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CN-121991044-A - Formononetin derivative containing piperidine-4-carbohydrazide and preparation method and application thereof

CN121991044ACN 121991044 ACN121991044 ACN 121991044ACN-121991044-A

Abstract

The invention discloses a formononetin derivative containing piperidine-4-carbohydrazide, and a preparation method and application thereof, and belongs to the technical field of pesticide synthesis. According to the invention, the piperidine-4-carbohydrazide group with excellent activity is introduced into the structure of formononetin, a series of piperidine-4-carbohydrazide formononetin derivatives are synthesized, and plant pathogenic fungi, especially Rhizoctonia solani, can be effectively inhibited by testing the true activity of the synthesized piperidine-4-carbohydrazide-containing formononetin derivatives for inhibiting plant pathogens.

Inventors

  • XUE WEI
  • PAN XIAOYAN
  • BAI XUEMEI
  • HU QINGXUE
  • GENG XIAOTING
  • Sun Mingman
  • XIN LANG
  • HAO GEFEI

Assignees

  • 贵州大学

Dates

Publication Date
20260508
Application Date
20260203

Claims (10)

  1. 1. A formononetin derivative containing piperidine-4-carbohydrazide, which is characterized by having the following structural formula: ; Wherein R is independently selected from one or more halogens, one or more C1-C6 alkyl groups, one or more C1-C6 substituted alkyl groups, and one or more C1-C6 substituted alkoxy groups.
  2. 2. The piperidine-4-carbohydrazide containing formononetin derivative according to claim 1, wherein R is independently one or more of halogen r=2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 3,4-di-F, 3,5-di-F, 3,4-di-Cl, alkyl r=4-CH 3 、4-CH 2 CH 3 , 4-CN, substituted alkyl r=3-CF 3 、4-CF 3 , substituted alkoxy r=4-OCF 3 .
  3. 3. A process for the preparation of the piperidine-4-carbohydrazide formononetin derivative according to claim 1 or 2, comprising the steps of: (1) Taking substituted phenylhydrazine and 1-Boc-4-piperidinecarboxylic acid as raw materials, adding HATU and DIPEA as catalysts, reacting at room temperature, pouring into water after the reaction is finished to precipitate a product, and filtering to obtain an intermediate a, wherein the structural formula of the intermediate a is as follows: ; (2) Taking the intermediate a as a raw material, removing boc protection under an acidic condition to obtain an intermediate b, wherein the structural formula of the intermediate b is as follows: ; (3) Taking formononetin and epibromohydrin as raw materials, heating and reacting in a solvent under alkaline condition, adding ice water after the reaction is finished to separate out a product, filtering, and removing impurities from filter residues to obtain an intermediate c; the structural formula of the intermediate c is as follows: ; (4) Taking the intermediate b and the intermediate c as raw materials, taking potassium carbonate as a catalyst, heating in a solvent for reaction, and purifying to obtain the formononetin derivative containing piperidine-4-carbohydrazide; the structural formula of the substituted phenylhydrazine is as follows: . Wherein R is independently selected from one or more halogens, one or more C1-C6 alkyl groups, one or more C1-C6 substituted alkyl groups, and one or more C1-C6 substituted alkoxy groups.
  4. 4. The preparation method of the catalyst according to claim 3, wherein the molar ratio of the substituted phenylhydrazine, the 1-Boc-4-piperidinecarboxylic acid, the HATU and the DIPEA in the step (1) is 1 to 2 (1 to 2) and 1 to 3, and the normal-temperature reaction time is 10 to 12 hours.
  5. 5. The preparation method according to claim 3, wherein the step of removing Boc protection in the step (2) comprises the steps of dissolving the intermediate a in acetonitrile, heating to 50-80 ℃, dropwise adding trifluoroacetic acid with a molar ratio of 1:5-10, heating and refluxing for 2-5 h, and removing Boc protection.
  6. 6. The preparation method of claim 3, wherein in the step (3), the molar ratio of the formononetin, the epibromohydrin and the potassium carbonate is 1 (1-4): 1-4, and the reaction time at normal temperature is 10-12 hours.
  7. 7. The preparation method according to claim 3, wherein in the step (4), the molar ratio of the intermediate b to the intermediate c to the K 2 CO 3 is 1 (1-2): 2-4, and the heating reflux time is 3-6 hours.
  8. 8. The method according to claim 3, wherein the purification step in step (4) is specifically performed by pouring the reaction system heated under reflux into ice water to precipitate a product, filtering, collecting the residue, and purifying by silica gel column chromatography (dichloromethane: methanol=15:1, v/v).
  9. 9. Use of a formononetin derivative containing 4-carbon-piperidine hydrazide according to claim 1 or 2 for the preparation of a medicament for inhibiting phytopathogenic fungi.
  10. 10. The use according to claim 9, wherein the plant pathogenic fungi comprise rhizoctonia solani Rs, phytophthora capsici Pc, sclerotium rot of colza sativa Ss, phomopsis kiwi fruit Ps, botrytis cinerea Bd, fusarium oxysporum Fo, gibberella wheat Fg, colletotrichum cyberneti Cg, fusarium oxysporum Foc and black spot of chinese cabbage Ab.

Description

Formononetin derivative containing piperidine-4-carbohydrazide and preparation method and application thereof Technical Field The invention belongs to the technical field of pesticide synthesis, and particularly relates to a formononetin derivative containing piperidine-4-carbohydrazide, and a preparation method and application thereof. Background Plant diseases, particularly diseases caused by fungi and bacteria, are one of the main factors threatening global agricultural production, leading to crop yield reduction and quality degradation. Chemical synthesis of pesticides has long played a central role in plant disease control. However, long-term, large-scale use of these drugs has raised serious problems including the development of pathogenic bacterial resistance, injury to non-target organisms (e.g., pollinating insects), threat of pesticide residues to the environment and food safety, and the like. Therefore, the development of novel, efficient, low-toxicity, environmentally friendly green pesticides has become a research hotspot in the current agricultural science and plant protection fields. Plant-derived green pesticides are an important direction of modern agricultural science research due to their environment-friendly properties. Such pesticides generally have multiple advantages of high bioactivity, low mammalian toxicity, high selectivity, and difficulty in inducing drug resistance. With the continuous improvement of the global requirements for ecological environment protection and the increasingly strict limit standards of pesticide residues, the development of plant source pesticides is widely valued in the field of international pesticides, and good development opportunities and wide market prospects are created for the plant source pesticides. At present, the discovery of lead compounds from plants and structural optimization have become an important strategy for the development of innovative pesticides. For example, pyrethrin isolated from pyrethrum, azadirachtin extracted from neem, and the like have all succeeded in significantly improving the stability and bioactivity of natural active ingredients by structural modification. Modern pharmaceutical chemistry research shows that the natural product can retain the advantage of environmental compatibility and improve the physicochemical property and pharmacodynamic property by reasonably structurally modifying the natural product. Therefore, the system develops the screening of the active ingredients of plant resources, and optimizes the structure of the plant resources by applying the modern synthetic chemistry technology, thereby becoming an effective way for developing novel plant source pesticides. The research direction not only meets the sustainable development requirement of agriculture, but also provides a scientific and feasible solution for solving the chemical pesticide resistance problem and environmental pressure. Formononetin is a typical isoflavone compound and is widely found in leguminous plants and various clover plants, including red clover, astragalus and Mao Huai. Research shows that formononetin has various biological activities including anti-inflammatory, anticancer and antitumor effects. Previous studies have focused mainly on the biological properties of formononetin and its potential contribution as a pharmacological compound when tested for certain diseases. In 2012, ren et al designed and synthesized a series of nitrogen-containing mustard formononetin derivatives, most of which showed stronger cytotoxicity than the anticancer drug chlorambucil, with a partial compound having an inhibitory effect IC 50 on SH-SY5Y of 2.08 μm, superior to that of melphalan (IC 50 =5.5 μm). In 2017, a class of formononetin derivatives containing aminodithioformate is synthesized, and part of the compounds have certain inhibition effects on various tumor cells EC-109, MGC-803 and PC-3. The anti-prostate cancer activity of compound 5 was increased by about 28-fold compared to the natural product formononetin. In 2019, yang et al designed and synthesized 3 compounds containing podophyllotoxin and formononetin, and evaluated anticancer efficacy. Pharmacological results showed that evaluation against the a549 lung tumor cell line determined that the IC 50 value of a portion of the compounds was 0.753 μm. In 2021, zuo et al designed and synthesized a series of formononetin derivatives with a substituted benzyloxy group at position 4 of isoflavone, and evaluated the vasodilation ability of these compounds by a linear electromyography system using an isolated rat mesenteric arterial ring model, a part of the compounds showed remarkable vasodilation effect in rat mesenteric arterial rings contracted by potassium ion induction, and had also a blood pressure lowering effect on Spontaneous Hypertensive Rats (SHR). Piperidine is a nitrogen-containing heterocyclic compound, and is an important pharmacophore and excellent heterocyclic structure in