.88,132.29,120.59,42.00,34.79,29.60.MS-ESI m/z:C8H9NS2[M+H]+:184.2870。
example 5 Synthesis of Compound S5
(1) The structural formula of compound S5 is as follows:
Figure BDA0003646332670000052
(2) the preparation method of the compound S5 is as follows:
the preparation method differs from example 1 in that: the same procedure as in example 1 was repeated except that 2-mercaptopyridine was replaced by 2-mercaptopyridine and n-butylmercaptan was replaced by allyl mercaptan.
(3) As a result:
compound S5 was obtained as a yellow oily liquid, yield: 56 percent;1H NMR(400MHz,Chloroform-d)δ:8.61(d,J＝4.8Hz,2H),7.08(t,J＝4.8Hz,1H),5.95-5.79(m,1H),5.19-5.04(m,2H),3.57-3.43(m,2H).13C NMR(100MHz,Chloroform-d)δ:170.78,156.76,131.25,118.22,116.84,40.45.MS-ESI m/z:C7H8N2S2[M+H]+:185.2750。
example 6 Synthesis of Compound S6
(1) The structural formula of compound S6 is as follows:
Figure BDA0003646332670000061
(2) the preparation method of the compound S6 is as follows:
the preparation method differs from example 1 in that: the same procedure as in example 1 was repeated except that 2-mercaptopyridine was replaced with 2-mercaptopyrimidine alone.
(3) As a result:
compound S6 was obtained as a colorless oily liquid, yield: 79 percent;1H NMR(400MHz,Chloroform-d)δ:8.61(d,J＝4.8Hz,2H),7.07(t,J＝4.8Hz,1H),2.86(t,J＝7.4Hz,2H),1.69(p,J＝7.4Hz,2H),1.43(h,J＝7.4Hz,2H),0.90(t,J＝7.3Hz,4H).13C NMR(100MHz,Chloroform-d)δ:172.19,157.93,117.89,38.46,30.91,21.77,13.75.MS-ESI m/z:C8H12N2S2[M+H]+:201.3180。
example 7 Synthesis of Compound S7
(1) The structural formula of compound S7 is as follows:
Figure BDA0003646332670000062
(2) the preparation method of the compound S7 is as follows:
the preparation method differs from example 1 in that: the same procedure as in example 1 was repeated except that 2-mercaptopyridine was replaced with 2-mercaptopyridine and n-butylmercaptan was replaced with isobutylmercaptan.
(3) As a result:
compound S7 was obtained as a colorless oily liquid, yield: 66 percent;1H NMR(400MHz,Chloroform-d)δ:8.61(d,J＝4.8Hz,2H),7.07(t,J＝4.8Hz,1H),2.76(d,J＝6.9Hz,2H),2.04-1.92(m,1H),1.02(d,J＝6.7Hz,6H).13C NMR(100MHz,Chloroform-d)δ:172.19,157.93,117.87,48.13,28.14,21.90.MS-ESI m/z:C8H12N2S2[M+H]+:201.3180。
example 8 Synthesis of Compound S8
(1) The structural formula of compound S8 is as follows:
Figure BDA0003646332670000063
(2) the preparation method of the compound S8 is as follows:
the preparation method differs from example 1 in that: only isobutyl mercaptan was used in place of n-butyl mercaptan, and the procedure was repeated as in example 1.
(3) As a result:
compound S8 was obtained as a colorless oily liquid, yield: 87 percent;1H NMR(400MHz,Chloroform-d)δ:8.45(dd,J＝5.0,1.7Hz,1H),7.75-7.57(m,2H),7.11-7.02(m,1H),2.69(d,J＝6.9Hz,2H),2.01-1.89(m,1H),1.01(d,J＝6.6Hz,6H).13C NMR(100MHz,Chloroform-d)δ:160.87,149.70,137.06,120.56,119.66,48.55,28.29,21.88.MS-ESI m/z:C9H13NS2[M+H]+:200.3300。
example 9 Synthesis of Compound S9
(1) The structural formula of compound S9 is as follows:
Figure BDA0003646332670000071
(2) the reaction formula of compound S9 is as follows:
Figure BDA0003646332670000072
(3) the preparation method of compound S9 is as follows:
2-Bromoquinoline (1mmol) was added to thiourea (1.1mmol) and the mixture was stirred under reflux in anhydrous ethanol for 4 h. The 2-mercaptoquinoline is obtained by separation by filtration or rotary evaporation of the solvent under vacuum and purification by recrystallization, washing or column chromatography. 2-mercaptoquinoline (1mmol) and isobutylthiol (1.5mmol) were dissolved in 10mL of Dichloromethane (DCM) at 0 deg.C. 1mmol of dichlorodicyanobenzoquinone (DDQ) was then added slowly in portions to the solution and the reaction mixture was stirred in an ice bath for 1 h. The progress of the reaction was monitored by thin layer chromatography. After completion, the solvent was removed by rotary evaporation and the crude compound was purified by column chromatography (ethyl acetate: petroleum ether, 1: 50) to afford the desired product S9.
(4) As a result:
compound S9 was obtained as a yellow oily liquid, yield: 49 percent;1H NMR(400MHz,Chloroform-d)δ:8.10(d,J＝8.7Hz,1H),8.00(d,J＝8.5Hz,1H),7.90(d,J＝8.7Hz,1H),7.78(dd,J＝8.1,1.5Hz,1H),7.73-7.64(m,1H),7.55-7.44(m,1H),2.75(d,J＝6.8Hz,2H),2.05-1.90(m,1H),1.03(d,J＝6.7Hz,6H).13C NMR(100MHz,Chloroform-d)δ:161.13,148.16,137.01,130.30,128.44,127.84,126.34,126.18,117.48,48.96,28.25,21.92.MS-ESI m/z:C13H15NS2[M+H]+:250.3900。
example 10 Synthesis of Compound S10
(1) The structural formula of compound S10 is as follows:
Figure BDA0003646332670000081
(2) the preparation method of the compound S10 is as follows:
the preparation method differs from example 9 in that: only n-propyl mercaptan was used in place of isobutyl mercaptan, and the rest was the same as in example 9.
(3) As a result:
compound S10 was obtained as a yellow oily liquid, yield: 57 percent;1H NMR(400MHz,Chloroform-d)δ:8.10(d,J＝8.7Hz,1H),8.03-7.97(m,1H),7.91(d,J＝8.7Hz,1H),7.77(dd,J＝8.1,1.5Hz,1H),7.72-7.66(m,1H),7.54-7.44(m,1H),2.83(t,J＝7.2Hz,2H),1.74(h,J＝7.3Hz,2H),1.00(t,J＝7.3Hz,3H).13C NMR(100MHz,Chloroform-d)δ:161.21,148.13,137.00,130.30,128.42,127.83,126.33,126.18,117.44,41.52,22.44,13.25.MS-ESI m/z:C12H13NS2[M+H]+:236.3630。
example 11 Synthesis of Compound S11
(1) The structural formula of compound S11 is as follows:
Figure BDA0003646332670000082
(2) the preparation method of compound S11 is as follows:
the preparation method differs from example 9 in that: only n-butylmercaptan was used in place of isobutylmercaptan, the same as in example 9.
(3) As a result:
compound S11 was obtained as a yellow oily liquid, yield: 46 percent;1H NMR(400MHz,Chloroform-d)δ:8.10(d,J＝8.7Hz,1H),8.00(d,J＝8.5Hz,1H),7.91(d,J＝8.7Hz,1H),7.78(dd,J＝8.1,1.5Hz,1H),7.73-7.66(m,1H),7.53-7.44(m,1H),2.85(t,J＝7.4Hz,2H),1.81-1.62(m,2H),1.43(h,J＝7.4Hz,2H),0.89(t,J＝7.3Hz,3H).13C NMR(100MHz,Chloroform-d)δ:161.20,148.15,137.00,130.29,128.42,127.83,126.32,126.17,117.40,39.26,31.10,21.78,13.76.MS-ESI m/z:C13H15NS2[M+H]+:250.3900。
example 12 Synthesis of Compound S12
(1) The structural formula of compound S12 is as follows:
Figure BDA0003646332670000083
(2) the preparation method of compound S12 is as follows:
the preparation method differs from example 9 in that: only allylmercaptan was used in place of isobutylmercaptan, the same as in example 9.
(3) As a result:
compound S12 was obtained as a yellow oily liquid, yield: 46 percent;1H NMR(400MHz,Chloroform-d)δ:8.09(d,J＝8.7Hz,1H),8.00(d,J＝8.4Hz,1H),7.86(d,J＝8.7Hz,1H),7.78(dd,J＝8.2,1.4Hz,1H),7.73-7.66(m,1H),7.49(t,J＝7.5Hz,1H),5.93-5.81(m,1H),5.20-5.07(m,2H),3.50(d,J＝7.4Hz,2H).13C NMR(100MHz,Chloroform-d)δ:160.71,148.11,136.91,132.30,130.30,128.45,127.83,126.36,126.21,119.64,117.55,42.41.MS-ESI m/z:C12H11NS2[M+H]+:234.3470。
example 13 Synthesis of Compound S13
(1) The structural formula of compound S13 is as follows:
Figure BDA0003646332670000091
(2) the preparation method of the compound S13 is as follows:
the preparation method differs from example 9 in that: p-fluorobenzenethiol was used alone in place of isobutylmercaptan, and the rest was the same as in example 9.
(3) As a result:
compound S13 was obtained as a white solid, yield: 49 percent;1H NMR(400MHz,Chloroform-d)δ:8.09(d,J＝8.7Hz,1H),8.02(d,J＝8.5Hz,1H),7.79(t,J＝8.5Hz,2H),7.75-7.68(m,1H),7.61-7.54(m,2H),7.54-7.47(m,1H),6.99(t,J＝8.6Hz,2H).13C NMR(100MHz,Chloroform-d)δ:162.69(d,J＝248.1Hz),159.68,148.13,137.42,131.81(d,J＝3.2Hz),130.96(d,J＝8.3Hz),130.50,128.47,127.87,126.49,117.43,116.56,116.34.MS-ESI m/z:C15H10FNS2[M+H]+:288.3704。
example 14 Synthesis of Compound S14
(1) The structural formula of compound S14 is as follows:
Figure BDA0003646332670000092
(2) the preparation method of compound S14 is as follows:
the preparation method differs from example 9 in that: only p-chlorothiophenol was used in place of the isobutylmercaptan, the rest was the same as in example 9.
(3) As a result:
compound S14 was obtained as a white solid, yield: 58 percent;1H NMR(400MHz,Chloroform-d)δ:8.01(d,J＝8.7Hz,1H),7.93(d,J＝8.5Hz,1H),7.72-7.68(m,2H),7.46-7.41(m,3H),7.19(dd,J＝5.8,2.8Hz,3H).13C NMR(100MHz,Chloroform-d)δ:159.41,148.16,137.50,136.41,135.08,133.72,130.54,129.42,129.36,128.51,127.88,126.54,117.31.MS-ESI m/z:C15H10ClNS2[M+H]+:304.8220。
example 15 Synthesis of Compound S15
(1) The structural formula of compound S15 is as follows:
Figure BDA0003646332670000101
(2) the preparation method of the compound S15 is as follows:
the preparation method differs from example 9 in that: only p-methylthiophenol was used in place of isobutylmercaptan, the same as in example 9.
(3) As a result:
compound S15 was obtained as a pink solid, yield: 45 percent;1H NMR(400MHz,Chloroform-d)δ:8.04(dd,J＝18.9,8.6Hz,2H),7.84(d,J＝8.6Hz,1H),7.79-7.73(m,1H),7.73-7.66(m,1H),7.53-7.43(m,3H),7.10(d,J＝8.0Hz,2H),2.30(s,3H).13C NMR(100MHz,Chloroform-d)δ:160.38,148.06,137.90,137.29,132.96,130.36,130.04,128.54,128.42,127.82,126.39,126.30,117.32,21.15.MS-ESI m/z:C16H13NS2[M+H]+:284.4070。
example 16 Synthesis of Compound S16
(1) The structural formula of compound S16 is as follows:
Figure BDA0003646332670000102
(2) the preparation method of the compound S16 is as follows:
the preparation method differs from example 1 in that: the same procedure as in example 1 was repeated except that mercaptobenzothiazole alone was used in place of 2-mercaptopyridine and n-propanethiol was used in place of n-butanethiol.
(3) As a result:
compound S16 was obtained as a colorless oily liquid, yield: 67%;1H NMR(400MHz,Chloroform-d)δ:7.87(d,J＝8.2Hz,1H),7.84-7.78(m,1H),7.48-7.38(m,1H),7.37-7.30(m,1H),2.94(t,J＝7.3Hz,2H),1.80(h,J＝7.3Hz,2H),1.04(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ:173.41,155.25,135.97,126.36,124.66,122.24,121.25,41.66,22.54,13.19.MS-ESI m/z:C10H11NS3[M+H]+:242.3850。
example 17 Synthesis of Compound S17
(1) The structural formula of compound S17 is as follows:
Figure BDA0003646332670000111
(2) the preparation method of compound S17 is as follows:
the preparation method differs from example 1 in that: only mercaptobenzothiazole was used in place of 2-mercaptopyridine, the remainder being the same as in example 1.
(3) As a result:
compound S17 was obtained as a colorless oily liquid, yield: 78 percent;1H NMR(400MHz,Chloroform-d)δ:7.87(d,J＝8.1Hz,1H),7.85-7.78(m,1H),7.47-7.39(m,1H),7.36-7.29(m,1H),2.97(t,J＝7.4Hz,2H),1.81-1.70(m,2H),1.51-1.40(m,2H),0.93(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ:173.43,155.26,135.97,126.35,124.65,122.23,121.25,39.44,31.15,21.75,13.75.MS-ESI m/z:C11H13NS3[M+H]+:256.4120。
example 18 Synthesis of Compound S18
(1) The structural formula of compound S18 is as follows:
Figure BDA0003646332670000112
(2) the preparation method of the compound S18 is as follows:
the preparation method differs from example 1 in that: the same procedure as in example 1 was repeated except that mercaptobenzothiazole alone was used in place of 2-mercaptopyridine and allyl mercaptan was used in place of n-butylmercaptan.
(3) As a result:
compound S18 was obtained as a colorless oily liquid, yield: 67%;1H NMR(400MHz,Chloroform-d)δ:7.87(d,J＝8.1Hz,1H),7.80(d,J＝8.0Hz,1H),7.47-7.39(m,1H),7.37-7.30(m,1H),5.95-5.83(m,1H),5.20(d,J＝10.5Hz,2H),3.59(d,J＝7.4Hz,2H).13C NMR(100MHz,Chloroform-d)δ:172.81,155.20,135.95,131.52,126.37,124.70,122.29,121.24,120.58,42.42.MS-ESI m/z:C10H9NS3[M+H]+:240.3690。
example 19 Synthesis of Compound S19
(1) The structural formula of compound S19 is as follows:
Figure BDA0003646332670000121
(2) the preparation method of compound S19 is as follows:
the preparation method differs from example 1 in that: only mercaptobenzothiazole was used in place of 2-mercaptopyridine and isobutylmercaptan was used in place of n-butylmercaptan, all the other things being equal to those in example 1.
(3) As a result:
compound S19 was obtained as a colorless oily liquid, yield: 72 percent;1H NMR(400MHz,Chloroform-d)δ:7.86(d,J＝8.1Hz,1H),7.84-7.77(m,1H),7.47-7.39(m,1H),7.37-7.29(m,1H),2.87(d,J＝6.8Hz,2H),2.10-1.97(m,1H),1.05(d,J＝6.7Hz,6H).13C NMR(100MHz,Chloroform-d)δ:173.41,155.29,135.98,126.35,124.64,122.23,121.25,49.06,28.49,21.84.MS-ESI m/z:C11H13NS3[M+H]+:256.4120。
example 20 Synthesis of Compound S20
(1) The structural formula of compound S20 is as follows:
Figure BDA0003646332670000122
(2) the preparation method of the compound S20 is as follows:
the preparation method differs from example 1 in that: only mercaptobenzothiazole was used in place of 2-mercaptopyridine and p-fluorophenylthiol was used in place of n-butylthiol, all the other things being equal to those in example 1.
(3) As a result:
compound S20 was obtained as a white solid in yield: 56 percent;1H NMR(400MHz,Chloroform-d)δ:7.89(d,J＝8.1Hz,1H),7.80(d,J＝8.0Hz,1H),7.68-7.61(m,2H),7.49-7.41(m,1H),7.37-7.31(m,1H),7.04(t,J＝8.6Hz,2H).13C NMR(100MHz,Chloroform-d)δ:171.39,163.58(d,J＝250.0Hz),155.23,136.24,132.73(d,J＝8.5Hz),130.76(d,J＝3.4Hz),126.77,125.22,122.74,121.571,117.01(d,J＝22.4Hz).MS-ESI m/z:C13H8FNS3[M+H]+:294.3924。
example 21 Synthesis of Compound S21
(1) The structural formula of compound S21 is as follows:
Figure BDA0003646332670000131
(2) the preparation method of compound S21 is as follows:
the preparation method differs from example 1 in that: except that mercaptobenzothiazole was used in place of 2-mercaptopyridine and p-chlorothiophenol was used in place of n-butylmercaptan, the procedure was as in example 1.
(3) As a result:
compound S21 was obtained as a white solid, yield: 54％；1H NMR(400MHz,Chloroform-d)δ:7.89(d,J＝8.2Hz,1H),7.78(d,J＝8.0Hz,1H),7.60-7.55(m,2H),7.44(t,J＝7.7Hz,1H),7.38-7.28(m,3H).13C NMR(100MHz,Chloroform-d)δ:135.96,134.99,133.64,133.49,130.65,129.71,126.57,125.04,122.42,121.33.MS-ESI m/z:C13H8ClNS3[M+H]+:310.8440。
Example 22 Synthesis of Compound S22
(1) The structural formula of compound S22 is as follows:
Figure BDA0003646332670000132
(2) the preparation method of compound S22 is as follows:
the preparation method differs from example 1 in that: only mercaptobenzothiazole was used in place of 2-mercaptopyridine and p-methylthiophenol was used in place of n-butylmercaptan, all the other things being equal to those of example 1.
(3) As a result:
compound S22 was obtained as a white solid, yield: 50 percent;1H NMR(400MHz,Chloroform-d)δ:7.88(d,J＝8.1Hz,1H),7.81–7.76(m,1H),7.54(d,J＝8.2Hz,2H),7.46-7.39(m,1H),7.36-7.29(m,1H),7.15(d,J＝7.9Hz,2H),2.33(s,3H).13C NMR(100MHz,Chloroform-d)δ:172.29,154.93,139.30,135.94,131.63,130.28,130.07,126.42,124.80,122.29,121.29,21.31.MS-ESI m/z:C14H11NS3[M+H]+:290.4290。
example 23 Synthesis of Compound S23
(1) The structural formula of compound S23 is as follows:
Figure BDA0003646332670000133
(2) the preparation method of compound S23 is as follows:
the preparation method differs from example 1 in that: only mercaptothiazole was used in place of 2-mercaptopyridine and n-butylmercaptan was used in place of n-butylmercaptan, all the other things being the same as in example 1.
(3) As a result:
compound S23 was obtained as a colorless oily liquid, yield: 64 percent;1H NMR(400MHz,Chloroform-d)δ:7.69(d,J＝3.4Hz,1H),7.29(d,J＝3.4Hz,1H),2.90(t,J＝7.2Hz,2H),1.77(h,J＝7.3Hz,2H),1.01(t,J＝7.3Hz,3H).13C NMR(100MHz,Chloroform-d)δ:170.36,144.28,120.68,41.31,22.51,13.16.MS-ESI m/z:C6H9NS3[M+H]+:192.3250。
example 24 Synthesis of Compound S24
(1) The structural formula of compound S24 is as follows:
Figure BDA0003646332670000141
(2) the preparation method of compound S24 is as follows:
the preparation method differs from example 1 in that: only mercaptothiazole was used in place of 2-mercaptopyridine, and the rest was the same as in example 1.
(3) As a result:
compound S24 was obtained as a colorless oily liquid, yield: 42%;1H NMR(400MHz,Chloroform-d)δ:7.69(d,J＝3.4Hz,1H),7.30(d,J＝3.3Hz,1H),2.93(t,J＝7.3Hz,2H),1.72(p,J＝7.4Hz,2H),1.43(h,J＝7.4Hz,2H),0.92(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ:170.38,144.29,120.67,39.11,31.15,21.71,13.75.MS-ESI m/z:C7H12NS3[M+H]+:206.3520。
example 25 Synthesis of Compound S25
(1) The structural formula of compound S25 is as follows:
Figure BDA0003646332670000142
(2) the preparation method of the compound S25 is as follows:
the preparation method differs from example 1 in that: the same procedure as in example 1 was repeated except that mercaptothiazole alone was used in place of 2-mercaptopyridine and p-allylmercaptan was used in place of n-butylmercaptan.
(3) As a result:
compound S25 was obtained as a colorless oily liquid, yield: 68 percent of;1H NMR(400MHz,Chloroform-d)δ:7.70(d,J＝3.4Hz,1H),7.30(d,J＝3.4Hz,1H),5.94-5.80(m,1H),5.27-5.16(m,2H),3.55(d,J＝7.4Hz,2H).13C NMR(100MHz,Chloroform-d)δ:169.71,144.24,131.81,120.75,120.21,42.16.MS-ESI m/z:C6H7NS3[M+H]+:190.3090。
example 26 Synthesis of Compound S26
(1) The structural formula of compound S26 is as follows:
Figure BDA0003646332670000151
(2) the preparation method of the compound S26 is as follows:
the preparation method differs from example 1 in that: only mercaptothiazole was used in place of 2-mercaptopyridine and p-isobutylmercaptan was used in place of n-butylmercaptan, all the other things being the same as in example 1.
(3) As a result:
compound S26 was obtained as a colorless oily liquid, yield: 48 percent;1H NMR(400MHz,Chloroform-d)δ:7.69(d,J＝3.4Hz,1H),7.30(d,J＝3.4Hz,1H),2.83(d,J＝6.9Hz,2H),2.09-1.93(m,1H),1.03(d,J＝6.7Hz,6H).13C NMR(100MHz,Chloroform-d)δ:170.39,144.33,120.69,48.71,28.44,21.82.MS-ESI m/z:C7H12NS3[M+H]+:206.3520。
example 27 Synthesis of Compound S27
(1) The structural formula of compound S27 is as follows:
Figure BDA0003646332670000152
(2) the reaction formula for compound S27 is as follows:
Figure BDA0003646332670000153
(3) the preparation method of compound S27 is as follows:
4-Chlorobenzothiophenol (1.4g, 10mmol) was added to 20mL of anhydrous dichloromethane, and sulfuryl chloride (810. mu.L, 10mmol) was added dropwise at 0 ℃ with stirring. The reaction mixture was stirred for 1 hour. Concentration at the same temperature and then under vacuum provided 4-chlorophenylhypochlorous sulfide as a brown yellow liquid which was used in the next step without further purification. The resulting solution of 4-chlorophenylhypochlorous sulfide (5mmol) in 10mL of anhydrous ether was added dropwise to a solution of thiazole-2-thiol (5mmol) in 10mL of anhydrous ether at room temperature. The reaction mixture was stirred for 12h, the solvent was removed to give a crude product, which was purified using column chromatography to give the desired product S27.
(4) As a result:
compound S27 was obtained as a yellow oily liquid, yield: 43 percent;1H NMR(400MHz,Chloroform-d)δ:7.73(d,J＝3.4Hz,1H),7.57-7.50(m,2H),7.35-7.29(m,3H).13C NMR(100MHz,Chloroform-d)δ:167.56,144.31,134.73,133.96,130.58,129.61,121.54.MS-ESI m/z:C9H6ClNS3[M+H]+:260.7840。
example 28 Synthesis of Compound S28
(1) The structural formula of compound S28 is as follows:
Figure BDA0003646332670000161
(2) the preparation method of the compound S28 is as follows:
the preparation process differs from example 27 in that: the procedure of example 27 was repeated except that p-chlorobenzenethiol was used instead of 4-chlorobenzenethiol.
(3) As a result:
compound S28 was obtained as a yellow oily liquid, yield: 33 percent;1H NMR(400MHz,Chloroform-d)δ:7.73(d,J＝3.4Hz,1H),7.63-7.56(m,2H),7.32(d,J＝3.4Hz,1H),7.04(t,J＝8.6Hz,2H).13C NMR(100MHz,Chloroform-d)δ:167.87,163.22(d,J＝249.5Hz),144.31,138.97(d,J＝9.1Hz),132.41(d,J＝8.5Hz),121.43,116.66(d,J＝22.3Hz).MS-ESI m/z:C9H6FNS3[M+H]+:244.3324。
example 29 Synthesis of Compound S29
(1) The structural formula of compound S29 is as follows:
Figure BDA0003646332670000162
(2) the preparation method of the compound S29 is as follows:
the preparation process differs from example 27 in that: the procedure of example 27 was repeated except that p-methylthiophenol was used in place of 4-chlorothiophenol.
(3) As a result:
compound S29 was obtained as a yellow oily liquid, yield: 45 percent;1H NMR(400MHz,Chloroform-d)δ:7.71(d,J＝3.4Hz,1H),7.50(d,J＝8.0Hz,2H),7.29(d,J＝3.4Hz,1H),7.15(d,J＝7.9Hz,2H),2.34(s,3H).13C NMR(100MHz,Chloroform-d)δ:144.15,139.04,131.93,130.20,130.02,121.05,21.29.MS-ESI m/z:C10H9NS3[M+H]+:240.3690。
example 30 Synthesis of Compound S30
(1) The structural formula of compound S30 is as follows:
Figure BDA0003646332670000171
(2) the preparation method of the compound S30 is as follows:
the preparation method differs from example 1 in that: the same procedure as in example 1 was repeated except that 2-mercaptopyridine was replaced with thiophenethiol alone and n-butylmercaptan was replaced with n-propylmercaptan.
(3) As a result:
compound S30 was obtained as a yellow oily liquid, yield: 57 percent;1H NMR(400MHz,Chloroform-d)δ:7.50(dd,J＝5.3,1.3Hz,1H),7.16(dd,J＝3.6,1.3Hz,1H),7.01(dd,J＝5.3,3.6Hz,1H),2.67(t,J＝7.3Hz,2H),1.71(h,J＝7.3Hz,2H),1.00(t,J＝7.3Hz,3H).13C NMR(100MHz,Chloroform-d)δ:135.87,135.77,132.40,127.89,41.33,22.66,13.28.MS-ESI m/z:C7H10S3[M+H]+:191.3370。
example 31 Synthesis of Compound S31
(1) The structural formula of compound S31 is as follows:
Figure BDA0003646332670000172
(2) the preparation method of the compound S31 is as follows:
the preparation method differs from example 1 in that: the same procedure as in example 1 was repeated except that thiophenethiol was used instead of 2-mercaptopyridine.
(3) As a result:
compound S31 was obtained as a yellow oily liquid, yield: 51 percent;1H NMR(400MHz,Chloroform-d)δ:7.50(dd,J＝5.3,1.3Hz,1H),7.16(dd,J＝3.6,1.3Hz,1H),7.01(dd,J＝5.3,3.6Hz,1H),2.69(t,J＝7.4Hz,2H),1.66(p,J＝7.3Hz,2H),1.42(h,J＝7.3Hz,2H),0.93(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ:135.87,135.78,132.41,127.89,39.04,31.46,21.81,13.85.MS-ESI m/z:C8H12S3[M+H]+:205.3640。
example 32 Synthesis of Compound S32
(1) The structural formula of compound S32 is as follows:
Figure BDA0003646332670000173
(2) the preparation method of compound S32 is as follows:
the preparation method differs from example 1 in that: the same procedure as in example 1 was repeated except that thiophene thiol was used instead of 2-mercaptopyridine and that p-allyl thiol was used instead of n-butyl mercaptan.
(3) As a result:
the obtained compoundThe material S32 was a yellow oily liquid, yield: 45 percent;1H NMR(400MHz,Chloroform-d)δ:7.49(dd,J＝5.3,1.3Hz,1H),7.27-7.21(m,1H),7.15(dd,J＝3.6,1.3Hz,1H),5.93-5.79(m,1H),5.32-5.14(m,2H),3.45(d,J＝7.3Hz,1H),3.34(d,J＝7.3Hz,1H).13C NMR(100MHz,Chloroform-d)δ:135.77,132.40,127.89,119.36,118.59,42.43,41.91.MS-ESI m/z:C7H8S3[M+H]+:189.3210。
example 33: test method and result of antifungal activity of disulfide bond compounds S1-S32
1) Disulfide bond compounds S1-S32 of the test agent.
2) Test strains: sclerotinia sclerotiorum, rhizoctonia solani, botrytis cinerea, fusarium graminearum, rice blast, phytophthora capsici, aspergillus flavus, penicillium expansum, brown rot of stone fruit and rhizopus stolonifer.
3) Antifungal activity test:
the test method comprises the following steps: the antibacterial activity was measured using potato dextrose agar medium (PDA medium). The preparation method comprises the following steps: firstly, cleaning and peeling potatoes, weighing 200g of potatoes, cutting the potatoes into small pieces, adding water, boiling the potatoes thoroughly (boiling for 20-30 minutes, the potato pieces can be punctured by a glass rod), filtering the potatoes by eight layers of gauze, heating the potatoes, adding 15g of agar, continuously heating, stirring the mixture evenly, adding glucose after the agar is dissolved, stirring the mixture evenly, slightly cooling the mixture, then supplementing the water to 1000 ml, subpackaging the mixture in conical bottles, plugging and binding the conical bottles, and sterilizing the mixture for 2 hours at 115 ℃ for later use. Respectively dissolving the compounds S1-S32 in DMSO, adding into a culture medium, uniformly mixing to make the concentrations of the compounds in the culture medium respectively 50 mug/mL, taking DMSO with equal concentration as a blank control, and taking the azoxystrobin and imazalil which are market drugs as positive controls. And (3) pouring the plates, cooling, inoculating bacteria respectively, culturing in an incubator at 25 ℃, and determining the bacteriostasis rate of each compound by taking blank control hypha to overgrow the culture dish as a limit. All experiments were performed in triplicate or in triplicate. The calculation of the bacteriostasis rate is carried out according to the following calculation formula:
the bacteriostasis rate is (blank control hypha diameter-hypha diameter)/(blank control hypha diameter-fungus cake diameter) × 100%.
The results of the activity test of the disulfide-bond compounds S1-S32 against 6 plant pathogenic fungi are shown in Table 1.
Inhibition ratio (%) of disulfide-bond-type compounds S1-S32 against 6 pathogenic fungi at 150 ppm in Table
Figure BDA0003646332670000181
Figure BDA0003646332670000191
As can be seen from Table 1, the disulfide compounds have a certain inhibitory effect on 6 plant fungal diseases at 50 ppm. Wherein, the inhibition effect of S1, S2 and S8 on rhizoctonia solani is more than 80 percent under 50ppm, and the inhibition effect of S1, S2 and S3 on sclerotinia sclerotiorum is more than 80 percent, which is obviously superior to the positive control azoxystrobin.
The results of the activity test of the disulfide compounds S1-S32 against 4 phytopathogenic fungi are shown in Table 2.
Inhibition ratio (%) of disulfide-bond-type compounds S1-S32 against 4 pathogenic fungi at 250 ppm in Table
Figure BDA0003646332670000192
Figure BDA0003646332670000201
As can be seen from Table 2, the disulfide compounds have a certain inhibitory effect on 4 fungal plant diseases at 50 ppm. Wherein 50ppm of the inhibitor has 100 percent of inhibition effect of S1-S8 and S23 on aspergillus flavus, 100 percent of inhibition effect of S23-S26 on penicillium expansum, 100 percent of inhibition effect of S1-S2, S7-S8, S26 and S28 on brown rot of stone fruit, and the inhibition effect is equivalent to that of a positive control drug of thiophanate methyl.
EC of partially highly active disulfide bond compound50The values are shown in Table 3.
Section 3 of TableEC of highly active compounds50Value (μ g/mL)
Figure BDA0003646332670000202
Figure BDA0003646332670000211
Note: "-" indicates that the correlation function was not tested.
As can be seen from Table 3, of the 32 compounds tested, 9 compounds (S1-S8, S14) had strong antifungal activity against Rhizoctonia solani, and their EC' S509.92-20.14 mu g/mL, and the activity is superior to that of the positive control azoxystrobin (EC)50> 50. mu.g/mL). 7 compounds (S1, S3, S5-S8 and S18) have strong antifungal activity on sclerotium of rape and the EC thereof5010.66-22.76 mug/mL, activity and azoxystrobin (EC)504.90 μ g/mL) was slightly inferior. 11 compounds (S3-S4, S7-S8, S18, S25-S26, S28-S29 and S31-S32) have strong antifungal activity on Botrytis cinerea (Botrytis cinerea) and EC thereof5012.84-48.84 mu g/mL, and partial compounds have activity superior to that of azoxystrobin (EC)5029.70 μ g/mL). 9 compounds (S1, S3-S8 and S14-S15) have strong antifungal activity on gibberella zeae, and the EC of the compounds50The activity of part of compounds is better than that of azoxystrobin (EC) when the compounds are 14.13-38.37 mu g/mL5033.31 μ g/mL). There are 12 compounds (S1-S8, S11, S13, S17 and S19) which have strong antifungal activity on the brown rot of stone fruit and the EC thereof505.92-10.42 mu g/mL, wherein 10 compounds EC50EC of < 10. mu.g/mL, S850The antibacterial activity is inferior to that of positive medicine thiophanate methyl (EC) when the concentration is 5.92 mu g/mL50＝0.13μg/mL)。
Example 34 method and results of testing the antibacterial Activity of disulfide Compounds S1 to S32
1) Reagent to be tested: disulfide bond compounds S1-S32
2) Test strains: rice bacterial leaf blight, citrus canker pathogen, potato phytophthora parasitica, escherichia coli, staphylococcus aureus, bacillus cereus, listeria monocytogenes, escherichia coli and salmonella enteritidis.
3) And (3) testing antibacterial activity:
the test method comprises the following steps: the strain used in this experiment was a strain frozen at-80 ℃ in the laboratory with 30% glycerol. The frozen strains were taken out, streaked on NB solid medium (beef extract: 3g, peptone: 5g, yeast powder: 1g, sucrose: 10g, agar: 15g, distilled water: 1L, pH 7.0; sterilized at 121 ℃ for 20min), NB solid medium (beef extract: 3g, peptone: 10g, sodium chloride: 5g, agar: 15g, distilled water: 1L, pH 7.0; sterilized at 121 ℃ for 20min) of a human bacterium and YEPD solid medium (yeast extract: 10g, peptone: 20g, glucose: 20g, agar: 15g, distilled water: 1L; sterilized at 121 ℃ for 20min) of a Candida bacterium, respectively, and cultured at constant temperature of 28 ℃ (37 ℃) until a single colony grew. Single colonies on the solid medium were picked up respectively on a plant bacterium NB liquid medium (beef extract: 3g, peptone: 5g, yeast powder: 1g, sucrose: 10g, distilled water: 1L; sterilized at 121 ℃ for 20min), a human bacterium NB liquid medium (beef extract: 3g, peptone: 10g, sodium chloride: 5g, distilled water: 1L, pH 7.0; sterilized at 121 ℃ for 20min) and a YEPD liquid medium of Candida (yeast extract: 10g, peptone: 20g, glucose: 20g, distilled water: 1L; sterilized at 121 ℃ for 20min), and shake-cultured at constant temperature of 28 ℃ (37 ℃) and 180rpm on a shaker at constant temperature of 180rpm until logarithmic phase. The strain in logarithmic growth phase was diluted to about 10 with the corresponding liquid medium6CFU/mL is ready for use. The compounds are respectively dissolved in DMSO, added into a liquid culture medium, and uniformly mixed to prepare a drug-containing liquid culture medium with the concentration of 200 mug/mL. Taking 50 μ L of medicated culture medium and the same volume of the medicated culture medium containing 106CFU/mL bacterial culture was added to the wells of a 96-well plate at a final dosing concentration of 100. mu.g/mL. 100 μ L of the same concentration of the bacterial suspension containing the same amount of DMSO was used as a control. Culturing 96-well plate in constant temperature incubator at 28 deg.C (37 deg.C) for 24-48 hr until control bacteria solution grows out, and measuring OD (OD) value of bacteria solution in the well on enzyme labeling instrument600). And OD values of 100. mu.L of the liquid medium and the drug at a concentration of 100. mu.g/mL were measured, and the OD values caused by the medium and the drug themselves were measuredAnd (6) correcting. The calculation formula of the corrected OD value and the inhibition rate is as follows:
correcting OD value-bacteria-containing culture medium OD value-sterile culture OD value;
the inhibition ratio (OD value of the control medium liquid after correction-OD value of the drug-containing medium after correction)/OD value of the control medium liquid after correction × 100%.
The results of the activity test of the disulfide compounds S1-S32 on 5 pathogenic bacteria are shown in Table 4.
Inhibition ratio (%) of disulfide bond-based Compounds S1 to S32 against 5 pathogenic bacteria at 4100 ppm
Figure BDA0003646332670000231
As can be seen from Table 4, the disulfide compounds have certain inhibitory effects on 5 bacterial diseases at 100 ppm. Wherein, the inhibition effect of S4-S6 on rice bacterial leaf blight is 100% under 100ppm, the inhibition effect of S4-S7 on citrus ulcer is 100%, and the inhibition effect is equivalent to the activity of positive control medicament of thiabendazole and econazole.
The MIC values of the partially disulfide-bonded highly active compounds are shown in Table 5.
TABLE 5 MIC values for some highly active compounds
Figure BDA0003646332670000232
Figure BDA0003646332670000241
As can be seen from table 5, of the 32 target compounds tested, 17 compounds have a good inhibitory effect on bacterial blight of rice (x.oryzae), and the MIC values thereof are 1.56-100 μ g/mL, wherein the MIC values of the compounds S5, S6 and S7 are 1.56, 6.25 and 12.5 μ g/mL respectively, which are all better than that of a positive control medicament, namely thiabendazole (MIC value of 100 μ g/mL); the 8 compounds have better inhibition effect on citrus canker (X.axonopodis), the MIC values of the compounds are 6.25-100 mu g/mL, wherein the MIC values of the compounds S6 and S7 are respectively 6.25 and 12.5 mu g/mL, and are respectively superior to that of a positive control drug and thiediazole copper (the MIC value is 100 mu g/mL); 3 compounds have better activity on the potato phytophthora parasitica (P.atroseptica), wherein the MIC of the compound S5 on the potato phytophthora parasitica (P.atroseptica) is 6.25 mu g/mL, which is better than that of the positive control medicament of thiabendazole copper (MIC > 100 mu g/mL). Most compounds have poor activity against E.coli (E.coli) and S.aureus (S.aureus) after reducing the drug potency, with MICs > 100. mu.g/mL. Wherein the MIC of compound S2 to escherichia coli (e.coli) is 100 μ g/mL, weaker than that of norfloxacin, a positive control drug (MIC is 0.39 μ g/mL); the MIC of compounds S5, S7, S9 to s.aureus (s.aureus) was 25 μ g/mL, the MIC of S8, S10 to s.aureus (s.aureus) was 50 μ g/mL, the MIC of S2, S6 to s.aureus (s.aureus) was 100 μ g/mL, and was weaker than that of norfloxacin, a positive control drug (MIC was 12.5 μ g/mL).
The results of the activity test of the disulfide compounds S1-S32 on 4 pathogenic bacteria are shown in Table 6.
Inhibition ratio (%) of disulfide-bond compounds S1-S32 against 4 pathogenic bacteria at Table 6100 ppm
Figure BDA0003646332670000251
As can be seen from Table 5, the disulfide compounds have a certain inhibitory effect on 4 bacterial diseases at 100 ppm. Wherein, the inhibiting effect of S11, S15-S17 and S20-S22 on Bacillus cereus is 100 percent under 100ppm, the inhibiting effect of S1, S10, S12, S15-S16, S21, S23-S24 and S28 on Listeria monocytogenes is 100 percent, and the inhibiting effect of S7, S14-S16, S24-S25 and S28-S32 on Escherichia coli is 100 percent. The activity of the polypeptide is equivalent to that of an epsilon-polylysine serving as a positive control drug.
The MIC values of the partially disulfide-bonded highly active compounds are shown in Table 7.
TABLE 7 MIC values for some highly active compounds
Figure BDA0003646332670000252
Figure BDA0003646332670000261
As can be seen from table 7, among the 32 target compounds tested, all of them had strong bactericidal activity against bacillus cereus (b.cereus), and their MICs were 1.56 to 100 μ g/mL, and among them, the MIC values of compounds S5, S6, S7, and S8 were 1.56 μ g/mL, which is superior to that of the positive drug ∈ -polylysine (MIC of 100 μ g/mL). The 29 compounds have good inhibition effect on L.monocytogenes (L.monocytogenes), and the MICs of the compounds are 3.12-100 mu g/mL, wherein the MICs of the compounds S5, S6, S7 and S8 are 3.12-6.25 mu g/mL, which are superior to those of a positive drug epsilon-polylysine, and the MICs of the compounds are 25 mu g/mL. The 37 compounds have good inhibition effect on escherichia coli (E.coli O157: H7), the MIC of the compounds is 6.25-100 mu g/mL, and the MIC value of the compound S15 is 6.25 mu g/mL and is better than that of a positive drug epsilon-polylysine (MIC is 25 mu g/mL). Only 3 compounds S5, S6 and S16 have good activity on salmonella enteritidis (S. enteritidis), and the MIC of the compound is 12.5-100 mu g/mL, which is superior to that of an epsilon-polylysine (MIC is more than 100 mu g/mL) which is a positive drug.
In conclusion, the disulfide bond compound has good inhibitory activity on pathogenic fungi and bacteria and has the characteristic of broad spectrum. The compound has simple synthesis method and cheap and easily obtained raw materials, and is expected to be developed into a novel antibacterial agent.
The above examples are intended to illustrate the disclosed embodiments of the invention and are not to be construed as limiting the invention. In addition, various modifications of the methods and compositions of the present invention as set forth herein will be apparent to those skilled in the art without departing from the scope and spirit of the invention. While the invention has been specifically described in connection with various specific preferred embodiments thereof, it should be understood that the invention should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described embodiments which are obvious to those skilled in the art to which the invention pertains are intended to be covered by the scope of the present invention.

Claims (9)

1. A disulfide bond compound characterized by: the compound is a disulfide bond heterocyclic compound and has the following general formula:
Figure FDA0003646332660000011
the specific general structure is respectively as follows:
Figure FDA0003646332660000012
2. the disulfide compounds of claim 1, wherein: r' in the general formulas (I) - (VI) is one of hydrogen, methyl, methoxy, fluorine and chlorine.
3. The disulfide compounds of claim 1, wherein: r' in the general formulas (I) - (VI) is one of aliphatic chains, benzene rings or other heterocyclic groups.
4. A method for producing the disulfide compound according to any one of claims 1 to 3, wherein: the compounds in the general formulas (I) to (VI) are prepared according to the formulas (I) to (VI) respectively:
the following formula:
Figure FDA0003646332660000013
equation 2:
Figure FDA0003646332660000014
formula III:
Figure FDA0003646332660000015
the formula (IV):
Figure FDA0003646332660000016
a fifth expression:
Figure FDA0003646332660000021
the formula is:
Figure FDA0003646332660000022
5. a method for preparing the disulfide compound according to claim 4, wherein: when R' in the compound of the general formula III contains a benzene ring, the compound is prepared according to the following formula:
Figure FDA0003646332660000023
wherein R' in the formula is an aliphatic chain.
6. Use of the disulfide compounds according to any one of claims 1 to 3 for the preparation of a medicament for the control of sclerotinia sclerotiorum, rhizoctonia solani, botrytis cinerea, gibberella graminearum, pyricularia oryzae, phytophthora capsici.
7. Use of the disulfide compounds according to any one of claims 1 to 3 for the preparation of a medicament for the prevention and treatment of Aspergillus flavus, Penicillium expansum, brownspot of stone fruit, Rhizopus stolonifer.
8. Use of the disulfide bond compounds as claimed in any one of claims 1 to 3 for preparing a medicament for controlling rice bacterial blight, citrus canker, potato phytophthora parasitica, escherichia coli, staphylococcus aureus, bacillus cereus, listeria monocytogenes, salmonella enteritidis.
9. The disulfide compounds of any one of claims 1 to 3 for use in the preparation of antibacterial agents.
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