Limonoids are a class of naturally occurring organic compounds belonging to the triterpenoid family, primarily found in citrus fruits and various plants such as neem (Azadirachta indica), andiroba (Carapa guaianensis), Cipadessa cinerascensa, Entandrophragma angolense, Chisocheton ceramicus Miq., Melia azedarach, Chisocheton lasiocarpus, Trichilia rubescens, Cipadessa baccifera, Khaya senegalensis, Khaya ivorensis, Aglaia Edulis, Azadirachta indica, Tetradium and other plants of the genus Cedrela and Swietenia. They are secondary metabolites produced by plants as a defense mechanism against herbivores and pathogens. Limonoids have garnered significant attention due to their wide range of biological activities, including anti-inflammatory, anticancer, antimicrobial, and insect-repellent properties. Their name is derived from "limon," meaning lemon, because they were first identified in citrus plants. They are generally bitter in taste and contribute to the characteristic flavor of certain fruits.
Chemical Composition and Structure
Limonoids have a tetranortriterpenoid structure, typically composed of a furan ring and a core triterpene skeleton. Their molecular structure is highly oxygenated and includes cyclic esters, lactones, and ketone groups. Some common limonoids include limonin, nomilin, and andirobin. Limonoids are structurally diverse, with variations in the side chains and functional groups contributing to their unique biological properties. These structural modifications influence their reactivity and interactions with biological systems, enhancing their therapeutic potential.
Physical Properties
Limonoids are typically crystalline or amorphous solids, with solubility in organic solvents such as ethanol, chloroform, and acetone, but they are insoluble in water. They exhibit a bitter taste, which is more pronounced in certain limonoid compounds, such as limonin found in citrus fruits. These compounds are generally stable at room temperature and retain their chemical properties under normal storage conditions. Due to their bitterness, limonoids can affect the flavor profile of products they are included in.
Production Process
Limonoids are extracted from plant sources through various methods, including:
Extraction: Plant material, such as fruit peels or seeds, is subjected to solvent extraction using ethanol, methanol, or hexane to separate the limonoids from other plant constituents.
Concentration: The extract is concentrated by evaporating the solvent, leaving behind the limonoid-rich fraction.
Purification: Limonoids are purified using techniques like chromatography, which helps isolate individual compounds such as limonin or nomilin. This step is essential for obtaining highly concentrated and pure forms for pharmaceutical and industrial applications.
Crystallization: In some cases, limonoids are crystallized to improve their purity and facilitate their incorporation into various formulations.
Applications
Medical: Limonoids have significant therapeutic applications due to their bioactive properties. They have been studied for their anticancer potential, particularly in inhibiting the proliferation of cancer cells and inducing apoptosis. Their anti-inflammatory and antioxidant activities make them useful in treatments for chronic diseases such as arthritis and cardiovascular conditions. Limonoids also exhibit antiviral, antifungal, and antibacterial properties, offering promise in combating infections.
Cosmetics: Due to their antioxidant and anti-inflammatory effects, limonoids are used in cosmetic formulations for skin care. They help protect the skin from oxidative stress and environmental damage while also promoting skin regeneration and healing. Limonoids are also included in insect-repellent formulations, particularly those derived from neem and andiroba oil, leveraging their natural insecticidal properties.
Food: In the food industry, limonoids are considered bioactive compounds that contribute to the health benefits of citrus fruits. Although they impart a bitter taste, their presence in citrus juice and other food products has been associated with improved digestive health and enhanced immune responses. Limonoids are sometimes used as natural preservatives due to their antimicrobial properties.
Agriculture and Insect Control: Limonoids, especially those derived from neem oil, are widely used in organic agriculture as natural pesticides. Their insecticidal properties make them effective in controlling pests without harming beneficial insects or the environment. They act by disrupting the reproductive cycle and feeding patterns of insects, offering an eco-friendly alternative to synthetic pesticides.
Environmental and Safety Considerations
Limonoids are generally regarded as safe for use in food, cosmetics, and pharmaceutical applications, particularly because they are naturally occurring compounds in many edible plants. However, due to their bitterness, their levels in food products are often regulated to ensure palatability. Limonoids used in insect control are non-toxic to humans and animals and pose no significant environmental hazards, making them an ideal component in sustainable pest management practices.
It is important to ensure that limonoids are extracted through environmentally friendly processes to minimize waste and preserve the ecosystems where limonoid-rich plants, such as neem or andiroba, grow.
References__________________________________________________________________________
Roy A, Saraf S. Limonoids: overview of significant bioactive triterpenes distributed in plants kingdom. Biol Pharm Bull. 2006 Feb;29(2):191-201. doi: 10.1248/bpb.29.191.
Abstract. The search for limonoids started long back when scientists started looking for the factor responsible for bitterness in citrus which has negative impact on citrus fruit and juice industry worldwide. The term limonoids was derived from limonin, the first tetranortriterpenoid obtained from citrus bitter principles. Compounds belonging to this group have exhibited a range of biological activities like insecticidal, insect antifeedant and growth regulating activity on insects as well as antibacterial, antifungal, antimalarial, anticancer, antiviral and a number of other pharmacological activities on humans. Although hundreds of limonoids have been isolated from various plants but, their occurrence in the plant kingdom is confined to only plant families of order Rutales and that too more abundantly in Meliaceae and Rutaceae, and less frequently in Cneoraceae and Harrisonia sp. of Simaroubaceae. Limonoids are highly oxygenated, modified terpenoids with a prototypical structure either containing or derived from a precursor with a 4,4,8-trimethyl-17-furanylsteroid skeleton. All naturally occurring citrus limonoids contain a furan ring attached to the D-ring, at C-17, as well as oxygen containing functional groups at C-3, C-4, C-7, C-16 and C-17. The structural variations of limonoids found in Rutaceae are less than in Meliaceae and are generally limited to the modification of A and B rings, the limonoids of Meliaceae are more complex with very high degree of oxidation and rearrangement exhibited in the parent limonoid structure. To counter the problem of bitterness in citrus juice and products genetic engineering of citrus to maximize the formation of limonoid glucosides for reducing limonoid bitterness is the focus of recent and future research. Regarding the biological activities of limonoids the investigations are to be directed towards detailed characterization, quantification, and designing a simple as well as versatile synthetic route of apparently important limonoids. Extraction methods too should be optimized; evaluation and establishment of pharmaco-dynamic and kinetic principles, and structure activity relationships should be a key goal associated with limonoids so that they can be safely introduced in our arsenal of pharmaceuticals to safeguard the humanity from the wrath of disease and its discomfort.
Gualdani R, Cavalluzzi MM, Lentini G, Habtemariam S. The Chemistry and Pharmacology of Citrus Limonoids. Molecules. 2016 Nov 13;21(11):1530. doi: 10.3390/molecules21111530.
Abstract. Citrus limonoids (CLs) are a group of highly oxygenated terpenoid secondary metabolites found mostly in the seeds, fruits and peel tissues of citrus fruits such as lemons, limes, oranges, pumellos, grapefruits, bergamots, and mandarins. Represented by limonin, the aglycones and glycosides of CLs have shown to display numerous pharmacological activities including anticancer, antimicrobial, antioxidant, antidiabetic and insecticidal among others. In this review, the chemistry and pharmacology of CLs are systematically scrutinised through the use of medicinal chemistry tools and structure-activity relationship approach. Synthetic derivatives and other structurally-related limonoids from other sources are include in the analysis. With the focus on literature in the past decade, the chemical classification of CLs, their physico-chemical properties as drugs, their biosynthesis and enzymatic modifications, possible ways of enhancing their biological activities through structural modifications, their ligand efficiency metrics and systematic graphical radar plot analysis to assess their developability as drugs are among those discussed in detail.
Tong YN, Guo J, Chen YF, Zhang GX. Antimicrobial limonoids from the seeds of Cipadessa cinerascensa. J Asian Nat Prod Res. 2022 Mar;24(3):238-244. doi: 10.1080/10286020.2021.1915996.
Abstract. Phytochemical investigation on the 90% EtOH extract of the seeds of Cipadessa cinerascensa led to the isolation of three new limonoids, cinerascenoids A-C (1-3). Structural elucidation of all the compounds were performed by spectral methods such as 1 D and 2 D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy. All the limonoids were in vitro evaluated for their antimicrobial activities against six pathogenic microorganisms. Limonoids 1 and 2 exhibited some activities against three Gram negative bacteria with MIC values less than 60 μg/ml.
Youn I, Wu Z, Papa S, Burdette JE, Oyawaluja BO, Lee H, Che CT. Limonoids and other triterpenoids from Entandrophragma angolense. Fitoterapia. 2021 Apr;150:104846. doi: 10.1016/j.fitote.2021.104846. Epub 2021 Feb 12. PMID: 33588006; PMCID: PMC8318517.
Nagini S, Palrasu M, Bishayee A. Limonoids from neem (Azadirachta indica A. Juss.) are potential anticancer drug candidates. Med Res Rev. 2024 Mar;44(2):457-496. doi: 10.1002/med.21988. Epub 2023 Aug 17. PMID: 37589457.
Limonoids 
