Quinazoline-4-one compounds containing 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole and preparation and use thereof

Abstract

The invention discloses a quinazoline-4-one compound containing 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole, a preparation method thereof and antibacterial activity thereof. The compound is represented by general formula (I), and quinazoline-4-one, 1,2-dibromoethane, methyl 4-piperidinate, 80% hydrazine hydrate, potassium hydroxide, carbon disulfide and different aromatic acids are used as raw materials to prepare the target compound through a five-step reaction. The invention introduces an active 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole unit into the quinazoline-4-one structure, and synthesizes a series of quinazoline-4-one compounds containing 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole units, and the compounds have good antibacterial activity.

Description

Technical Field

[0001] The invention belongs to the field of chemical technology, and specifically relates to a quinazoline-4-one compound containing 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole, a preparation method thereof, and a use thereof for inhibiting bacteria such as rice bacterial leaf blight pathogen, citrus canker pathogen and rice bacterial leaf streak pathogen. Background Art

[0002] Plant diseases caused by pathogenic bacteria are becoming a global concern, seriously threatening agricultural production and sustainable development of mankind (Wang, L.; Li, C.; et al.; J. Agric. Food Chem. 2013, 61, 8632–8640. Shi, J.; Ding, M.; et al.; J. Agric. Food Chem. 2020, 68, 9613-9623.). For example, Xanthomonas oryzae is a rod-shaped Gram-negative bacterium first discovered in Fukuoka Prefecture, Japan in 1884 that can be spread by monopolar flagella. This bacterium usually enters rice leaves through the hydration pores at the leaf tips and margins, and then reproduces in the intercellular spaces. It has been documented ( DO;Ronald,PCet al.;Mol.Plant Pathol.2006,7,303–324.), Xanthoceras oryzae reduces rice yields by 50% in some parts of Asia (Huang,N.;Angeles,ER;et al.Theor.Appl.Genet.1997,95,313–320.). As for another bacterium, Xanthoceras oryzae, which is the cause of bacterial leaf streaks in rice, it invades rice leaves through stomata or wounds, colonizes in the intercellular spaces of the mid-leaf, and produces pale yellow and water-soaked lesions along the veins (Wan,X.;Yang,J.;et al;Infect.,Genet.Evol.2021,94,105008.). Although there are some antimicrobial agents currently on the market that can combat these diseases, the increasing resistance of pathogens to existing antibiotics and the associated environmental risks due to overuse and misuse of antibiotics have made it urgent to discover new agricultural antimicrobial agents with novel molecular structures, excellent antimicrobial properties, unique mechanisms of action, and good environmental compatibility.

[0003] As an important class of nitrogen-containing heterocyclic compounds, the skeleton of quinazolin-4-one exists in more than 200 natural alkaloids. Quinazolin-4-one and its derivatives have a wide range of pharmacological and insecticidal activities, including antibacterial (Wang, X.; Li, P.; Li, Z.; et al; J. Agric. Food Chem. 2013, 61, 9575–9582.), antifungal (Mohamed, MS; Kamel, MM; et al; Eur. J. Med. Chem. 2010, 45, 3311–3319.), antiviral (Kumar, KS; Ganguly, S.; et al; Eur. J. Med. Chem. 2010, 45, 5474–5479.), antitumor (Mohamed, MA; Ayyad, RR; et al; J. Agric. Food Chem. 2013, 61, 9575–9582.), and antifungal (Mohamed, MS; Kamel, MM; et al; Eur. J. Med. Chem. 2010, 45, 3311–3319.). al;Eur.J.Med.Chem.2016,112,106–113.) and insecticidal (Hekal,MH; Ali,YM; et al;Bioorg.Chem.2023,133,106436.) effects. Some quinazolin-4-one derivatives have entered the market as approved drugs and pesticides, including the fungicide Fluquinconazole, the sedative Cloroqualone, the analgesic Diproqualone and the antibiotic Albaconazole.

[0004] In addition, 1,2,4-triazole [3,4-b][1,3,4] thiadiazole ring is characterized by the fusion of 1,2,4-triazole ring and 1,3,4-thiadiazole heterocycle. Due to its wide range of biological activities, such as antibacterial (Badr, SMI; Barwa, RMB Bioorg. Med. Chem. 2011, 19, 4506-4512.), antifungal (Gao, W.; Zhang, Y.; et al; J. Agric. Food Chem. 2022, 70, 10170-10181.), anticancer (Sunil, D.; Isloor, AM; Shetty, P.; et al; Arab. J. Chem. 2010, 3, 211-217.), anti-inflammatory (Mathew, V.; Keshavayya, J.; et al; J. Chem. 2013, 4, 214-215). al;Eur.J.Med.Chem.2006,41,1048–1058.) and other effects. Compared with thiadiazole and triazole analogs, 1,2,4-triazole [3,4-b][1,3,4] thiadiazole derivatives often show higher biological activity due to the fusion effect (Zhao, B.; Fan, S.; Fan, Z.; et al; J.Agric.Food Chem.2018,66,12439-12452.).

[0005] Third, the piperidine ring and its oxidized form (i.e., pyridine ring) are the most common nitrogen-containing heterocycles in drug molecules (Liu, Z.; He, JH; et al; J. Am. Chem. Soc. 2022, 144, 4810-4818.). Under physiological pH conditions, the basic nitrogen atom of the piperidine ring tends to be positively ionized, and the inherent solubility of this ring makes it particularly suitable for the development of bioactive molecules (Ding, M.; Wu, N.; et al; J. Agric. Food Chem. 2022, 70, 10100-10110.). Among piperidine derivatives, the 4-piperidinyl part often appears as a linker in some commercial drugs, such as the anti-ischemic drug Lubeluzole, the drug Donepezil for the treatment of Alzheimer's disease, the antihypertensive drug Ketanserin, the anticonvulsant Ifenprodil, etc.

[0006] In summary, in order to find a new fungicide with high activity, low toxicity, low residue and environmental friendliness, the present invention introduces a 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole unit at the 3-position of quinazolinone through a 1-ethyl-piperidine ring as a bridging group according to the principle of active unit splicing, and conducts an antibacterial activity test on it, in order to screen out compounds with higher bactericidal activity, which will provide a certain theoretical reference for the creation of new fungicides. Summary of the invention

[0007] The present invention aims to provide a quinazoline-4-one compound containing 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole, a preparation method and a use thereof, wherein the compound has good inhibitory activity against bacteria.

[0008] To achieve the above object, the present invention proposes the following technical solutions:

[0009] A quinazoline-4-one compound containing a 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole unit, the general structural formula of which is as follows:

[0010]

[0011] Wherein: R is phenyl, o- / m- / p-fluoro-phenyl, o- / m- / p-methyl-phenyl, o- / m- / p-nitro-phenyl, o- / m- / p-chlorophenyl, o- / m- / p-bromo-phenyl, o- / m- / p-methoxyphenyl, o- / m- / p-trifluoromethyl-phenyl, p-cyano-phenyl, p-tert-butyl-phenyl, p-trifluoromethoxy-phenyl, 3,4,5-trimethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethoxy-phenyl, pyridin-2 / 3 / 4-yl, thiophen-2 / 3-yl, furan-2 / 3-yl.

[0012] The synthesis method of the quinazoline-4-one compound containing 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole unit is obtained by using quinazoline-4-one, 1,2-dibromoethane, methyl 4-piperidinic acid ester, 80% hydrazine hydrate, potassium hydroxide, carbon disulfide and different aromatic acids as raw materials through the following five steps:

[0013] (1) Using quinazolin-4-one and 1,2-dibromoethane as raw materials, sodium hydride as an acid-binding agent, and N,N-dimethylformamide as a solvent, 3-(2-bromoethyl)quinazolin-4(3H)-one (intermediate 1) was prepared;

[0014]

[0015] (2) Using intermediate 1 and methyl 4-piperidinol carboxylate as raw materials, potassium carbonate as a catalyst, and acetonitrile as a solvent, 1-(2-(4-oxoquinazolin-3(4H)-yl)-piperidine-4-carboxylic acid methyl ester (Intermediate 2) was prepared;

[0016]

[0017] (3) Using intermediate 2 and 80% hydrazine hydrate as raw materials and water as solvent, 1-(2-(4-oxoquinazolin-3(4H)-yl)-piperidine-4-carbohydrazide (intermediate 3) was prepared;

[0018]

[0019] (4) Using intermediate 3, potassium hydroxide and carbon disulfide as raw materials, ethanol as solvent, and 10% dilute hydrochloric acid to adjust the pH to 7, 3-(2-(4-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (intermediate 4) was prepared;

[0020]

[0021] (5) Using intermediate 4 and different aromatic acids as raw materials and phosphorus oxychloride as a dehydrating agent, quinazoline-4-one compounds containing [1,2,4]triazole[3,4-b][1,3,4]thiadiazole (target compound A) were prepared:

[0022]

[0023] The compounds of formula (I) have certain inhibitory activity against bacteria such as rice bacterial blight, citrus canker and tobacco bacterial wilt, and some compounds show excellent antibacterial activity, so they can be used as active ingredients of fungicides, that is, in the preparation of antibacterial pesticides.

[0024] The present invention has the following characteristics:

[0025] The invention introduces a biologically active 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole unit into a quinazoline-4-one structure, and synthesizes a series of quinazoline-4-one compounds containing the 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole unit. The compounds introduce the 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole unit with good antibacterial activity. After cell permeability, cell morphology and in vitro and in vivo antibacterial activity tests, it is found that the quinazoline-4-one compounds containing the 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole unit have good antibacterial activity. DETAILED DESCRIPTION

[0026] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0027] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0028] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0029] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present application description and examples are exemplary only.

[0030] Example 1

[0031] (1) Preparation of 3-(2-bromoethyl)quinazoline-4(3H)-one:

[0032] Add quinazolin-4-one and DMF to a 50 mL round-bottom flask, slowly add sodium hydride, stir at room temperature for 4 h, then transfer to a constant pressure dropping funnel (A), add 1,2-dibromoethane (B) to another 100 mL round-bottom flask, drop B with A, react at 60-70°C for 10-11 h, monitor the reaction by TLC, stop the reaction after the raw material is completely converted, cool to room temperature, add 30 mL of water, extract with ethyl acetate, dry the organic layer, and perform column chromatography with petroleum ether / ethyl acetate = 5 / 1 (v / v) to obtain a white solid;

[0033] Molar ratio: quinazolin-4-one: sodium hydride: 1,2-dibromoethane = 1:1.5:1.1;

[0034] Reaction temperature: 60-70°C;

[0035] Reaction time: 10-11h;

[0036] (2) Preparation of methyl 1-(2-(4-oxoquinazoline-3(4H)-yl)piperidine-4-carboxylate:

[0037] Add 3-(2-bromoethyl)quinazolin-4-one, potassium carbonate and acetonitrile to a 100 mL round-bottom flask, stir for 30 min, add methyl 4-piperidinate, heat to 100-110°C and reflux for 5-7 h. Detect the reaction by TLC. As the reaction proceeds, the solution changes from colorless to brown. Stop the reaction after the raw material is completely converted, filter, concentrate the filtrate, and recrystallize with ethyl acetate and petroleum ether to obtain a white solid.

[0038] Molar ratio: 3-(2-bromoethyl)quinazolin-4-one: methyl 4-piperidincarboxylate: potassium carbonate = 1:1.1:1.1;

[0039] Reaction temperature: 100-110°C;

[0040] Reaction time: 5-7h;

[0041] (3) Preparation of 1-(2-(4-oxoquinazoline-3(4H)-yl)piperidine-4-carbohydrazide:

[0042] Add methyl 1-(2-(4-oxoquinazolin-3(4H)-yl)piperidine-4-carboxylate to an aqueous solution containing 80% hydrazine hydrate, stir at room temperature for 10 to 12 hours, filter the formed precipitate, wash with methanol, and dry to obtain a white solid;

[0043] Molar ratio: 1-(2-(4-oxoquinazolin-3(4H)-yl)piperidine-4-carboxylic acid methyl ester: 80% hydrazine hydrate = 1:5;

[0044] Reaction temperature: 20-25°C;

[0045] Reaction time: 10-12h;

[0046] (4) Preparation of 3-(2-(4-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one:

[0047] Dissolve 1-(2-(4-oxoquinazoline-3(4H)-yl)piperidine-4-carbohydrazide in an ethanol solution containing potassium hydroxide and carbon disulfide, stir at room temperature for 10-12 hours, filter the generated potassium dithiocarbamate, wash with ethanol, dry, add ethanol and 80% hydrazine hydrate to react, heat to 80-90°C and reflux for 5-6 hours, dissolve the formed precipitate in cold water, and neutralize with dilute hydrochloric acid. The obtained precipitate is filtered, washed with water, dried, and then recrystallized from ethanol to prepare triazole E;

[0048] Molar ratio: 1-(2-(4-oxoquinazoline-3(4H)-yl)piperidine-4-carbohydrazide: potassium hydroxide: carbon disulfide: 80% hydrazine hydrate = 1:1.5:1.5:13.8;

[0049] Reaction temperature: 20-25°C, 80-90°C;

[0050] Reaction time: 10-12h, 5-6h;

[0051] (5) Preparation of 3-(2-(4-(6-phenyl-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one:

[0052] 3-(2-(4-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one was mixed with benzoic acid in a POCl3 solution and heated under reflux for 6-7 hours, and then cooled to room temperature. Then, the mixture was poured into cold water, and the excess POCl3 was neutralized with a saturated aqueous solution of NaHCO3. The formed precipitate was filtered, dried, and then crystallized from methanol to obtain the target compound A1 with a yield of 88% and mp of 184-186°C;

[0053] Molar ratio: 3-(2-(4-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one:benzoic acid = 1:1.2;

[0054] Reaction temperature: 110-120°C;

[0055] Reaction time: 6 to 7 hours.

[0056] Example 2

[0057] The same as Example 1, except that in step (5), benzoic acid is replaced by 2-methylbenzoic acid to produce 3-(2-(4-(6-(2-methylphenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A2) with a yield of 87% and mp of 162-164°C.

[0058] Example 3

[0059] The same as Example 1, except that in step (5), benzoic acid is replaced by 3-methylbenzoic acid to generate 3-(2-(4-(6-(3-methylphenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A3) with a yield of 78% and mp of 165-167°C.

[0060] Example 4

[0061] Same as Example 1, except that in step (5), benzoic acid is replaced by 4-methylbenzoic acid to produce 3-(2-(4-(6-(4-methylphenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A4) with a yield of 54% and mp of 109-111°C.

[0062] Example 5

[0063] The same as Example 1, except that in step (5), benzoic acid is replaced by 2-fluorobenzoic acid to generate 3-(2-(4-(6-(2-fluorophenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A5) with a yield of 75% and mp of 187-189°C.

[0064] Example 6

[0065] The same as Example 1, except that in step (5), benzoic acid is replaced by 3-fluorobenzoic acid to generate 3-(2-(4-(6-(3-fluorophenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A6) with a yield of 63% and mp of 159-162°C.

[0066] Example 7

[0067] Same as Example 1, except that in step (5), benzoic acid is replaced by 4-fluorobenzoic acid to generate 3-(2-(4-(6-(4-fluorophenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A7) with a yield of 72% and mp of 178-181°C.

[0068] Example 8

[0069] The same as Example 1, except that in step (5), benzoic acid is replaced by 2-chlorobenzoic acid to generate 3-(2-(4-(6-(2-chlorophenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A8) with a yield of 76% and mp of 171-173°C.

[0070] Example 9

[0071] Same as Example 1, except that in step (5), benzoic acid is replaced by 3-chlorobenzoic acid to generate 3-(2-(4-(6-(3-chlorophenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A9) with a yield of 86% and mp of 197-199°C.

[0072] Example 10

[0073] Same as Example 1, except that in step (5), benzoic acid is replaced by 4-chlorobenzoic acid to generate 3-(2-(4-(6-(4-chlorophenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 10 ), yield 86%, mp 202-204°C.

[0074] Embodiment 11

[0075] Same as Example 1, except that in step (5), benzoic acid is replaced by 2-bromobenzoic acid to generate 3-(2-(4-(6-(2-bromophenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 11 ), yield 88%, mp 175-177℃.

[0076] Example 12

[0077] Same as Example 1, except that in step (5), benzoic acid is replaced by 3-bromobenzoic acid to generate 3-(2-(4-(6-(3-bromophenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 12 ), yield 83%, mp 191-193℃.

[0078] Example 13

[0079] Same as Example 1, except that in step (5), benzoic acid is replaced by 4-bromobenzoic acid to generate 3-(2-(4-(6-(4-bromophenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 13 ), yield 92%, mp 206-208℃.

[0080] Embodiment 14

[0081] Same as Example 1, except that in step (5), benzoic acid is replaced by 2-trifluoromethylbenzoic acid to generate 3-(2-(4-(6-(2-trifluoromethylphenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 14 ), yield 68%, mp 142-144 ℃.

[0082] Embodiment 15

[0083] Same as Example 1, except that in step (5), benzoic acid is replaced by 3-trifluoromethylbenzoic acid to generate 3-(2-(4-(6-(3-trifluoromethylphenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 15 ), yield 79%, mp 171-173℃.

[0084] Example 16

[0085] Same as Example 1, except that in step (5), benzoic acid is replaced by 4-trifluoromethylbenzoic acid to generate 3-(2-(4-(6-(4-trifluoromethylphenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 16 ), yield 79%, mp 170-172℃.

[0086] Embodiment 17

[0087] Same as Example 1, except that in step (5), benzoic acid is replaced by 2-nitrobenzoic acid to generate 3-(2-(4-(6-(2-nitrophenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 17 ), yield 50%, mp 151-153℃.

[0088] Embodiment 18

[0089] Same as Example 1, except that in step (5), benzoic acid is replaced by 3-nitrobenzoic acid to generate 3-(2-(4-(6-(3-nitrophenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 18 ), yield 39%, mp 165-167℃.

[0090] Embodiment 19

[0091] Same as Example 1, except that in step (5), benzoic acid is replaced by 4-nitrobenzoic acid to generate 3-(2-(4-(6-(4-nitrophenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 19 ), yield 67%, mp 219-221 ℃.

[0092] Embodiment 20

[0093] Same as Example 1, except that in step (5), benzoic acid is replaced by 2-methoxybenzoic acid to generate 3-(2-(4-(6-(2-methoxyphenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 20 ), yield 76%, mp 225-227℃.

[0094] Embodiment 21

[0095] Same as Example 1, except that in step (5), benzoic acid is replaced by 3-methoxybenzoic acid to generate 3-(2-(4-(6-(3-methoxyphenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A) 21), yield 71%, mp 125-127℃.

[0096] Embodiment 22

[0097] Same as Example 1, except that in step (5), benzoic acid is replaced by 4-methoxybenzoic acid to generate 3-(2-(4-(6-(4-methoxyphenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 22 ), yield 90%, mp>300℃.

[0098] Embodiment 23

[0099] Same as Example 1, except that in step (5), benzoic acid is replaced by 4-trifluoromethoxy-benzoic acid to generate 3-(2-(4-(6-((4-trifluoromethoxy)phenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 23 ), yield 77%, mp 157-159℃.

[0100] Embodiment 24

[0101] Same as Example 1, except that in step (5), benzoic acid is replaced by 4-cyanobenzoic acid to generate 3-(2-(4-(6-(4-cyanophenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 24 ), yield 76%, mp 189-191°C.

[0102] Embodiment 25

[0103] Same as Example 1, except that in step (5), benzoic acid is replaced by 4-tert-butylbenzoic acid to generate 3-(2-(4-(6-(4-tert-butylphenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 25 ), yield 62%, 165-167℃.

[0104] Embodiment 26

[0105] Same as Example 1, except that in step (5), benzoic acid is replaced by pyridine-4-carboxylic acid to generate 3-(2-(4-(6-(pyridin-4-yl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 26 ), yield 89%, mp 198-200℃.

[0106] Embodiment 27

[0107] Same as Example 1, except that in step (5), benzoic acid is replaced by pyridine-3-carboxylic acid to generate 3-(2-(4-(6-(pyridin-3-yl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 27 ), yield 86%, mp 193-195℃.

[0108] Embodiment 28

[0109] Same as Example 1, except that in step (5), benzoic acid is replaced by pyridine-2-carboxylic acid to generate 3-(2-(4-(6-(pyridin-2-yl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 28 ), yield 79%, mp 296-298°C.

[0110] Embodiment 29

[0111] Same as Example 1, except that in step (5), benzoic acid is replaced by thiophene-3-carboxylic acid to generate 3-(2-(4-(6-(thiophene-3-yl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 29 ), yield 85%, mp 276-278°C.

[0112] Embodiment 30

[0113] Same as Example 1, except that in step (5), benzoic acid is replaced by thiophene-2-carboxylic acid to generate 3-(2-(4-(6-(thiophen-2-yl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 30 ), yield 80%, mp 237-239°C.

[0114] Embodiment 31

[0115] Same as Example 1, except that in step (5), benzoic acid is replaced by furan-3-carboxylic acid to generate 3-(2-(4-(6-(furan-3-yl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 31 ), yield 56%, mp218-220℃.

[0116] Embodiment 32

[0117] Same as Example 1, except that in step (5), benzoic acid is replaced by furan-2-carboxylic acid to generate 3-(2-(4-(6-(furan-2-yl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 32 ), yield 80%, mp 237-239°C.

[0118] Embodiment 33

[0119] Same as Example 1, except that in step (5), benzoic acid is replaced by 3,4,5-trimethoxybenzoic acid to generate 3-(2-(4-(6-(3,4,5-trimethoxyphenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 33 ), yield 89%, mp 231-233°C.

[0120] Embodiment 34

[0121] Same as Example 1, except that in step (5), benzoic acid is replaced by 3,5-dimethoxybenzoic acid to generate 3-(2-(4-(6-(3,5-dimethoxyphenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 34 ), yield 77%, mp 101-103℃.

[0122] Embodiment 35

[0123] Same as Example 1, except that in step (5), benzoic acid is replaced by 3,4-dimethoxybenzoic acid to generate 3-(2-(4-(6-(3,4-dimethoxyphenyl)-[1,2,4]triazol[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one (target compound A 35), yield 57%, mp 111-113℃.

[0124] The physicochemical properties of the quinazoline-4(3H)-one derivative containing [1,2,4]triazole[3,4-b][1,3,4]thiadiazole synthesized in Example 1-35 are shown in Table 1. The H NMR spectrum ( 1 HNMR), carbon spectrum ( 13 The C NMR) and HRMS data are shown in Table 2.

[0125] Table 1, Example A1-A 35 Physicochemical properties of the obtained target compound

[0126]

[0127] Table 2. NMR spectrum data of target compounds

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139] The use of the compound is illustrated below by experiments.

[0140] Test Example 1

[0141] (1) Experimental test method for anti-plant pathogenic bacteria activity (turbidity method)

[0142] The turbidity method was used, with Xanthoceras oryzae, Xanthoceras citri citri and Xanthoceras oryzae as test objects, and the commercial fungicide chloramphenicol as a positive control agent, to screen the in vitro antibacterial activity of the compound of formula (I) at sample concentrations of 100, 50, 25, 12.5 and 6.25 μg / mL.

[0143] The drug and control drug were prepared into concentrations of 100, 50, 25, 12.5 and 6.25 μg / mL, respectively, and added to the test tubes of NB liquid culture medium, and the OD value was measured, which was the OD value of the sterile culture medium. Then the test bacteria were inoculated, and cultured in a constant temperature shaker at 28°C and 180 rpm for 24 to 48 hours. The OD value of the bacterial solution of each concentration was measured on a spectrophotometer, which was the OD value of the bacterial culture medium. The corresponding EC was calculated 50 value.

[0144] (2) In vitro antibacterial test results, as shown in Tables 3 and 4

[0145] From the following antibacterial activity test experiment, it can be seen that, with commercialized chlorothalonil as the positive control drug, the compound represented by formula (I) of the present invention exhibits certain inhibitory activity against rice bacterial leaf blight pathogen, citrus canker pathogen, and rice bacterial leaf streak pathogen. 50 Among the tests, 10 compounds showed higher EC resistance to Xanthomonas oryzae than the control BMT. 50 Among them, compound A29 has the best activity, EC 50 The value was 4.1 μg / mL, which was lower than that of control BMT (EC 50 =67.7 μg / mL) was increased by nearly 16.5 times. The EC of compound A7 against citrus canker 50 The value was 17.1 μg / mL, which was better than the control BMT (EC 50 =82.3 μg / mL). In addition, compared with the control BMT, the EC of compound A28 50 The value (13.7vs 86.9μg / mL) showed better activity against oryzae leaf streak fungus.

[0146] Table 3. Compound A1-A 35 In vitro antibacterial activity against experimental bacteria Xanthomonas oryzae, Xanthomonas citri var. oryzae and Xanthomonas oryzae

[0147]

[0148]

[0149] a The average of three trials. b The bactericide Bismerthiazol(BMT) was used as the positive control.

[0150] Table 4. EC values ​​of some compounds against Xanthomonas citri citri, Xanthomonas oryzae and Xanthomonas oryzae 50 value

[0151]

[0152]

[0153] a Molecular weight (calculated from www.molinspiration.com). b Logarithmof the partition coefficient between n-octanol and water(determined using theChemBioOffice 14.0). c Number of hydrogen-bond acceptors. d Number of hydrogen-bond donors. e Number of rotatable bonds. f The commercialized bactericideBismerthiazol.

[0154] Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium.

[0155] Inhibition rate = (corrected control medium OD value - corrected sample medium OD value) / corrected control medium OD value × 100%

[0156] Tables 3 and 4 show the results of the antibacterial activity test of the compounds of formula (I) against the tested plant bacteria.

[0157] The compounds A7, A8, A10, A12, A13, A16, A26, A27, A28 and A30 in the present invention have excellent inhibitory activity against citrus canker pathogen; the compounds A5, A6, A22, A30, A32 and A33 show significant inhibitory activity against bacterial leaf streak pathogen; the compounds A5, A6, A7, A16, A22, A25, A30, A32, A33, A34 and A35 have significant inhibitory ability against rice bacterial leaf blight pathogen.

[0158] When the compounds of the present invention are used as fungicides, they can be mixed with other carriers and diluents permitted in plant protection to prepare them into various commonly used dosage forms, such as mixtures, granules, aqueous emulsions, etc. They can also be mixed with other pesticides such as fungicides, insecticides, herbicides, plant growth regulators, etc. or used simultaneously.

[0159] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A quinazoline-4-one compound containing 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole, characterized in that: The quinazoline-4-one compound containing 1,2,4-triazole [3,4-b] thiadiazole units with 4-piperidinyl as the bridging group has the following general formula (I): Wherein: R is phenyl, o- / m- / p-fluoro-phenyl, o- / m- / p-methyl-phenyl, o- / m- / p-nitro-phenyl, o- / m- / p-chlorophenyl, o- / m- / p-bromo-phenyl, o- / m- / p-methoxyphenyl, o- / m- / p-trifluoromethyl-phenyl, p-cyano-phenyl, p-tert-butyl-phenyl, p-trifluoromethoxy-phenyl, pyridin-2 / 3 / 4-yl, thiophen-2 / 3-yl, furan-2 / 3-yl, 3,4,5-trimethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethoxy-phenyl.

2. The method for preparing a quinazoline-4-one compound containing 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole according to claim 1, characterized in that: The method is prepared from quinazoline-4-one, 1,2-dibromoethane, methyl 4-piperidinate, 80% hydrazine hydrate, potassium hydroxide, carbon disulfide and different aromatic acids as raw materials, and comprises the following steps: (1) Using quinazolin-4-one and 1,2-dibromoethane as raw materials, sodium hydride as an acid-binding agent, and N,N-dimethylformamide as a solvent, 3-(2-bromoethyl)quinazolin-4(3H)-one was prepared to obtain intermediate 1; (2) Using intermediate 1 and methyl 4-piperidinol carboxylate as raw materials, potassium carbonate as a catalyst, and acetonitrile as a solvent, 1-(2-(4-oxoquinazolin-3(4H)-yl)-piperidine-4-carboxylate was prepared to obtain intermediate 2; (3) Using intermediate 2 and 80% hydrazine hydrate as raw materials and water as solvent, 1-(2-(4-oxoquinazolin-3(4H)-yl)-piperidine-4-carbohydrazide was prepared to obtain intermediate 3; (4) Using intermediate 3, potassium hydroxide and carbon disulfide as raw materials, ethanol as solvent, and 10% dilute hydrochloric acid to adjust the pH to 7, 3-(2-(4-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one was prepared, namely intermediate 4; (5) Using intermediate 4 and different aromatic acids as raw materials and phosphorus oxychloride as a dehydrating agent, quinazoline-4-one compounds containing [1,2,4]triazole[3,4-b][1,3,4]thiadiazole are prepared, namely, compounds of formula (I).

3. The use of quinazoline-4-one compounds containing 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole as claimed in claim 1, characterized in that: Compounds A7, A8, A10, A12, A13, A16, A26, A27, A28 and A30 are used to prepare drugs for preventing and treating citrus canker pathogens, wherein: A7: 3-(2-(4-(6-(4-fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A8: 3-(2-(4-(6-(2-chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A10: 3-(2-(4-(6-(4-chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A12: 3-(2-(4-(6-(3-bromophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A13: 3-(2-(4-(6-(4-bromophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A16: 3-(2-(4-(6-(4-trifluoromethylphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A26: 3-(2-(4-(6-(pyridin-4-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A27: 3-(2-(4-(6-(pyridin-3-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A28: 3-(2-(4-(6-(pyridin-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A30: 3-(2-(4-(6-(Thiophen-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one.

4. The use of quinazoline-4-one compounds containing 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole as claimed in claim 1, characterized in that: Compounds A5, A6, A22, A30, A32 and A33 are used to prepare drugs for preventing and treating bacterial leaf streak pathogens, wherein: A5: 3-(2-(4-(6-(2-fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A6: 3-(2-(4-(6-(3-fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A22: 3-(2-(4-(6-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A30: 3-(2-(4-(6-(thiophen-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A32: 3-(2-(4-(6-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A33: 3-(2-(4-(6-(3,4,5-trimethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one.

5. The use of quinazoline-4-one compounds containing 1,2,4-triazole [3,4-b] [1,3,4] thiadiazole as claimed in claim 1, characterized in that: Compounds A5, A6, A7, A16, A22, A25, A30, A32, A33, A34 and A35 are used to prepare drugs for controlling rice bacterial blight, wherein: A5: 3-(2-(4-(6-(2-fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A6: 3-(2-(4-(6-(3-fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A7: 3-(2-(4-(6-(4-fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A16: 3-(2-(4-(6-(4-trifluoromethylphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A22: 3-(2-(4-(6-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A25: 3-(2-(4-(6-(4-(tert-butyl)phenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A30: 3-(2-(4-(6-(thiophen-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A32: 3-(2-(4-(6-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A33: 3-(2-(4-(6-(3,4,5-trimethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A34: 3-(2-(4-(6-(3,5-dimethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one; A35: 3-(2-(4-(6-(3,4-dimethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)piperidin-1-yl)ethyl)quinazolin-4(3H)-one.

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