Azadirachtin

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Azadirachtin
Azadirachtin.png
Azadirachtin model.png
Names
Preferred IUPAC name
Dimethyl (2aR,2a1R,3S,4S,4aR,5S,7aS,8S,10R,10aS)-10-(acetyloxy)-3,5-dihydroxy-4-[(1aR,2S,3aS,6aS,7S,7aS)-6a-hydroxy-7a-methyl-3a,6a,7,7a-tetrahydro-2,7-methanofuro[2,3-b]oxireno[2,3-e]oxepin-1a(2H)-yl]-4-methyl-8-{{#parsoidfragment:0}}{[(2E)-2-methylbut-2-enoyl]oxy}octahydro-1H,7H-naphtho[1,8-bc:4,4a-c′]difuran-5,10a(8H)-dicarboxylate
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.115.924 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C35H44O16/c1-8-15(2)24(38)49-18-12-19(48-16(3)36)32(26(39)43-6)13-46-21-22(32)31(18)14-47-34(42,27(40)44-7)25(31)29(4,23(21)37)35-20-11-17(30(35,5)51-35)33(41)9-10-45-28(33)50-20/h8-10,17-23,25,28,37,41-42H,11-14H2,1-7H3/b15-8+/t17-,18+,19-,20+,21-,22-,23-,25+,28+,29-,30+,31+,32+,33+,34+,35+/m1/s1 Yes check.svgY
    Key: FTNJWQUOZFUQQJ-NDAWSKJSSA-N Yes check.svgY
  • O=C(OC)[C@@]1(O)OC[C@]82[C@@H](OC(=O)/C(=C/C)C)C[C@@H](OC(=O)C)[C@@]7(C(=O)OC)CO[C@@H]([C@@H](O)[C@](C)([C@H]12)[C@]64O[C@]6([C@@H]3[C@@]5(O)/C=C\O[C@H]5O[C@H]4C3)C)[C@@H]78
Properties
C35H44O16
Molar mass 720.721 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Azadirachtin, a chemical compound belonging to the limonoid group, is a secondary metabolite present in neem seeds. It is a highly oxidized tetranortriterpenoid.

Contents

Chemical synthesis

Azadirachtin has a complex molecular structure, with 16 stereogenic centres, 7 of which are tetrasubstituted. This makes its total synthesis from simple chemicals extremely challenging.

The first total synthesis took 22 years of work in the research group of Steven Ley at the University of Cambridge. The synthesis, published in 2007, is regarded as a landmark in total synthesis. [1] [2] [3] It involves 71 reaction steps (48 steps in the longest linear sequence) with a yield of 0.00015%. [1] The described synthesis was a relay approach, with the required, heavily functionalized decalin intermediate being made by total synthesis on a small scale, but being derived from the natural product itself for the gram-scale operations required to complete the synthesis. Chemical synthesis is not suitable for production, but was used to develop expertise and methodology in organic synthesis.

Occurrence

Azadirachtin is found in the neem tree, Azadirachta indica , from which its name is derived, as well as Azadirachta excelsa . [4] It is found in all parts of the tree but the highest concentration is in the seeds (0.2 to 0.8 percent by weight). [5] It was first isolated pure in 1968 following the antifeedant activity towards the desert locust (Schistocerca gregaria), [6] but its chemical structure was finally established later in the 1980s. [7]

Use

it is now known to affect over 200 species of insects, by acting mainly as an antifeedant and growth disruptor. Azadirachtin exhibits considerable toxicity towards African cotton leafworm (Spodoptera littoralis), which are resistant to a commonly used biological pesticide, Bacillus thuringiensis . Azadirachtin fulfills many of the criteria needed for a good insecticide. Azadirachtin is biodegradable (it degrades within 100 hours when exposed to light and water) and shows very low toxicity to mammals (the LD50 in rats is > 3,540 mg/kg making it practically non-toxic).

Many more compounds, related to azadirachtin, are present in the seeds as well as in the leaves and the bark of the neem tree which also show strong biological activities among various pest insects [8] [9] Effects of these preparations on beneficial arthropods are generally considered to be minimal [ citation needed ]. Some laboratory and field studies have found neem extracts to be compatible with biological control. Because pure neem oil contains other insecticidal and fungicidal compounds in addition to azadirachtin, it is generally mixed at a rate of 1 US fluid ounce per US gallon (7.8 mL/L) of water when used as a pesticide.

Azadirachtin is the active ingredient in many pesticides including TreeAzin, [10] AzaMax, [11] BioNEEM, [12] AzaGuard, [13] and AzaSol, [14] Terramera Proof [15] and Terramera Cirkil. [16]

Azadirachtin has a synergistic effect with the biopesticide Beauveria bassiana . [17]

Nimbecidine is a natural product insecticide mix which is mostly azadirachtin, with some other limonoids. [18]

Mechanism of action

Azadirachtin interferes with a wide variety of insect pathways. [19]

Biosynthesis

The biosynthesis of azadirachtin is complex and only partially understood, as is the case for limonoids in general, but the first part of the sequence is established. [20] [21] Using transcriptome and genome mining and phylogenetic and homologous analysis, candidate genes were identified. They were heterologously expressed in Nicotiana benthamiana , and thus the metabolic steps were characterised and several of the purported intermediates isolated and characterised by NMR. Although the enzymes involved in the first part of the synthesis from 2,3-oxidosqualene to azadirone were characterised, it is not certain that the steps follow the order in the scheme. [20] The later steps in the scheme from azadirone to azadirachtin are speculative. [21]

Biosynthetic pathway and prediction of azadirachtin.jpg

See also

References

  1. 1 2 Jauch, Johann (13 December 2007). "Total Synthesis of Azadirachtin—Finally Completed After 22 Years". Angewandte Chemie International Edition. 47: 34–37.
  2. ↑ Veitch GE, Beckmann E, Burke BJ, Boyer A, Maslen SL, Ley SV (2007). "Synthesis of azadirachtin: a long but successful journey". Angew. Chem. Int. Ed. Engl. 46 (40): 7629–32. doi:10.1002/anie.200703027. PMID   17665403.
  3. ↑ Sanderson K (August 2007). "Chemists synthesize a natural-born killer". Nature. 448 (7154): 630–1. Bibcode:2007Natur.448Q.630S. doi: 10.1038/448630a . PMID   17687288.
  4. ↑ Morgan, E. David (15 June 2009). "Azadirachtin, a scientific gold mine". Bioorg Med Chem. 17 (12): 4096–4105.
  5. ↑ Ermel, K. (1995). "Chapter 2.3 Azadirachtin content of neem seed kernels from different parts of the world". In Schmutterer, Heinrich (ed.). The Neem Tree. Weinheim, Germany: VCH Verlagsgesellschaft mbH. pp. 89–92. ISBN   3-527-30054-6.
  6. ↑ Butterworth, J; Morgan, E (1968). "Isolation of a Substance that suppresses Feeding in Locusts". Chemical Communications (1): 23. doi:10.1039/C19680000023.
  7. ↑ Broughton, Howard B.; Ley, Steven V.; Slawin, Alexandra M. Z.; Williams, David J.; Morgan, E. David (1986). "X-ray crystallographic structure determination of detigloyldihydroazadirachtin and reassignment of the structure of the limonoid insect antifeedant azadirachtin". J Chem Soc Chem Commun 1986;1365(1):46. 1365 (1): 46.
  8. ↑ Senthil-Nathan, S.; Kalaivani, K.; Murugan, K.; Chung, G. (2005). "The toxicity and physiological effect of neem limonoids on Cnaphalocrocis medinalis (Guenée) the rice leaffolder". Pesticide Biochemistry and Physiology. 81 (2): 113. doi:10.1016/j.pestbp.2004.10.004.
  9. ↑ Senthil-Nathan, S.; Kalaivani, K.; Murugan, K.; Chung, P.G. (2005). "Effects of neem limonoids on malarial vector Anopheles stephensi Liston (Diptera: Culicidae)". Acta Tropica. 96 (1): 47–55. doi:10.1016/j.actatropica.2005.07.002. PMID   16112073.
  10. ↑ "TreeAzin Systemic Insecticide". BioForest Technologies. Retrieved 2014-06-03.
  11. ↑ "Our Products". ParryAmerica, Inc. Archived from the original on 2015-02-19. Retrieved 2015-02-18.
  12. ↑ "Insecticide With Neem Oil Concentrate 16oz | Safer® Brand 5612". www.saferbrand.com. Archived from the original on 2016-10-02. Retrieved 2016-09-28.
  13. ↑ "AzaGuard Botanical Insecticide Nematacide Specimen Label" (PDF). Biosafe Systems, LLC. Archived from the original (PDF) on 2016-03-04. Retrieved 2015-02-18.
  14. ↑ "AzaSol – Arborjet". arborjet.com. Retrieved 2017-06-16.
  15. ↑ "Terramera – Proof". terramera.com. Retrieved 2018-09-20.
  16. ↑ "Terramera – Cirkil". terramera.com. Retrieved 2018-09-20.
  17. ↑ Vyas, RV; Jani, JJ; Yadav, DN (1992). "Effect of some natural pesticides on entomogenous muscardine fungi". Indian Journal of Experimental Biology . 30 (5). National Institute of Science Communication and Policy Research: 435–6. ISSN   0019-5189. PMID   1459622. S2CID   29326838.
  18. ↑ Fountain, Michelle T.; Hopkin, Steve P. (2005). "Folsomia candida (Collembola): A "Standard" Soil Arthropod". Annual Review of Entomology . 50 (1). Annual Reviews: 201–222. doi:10.1146/annurev.ento.50.071803.130331. ISSN   0066-4170. PMID   15355236.
  19. 1 2 3 4 5 Kilani-Morakchi, Samira; Morakchi-Goudjil, Houda; Sifi, Karima (20 July 2021). "Azadirachtin-Based Insecticide: Overview, Risk Assessments, and Future Directions". Frontiers in Agronomy. 3 676208. doi: 10.3389/fagro.2021.676208 .
  20. 1 2 De La Peña, Ricardo; Hodgson, Hannah; Chun-Ting Liu, Jack; Stephenson, Michael J. (27 January 2023). "Complex scaffold remodeling in plant triterpene biosynthesis". Science. 379 (6630): 361–368.
  21. 1 2 Su, Xinyao; Liang, Zhipeng; Xue, Qiang; Liu, Jia (4 November 2023). "A comprehensive review of azadirachtin: physicochemical properties, bioactivities, production, and biosynthesis". Acupuncture and Herbal Medicine. 3 (4): 256–270.
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