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).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Azadirachtin, a chemical compound belonging to the limonoid group, is a secondary metabolite present in neem seeds. It is an insecticide used particularly in organic farming.

Contents

Occurrence

Azadirachtin is found in the neem tree, Azadirachta indica , from which its name is derived, as well as Azadirachta excelsa . [1] 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). [2] It was first isolated pure in 1968 following the antifeedant activity towards the desert locust (Schistocerca gregaria), [3] but its chemical structure was finally established later in the 1980s. [4]

Use

The neem tree has been used for > 2,000 years in India for the control of insect pests. [5] Azadirachtin is the major active component and is responsible for 72 to 90% of the biological activity. [5] There are >100 limonoids in neem extracts, some of which are insecticidally active. [1] Normally an unpurified extract is sold, which is known to delay resistance, when compared to pure azadirachtin. [1] It is active against > 600 species, [1] showing both antifeedant and insecticidal activity, although its insecticidal activity is more relevant for its commercial use. [6] It is categorised by the EPA as a biopesticide and is approved for organic farming. In California, a state with good usage data, 2585 kg were used in 2023. [7] The list of azadirachtin containing products is long; [1] Kiliani lists 15 of them and mentions dozens more. [5]

Toxicity and ecotoxicity

Azadirachtin fulfills many of the criteria needed for a good insecticide. It shows very low toxicity to mammals. Its LD50 in rats is > 5000 mg/kg. [8] It degrades rapidly in the environment. [9] The risk to bees and other non-target arthropods is low. [9] There is a low risk of killing beneficials apart from ladybird and lacewing. [9] Azadirachtin is very toxic to aquatic organisms. [9]

Mechanism of action

Azadirachtin interferes with a wide variety of insect pathways. [5]

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. [10] [11] [12] It involves 71 reaction steps (48 steps in the longest linear sequence) with a yield of 0.00015%. [10] 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.

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. [13] [14] 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. [13] The later steps in the scheme from azadirone to azadirachtin are speculative. [14]

Biosynthetic pathway and prediction of azadirachtin.jpg

See also

References

  1. 1 2 3 4 5 Morgan, E. David (15 June 2009). "Azadirachtin, a scientific gold mine". Bioorg Med Chem. 17 (12): 4096–4105.
  2. ↑ 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.
  3. ↑ Butterworth, J; Morgan, E (1968). "Isolation of a Substance that suppresses Feeding in Locusts". Chemical Communications (1): 23. doi:10.1039/C19680000023.
  4. ↑ 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.
  5. 1 2 3 4 5 6 7 8 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 .
  6. ↑ Isman, Murray (August 2002). "Insect antifeedants". Pesticide Outlook. 13 (4): 152–157.
  7. ↑ "Pesticide Use Reporting – 2023 Summary Data". State of California Department of Pesticide Regulation. 2025. Retrieved 6 December 2025.
  8. ↑ Raizada, R.B.; Srivastava, M.K.; Kaushal, R.A.; Singh, R.P (May 2001). "Azadirachtin, a neem biopesticide: subchronic toxicity assessment in rats". Food and Chemical Toxicology. 39 (5): 477–483.
  9. 1 2 3 4 Arena, M; Auteri, D.; Barmaz, S.; Brancato, A. (15 March 2018). "Conclusion on the peer review of the pesticide risk assessment of the active substance azadirachtin (Margosa extract)". ). EFSA Journal. 16 (9): 5234, 31 pp.
  10. 1 2 Jauch, Johann (13 December 2007). "Total Synthesis of Azadirachtin—Finally Completed After 22 Years". Angewandte Chemie International Edition. 47: 34–37.
  11. ↑ 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.
  12. ↑ 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.
  13. 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.
  14. 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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