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Revision as of 21:41, 6 August 2011 editCheMoBot (talk | contribs)Bots141,565 edits Updating {{chembox}} (no changed fields - added verified revid - updated 'DrugBank_Ref', 'UNII_Ref', 'ChEMBL_Ref', 'ChEBI_Ref') per Chem/Drugbox validation (report [[Wikipedia_talk:WikiProject_Ch← Previous edit		Latest revision as of 15:42, 29 July 2024 edit undoCedrusaurum (talk | contribs)64 editsm →Occurrence and use: Replaced a linkTag: Visual edit
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	{{chembox		{{chembox
			|Watchedfields = changed
	| verifiedrevid = 443408743		|verifiedrevid = 443410207
	| ImageFile = Azadirachtin.png		|ImageFile = Azadirachtin.png
	| ImageSize = 200px		|ImageSize = 200px
	|ImageFile1 = Azadirachtin_model.png		|ImageFile1 = Azadirachtin_model.png
	| ImageSize1 = 300px		|ImageSize1 = 200px
		⚫	|PIN = Dimethyl (2a''R'',2a<sup>1</sup>''R'',3''S'',4''S'',4a''R'',5''S'',7a''S'',8''S'',10''R'',10a''S'')-10-(acetyloxy)-3,5-dihydroxy-4-oxirenooxepin-1a(2''H'')-yl]-4-methyl-8-<nowiki/>{oxy}octahydro-1''H'',7''H''-naphthodifuran-5,10a(8''H'')-dicarboxylate
	| <--- ! the character &#x200b; is used so that layout and breaking can be proper. Feel free to remove them and then it'll be uglier. --->
		⚫	|Section1 = {{Chembox Identifiers
	| IUPACName = dimethyl (2a''R'',3''S'',4''S'',''R'',''S'',7a''S'',8''S'',10''R'',10a''S'',10b''R'')- 10-(acetyloxy)- 3,5-dihydroxy- 4-dodec- 3-en- 9-yl]- 4-methyl- 8-{oxy}octahydro- 1''H''-furonaphthofuran- 5,10a(8''H'')-dicarboxylate
			|CASNo_Ref = {{cascite|correct|CAS}}
⚫	| OtherNames = dimethyl (2a''R'',3''S'',4''S'',4a''R'',5''S'',7a''S'',8''S'',10''R'',10a''S'',10b''R'')- 10-acetoxy- 3,5-dihydroxy- 4-oxirenooxepin- 1a(2''H'')-yl]- 4-methyl- 8-{oxy}octahydro- 1''H''-naphthodifuran- 5,10a(8''H'')-dicarboxylate
		⚫	|CASNo = 11141-17-6
⚫	| Section1 = {{Chembox Identifiers
			|UNII_Ref = {{fdacite|correct|FDA}}
⚫	| CASNo = 11141-17-6
			|UNII = O4U1SAF85H
	| PubChem = 5281303		|PubChem = 5281303
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}= {{chemspidercite|correct|chemspider}}= {{chemspidercite|correct|chemspider}}= {{chemspidercite|correct|chemspider}}= {{chemspidercite|correct|chemspider}}= {{chemspidercite|correct|chemspider}}= {{chemspidercite|correct|chemspider}}= {{chemspidercite|correct|chemspider}}
			|ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 4444685		|ChemSpiderID = 4444685
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			|KEGG_Ref = {{keggcite|correct|kegg}}
	| KEGG = C08748
	| ChEBI_Ref = {{ebicite|correct|EBI}}		|KEGG = C08748
			|ChEBI_Ref = {{ebicite|correct|EBI}}
	| ChEBI = 2942		|ChEBI = 2942
	| SMILES = O=C(OC)1(O)OC82(OC(=O)/C(=C/C)C)C(OC(=O)C)7(C(=O)OC)CO((O)(C)(12)64O6(35(O)/C=C\O5O4C3)C)78		|SMILES = O=C(OC)1(O)OC82(OC(=O)/C(=C/C)C)C(OC(=O)C)7(C(=O)OC)CO((O)(C)(12)64O6(35(O)/C=C\O5O4C3)C)78
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	| StdInChI=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		|StdInChI=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
			|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}= {{stdinchicite|correct|chemspider}}= {{stdinchicite|correct|chemspider}}= {{stdinchicite|correct|chemspider}}= {{stdinchicite|correct|chemspider}}= {{stdinchicite|correct|chemspider}}= {{stdinchicite|correct|chemspider}}= {{stdinchicite|correct|chemspider}}
	| StdInChIKey = FTNJWQUOZFUQQJ-NDAWSKJSSA-N		|StdInChIKey = FTNJWQUOZFUQQJ-NDAWSKJSSA-N
⚫	}}
⚫	| Section2 = {{Chembox Properties
⚫	| C=35|H=44|O=16
	| MolarMass = 720.714 g/mol
	| Appearance =
	| Density =
	| MeltingPt =
	| BoilingPt =
	| Solubility =
⚫	}}
	| Section3 = {{Chembox Hazards
	| MainHazards =
	| FlashPt =
	| Autoignition =
	}}
	}}		}}
		⚫	|Section2 = {{Chembox Properties
⚫	'''Azadirachtin''' is a ] compound belonging to the ]. It is a ] present in the ] tree seeds. Azadirachtin is a highly oxidised ] which boasts a plethora of oxygen functionality, comprising an ], acetal, ], and tetra-substituted ] as well as a variety of ]s.
		⚫	|C=35|H=44|O=16
		⚫	}}
		⚫	}}
		⚫	'''Azadirachtin''', a ] compound belonging to the ] group, is a ] present in ] seeds. It is a highly oxidized ] which boasts a plethora of oxygen-bearing functional groups, including an ], acetal, ], tetra-substituted ] and a variety of ]s.
	== Chemistry ==		== Chemical synthesis ==
			Azadirachtin has a complex molecular structure; it presents both secondary and tertiary hydroxyl groups and a ] ether in its ], alongside 16 stereogenic centres, 7 of which are tetrasubstituted. These characteristics explain the great difficulty encountered when trying to prepare this compound from simple precursors, using methods of ].
	Azadirachtin has a complex molecular structure, and as a result the first synthesis was not published for over 22 years after the compound's discovery. The first total synthesis was completed by ]<ref>{{cite journal | title = Synthesis of Azadirachtin: A Long but Successful Journey | author = Gemma E. Veitch, Edith Beckmann, Brenda J. Burke, Alistair Boyer, Sarah L. Maslen, Steven V. Ley | doi = 10.1002/anie.200703027 | year = 2007 | journal = Angewandte Chemie International Edition | volume = 46 | pages = 7629 | pmid = 17665403 | issue = 40}}</ref> in 2007. Both secondary and tertiary hydroxyl groups and ] ether are present and the ] reveals 16 stereogenic centres, 7 of which are tetrasubstituted. These characteristics explain the great difficulty encountered when trying to produce it by a synthetic approach. The described synthesis was actually a relay approach, with the heavily functionalized ] being made by total synthesis in a small scale but also being derived from the natural product itself for the purpose of obtaining gram amounts of the material to complete the synthesis.		Hence, the first total synthesis was published over 22 years after the compound's discovery: this first synthesis was completed by the research group of ] at the ] in 2007.<ref name="pmid17665403">{{cite journal |vauthors=Veitch GE, Beckmann E, Burke BJ, Boyer A, Maslen SL, Ley SV | title = Synthesis of azadirachtin: a long but successful journey | journal = Angew. Chem. Int. Ed. Engl. | volume = 46 | issue = 40 | pages = 7629–32 | year = 2007 | pmid = 17665403 | doi = 10.1002/anie.200703027 }}</ref><ref name="pmid17687288">{{cite journal | author = Sanderson K | title = Chemists synthesize a natural-born killer | journal = Nature | volume = 448 | issue = 7154 | pages = 630–1 |date=August 2007 | pmid = 17687288 | doi = 10.1038/448630a | bibcode = 2007Natur.448Q.630S | doi-access = free }}</ref> The described synthesis was a ], with the required, heavily functionalized ] 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.
	== Occurrence and Use ==		== Occurrence and use ==
		⚫	Initially found to be active as a feeding inhibitor towards the ] (''Schistocerca gregaria''),<ref>{{cite journal | title = Isolation of a Substance that suppresses Feeding in Locusts | last1 = Butterworth | first1 = J | last2 = Morgan | first2 = E | journal = Chemical Communications | year = 1968 | issue = 1 | pages = 23 | doi = 10.1039/C19680000023 }}</ref> it is now known to affect over 200 species of ], by acting mainly as an antifeedant and growth disruptor. Azadirachtin exhibits considerable toxicity towards ] (''Spodoptera littoralis''), which are resistant to a commonly used biological pesticide, '']''. Azadirachtin fulfills many of the criteria needed for a good ]. Azadirachtin is ] (it degrades within 100 hours when exposed to light and water) and shows very low ] to ] (the {{LD50}} in rats is > 3,540&nbsp;mg/kg making it practically non-toxic).
		⚫	This compound is found in the seeds (0.2 to 0.8 percent by weight) of the ] tree, '']'' (hence the prefix aza does not imply an ], but refers to the ]). 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 <ref>{{cite journal | author = Senthil-Nathan, S. | author2 = Kalaivani, K. | author3 = Murugan, K. | author4 = Chung, G. | year = 2005 | title = The toxicity and physiological effect of neem limonoids on Cnaphalocrocis medinalis (Guenée) the rice leaffolder | doi = 10.1016/j.pestbp.2004.10.004 | journal = Pesticide Biochemistry and Physiology | volume = 81 | issue = 2 | pages = 113}}</ref><ref>{{cite journal | author = Senthil-Nathan, S. | author2 = Kalaivani, K. | author3 = Murugan, K. | author4 = Chung, P.G. | year = 2005 | title = Effects of neem limonoids on malarial vector Anopheles stephensi Liston (Diptera: Culicidae) | doi = 10.1016/j.actatropica.2005.07.002 | journal = Acta Tropica | volume = 96 | pages = 47–55 | pmid = 16112073 | issue = 1}}</ref> Effects of these preparations on beneficial arthropods are generally considered to be minimal {{Citation needed|date=July 2020}}. 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 {{convert|1|USfloz/USgal|mL/L}} of water when used as a pesticide.
⚫	It was initially found to be active as a feeding inhibitor towards the ] (''Schistocerca gregaria''),<ref>{{cite journal | title = Isolation of a Substance that suppresses Feeding in Locusts | last1 = Butterworth | first1 = J | last2 = Morgan | first2 = E | journal = Chemical Communications (London) | year = 1968 | issue = 1 | pages = 23 | doi = 10.1039/C19680000023 }}</ref> it is now known to affect over 200 species of ], by acting mainly as an antifeedant and growth disruptor, and as such it possesses considerable toxicity toward insects (LD<sub>50</sub>(''S. littoralis''): 15 μg/g). It fulfills many of the criteria needed for a natural ] if it is to replace synthetic compounds. Azadirachtin is ] (it degrades within 100 hours when exposed to light and water) and shows very low ] to ] (the {{LD50}} in rats is > 3,540 mg/kg making it practically non-toxic).
			Azadirachtin is the active ingredient in many pesticides including TreeAzin,<ref>{{cite web |url=http://www.bioforest.ca/index.cfm?fuseaction=content&menuid=12&pageid=1012 |title=TreeAzin Systemic Insecticide |publisher=BioForest Technologies |access-date=2014-06-03}}</ref> AzaMax,<ref>{{cite web |url=http://www.parryamerica.com/our-productsp2.html |title=Our Products |publisher=ParryAmerica, Inc. |access-date=2015-02-18 |archive-url=https://web.archive.org/web/20150219070448/http://www.parryamerica.com/our-productsp2.html |archive-date=2015-02-19 |url-status=dead}}</ref> BioNEEM,<ref>{{Cite web|url=http://www.saferbrand.com/safer-brand-bioneem-insecticide-with-neem-oil-concentrate-16-oz-5612|title=Insecticide With Neem Oil Concentrate 16oz {{!}} Safer® Brand 5612|website=www.saferbrand.com|access-date=2016-09-28|archive-url=https://web.archive.org/web/20161002101655/http://www.saferbrand.com/safer-brand-bioneem-insecticide-with-neem-oil-concentrate-16-oz-5612|archive-date=2016-10-02|url-status=dead}}</ref> AzaGuard,<ref>{{cite web |url=http://www.biosafesystems.com/assets/azaguard-specimen.pdf |title=AzaGuard Botanical Insecticide Nematacide Specimen Label |publisher=Biosafe Systems, LLC |access-date=2015-02-18 |archive-date=2016-03-04 |archive-url=https://web.archive.org/web/20160304000227/http://www.biosafesystems.com/assets/azaguard-specimen.pdf |url-status=dead }}</ref> and AzaSol,<ref>{{Cite web|url=http://arborjet.com/product/azasol/|title=AzaSol – Arborjet|website=arborjet.com|language=en-US|access-date=2017-06-16}}</ref> Terramera Proof <ref>{{Cite web|url=https://www.terramera.com/products/|title=Terramera – Proof|website=terramera.com|language=en-US|access-date=2018-09-20}}</ref> and Terramera Cirkil.<ref>{{Cite web|url=https://www.terramera.com/products/|title=Terramera – Cirkil|website=terramera.com|language=en-US|access-date=2018-09-20}}</ref>
⚫	This compound is found in the seeds (0.2 to 0.8 percent by weight) of the ] tree, '']'' (hence the prefix aza does not imply an ], but refers to the ] species name). 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 <ref>{{cite journal | author = Senthil-Nathan, S., Kalaivani, K., Murugan, K., Chung, G. | year = 2005 | title = The toxicity and physiological effect of neem limonoids on Cnaphalocrocis medinalis (Guenée) the rice leaffolder | doi = 10.1016/j.pestbp.2004.10.004 | journal = Pesticide Biochemistry and Physiology | volume = 81 | issue = 2 | pages = 113}}</ref><ref>{{cite journal | author = Senthil-Nathan, S., Kalaivani, K., Murugan, K., Chung, P.G. | year = 2005 | title = Effects of neem limonoids on malarial vector Anopheles stephensi Liston (Diptera: Culicidae) | doi = 10.1016/j.actatropica.2005.07.002 | journal = Acta Tropica | volume = 96 | pages = 47 | pmid = 16112073 | issue = 1}}</ref> Effects of these preparations on beneficial arthropods are generally considered to be minimal. 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 additional to azadirachtin, it is generally mixed at a rate of 1 ounce per gallon (7.8 ml/l) of water when used as a pesticide.
			Azadirachtin has a synergistic effect with the ] agent '']''.<ref name="Vyas-et-al-1992">{{cite journal | last1=Vyas | first1=RV | last2=Jani | first2=JJ | last3=Yadav | first3=DN | title=Effect of some natural pesticides on entomogenous muscardine fungi | journal=] | publisher=] | volume=30 | issue=5 | year=1992 | issn=0019-5189 | pmid=1459622 | pages=435–6 | s2cid=29326838}}</ref>
	== Biosynthesis ==
			] is a natural product insecticide mix which is mostly azadirachtin, with some other ]s.<ref name="Fountain-Hopkin-2005">{{cite journal | last1=Fountain | first1=Michelle T. | author1-link=Michelle Fountain| last2=Hopkin | first2=Steve P. | title=''Folsomia candida'' (Collembola): A "Standard" Soil Arthropod | journal=] | publisher=] | volume=50 | issue=1 | year=2005 | issn=0066-4170 | doi=10.1146/annurev.ento.50.071803.130331 | pages=201–222| pmid=15355236 }}</ref>
⚫	Azadirachtin is formed via an elaborate biosynthetic pathway, but is believed that the steroid ] is the precursor to the neem ] secondary metabolites. Tirucallol is formed from two units of ] (FPP) to form a C<sub>30</sub> triterpene, but then loses three methyl groups to become a C<sub>27</sub> steroid. Tirucallol undergoes an allylic isomerization to form ], which is then oxidized. The oxidized butyrospermol subsequently rearranges via a ] to form apotirucallol.
			== Mechanism of action ==
⚫	Apotirucallol becomes a tetranortriterpenoid when the four terminal carbons from the side chain are cleaved off. The remaining carbons on the side chain cyclize to form a ] ring and the molecule is oxidized further to form azadirone and azadiradione. The third ring is then opened and oxidized to form the C-seco-limonoids such as ], ] and ], which has been ] with a molecule of ], which is derived from ]. It is currently proposed that the target molecule is arrived at by biosynthetically converting azadirone into salanin, which is then heavily oxidized and cyclized to reach azadirachtin.
			Azadirachtin interferes with a wide variety of insect pathways.<ref name=KM>{{cite journal |last1=Kilani-Morakchi |first1=Samira |last2=Morakchi-Goudjil |first2=Houda |last3=Sifi |first3=Karima |title=Azadirachtin-Based Insecticide: Overview, Risk Assessments, and Future Directions |journal=Frontiers in Agronomy |date=20 July 2021 |volume=3 |pages=676208 |doi=10.3389/fagro.2021.676208|doi-access=free }}</ref>
			* The substance acts as an ]. It antagonizes both ] (mainly 20E) and ] activities by reducing secretion of ] (PTTH) and ]s from the ] complex. This neuroendocrine disruption reduces ]. It also causes degeneration of other neuroendocrine glands.<ref name=KM/>
			* The substance disrupts reproductive functions, going as far as sterility in some insects. This is partially due to the aforementioned neuroendocrine disruption surrounding 20E and JH. It could also affect yolk protein and vitallogenin synthesis. It also reduces mating success by deterrence.<ref name=KM/>
			* The substance also deters feeding, making it an ]. It disrupts the sense of smell to the point that some insects would rather starve than eat azadirachtin-laced food. If the insect ingests the compound, the substance further inhibits digestive enzymes and could leave an aversive taste memory by activating dopaminergic neurons.<ref name=KM/>
			* Azadirachtin additionally has a long list of cellular and molecular targets. It upregulates p53, disrupts protein synthesis possibly through binding to Hsp60, and changes the expression of many other pathways.<ref name=KM/>
	== See also ==		== Biosynthesis ==
		⚫	Azadirachtin is formed via an elaborate biosynthetic pathway, but is believed that the steroid ] is the precursor to the neem ] secondary metabolites. Tirucallol is formed from two units of ] (FPP) to form a C<sub>30</sub> triterpene, but then loses three methyl groups to become a C<sub>27</sub> steroid. Tirucallol undergoes an allylic isomerization to form ], which is then oxidized. The oxidized butyrospermol subsequently rearranges via a ] to form ].
		⚫	Apotirucallol becomes a tetranortriterpenoid when the four terminal carbons from the side chain are cleaved off. The remaining carbons on the side chain cyclize to form a ] ring and the molecule is oxidized further to form azadirone and ]. The third ring is then opened and oxidized to form the C-seco-limonoids such as ], ] and ], which has been ] with a molecule of ], which is derived from ]. It is currently proposed that the target molecule is arrived at by biosynthetically converting azadirone into salanin, which is then heavily oxidized and cyclized to reach azadirachtin.
			== See also ==
			* ] (AFRI)
	* ]		* ]
	* ]		* ]
	* ]		* ]
			* ], another chemical isolated from ''Azadirachta indica'' also thought to contribute to the biological activity of neem
	== References ==		== References ==
	{{reflist|2}}		{{reflist|30em}}
	== External links ==		== External links ==
			* {{cite book |title=Neem: A Tree For Solving Global Problems |date=1992 |publisher=National Research Council (US) Panel on Neem |doi=10.17226/1924 |pmid=25121266 |isbn=978-0-309-04686-2 |url=https://doi.org/10.17226/1924}}
	*		*
	*		*
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