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57-411: Azadirachtin has a complex molecular structure; it presents 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 . Hence,

114-500: 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 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

171-401: A C 27 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

228-481: 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 LD 50 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

285-400: A guard tube, followed by 10mL acetonitrile . The solution is cooled to 0 °C, and 0.5ml of concentrated sulfuric acid is slowly added while stirring. The reaction is left until the room temperature is reached and mixed once again for 6 hours. Thin-layer chromatography monitored the completion of the reaction. After completion, the flask was immersed in an ice bath, and aqueous ammonia

342-452: A more stable allyl carbocation at the C-13 and deprotonation of H-17 to form a diene . Successive intramolecular attack of the H on the tertiary carbocation leads to a 180 rotation of bond between C-8 and C-14 and ring closure to produce the rearranged product with cyclic ether : Isonimbin. To obtain this product, nimbin was taken in a 100mL single-necked round bottom flask fitted with

399-580: A nonsteroidal anti-inflammatory, at 100 μm: - Heat-induced hemolysis - Hypotonicity-induced hemolysis - Lipoxygenase inhibition activity - Proteinase inhibition assay For all the experiences, N1, N2, and N3 dose-dependently were efficient in inhibiting the hypotonicity and heat-induced hemolysis, lipoxygenase , and proteinase. Moreover, they inhibit better and more effectively with high concentration. To detect intracellular reactive oxygen species (ROS) generation by induced inflammation (LPS) in zebrafish, an oxidation-sensitive fluorescent DCF-DA sample

456-442: A shine to the finished product as well as to solvent weld printed parts. In the laboratory, THF is a popular solvent when its water miscibility is not an issue. It is more basic than diethyl ether and forms stronger complexes with Li , Mg , and boranes . It is a popular solvent for hydroboration reactions and for organometallic compounds such as organolithium and Grignard reagents . Thus, while diethyl ether remains

513-427: A wide liquid range, THF is a versatile solvent . It is an isomer of another solvent, butanone . About 200,000 tonnes of tetrahydrofuran are produced annually. The most widely used industrial process involves the acid-catalyzed dehydration of 1,4-butanediol . Ashland/ISP is one of the biggest producers of this chemical route. The method is similar to the production of diethyl ether from ethanol . The butanediol

570-545: Is an aprotic solvent with a dielectric constant of 7.6. It is a moderately polar solvent and can dissolve a wide range of nonpolar and polar chemical compounds. THF is water-miscible and can form solid clathrate hydrate structures with water at low temperatures. THF has been explored as a miscible co-solvent in aqueous solution to aid in the liquefaction and delignification of plant lignocellulosic biomass for production of renewable platform chemicals and sugars as potential precursors to biofuels . Aqueous THF augments

627-581: Is derived from condensation of acetylene with formaldehyde followed by hydrogenation . DuPont developed a process for producing THF by oxidizing n -butane to crude maleic anhydride , followed by catalytic hydrogenation. A third major industrial route entails hydroformylation of allyl alcohol followed by hydrogenation to 1,4-butanediol . THF can also be synthesized by catalytic hydrogenation of furan . This allows certain sugars to be converted to THF via acid-catalyzed digestion to furfural and decarbonylation to furan, although this method

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684-405: Is extracted at 1000 ppm cold to maintain the antifungal activity. because of the presence of its main compounds including nimbin in their purest form. A high concentration of neem oil increases the action of nimbin on fungi and thus its antifungal activity. A study showed that by mixing neem oil with n -hexane or with 90% methanol , nimbin's antifungal activity could be distinguished. Indeed, it

741-431: Is found in multiple Asian countries such as China, Thailand, and India. Nimbin is part of the chemical family of limonoids and triterpenoids . Nimbin was first extracted in 1942 from neem seeds by Siddiqi et al . Its molecular formula was established by mass-spectrometry along with salannin , a compound whose chemical formula and properties are very close those of nimbin. Nimbin can be extracted from different parts of

798-404: Is from the neem bark extract also called NBE. There has been an experiment in vitro where NBE could inhibit the pathologic effects of SARS-COV-2 infection on a human lung cell model. This proves that even though it isn't a direct experiment, we can anticipate that NBE-derived compounds such as nimbin will be able to prevent SARS-COV-2 infection of nasal and lung tissue in vivo as well. Nimbin

855-412: 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, AzaMax, BioNEEM, AzaGuard, and AzaSol, Terramera Proof and Terramera Cirkil. Azadirachtin has a synergistic effect with the biocontrol agent Beauveria . Nimbecidine is a natural product insecticide mix which

912-547: Is highly flammable. One danger posed by THF is its tendency to form the explosive compound 2-hydroperoxytetrahydrofuran upon reaction with air: To minimize this problem, commercial supplies of THF are often stabilized with butylated hydroxytoluene (BHT). Distillation of THF to dryness is unsafe because the explosive peroxides can concentrate in the residue. The tetrahydrofuran ring is found in diverse natural products including lignans , acetogenins , and polyketide natural products. Diverse methodology has been developed for

969-445: Is more antifeedant and insecticidal than nimbin and nimbinolide. Therefore, these photo-oxidation products prevent the development of insects in neem. However, more research must be conducted to study their activity against other pest species. Nimbin has an antifungal activity like other neem compounds. Neem oil used against phytopathogenic fungi such as Fusarium oxysporum or Sclerotinia . Against rust pathogens, neem oil

1026-438: Is mostly azadirachtin, with some other limonoids . Azadirachtin interferes with a wide variety of insect pathways. Azadirachtin is formed via an elaborate biosynthetic pathway, but is believed that the steroid tirucallol is the precursor to the neem triterpenoid secondary metabolites. Tirucallol is formed from two units of farnesyl diphosphate (FPP) to form a C 30 triterpene, but then loses three methyl groups to become

1083-535: Is much important than nimbin's and salannin's and therefore it could be the most potent neem metabolite against bacteria. However, according to another study, neem's antimicrobial effect relies also heavily on the other neem metabolites (including nimbin) but more researches must be carried out on this topic. Nimbin is one of the insecticidally active compounds naturally present in neem. It justifies its presence in pesticidal and pharmacological products. This natural pesticide has significant potential because of

1140-527: Is not verified for the N2 molecule. However, its hypoglycemic effect on β cells has been evaluated with insulin . Abnormal β cells in people with diabetes are one of the causes of the dysfunction of the insulin system. A study on zebrafish embryos has made it possible to evaluate the cytotoxic effects of nimbin molecules on the larvae of these fish. N2 then serves as an antioxidant protection against β cells and anti- hyperglycemic activity. The insulin system

1197-455: Is not widely practiced. THF is thus derivable from renewable resources. In the presence of strong acids , THF converts to a linear polymer called poly(tetramethylene ether) glycol (PTMEG), also known as polytetramethylene oxide (PTMO): This polymer is primarily used to make elastomeric polyurethane fibers like Spandex . The other main application of THF is as an industrial solvent for polyvinyl chloride (PVC) and in varnishes . It

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1254-479: Is often used in medicine as an anti-inflammatory , anti-cancer , or antioxidant . Its toxicity to mammals is very low, negligible, and not targeted to other living beings. Nimbin can be used for people with diabetes because it has an anti-diabetic effect, especially when it is modified and transformed into semi-natural molecules such as N2 (semisynthetic nimbin analog N2) or N3 (deacetylnimbin N3). This effectiveness

1311-456: Is often used industrially to degrease metal parts. THF is used as a component in mobile phases for reversed-phase liquid chromatography . It has a greater elution strength than methanol or acetonitrile , but is less commonly used than these solvents. THF is used as a solvent in 3D printing when printing with PLA , PETG and substantially similar filaments. It can be used to clean clogged 3D printer parts, to remove extruder lines and add

1368-424: Is one of the best-ranked drugs among the selected natural products showing an inhibitory effect for spike glycoprotein and ACE2 along with curcumin . Nimbin is part of the family of triterpenoids , sub-category of terpenoids , that are known to have biological properties such as anti-viral properties. For the dengue virus (also called DENV NS2B-NS3) infection it shows potential in silico only. The envelope of

1425-423: Is only observed against some phytopathogenic fungi when using the extract mixed with 90% methanol where it has a marginal inhibitory activity. However, for the extract mixed with n -hexane no activity is detected against the other fungi. Another study showed that when the oil is mixed with ethanol , neem compounds such as nimbin acted as an inhibitor on fungal colonies. This is observed when nimbin's concentration

1482-424: Is then heavily oxidized and cyclized to reach azadirachtin. Tetrahydrofuran Tetrahydrofuran ( THF ), or oxolane , is an organic compound with the formula (CH 2 ) 4 O. The compound is classified as heterocyclic compound , specifically a cyclic ether . It is a colorless, water- miscible organic liquid with low viscosity . It is mainly used as a precursor to polymers. Being polar and having

1539-414: Is then purified by repeating different silica gel column chromatography with hexane and ethyl acetate (70:30) as a solvent . This method can obtain 600 mg of nimbin out of 300 g of neem seed kernels. To extract nimbin out of neem seeds, supercritical carbon dioxide can be used because of its low critical temperature and pressure and its low toxicity, which is why this method is mainly used in

1596-572: Is then restored. This study showed that N2 had no toxic impact on these individuals health and development. But a high concentration could be dangerous if used excessively. There are a few studies regarding the antimicrobial activity of nimbin. However, Nimbin has an antimicrobial activity only against few bacteria species. The antimicrobial effects of neem metabolites can be studied by HCL characterization. An agar diffusion test allows us to study this activity against bacteria like Bacillus cereus or Escherichia coli . These bacteria present in

1653-467: Is traditionally dried by distillation from an aggressive desiccant such as elemental sodium , molecular sieves have been shown to be superior water scavengers. In the presence of a solid acid catalyst , THF reacts with hydrogen sulfide to give tetrahydrothiophene . THF is a Lewis base that bonds to a variety of Lewis acids such as I 2 , phenols , triethylaluminum and bis(hexafluoroacetylacetonato)copper(II) . THF has been classified in

1710-426: Is when one molecule forms a cavity where our targeted molecule can be. CDs are used since they have a hydrophilic outer surface but a hydrophobic central cavity (where nimbin will be). The preparation of its saturated solution assessed the water solubility of the nimbin/CD complex. The results show that the water solubility of nimbin in the inclusion complex, compared with native nimbin, was remarkably increased by

1767-562: The ECW model and it has been shown that there is no one order of base strengths. Many complexes are of the stoichiometry MCl 3 (THF) 3 . THF is a relatively acutely nontoxic solvent, with the median lethal dose (LD 50 ) comparable to that for acetone . However, chronic exposure is suspected of causing cancer. Reflecting its remarkable solvent properties, it penetrates the skin, causing rapid dehydration. THF readily dissolves latex and thus should be handled with nitrile rubber gloves. It

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1824-601: The ED50 value for 6-homodesacetylnimbin illustrates moderate activity. Thus, steric hindrance through the presence of a large group or a lactone ring over the C-28 position may be crucial to transmit cytotoxic activity. The use of nimbin as a biopesticide or herbal medicine is limited by its low water solubility and bioavailability. To increase its water solubility, nimbin was put in an inclusion complex with different kinds of cyclodextrins (also called CDs). An inclusion complex

1881-613: The SARS COV-2 or the dengue virus . However, that hasn't been demonstrated in humans and only in laboratory settings. It was a derivative of nimbin (named N2) that was used in laboratories for the dengue virus and other uses like antimicrobial. Nimbin is relatively hydrophobic , and there has been a study to make it more hydrophilic with an inclusion complex which can be helpful to enable its direct use. Nimbin can be quantified in neem using advanced mass spectrometry or HPLC techniques. The concentration of this chemical in

1938-506: The dengue virus makes it so that the viral entry in the host cell is facilitated. Nimbin work against this envelope by blocking the virus from entering. It has shown that it is effective on all four types of dengue viruses (dengue 1-4) in silico. An anti-inflammatory role has been demonstrated in both in vitro and in vivo models using nonsteroidal tetranortriterpenoid, nimbin (N1), and its analogs (N2 and N3). They were able to improve wound healing by cell proliferation and to reduce

1995-644: 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 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

2052-470: The reactive oxygen species (a type of unstable molecule that contains oxygen and that easily reacts with other molecules in a cell). For the experiences, all the reactions were produced with the commercially available starting materials without any further purifications. Nimbin has been isolated from the raw neem seed by crude extraction using methanol (MeOH), enriched neem fraction, and purified by doing multiple columns to obtain pure nimbin (N1). To obtain

2109-409: The actual need for a natural pesticide to protect plants from contaminations and insects. Endophytes , whose role is to protect the tree from herbivore insects, can also produce nimbin in the neem tree. Nimbin can be photo-oxidized under laboratory conditions to obtain nimbinolide and isonimbinolide. These products reportedly have some insecticidal effects against some pest species. Isonimbolide

2166-438: The derivatives N2 and N3, nimbin (N1) has been deacetylated using 1.1 equiv of K 2 CO 3 /MeOH under ambient conditions. Then both compounds were purified using a silica gel column. The effects of mimbin were tested in cell-free and cell lines by the influence of lipopolysaccharide (LPS). Human red blood cell membrane (HBRC) stabilization has been employed to evaluate the anti-inflammatory property. HBRC membrane resembles

2223-526: The extraction. In this case, methanol can be used as a co-solvent because it's a substantial donor of hydrogen bonds which is responsible for its high solvent power. However, using methanol as a co-solvent will only increase the extraction yield by 5% (which gives a yield of approximately 90%). Therefore, using a co-solvent is not worth it regarding the manipulation's cost, difficulty, and toxicity. Some experimental parameters can have an impact on nimbin's extraction yield using this method. An increase in

2280-473: 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. 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

2337-412: The gram-scale operations required to complete the synthesis. Initially found to be active as a feeding inhibitor towards the desert locust ( Schistocerca gregaria ), 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

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2394-486: The hydrolysis of glycans from biomass and dissolves the majority of biomass lignin making it a suitable solvent for biomass pretreatment. THF is often used in polymer science. For example, it can be used to dissolve polymers prior to determining their molecular mass using gel permeation chromatography . THF dissolves PVC as well, and thus it is the main ingredient in PVC adhesives. It can be used to liquefy old PVC cement and

2451-488: The industry. Even if supercritical carbon dioxide can sometimes fail to extract effectively organic compounds out of a product, extraction yields of nimbin out of neem seeds using this method are relatively high. In fact, under specific experimental conditions (305 K, 23 MPa and a carbon dioxide flow rate of 0.62 cm /min) an extraction yield of approximately 85% can be obtained for 2 g of neem . A co-solvent can also be added to supercritical carbon dioxide to enhance

2508-503: The lysosomal membrane components. Therefore, the effects of nimbin and derivatives on the stabilization of the HRBC membrane could be deduced from the stabilization of the lysosomal membrane. The reaction of nimbin was tested on hemolysis of human red blood cells induced by heat and hypotonicity. Four experiences were performed in vitro with different concentrations of N1, N2, and N3 (25, 50, 100, and 150 μm) and then compared to diclofenac,

2565-433: The neem leaves and semi-synthetically modified into a nimbin's derived molecule to improve the bioefficacy of the compound. A new product has been formed to induce steric hindrance by transesterifying the alkyl group in the –COOMe moiety of nimbolide using Titanium isopropoxide and ethanol 6-homodesacetylnimbin that has been identified through spectroscopic and crystallographic methods: IR band at 1712 cm for

2622-486: The neem tree with a solvent or supercritical carbon dioxide . Nimbin is used for different purposes because it has multiple properties such as insecticide , antiviral , antimicrobial , anti-inflammatory , and anti-fungal . Nimbin was commonly used in traditional Indian and Chinese medicine . For example, it can be used to treat skin conditions like eczema and psoriasis . Studies have also shown that it can be used to treat diseases caused by viruses such as

2679-475: The plant (among other chemicals) can be impacted by various factors such as the different parts of the tree in which they can be found or tree age. Nimbin can be found in neem leaves, seeds and bark. This molecule can also be found in neem oil at 0.12%. Among the metabolites present in neem, nimbin is the least present chemical compound. Nimbin biosynthesis is not influenced by environmental conditions (temperature, rainfall, humidity…) because neem trees from

2736-472: The pressure or of the carbon dioxide flow rate will increase the extraction yield. However, an increase in the temperature or of the average particle size of nimbin will decrease the extraction yield. If methanol is used as a co-solvent, an increase in its concentration will improve the extraction yield. The mechanism involves H ion coordination with ethereal oxygen of the C-ring followed by cleavage to form

2793-417: The product and 1778 cm for nimbolide, elution at 26,31 min for the product and 20,76 min for nimbolide. The cytotoxic property of 6-homodesacetylnimbin was determined and compared with nimbolide, 6-desacetylnimbin, and nimbin. The absence of any activity and very little activity presented by nimbin and 6-desacetylnimbin shows that the lactone ring in nimbolide is crucial for anticancer activity. However,

2850-432: The same agro-climatic zone can have very different nimbin concentrations. Therefore, genetics can explain these differences in nimbin concentration in neem trees. Solvents can be used to extract nimbin out of neem seed kernels. The kernels are powdered and defatted with hexane and methanol . The product obtained is then filtered, concentrated under pressure and separated with ethyl acetate and water. The final crude

2907-480: The soil have the property to induce in many cultivated plants a systemic resistance against various phytopathogenic agents. This is why neem is chosen to fight against these bacteria . Cultures of these bacteria in Petri dishes then cover the nutrient agar. Zones of inhibition on certain parts of the agar can be observed, characterizing nimbin's antimicrobial side. The concentration of azadirachtin in neem extracts

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2964-414: The solubilizing effects of different CDs. Nimbin has antiviral properties. It could stop the virus from attaching to the cell since nimbin has a high bonding affinity to the viruses studied so far. Another possibility is that if the virus is already bond to its host cell, nimbin would inhibit its replicatation inside the host cell. However, nimbin's action is still unclear, and it may also depend on

3021-457: The solvent of choice for some reactions (e.g., Grignard reactions), THF fills that role in many others, where strong coordination is desirable and the precise properties of ethereal solvents such as these (alone and in mixtures and at various temperatures) allows fine-tuning modern chemical reactions. Commercial THF contains substantial water that must be removed for sensitive operations, e.g. those involving organometallic compounds . Although THF

3078-498: The synthesis of substituted THFs. Tetrahydrofuran is one of the class of pentic cyclic ethers called oxolanes . There are seven possible structures, namely, Nimbin (chemical) Nimbin is a triterpenoid isolated from the neem tree ( Azadirachta indica ). Nimbin is thought to be responsible for much of the biological activities of neem oil , and is reported to have anti-inflammatory , antipyretic , fungicidal , antihistamine and antiseptic properties. The neem tree

3135-421: The type of virus. Nimbin is one of the molecules studied to see its effects on SARS-COV-2 . It was first used because of its high binding affinity towards spike glycoprotein of SARS-COV-2. Nimbin can bond to ACE2 , the cellular receptor of SARS-COV2 . The main goal was that nimbin would get linked to the virus and that the binding would be stronger than the one between the virus and the host cell. Nimbin

3192-429: Was added slowly until the pH reached 7-8. The solution was concentrated under reduced pressure using a rotary evaporator , poured into ice-cold water, and extracted using ethyl acetate . The crude product extract was purified using flash (under nitrogen) column chromatography , and the pure product was eluted at 16% ethyl acetate in hexane. (Isonimbin - Yield: 62%). Nimbolide a natural compound has been isolated from

3249-554: Was used. The larvae were treated with N1, N2, and N3 at different concentrations (25 and 100 μm). As a result, Zebrafish larvae treated with N1, N2, and N3 have been shown to reduce inflammation by decreased in intracellular ROS levels. The results of the experience confirm that nimbin and its derivatives N1, N2, and N3 have an anti-inflammatory propertie and were able to decrease the ROS levels induced by LPS in both in vivo and in vitro . The neem tree has valuable properties for health and

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