哌嗪类农药生物活性及作用机理的研究进展与展望

doi:10.1016/j.jia.2025.06.005

摘要/Abstract

摘要：

哌嗪是一种含氮杂环化合物，在化合物的结构衍生物中通常用作中间连接基团。含哌嗪的杂环类药物在医学上有许多商业用途，也用于农药。例如，哌嗪环是系统性杀菌剂嗪氨灵的关键结构元素。哌嗪因其对哺乳动物急性毒性低而备受关注，成为近年来杂环农药研究的热点之一。哌嗪类衍生物的农药活性及其作用机理已被广泛研究。本文对1971-2025年间哌嗪类衍生物的农药生物活性和作用机理进行了综述。讨论了哌嗪类衍生物的农业抗真菌、杀虫、抗植物病毒、除草、杀螨和抗细菌活性，并综述了相关衍生物的分子作用机理。此外，我们还提出了哌嗪结构的未来衍生方向，并对其抗植物病毒和抗菌作用机制的发展方向进行了展望。

Abstract:

Piperazine is a nitrogen-containing heterocyclic compound that is commonly used as an intermediate linking group in the structural derivation of compounds. Heterocyclic drugs containing piperazine have many commercial uses in medicine and are also used in pesticides. For example, the piperazine ring is a key structural element of the systemic fungicide Triforine. Piperazine is an attractive option because of its low acute toxicity to mammals, and it has become one of the hotspots of heterocyclic pesticide research in recent years. The pesticidal activity and mechanism of piperazine derivatives have been studied extensively. Herein, a comprehensive review of the research on the pesticidal bioactivity and mechanism of action of piperazine derivatives from 1971 to 2025 is presented. The agriculturally relevant antifungal, insecticidal, anti-plant virus, herbicidal, acaricidal, and antibacterial activities are discussed and the molecular mechanism of action of related piperazine derivatives is summarized. In addition, we also propose the future derivation direction of piperazine structures and look forward to the development of the anti-plant virus and anti-bacterial action mechanisms.

Key words: piperazine derivatives , pesticidal activities , structure–activity relationship mechanism of action , research progress

Yanju Wang, Baoan Song. 哌嗪类农药生物活性及作用机理的研究进展与展望[J]. Journal of Integrative Agriculture, 2026, 25(5): 1760-1787.

Yanju Wang, Baoan Song. Recent research progress and outlook on the bioactivities and mechanism of piperazine pesticides[J]. Journal of Integrative Agriculture, 2026, 25(5): 1760-1787.

参考文献

An L, Yang L, Yan T S, Yi M Y, Liu S S, Li H, Bao X P. 2024. Synthesis and agricultural antimicrobial evaluation of new quinazoline derivatives containing both a piperazine linker and the N-acetyl moiety. Pest Management Science, 80, 5307–5321.

Bai L, Wei C L, Zhang J, Song R J. 2023. Design, Synthesis, and anti-PVY biological activity of 1, 3, 5-triazine derivatives containing piperazine structure. International Journal of Molecular Sciences, 24, 8280.

Barron E J, Zhang Y L, Zawacki F J, Lyga J W, Theodoridis G. 2006. Insecticidal 3-(D ihaloalkenyl) Phenyl Derivatives. WO Patent WO2006047438A2. 2006-05-04.

Brown D, Woodcock D. 1975. Structure-activity relationships in fungitoxicants related to triforine and chloraniformethan. I. synthesis and fungitoxicity to Erysiphe graminis on barley. Pesticide Science, 6, 347–362.

Cai M Y, Li Z, Fan F, Huang Q C, Shao X S, Song G H. 2010. Design and synthesis of novel insecticides based on the serotonergic ligand 1-[4-aminophenyl) ethyl]-4-[3-(trifluoromethyl)-phenyl] piperazine (PAPP). Journal of Agricultural and Food Chemistry, 58, 2624–2629.

Cai M Y, Li Z, Huang Q C, Song G H. 2008. [1-(Arylmethyl) piperidin-4-yl] oxy-(trifluoromethyl)-pyridines: Ketanserin analogues with insect growth regulating activity. Chemistry & Biodiversity, 5, 1844–1855.

Carreño Otero A L, Vargas Méndez L Y, Duque L J E, Kouznetsov V V. 2014. Design, synthesis, acetylcholinesterase inhibition and larvicidal activity of girgensohnine analogs on Aedes aegypti, vector of dengue fever. European Journal of Medicinal Chemistry, 78, 392–400.

Carter G A, Summers L A, Wain R L. 1972. Investigations on fungicides: XIV. Fungitoxicity of N-(2, 2, 2 -trichloro-1 -methoxyethyl)-formamide and related compounds. Annals of Applied Biology, 70, 233–243.

Cassayre J, Molleyres L P, Maienfisch P, Cederbaum F, Corsi C, Pitterna T. 2005. Piperazin Derivatives and Their Use in Controlling Pests. WO Patent WO2005115146A1. 2005-12-08.

Chandra R, Pandey O P, Sengupta S K. 2005. Organophosphorus derivatives containing piperazine dithiosemicarbazones as chemotherapeutants against fungal pathogens of sugarcane. Journal of Agricultural and Food Chemistry, 53, 2181–2184.

Chen J L, Zhang M, Yuan C M, Zhang T, Wu Z B, Li T T, Robin Chi Y G. 2024. Design, synthesis, and antifungal activity of acrylamide derivatives containing trifluoromethylpyridine and piperazine. Journal of Agricultural and Food Chemistry, 72, 11360−11368.

Chen X L, Jia H W, Li Z, Xu X Y. 2019. Synthesis and nematicidal evaluation of 1, 2, 3-benzotriazin-4-one derivatives containing piperazine as linker against Meloidogyne incognita. Chinese Chemical Letters, 30, 1207–1213.

Deshmukh T R, Khare S P, Krishna V S, Sriram D, Sangshetti J N, Khedkar V M, Shingate B B. 2020. Synthesis, bioevaluation and molecular docking study of new piperazine and amide linked dimeric 1, 2, 3-triazoles. Synthetic Communications, 50, 271–288.

Downham R, Sibley G E M, Payne L J, Edwards P, Davies G M. 2008. 2- [ (2-Substituted) -Indolizin-3-Yl] -2-Oxo-Acetamide Derivatives as Antifungal Agents. WO Patent WO2008062182A1. 2008-05-29.

Dubey R, Chaudhary N, Kumar R, Panwar H. 2014. Study of mesoionic compounds: Synthesis and pharmacological evaluation of several 2- [{(4-substituted-1-sulphonyl) sydnon-3-yl}]-1, 3, 4-thiadiazino (6, 5-b) indoles as antimicrobial, insecticidal and antihelmintic agents. Oriental Journal of Chemistry, 30, 271–278.

Dunbar J E. 1965. Beta, Beta’-Bis (Substituted Sulfonylthio) Diethyl Piperazine. US Patent US3185693A. 1965-05-25.

Fan W Q, Zhang S Y, Yang N, Li Y H, Zhang X, Niu C W, Liu X H, Wang B L. 2025. Studies on the synthesis, crystal structures, biological activities and molecular docking of novel natural methylxanthine derivatives containing piperazine moiety. Molecular Diversity, 29, 2129–2142.

Fancher L W. 1980. Piperazine Phosphates and Phosphonate Insecticides. US Patent US4225595A. 1980-09-30.

Fang H B, Chen Z F, Hua X W, Liu W R, Xue C M, Liu Y, Zhu X H, Yuan M, Cheng S, Wang B X, Ru J, Bazhanau D, Cui Y H. 2022. Synthesis and biological activity of amide derivatives derived from natural product Waltherione F. Medicinal Chemistry Research, 31, 485–496.

Fondren V H. 1964. Piperazine-Carbon Disulfide Complex for Killing Roache. US Patent US3152040A. 1964-10-04.

Fuchs A, Doma S, Vörös J. 1971. Laboratory and greenhouse evaluation of a new systemic fungicide, N, N’-bis- (1-formamido-2, 2, 2-trichloroethyl) -piperazine (CELA W 524). Netherlands Journal of Plant Pathology, 77, 42–54.

Gao H, Zhang X, Pu X J, Zheng X, Liu B, Rao G X, Wan C P, Mao Z W. 2019. 2-Benzoylbenzofuran derivatives possessing piperazine linker as anticancer agents. Bioorganic & Medicinal Chemistry Letters, 29, 806–810.

Gibbons D, Morrissey C, Mineau P. 2015. A review of the direct and indirect effects of neonicotinoids and fipronil on vertebrate wildlife. Environmental Science and Pollution Research, 1, 103–118.

Goulson D. 2013. An overview of the environmental risks posed by neonicotinoid insecticides. Journal of Applied Ecology, 4, 977–987.

Grohe K, Petersen U, Kuck K H. 1984. Mikrobizide Mittel Auf Chinoloncarbonsäeure Basis. DE Patent DE3248507A. 1984-07-05.

Han F, Yan R, Zhang M, Xiang Z, Wu Q L, Li J K. 2020. Synthesis and bioactivities of phenazine-1-carboxylic piperazine derivatives. Natural Product Research, 34, 1282–1287.

He F Q, Liu X H, Wang B L, Li Z M. 2006. Synthesis and biological activity of new 1-[4-(substituted)-piperazin-1-ylmethyl]-1H-benzotriazole. Journal of Chemical Research, 2006, 809–812.

He J, Tang X M, Liu T T, Peng F, Zhou Q, Liu L W, He M, Xue W. 2021. Synthesis and antibacterial activity of novel myricetin derivatives containing sulfonylpiperazine. Chemical Papers, 75, 1021–1027.

Hladik M L, Main A R, Goulson D. 2018. Environmental risks and challenges associated with neonicotinoid insecticides. Environmental Science & Technology, 6, 3329–3335.

Huang Y Z, Zhang B, Li J, Liu H C, Zhang Y C, Yang Z, Liu D W. 2019. Design, synthesis, biological evaluation and docking study of novel indole-2-amide as anti-inflammatory agents with dual inhibition of COX and 5-LOX. European Journal of Medicinal Chemistry, 180, 41–50.

Ihori Y, Inoue S, Shibayama K, Chiang C C, Oshiki K, Nishimura S. 2016. Amidine Compound and Bactericidal Agent. JP Patent JP2016222654A. 2016-12-28.

Ihori Y, Watanabe S, Inoue S, Kang C K, Shiinoki Y. 2018. Guanidine Compound and Fungicide. WO Patent WO2018097126A1. 2018-05-31.

Ji J, Shao W B, Chu P L, Xiang H M, Qi P Y, Zhou X, Wang P Y, Yang S. 2022. 1,3,4-Oxadiazole derivatives as plant activators for controlling plant viral diseases: Preparation and assessment of the effect of auxiliaries. Journal of Agricultural and Food Chemistry, 70, 7929–7940.

Jiang D H, Chen J X, Zan N N, Li C Y, Hu D Y, Song B A. 2021a. Discovery of novel chromone derivatives containing a sulfonamide moiety as anti-ToCV agents through the tomato chlorosis virus coat protein-oriented screening method. Journal of Agricultural and Food Chemistry, 69, 12126–12134.

Jiang D H, Zhang J, He H F, Li J, Hu D Y, Song B A. 2021b. Discovery of novel chromone derivatives containing a sulfonamide moiety as potential anti-TSWV agents. Bioorganic & Medicinal Chemistry Letters, 53, 128431.

Knutsson S, Engdahl C, Kumari R, Forsgren N, Lindgren C, Kindahl T, Kitur S, Wachira L, Kamau L, Ekström F, Linusson A. 2018. Noncovalent inhibitors of mosquito acetylcholinesterase 1 with resistance-breaking potency. Journal of Medicinal Chemistry, 61, 10545–10557.

Krupke C H, Holland J D, Long E Y, Eitzer B D. 2017. Planting of neonicotinoid-treated maize poses risks for honey bees and other non-target organisms over a wide area without consistent crop yield benefit. Journal of Applied Ecology, 5, 1449–1458.

Lambert W T, Buysse A M, Wessels F J. 2020. Discovery of novel insecticidal 3-aminopyridyl ureas. Pest Management Science, 76, 497–508.

Lee B H, Larsen M J, Kubiak T M. 2005. Novel Anthelmintic and Insecticidal Compositions. US Patent US2005032810A1. 2005-02-10.

Lee C H, Kim H W, Lee H S. 2009. Acaricidal properties of piperazine and its derivatives against house-dust and stored-food mites. Pest Management Science, 65, 704–710.

Li C Y, Song R J, He S Q, Wu S K, Wu S, Wu Z X, Hu D Y, Song B A. 2022. First d iscovery of imidazo [1, 2-a] pyridine mesoionic compounds incorporating a sulfonamide moiety as antiviral agents. Journal of Agricultural and Food Chemistry, 70, 7375–7386.

Li G Y, Yan S G, Jiang S, Qian X H, Huang Q C, Zhang R. 2008. Synthesis of piperazine derivatives containing pyridinemethyl/thiazolemethyl and their biological activities. Chinese Journal of Chemistry, 028, 2001–2006. (in Chinese)

Li J, Zan N N, He H F, Hu D Y, Song B A. 2023. Piperazine derivatives containing the α-ketoamide moiety discovered as potential anti-tomato spotted wilt virus agents. Journal of Agricultural and Food Chemistry, 71, 6301−6313.

Li X J, Zhang Q, Zhang A L, Gao J M. 2012. Metabolites from Aspergillus fumigatus, an endophytic fungus associated with Melia azedarach, and their antifungal, antifeedant, and toxic activities. Journal of Agricultural and Food Chemistry, 60, 3424–3431.

Li Z, Song G H, Cai M Y, Huang Q C, Peng Y Q. 2009. Piperazine Derivatives and their Application. CN Patent CN101381342A. 2009-03-11. (in Chinese)

Li Z B, Chen Z, Chen A L, Zhang S Y, Liu Y Q, Yang B. 2015. Synthesis and insecticidal activity of 7-(1-carbonyl-piperazin-4-yl) methyl-camptothecin derivatives. Chinese Journal of Pesticide Science, 17, 136–142. (in Chinese)

Li Z G, Huang R Q, Shao R L, Ma J A. 2000. Study on morpholine (piperidine or piperazine) substituted α-acetylaminoalkylphosphonic acid diphenyl esters. Chinese Journal of Synthetic Chemistry, 2, 130–133. (in Chinese)

Liu A P, Hu L, Huang M Z, Liu M H, Gao D L, Li W, Pei H, Wang E L, Liu X P, Nie S Q. 2017. Dihalopropenyl Ether Compounds and Preparation and Application. CN Patent CN107298652A. 2017-10-27. (in Chinese)

Liu C L, Yang J C, Song Y Q, Li M, Li K K, Wu J. 2012. Dihalide Propylene Ether Compound Containing Piperazine Carbamic Acid Ester and Application. CN Patent CN102464612A. 2012-05-23. (in Chinese)

Liu C L, Yang J C, Wang J F, Li M, Zhang H, Ma S C, Luo Y M. 2010. Piperazine-Contained Propylene Ether Dihalide Compound and Applications. CN Patent CN101921228A. 2010-12-22. (in Chinese)

Liu F, Cao X, Zhang T, Xing L, Sun Z L, Zeng W, Xin H, Xue W. 2023. Synthesis and biological activity of myricetin derivatives containing pyrazole piperazine amide. International Journal of Molecular Sciences, 24, 10442.

Liu J B, Li Y X, Chen Y W, Hua X W, Wan Y Y, Wei W, Song H B, Yu S J, Zhang X, Li Z M. 2015. Design, synthesis, antifungal activities and SARs of (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives. Chinese Journal of Chemistry, 33, 1269–1275.

Liu S Y, Li M, Ou X M, Pei H, Liu L J, Wang X Z. 2011. Spinosad Derivatives, Preparation Method Thereof, and Application of Spinosad Derivatives Used as Insecticide. CN Patent CN102190694A. 2011-09-21. (in Chinese)

Liu Y Q, Zhang J X, Zhao Z M, Ma Q, Feng J X, Yang G Z, Shang X F. 2018. Application of Neocryptolepine Derivative in Prevention and Treatment of Plant Source Pathogen. CN Patent CN109090123A. 2018-12-28. (in Chinese)

Lorsbach B A, Ruiz J M, Sparks T C, Sullenberger M T, Morrison I M, Webster J D. 2007. N-Substituted Piperazines. US Patent US2007004750A1. 2007-01-04.

Lou M S, Li S, Jin F R, Yang T B, Song R J, Song B A. 2024. Pesticide engineering from natural vanillin: Recent advances and a perspective. Engineering, 43, 241–257.

Ma J M, Ma M W, Sun L H, Zeng Z. 2015. Synthesis, herbicidal evaluation, and structure-activity relationship of benzophenone oxime ether derivatives. Journal of Chemistry, 2015, 1–8.

Ma S Y, Ding Y G, Tuo X X, Wang G Q, Liu H W, Meng J, Zhang T H, Liu L W, Qi P Y, Zhou X, Yang S. 2024. Design, synthesis, and evaluation of novel 3-(piperazin-1-yl) propan-2-ol-modified carbazole derivatives targeting the bacterial membrane. Arabian Journal of Chemistry, 17, 105850–105862.

Mao Z W, Zheng X, Qi Y, Zhang M D, Huang Y, Wan C P, Rao G X. 2016. Synthesis and biological evaluation of novel hybrid compounds between chalcone and piperazine as potential antitumor agents. Royal Society of Chemistry Advances, 6, 7723–7727.

McGrath J J. 1960. Insecticidal Composition Comprising an Acylated Piperazine and a Member of Group of Pyrethrin and Allethrin. US Patent US2955071A. 1960-10-04.

Mei X D, Zhang L X, Ning J, Zhang T, Dong M Y, Si W J. 2014. N-Alkylated O-Benzene Dicarboximido Piperazine Derivative and its Synergistic Composition. CN Patent CN103951605A. 2014-07-30. (in Chinese)

Mistry B, Patel R V, Keum Y S, Kim D H. 2017. Synthesis of N-Mannich bases of berberine linking piperazine moieties revealing anticancer and antioxidant effects. Saudi Journal of Biological Sciences, 24, 36–44.

Mohammadi A, Khalili B, Tahavor M. 2015. Novel push–pull heterocyclic azo disperse dyes containing piperazine moiety: Synthesis, spectral properties, antioxidant activity and dyeing performance on polyester fibers. Spectrochimica Acta (Part A: Molecular and Biomolecular Spectroscopy), 150, 799–805.

Nagai K, Sunazuka T, Shiomi K, Harder A, Turberg A, Omura S. 2003. Synthesis and biological activities of novel 4´´alkylidene Avermectin derivatives. Bioorganic & Medicinal Chemistry Letters, 13, 3943–3946.

Nagalakshmamma V, Venkataswamy M, Pasala C, Umamaheswari A, Thyagaraju K, Nagaraju C, Chalapathi P V. 2020. Design, synthesis, anti-tobacco mosaic viral and molecule docking simulations of urea/thiourea derivatives of 2-(piperazine-1-yl)-pyrimidine and 1-(4-Fluoro/4-Chloro phenyl)-piperazine and 1-(4-Chloro phenyl)-piperazine - A study. Bioorganic Chemistry, 102, 104084.

Novack G D, Starkand L G, Peterson S L. 1978. Anticonvulsant effects of benzhydryl piperazines on pentylenetetrazol-induced seizures in mice. Neuropharmacology, 17, 659–663.

Ogawa M, Okamoto T, Nishimura A. 2008. Phenylguanidine Derivative or Salt Thereof, and Pest Control Agent Containing Them as Active Ingredient. WO Patent WO2008029810A1. 2008-03-13.

Palaska E, Ünlü S, Erdoǵan H, Safak C, Gümüsel B, Sunal R. 1993. 1-(3-Methyl-2-benzoxazolinone-6-yl)-2-(4-substituted piperazine-1-yl) ethanones and ethanols: Analgesic and antiinflammatory activities. European Journal of Medicinal Chemistry, 28, 963–967.

Patil M, Poyil A N, Joshi S D, Patil S A, Bugarin A. 2019. Design, synthesis, and molecular docking study of new piperazine derivative as potential antimicrobial agents. Bioorganic Chemistry, 92, 103217.

Peng Z, Wang M H. 2018. Design, synthesis and biological activity of novel fluoropyridine piperazine derivatives. Agrocheincals, 57, 641–644. (in Chinese)

Petersen U, Grohe K, Kuck K H. 1984. Bakterizide Mittel Auf Chinoloncarbonsäeure-Basis. DE Patent DE3308909A1. 1984-09-13.

Pulina N A, Kozhukhar V Y, Syropyatov B Y, Alikina N V, Rubtsov A E. 2018. Preparation of 2-(4-Bromophenylamino)-1-(Piperazin-1-Yl)-4-Phenylbut-2-Ene-1, 4-Dione Hydrochloride as Insecticide with Low Toxicity. RU Patent RU2644162C2. 2018-02-08.

Puopolo G, Cimmino A, Palmieri M C, Giovannini O, Evidente A, Pertot I. 2014. Lysobacter capsica AZ78 produces cyclo (l-Pro-l-Tyr), a 2, 5-diketopiperazine with toxic activity against sporangia of Phytophthora infestans and Plasmopara viticola. Journal of Applied Microbiology, 117, 1168–1180.

Qiao C H, Ye Y H, Wang L L. 2013. Application of Benzofurazan Oxide Derivative in Production of Pesticide Formulations for Preventing and Controlling Plant Pathogenic Fungi. CN Patent CN103004799A. 2013-04-03. (in Chinese)

Rao J R, Liu L W, Zeng D, Wang M W, Xiang M, Yang S. 2020. Antibiotic activities of propanolamine containing 1,4-benzoxazin-3-ones against phytopathogenic bacteria. Royal Society of Chemistry Advances, 10, 682–688.

Reddy R C K, Rasheed S, Rao D S, Adam S, Reddy Y V R, Raju C N. 2013. New urea and thiourea derivatives of piperazine doped with febuxostat: Synthesis and evaluation of anti-TMV and antimicrobial activities. The Scientific World Journal, 2013, 1–10.

Schnatterer S, Maier M, Petry F, Knauf W, Seeger K. 2008. 1-Phenyl-3-Piperazine-Pyrazoles and Pesticidal Compositions of Matter Thereof. US Patent US20080113998A1. 2008-05-15.

Shao C L, Li D B, Jiao Y H, Mou X F, Wei M Y. 2018. Quinolinone-Containing Tetracyclic Compounds, Preparation Method and Uses. CN Patent CN108676004A. 2018-10-19. (in Chinese)

Shao W B, Zheng Y T, Liu J M, Fu Y H, Qi P Y, Zhou X, Wu Z B, Wang P Y, Yang S. 2020. Antibacterial activities against Ralstonia solanacearum and X. oryzae pv. oryzae of 6-chloro-4-(4-substituted piperazinyl) quinazoline derivatives. Bioorganic & Medicinal Chemistry Letters, 30, 126912.

Shen Y, Wang J Y, Song G H. 2014. Ionic liquid-supported synthesis of piperazine derivatives as potential insecticides. Molecular Diversity, 18, 195–202.

Sherald J L, Sisler H D. 1975. Ant ifungal mode of action of triforine. Pesticide Biochemistry and Physiology, 5, 477–488.

Shi J, Ding M H, Luo N, Wan S R, Li P J, Li J H, Bao X P. 2020. Design, synthesis, crystal structure, and antimicrobial evaluation of 6-fluoroquinazolinylpiperidinyl-containing 1, 2, 4-triazole mannich base derivatives against phytopathogenic bacteria and fungi. Journal of Agricultural and Food Chemistry, 68, 9613−9623.

Shu F, Xiong Y K, Han M. 2016. Overview of China’s pesticide production and use in 2015. Pesticide Science and Administration, 7, 1–6. (in Chinese)

Silva D P B, Florentino I F, Oliveira L P, Lino R C, Galdino P M, Menegatti R, Costa E A. 2015. Anti-nociceptive and anti-inflammatory activities of 4-[(1-phenyl-1H-pyrazol-4-yl) methyl] 1-piperazine carboxylic acid ethyl ester: A new piperazine derivative. Pharmacology, Biochemistry and Behavior, 137, 86–92.

Silverman I R, Ali S F, Cohen D H, Lyga J W, Simmons K A, Cullen T G. 1997. Insecticidal N-Heterocyclylalkyl- or N-[(Polycyclyl)-Alkyl]-N’-Substituted Piperazines. WO Patent WO9726252A1. 1997-07-24.

Stanley D A, Russell A L, Morrison S J, Rogers C, Raine N E. 2016. Investigating the impacts of field-realistic exposure to a neonicotinoid pesticide on bumblebee foraging, homing ability and colony growth. Journal of Applied Ecology, 5, 1440–1449.

Sun H Y, Li H, Wang J Y, Song G H. 2018. Synthesis and nematicidal activity of piperazinedione derivatives based on the natural product Barettin. Chinese Chemical Letters, 29, 977–980.

Sun R Q, Liu R, Zhou C, Ren Z H, Guo L, Ma Q, Fan W X, Qiu L Q, Yu H J, Shao G, Cao R H. 2015. Synthesis and biological evaluation of piperazine group-linked bivalent β-carbolines as potential antitumor agents. Medicinal Chemistry Communications, 6, 2170–2174.

Suzuki J, Ootaka A, Onoue S, Onoue M. 2021. Synthesis and acaricidal activity of phenylpiperazine derivatives. Journal of Pesticide Science, 46, 189–197.

Takashi N, Toshinobu T, Katsunori T, Masaru M. 1993. Cinnamyl Piperazine Derivatives Method of Manufacturing the Same and Agricultural/Horticultural Fungicides Containing Cinnamyl Piperazine Derivatives. EP Patent EP0551617A2. 1993-07-21.

Tetenbaum M T, Degginger E R. 1972. Meth od of Comnating Nematodes Emplpying N, N-Disubstituted-2, 5-Diketopiperazines. US Patent US3692908A. 1972-09-19.

Velten R, Arlt A, Horstmann S, Vermeer A, Horn K. 2018. Use of Disubstituted Benzenes to Control Insecticide-Resistant Pests. WO-Patent WO2018202681A1. 2018-11-08.

Wang B L, Li Z M, Zhang L Y, Zhang Y, Zhang X, Li Y H. 2015a. Triazole Mannich Base Compounds Containing Trifluoromethyl and Piperazine, as Well as Preparation Methods and Application of Triazole Mannich Base Compounds. CN Patent CN105111192A. 2015-12-02. (in Chinese)

Wang B L, Liu X H, Zhang X L, Zhang J F, Song H B, Li Z M. 2011. Synthesis, structure and biological activity of novel 1, 2, 4-triazole mannich bases containing a substituted benzylpiperazine moiety. Chemical Biology & Drug Design, 78, 42–49.

Wang B L, Shi Y X, Ma Y, Liu X H, Li Y H, Song H B, Li B J, Li Z M. 2010. Synthesis and biological activity of some novel trifluoromethyl-substituted 1, 2, 4-triazole and bis (1, 2, 4-triazole) Mannich bases containing piperazine rings. Journal of Agricultural and Food Chemistry, 58, 5515–5522.

Wang B L, Shi Y X, Zhan Y Z, Zhang L Y, Zhang Y, Wang L Z, Zhang X, Li Y H, Li Z M, Li B J. 2015b. Synthesis and biological activity of novel furan/thiophene and piperazine-containing (bis) 1, 2, 4-triazole Mannich bases. Chinese Journal of Chemistry, 33, 1124–1134.

Wang B L, Shi Y X, Zhang S J, Ma Y, Wang H X, Zhang L Y, Wei W, Liu X H, Li Y H, Li Z M, Li B J. 2016a. Syntheses, biological activities and SAR studies of novel carboxamide compounds containing piperazine and arylsulfonyl moieties. European Journal of Medicinal Chemistry, 117, 167–178.

Wang B L, Zhan Y Z, Zhang L Y, Zhang Y, Zhang X, Li Z M. 2015c. Synthesis and fungicidal activities of novel 1, 2, 4-triazole thione derivatives containing 1, 2, 3-triazole and substituted piperazine moieties. Phosphorus, Sulfur, and Silicon and the Related Elements, 191, 1–7.

Wang B L, Zhang L Y, Liu X H, Ma Y, Zhang Y, Li Z M, Zhang X. 2017. Synthesis, biological activities and SAR studies of new 3-substitutedphenyl-4-substitutedbenzylideneamino-1, 2, 4-triazole Mannich bases and bis-Mannich bases as ketol-acid reductoisomerase inhibitors. Bioorganic & Medicinal Chemistry Letters, 27, 5457–5462.

Wang B L, Zhang L Y, Zhan Y Z, Zhang Y, Zhang X, Wang L Z, Li Z M. 2016b. Synthesis and biological activities of novel 1, 2, 4-triazole thiones and bis (1, 2, 4-triazole thiones) containing phenylpyrazole and piperazine moieties. Journal of Fluorine Chemistry, 184, 36–44.

Wang B L, Zhang Y, Liu X H, Zhang L Y, Zhan Y Z, Zhang X, Wang L Z, Li Y H, Li Z M. 2016c. Synthesis and biological activity of novel dimethylpyrazole and piperazine-containing (bis) 1, 2, 4-triazole derivatives. Phosphorus, Sulfur, and Silicon and the Related Elements, 192, 34–41.

Wang L L, Li C, Zhang Y Y, Qiao C H, Ye Y H. 2013. Synthesis and biological evaluation of benzofuroxan derivatives as fungicides against phytopathogenic fungi. Journal of Agricultural and Food Chemistry, 61, 8632–8640.

Wang M H, Peng Z, Cui H Q , Cui J Q, Xu L Z. 2018a. Fluoropyridine-Containing Piperazine Amide Compounds and Application. CN Patent CN108822082A. 2018-11-16. (in Chinese)

Wang M H, Peng Z, Xu L Z, Cui J Q. 2018b. Fluorinated Pyridyl Piperazine Urea Compound and its Application. CN Patent CN108640871A. 2018-10-12. (in Chinese)

Wang M H, Xu L Z, Peng Z, Cui H Q, Sun J X. 2019. Fluorine-Containing Pyridine Acyl Piperazine Compound and Application. CN Patent CN109336882A. 2019-02-15. (in Chinese)

Wang M H, Zhu H B, Peng Z, Xu L Z. 2018c. Fluorine-Containing Pyridine Piperazine Imidazole Urea and its Application. CN Patent CN108675991A. 2018-10-19. (in Chinese)

Wang M J, Zhao X B, Wu D, Liu Y Q, Zhang Y, Nan X, Liu H, Yu H, T, Hu G F, Yan L T. 2014. Design, synthesis, crystal structure, insecticidal activity, molecular docking, and QSAR studies of novel N3-substituted imidacloprid derivatives. Journal of Agricultural and Food Chemistry, 62, 5429−5442.

Wang P Y, Xiang M, Luo M, Liu H W, Zhou X, Wu Z B, Liu L W, Li Z, Yang S. 2020. Novel piperazine-tailored ursolic acid hybrids as significant antibacterial agents targeting phytopathogens Xanthomonas oryzae pv. oryzae and X. axonopodis pv. citri probably directed by activation of apoptosis. Pest Management Science, 76, 2746–2754.

Wang Q M, Li Y Q, Ding Y, Ding G F. 2016. Copper Dithiocarbamate Derivative and Preparation and Application Thereof. CN Patent CN105712916A. 2018-04-27. (in Chinese)

Wang X G, Li S Y, Liu D Y, Li H D, Song R J, Hu D Y. 2024. Novel aurone-derived piperazine sulfonamides: Development and mechanisms of action as immunostimulants against plant bacterial diseases. Pesticide Biochemistry and Physiology, 202, 105955.

Wang Y J, Luo Y Q, Li X, Chen F F, Zhang X J, Yu L, Song R J, Song B A. 2025. A vanillin-derived inhibitor of aggregates via targeting intrinsically disordered regions of phytoviral nucleocapsid protein. Aggregate, 6, e725.

Wei C L, Zhao C N, Li J, Li C Y, Song B A, Song R J. 2024. Innovative Arylimidazole-fused phytovirucides via carbene-catalyzed [3+4] cycloaddition: Locking viral cell-to-cell movement by out-competing virus capsid-host interactions. Advanced Science, 11, 2309343.

Wood T J, Goulson D. 2017. The environmental risks of neonicotinoid pesticides: A review of the evidence post 2013. Environmental Science and Pollution Research, 21, 17285–17325.

Wu Q L, Han F, Yan R, Li J K. 2017. Phenazine-1-Piperazinecarbo-xaldehyde Compound and Application. CN Patent CN107188858A. 2017-09-22. (in Chinese)

Wu Q L, Li Y Q, Yang X L, Ling Y. 2012a. Facile total synthesis and bioactivity of Aspernigerin. Chinese Journal of Organic Chemistry, 32, 1498–1502. (in Chinese)

Wu Q L, Li Y Q, Yang X L, Ling Y. 2012b. Synthesis and bioactivity of Aspernigerin analogues. Chinese Journal of Organic Chemistry, 32, 747–754. (in Chinese)

Wu Q L, Ling Y. 2016. Applications of piperazine analogues in agrochemicals discovery. Agrochemicals, 55, 785–789. (in Chinese)

Wu W N, Jiang Y M, Fei Q, Du H T, Yang M F. 2020. Synthesis and antifungal activity of novel 1,2,4-triazole derivatives containing an amide moiety. Journal of Heterocyclic Chemistry, 57, 1379–1386.

Xiang M, Song Y L, Ji J, Zhou X, Liu L W, Wang P Y, Wu Z B, Li Z, Yang S. 2020. Synthesis of novel 18β-glycyrrhetinic piperazine amides displaying significant in vitro and in vivo antibacterial activities against intractable plant bacterial diseases. Pest Management Science, 76, 2959–2971.

Xie J L, Xu W T, Song H J, Liu Y X, Zhang J J, Wang Q M. 2020. Synthesis and antiviral/fungicidal/insecticidal activities study of novel chiral indole diketopiperazine derivatives containing acylhydrazone moiety. Journal of Agricultural and Food Chemistry, 68, 5555−5571.

Xie Y, Xu Y, Liu C L, Guan A Y, Ban L F, Ding F, Peng W. 2017. Intermediate derivatisation method in the discovery of new acaricide candidates: Synthesis of N-substituted piperazine derivatives and their activity against phytophagous mites. Pest Management Science, 73, 945–952.

Xu G F, Yang X L, Jiang B B, Lei P, Liu X L, Wang Q M, Zhang X B, Ling Y. 2016. Synthesis and bioactivities of novel piperazine-containing 1, 5-diphenyl-2-penten-1-one analogues from natural product lead. Bioorganic & Medicinal Chemistry Letters, 26, 1849–1853.

Xu X Y, Li Z, Chen X L, Li W, Jia H W, Cao X F, Shao X S, Xu Z P. 2018. Nitrogen-Containing Heterocyclic Compound Having Nematicidal Activity, its Preparation Method and Application. CN Patent CN108276352A. 2018-07-13. (in Chinese)

Xue W, Zhang X, Zhu X S, Wang Z B, Chen Y T, Zhang D Y, Lv X Y. 2014. Preparation Methods and Applications of 1, 3, 4-Thiadiazole Amide Derivatives Containing Nitrogen Heterocyclic Rings. CN Patent CN104086508A. 2014-10-08. (in Chinese)

Yan B R, Lü X Y, Du H, Bao X P. 2016. Design, synthesis and biological activities of novel quinazolinone derivatives bearing 4-phenyl-5-thioxo-1,2,4-triazole Mannich bases. Chinese Journal of Organic Chemistry, 36, 207–212. (in Chinese)

Yang J C, Li M, Wu Q, Chang X H. 2014. Design, synthesis and insecticidal activities of novel dichloro-allyloxy-phenol derivatives containing piperazinyl. Agrocheincals, 8, 555–557. (in Chinese)

Yıldız M. 2020. Design, synthesis, characterization, and antimicrobial activity of novel piperazine substituted 1, 4-benzoquinones. Journal of Molecular Structure, 1203, 127422.

Yin X D, Sun Y, Kobla Lawoe R, Yang G Z, Liu Y Q, Shang X F, Liu H, Yang Y D, Zhu J K, Huang X L. 2019. Synthesis and anti-phytopathogenic activity of 8-hydroxyquinoline derivatives. Royal Society of Chemistry Advances, 9, 30087.

Yu X L, Wei P, Wang Z W, Liu Y X, Wang L Z, Wang Q M. 2015. Design, synthesis, antiviral activity and mode of action of phenanthrene-containing N-heterocyclic compounds inspired by the phenanthroindolizidine alkaloid antofine. Pest Management Science, 72, 371–378.

Yu Z Y, Shi G Y, Sun Q, Jin H, Teng Y, Tao K, Zhou G P, Liu W, Wen F, Hou T P. 2009. Design, synthesis and in vitro antibacterial/antifungal evaluation of novel 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7 (1-piperazinyl) quinoline-3-carboxylic acid derivatives. European Journal of Medicinal Chemistry, 44, 4726–4733

Yuan T, Wang Z X, Liu D, Zeng H N, Liang J C, Hu D Y, Gan X H. 2022. Ferulic acid derivatives with piperazine moiety as potential antiviral agents. Pest Management Science, 78, 1749–1758.

Zelechowski K, Gołębiewski1 W M, Krawczyk M. 2015. Synthesis and fungicidal activity of 2-(diphenylmethyl)-3-arylisoxazolidine-5-carboxamides. Monatshefte Fur Chemie, 146, 1895–1905.

Zeng L M, Jin H, Lu D X, Yang X Y, Pan L, Cui H Y, He X F, Qiu H D, Qin B. 2015. Isolation and identification of chemical constituents from the bacterium Bacillus sp. and their nematicidal activities. Journal of Basic Microbiology, 55, 1239–1244.

Zeng W, Sun Z L, Liu Y, Zhou Q, Zhang Y F, Qiu Y J, Fu H, Zou H Q, Pu H T, Xue W. 2024. Design and research of new virulence factor inhibitors for plant bacterial disease control. Arabian Journal of Chemistry, 17, 106042.

Zhang A W, Zhang H Z, Wang R H, He H F, Song B A, Song R J. 2024. Bactericidal bissulfone B7 targets bacterial pyruvate kinase to impair bacterial biology and pathogenicity in plants. Science China Life Sciences, 67, 391–402.

Zhang G, Aldrich C C. 2019. Macozinone: Revised synthesis and crystal structure of a promising new drug for treating drug-sensitive and drug-resistant tuberculosis. Acta Crystallographica (Section C: structural Chemistry), 75, 1031–1035.

Zhang G L, Wang Z C, Li C P, Chen D P, Li Z R, Li Y, Ouyang G P. 2024. Discovery of tryptanthrin analogues bearing F and piperazine moieties as novel phytopathogenic antibacterial and antiviral agents. Pest Management Science, 80, 1026–1038.

Zhang N, Li H, Zhou Y, Hu W, Zhang Z X. 2014. Dissipation and residue of triforine in strawberry and soil. Environmental Monitoring and Assessment, 186, 1377–1384.

Zhang W, Guo S X, Wang Y, Tu H, Yu L J, Zhao Z C, Wang Z C, Wu J. 2022. Novel trifluoromethylpyridine piperazine derivatives as potential plant activators. Frontiers in Plant Science, 13, 1086057

Zhang W, Guo S X, Wang Y, Wu Y K, Yu L J, Wu J. 2023. Trifluoromethylpyridine piperazine derivatives: Synthesis and anti-plant virus activity. Pest Management Science, 79, 2571–2580.

Zhang W B, Jin F R, Wu S, Zhao C N, He H F, Wu Z X, Hu D Y, Song B A. 2024. Development of imidazo [1, 2-a] pyridines containing sulfonyl piperazines as potential antivirals against tomato spotted wilt virus. Journal of Agricultural and Food Chemistry, 72, 23118–23130.

Zhang Y, Li Z M, Song H B, Wang B L. 2018a. Synthesis, structure and biological activities of novel 2-(trifluoromethyl)- 6-arylimidazo [2, 1-b] [1, 3, 4]-thiadiazole (bis-) Mannich base derivatives containing substituted piperazine moiety. Chinese Journal of Chemistry, 36, 635–638. (in Chinese)

Zhang Y, Liu X H, Zhan Y Z, Zhang L Y, Li Z M, Li Y H, Zhang X, Wang B L. 2016a. Synthesis and biological activities of novel 5-substituted-1, 3, 4-oxadiazole Mannich bases and bis-Mannich bases as ketol-acid reductoisomerase inhibitors. Bioorganic & Medicinal Chemistry Letters, 26, 4661–4665.

Zhang Y, Wang B L, Zhan Y Z, Zhang L Y, Li Y H, Li Z M. 2016b. Synthesis and biological activities of novel 5-(pyridine-3-yl)-1, 2, 4-triazole Mannich bases and bis-Mannich bases containing piperazine moiety. Chemical Journal of Chinese Universities-Chinese, 37, 1100–1107. (in Chinese)

Zhang Y, Zhan Y Z, Ma Y, Hua X W, Wei W, Zhang X, Song H B, Li Z M, Wang B L. 2018b. Synthesis, crystal structure and 3D-QSAR studies of antifungal (bis-) 1, 2, 4-triazole Mannich bases containing furyl and substituted piperazine moieties. Chinese Chemical Letters, 29, 441–446.

Zheng Y, Shi D T, Song D D, Chen K, Wen F L, Zhang J L, Xue W, Wu Z B. 2024. Novel mandelic acid derivatives containing piperazinyls as potential candidate fungicides against monilinia fructicola: Design, synthesis and mechanism study. Bioorganic Chemistry, 151, 107647.

Zhi X Y, Jiang L Y, Li T, Song L L, Wu L J, Cao H, Yang C. 2020. Natural product-based semisynthesis and biological evaluation of thiol/amino-Michael adducts of xanthatin derived from Xanthium strumarium as potential pesticidal agents. Bioorganic Chemistry, 97, 103696.

Zhou Q, Tang X M, Chen S, Zhan W L, Hu D, Zhou R, Sun N, Wu Y J, Xue W. 2022. Design, synthesis, and antifungal activity of novel chalcone derivatives containing a piperazine fragment. Journal of Agricultural and Food Chemistry, 70, 1029−1036.

Zhou W J, Zhang L, Xiao W, Chen H J, Wu W N, Ouyang G P. 2016. Synthesis and biological activity of anthranilic diamide derivatives incorporating 1, 3, 4-oxadiazole or nitrogen-containing saturated heterocyclic moieties. Journal of Heterocyclic Chemistry, 54, 1423–1429.