Azadirachtin
Template:Chembox Azadirachtin, a chemical compound belonging to the limonoid group, is a secondary metabolite present in neem seeds. It is a highly oxidized tetranortriterpenoid.
Chemical synthesis
Azadirachtin has a complex molecular structure, which contains many oxygen-bearing functional groups, including an enol ether, acetal, hemiacetal, tetra-substituted epoxide and a variety of carboxylic esters as well as both secondary and tertiary hydroxyl groups and a tetrahydrofuran ether in its molecular structure, 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 synthetic organic chemistry.
The first total synthesis was published over 22 years after the compound's discovery: this first synthesis was completed by the research group of Steven Ley at the University of Cambridge in 2007.<ref name="pmid17665403">Template:Cite journal</ref><ref name="pmid17687288">Template:Cite journal</ref> 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.
Occurrence and use
Initially found to be active as a feeding inhibitor towards the desert locust (Schistocerca gregaria),<ref>Template:Cite journal</ref> 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 Template:LD50 in rats is > 3,540 mg/kg making it practically non-toxic).
This compound is found in the seeds (0.2 to 0.8 percent by weight) of the neem tree, Azadirachta indica (hence the prefix aza does not imply an aza compound, but refers to the scientific 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>Template:Cite journal</ref><ref>Template:Cite journal</ref> Effects of these preparations on beneficial arthropods are generally considered to be minimal Template: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 Template:Convert of water when used as a pesticide.
Azadirachtin is the active ingredient in many pesticides including TreeAzin,<ref>Template:Cite web</ref> AzaMax,<ref>Template:Cite web</ref> BioNEEM,<ref>Template:Cite web</ref> AzaGuard,<ref>Template:Cite web</ref> and AzaSol,<ref>Template:Cite web</ref> Terramera Proof <ref>Template:Cite web</ref> and Terramera Cirkil.<ref>Template:Cite web</ref>
Azadirachtin has a synergistic effect with the biopesticide Beauveria bassiana.<ref name="Vyas-et-al-1992">Template:Cite journal</ref>
Nimbecidine is a natural product insecticide mix which is mostly azadirachtin, with some other limonoids.<ref name="Fountain-Hopkin-2005">Template:Cite journal</ref>
Mechanism of action
Azadirachtin interferes with a wide variety of insect pathways.<ref name=KM>Template:Cite journal</ref>
- The substance acts as an insect growth regulator. It antagonizes both ecdysteroid (mainly 20E) and juvenile hormone activities by reducing secretion of prothoracicotropic hormone (PTTH) and allatotropins from the corpus cardiacum complex. This neuroendocrine disruption reduces pupation. 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 antifeedant. 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/>
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.<ref>Template:Cite journal</ref> 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.Template:Cn
See also
- Arid Forest Research Institute (AFRI)
- Neem
- Neem cake
- Neem oil
- Nimbin, another chemical isolated from Azadirachta indica also thought to contribute to the biological activity of neem