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 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 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 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.
Extraction of nimbin from neem
Quantification of nimbin in neem Nimbin can be quantified in neem using advanced mass spectrometry or HPLC techniques. The concentration of this chemical in 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 the same agro-climatic zone can have very different nimbin concentrations. Therefore, genetics can explain these differences in nimbin concentration in neem trees.
Extraction with a solvent 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 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.
Extraction with supercritical carbon dioxide 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 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 cm3/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 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 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.
Synthesis and derived molecules
Rearrangement of nimbin to isonimbin The mechanism involves H+ ion coordination with ethereal oxygen of the C-ring followed by cleavage to form 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 180o 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 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 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%).
Semi-synthetic modification to a nimbin derivative: nimbolide to 6-homodesacetylnimbin and 6-desacetylnimbin Nimbolide a natural compound has been isolated from the neem leaves and semi-synthetically modified into a nimbin's derived molecule to improve the bioefficacy of the compound.
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