Azadirachtin, a

chemical A chemical substance is a form of matter having constant chemical composition and characteristic properties. Some references add that chemical substance cannot be separated into its constituent elements by physical separation methods, i.e., w ...

compound belonging to the

limonoid Limonoids are phytochemicals of the triterpenoid class which are abundant in sweet or sour-scented citrus fruit and other plants of the families Cucurbitaceae, Rutaceae, and Meliaceae. Certain limonoids are antifeedants such as azadirachtin from ...

group, is a

secondary metabolite Secondary metabolites, also called specialised metabolites, toxins, secondary products, or natural products, are organic compounds produced by any lifeform, e.g. bacteria, fungi, animals, or plants, which are not directly involved in the norma ...

present in

neem ''Azadirachta indica'', commonly known as neem, nimtree or Indian lilac, is a tree in the mahogany family Meliaceae. It is one of two species in the genus '' Azadirachta'', and is native to the Indian subcontinent and most of the countries in Afr ...

seeds. It is a highly oxidized

tetranortriterpenoid The tetranortriterpenoid class of chemical compounds most noted for the chemical azadirachtin, extracted from the neem tree (''Azadirachta indica'') that displays insecticidal properties. Azadirachtin mimics insect hormones called ecdysones that reg ...

which boasts a plethora of oxygen-bearing functional groups, including an

enol ether In organic chemistry an enol ether is an alkene with an alkoxy substituent. The general structure is R2C=CR-OR where R = H, alkyl or aryl. A common subfamily of enol ethers are vinyl ethers, with the formula ROCH=CH2. Important enol ethers includ ...

, acetal,

hemiacetal A hemiacetal or a hemiketal has the general formula R1R2C(OH)OR, where R1 or R2 is hydrogen or an organic substituent. They generally result from the addition of an alcohol to an aldehyde or a ketone, although the latter are sometimes called hemi ...

, tetra-substituted

epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...

and a variety of

carboxylic ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides a ...

Chemical synthesis

Azadirachtin has a complex molecular structure; it presents both secondary and tertiary hydroxyl groups and a

tetrahydrofuran Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...

ether in its

molecular structure Molecular geometry is the three-dimensional arrangement of the atoms that constitute a molecule. It includes the general shape of the molecule as well as bond lengths, bond angles, torsional angles and any other geometrical parameters that deter ...

, 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 Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J ...

. 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

Steven Ley Steven Victor Ley (born 10 December 1945) is Professor of Organic Chemistry in the Department of Chemistry at the University of Cambridge, and is a Fellow of Trinity College, Cambridge. He was President of the Royal Society of Chemistry (2000� ...

at the

University of Cambridge The University of Cambridge is a public collegiate research university in Cambridge, England. Founded in 1209 and granted a royal charter by Henry III in 1231, Cambridge is the world's third oldest surviving university and one of its most pr ...

in 2007. The described synthesis was a relay approach, with the required, heavily functionalized

decalin Decalin (decahydronaphthalene, also known as bicyclo .4.0ecane and sometimes decaline), a bicyclic organic compound, is an industrial solvent. A colorless liquid with an aromatic odor, it is used as a solvent for many resins or fuel additives. I ...

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 The desert locust (''Schistocerca gregaria'') is a species of locust, a periodically swarming, short-horned grasshopper in the family Acrididae. They are found primarily in the deserts and dry areas of northern and eastern Africa, Arabia, and sou ...

(''Schistocerca gregaria''), it is now known to affect over 200 species of

insects Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body (head, thorax and abdomen), three pairs of j ...

, by acting mainly as an antifeedant and growth disruptor. It was recently found that azadirachtin possesses 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 Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...

mammals Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...

(the 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

tree, ''

Azadirachta indica ''Azadirachta indica'', commonly known as neem, nimtree or Indian lilac, is a tree in the mahogany family Meliaceae. It is one of two species in the genus ''Azadirachta'', and is native to the Indian subcontinent and most of the countries in Afr ...

'' (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 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 addition to azadirachtin, it is generally mixed at a rate of of water when used as a pesticide. Azadirachtin is the active ingredient in many pesticides including TreeAzin, AzaMax, BioNEEM, AzaGuard, and AzaSol, Terramera Proof and Terramera Cirkil. Azadirachtin has a synergistic effect with the

biocontrol Biological control or biocontrol is a method of controlling pests, such as insects, mites, weeds, and plant diseases, using other organisms. It relies on predation, parasitism, herbivory, or other natural mechanisms, but typically also in ...

agent ''

Beauveria ''Beauveria'' is a genus of asexually-reproducing fungi allied with the ascomycete family Cordycipitaceae. Its several species are typically insect pathogens. The sexual states (teleomorphs) of ''Beauveria'' species, where known, are species o ...

''.

Nimbecidine Azadirachtin, a chemical compound belonging to the limonoid group, is a secondary metabolite present in neem seeds. It is a highly oxidized tetranortriterpenoid which boasts a plethora of oxygen-bearing functional groups, including an enol ether, ...

is a natural product insecticide mix which is mostly azadirachtin, with some other

Mechanism of action

Azadirachtin interferes with a wide variety of insect pathways. * The substance acts as a insect growth regulator. It antagonizes both

ecdysteroid Ecdysteroids are arthropod steroid hormones that are mainly responsible for molting, development and, to a lesser extent, reproduction; examples of ecdysteroids include ecdysone, ecdysterone, turkesterone and 2-deoxyecdysone. These compounds are ...

(mainly 20E) and

juvenile hormone Juvenile hormones (JHs) are a group of acyclic sesquiterpenoids that regulate many aspects of insect physiology. The first discovery of a JH was by Vincent Wigglesworth. JHs regulate development, reproduction, diapause, and polyphenisms.The chem ...

activities by reducing secretion of

prothoracicotropic hormone Prothoracicotropic hormone (PTTH) was the first insect hormone to be discovered.The chemical symbol for prothoracicotropic hormone is (C64H102N16O19S2). It was originally described simply as "brain hormone" by early workers such as Stefan Kopeć (1 ...

(PTTH) and allatotropins from the

corpus cardiacum Insect physiology includes the physiology and biochemistry of insect organ systems. Although diverse, insects are quite similar in overall design, internally and externally. The insect is made up of three main body regions (tagmata), the head, thor ...

complex. This neuroendocrine disruption reduces

pupation A pupa ( la, pupa, "doll"; plural: ''pupae'') is the life stage of some insects undergoing transformation between immature and mature stages. Insects that go through a pupal stage are holometabolous: they go through four distinct stages in thei ...

. It also causes degeneration of other neuroendocrine glands. * 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. * The substance also deters feeding, making it an

antifeedant Antifeedants are organic compounds produced by plants to inhibit attack by insects and grazing animals. These chemical compounds are typically classified as secondary metabolites in that they are not essential for the metabolism of the plant, but i ...

. 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. * 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.

Biosynthesis

Azadirachtin is formed via an elaborate biosynthetic pathway, but is believed that the steroid tirucallol is the precursor to the neem

triterpenoid Triterpenes are a class of chemical compounds composed of three terpene units with the molecular formula C30H48; they may also be thought of as consisting of six isoprene units. Animals, plants and fungi all produce triterpenes, including squal ...

secondary metabolites. Tirucallol is formed from two units of farnesyl diphosphate (FPP) to form a C₃₀ triterpene, but then loses three methyl groups to become a C₂₇ steroid. Tirucallol undergoes an allylic isomerization to form butyrospermol, which is then oxidized. The oxidized butyrospermol subsequently rearranges via a Wagner-Meerwein 1,2-methyl shift to form apotirucallol. 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 furan 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 nimbin, nimbidinin and salannin, which has been

esterified In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

with a molecule of tiglic acid, which is derived from L-isoleucine. 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.

References

External links

* {{cite book , title=Neem: A Tree For Solving Global Problems , date=1992 , publisher=National Research Council (US) Panel on Neem , isbn=978-0-309-04686-2 , url=https://doi.org/10.17226/1924}
PDF Copy

Neem: The wonder tree
Plant toxin insecticides Terpenes and terpenoids Acetate esters Epoxides Polyols Carboxylate esters Methyl esters Alkene derivatives Oxygen heterocycles Enones