Thymol

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Thymol
IUPAC name

2-Isopropyl-5-methylphenol
Identifiers
CAS number 89-83-8 YesY
ChemSpider 21105998 YesY
UNII 3J50XA376E YesY
DrugBank DB02513
KEGG D01039 YesY
ChEBI CHEBI:27607 YesY
ChEMBL CHEMBL29411 YesY
ATCvet code QP53AX22
Jmol-3D images Image 1
Properties
Molecular formula C10H14O
Molar mass 150.22 g mol−1
Density 0.96 g/cm3
Melting point

51 °C, 324 K, 124 °F
Boiling point

232 °C, 505 K, 450 °F
Solubility in water Insoluble in water[1]
 YesY (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Thymol (also known as 2-isopropyl-5-methylphenol, IPMP) is a natural monoterpene phenol derivative of cymene, C10H14O, isomeric with carvacrol, found in oil of thyme, and extracted from Thymus vulgaris (common thyme) and various other kinds of plants as a white crystalline substance of a pleasant aromatic odor and strong antiseptic properties. Thymol also provides the distinctive, strong flavor of the culinary herb thyme, also produced from T. vulgaris.

Contents

Biological activity [edit]

Thymol is part of a naturally occurring class of compounds known as biocides, with strong antimicrobial attributes when used alone or with other biocides such as carvacrol. In addition, naturally-occurring biocidal agents such as thymol can reduce bacterial resistance to common drugs such as penicillin.[2] Numerous studies have demonstrated the antimicrobial effects of thymol, ranging from inducing antibiotic susceptibility in drug-resistant pathogens to powerful antioxidant properties.[3] Research demonstrates that naturally occurring biocides such as thymol and carvacrol reduce bacterial resistance to antibiotics through a synergistic effect,[2] and thymol has been shown to be an effective fungicide,[4] particularly against fluconazole-resistant strains. This is especially relevant given that opportunistic Candida (fungus) infections can cause severe systemic infections in immunocompromised patients and current treatments are highly toxic, often result in drug-resistant Candida strains, and have low efficacy. Compounds in the essential oils of one type of oregano have demonstrated antimutagenic effects, and in particular carvacrol (isomeric with thymol) and thymol were demonstrated to have a strong antimutagenic effect.[5] In addition, there is evidence that thymol has antitumor properties.[6] Though the exact mechanism is unknown, there is evidence to suggest that thymol possesses at least some of its biocidal properties via membrane disruption.[7]

Chemistry [edit]

Thymol is only slightly soluble in water at neutral pH, but it is extremely soluble in alcohols and other organic solvents. It is also soluble in strongly alkaline aqueous solutions due to deprotonation of the phenol.

Synonyms include isopropyl-m-cresol, hydroxycymene,[8] 1-methyl-3-hydroxy-4-isopropylbenzene, 2-hydroxy-1-isopropyl-4-methylbenzene; 3-hydroxy-p-cymene, 3-methyl-6-isopropylphenol, 5-methyl-2-(1-methylethyl)phenol, 5-methyl-2-isopropyl-1-phenol, 5-methyl-2-isopropylphenol, 6-isopropyl-3-methylphenol, 6-isopropyl-m-cresol, Apiguard, NSC 11215, NSC 47821, NSC 49142, thyme camphor, m-thymol, and p-cymen-3-ol.[9]

Thymol has a refractive index of 1.5208[10] and an experimental dissociation exponent (pKa) of 10.59 ± 0.10.[11] Thymol absorbs maximum UV radiation at 274 nm.[12]

History [edit]

The Ancient Egyptians used thymol and carvacrol in the form of a preparation from the thyme plant (a member of the mint family), because of their ability to preserve mummies. Thymol and carvacrol are now known to kill bacteria and fungi, making thyme well suited for such purposes.

In Ancient Greece, thyme was widely used for its aromatic qualities, being burned as incense in sacred temples. Thyme was also a symbol of courage and admiration with the phrase "the smell of thyme" being a saying that reflected praise unto its subject. Thyme's association with bravery continued throughout medieval times when it was a ritual for women to give their knights a scarf that had a sprig of thyme placed over an embroidered bee. Since the 16th century, thyme oil has been used for its antiseptic properties, both as mouthwash and a topical application.

The bee balms Monarda fistulosa and Monarda didyma, North American wildflowers, are natural sources of thymol. The Blackfoot Native Americans recognized this plant's strong antiseptic action, and used poultices of the plant for skin infections and minor wounds. A tisane made from the plant was also used to treat mouth and throat infections caused by dental caries and gingivitis.[13]

The crystalline substance thymol was discovered by Caspar Neumann in 1719[clarification needed]. The chemical was synthesized in pure form in 1842 by von M. Lallemand, who used elementary chemical analysis to characterize it by determining the correct ratio of carbon, hydrogen, and oxygen that make up the thymol molecule. Friedlieb Ferdinand Runge also studied the chemistry of this substance. Alain Thozet and M. Perrin first published the crystal structure analysis with the exact determination of the structural atoms.

Uses [edit]

Thymol

Thymol has antimicrobial activity because of its phenolic structure, and has shown antibacterial activity against bacterial strains including Aeromoans hydrophila and Staphylococcus aureus.[14] This antibacterial activity is caused by inhibiting growth and lactate production, and by decreasing cellular glucose uptake.[15] Thymol has been used in alcohol solutions and in dusting powders for the treatment of tinea or ringworm infections, and was used in the United States to treat hookworm infections.[16] It is also used as a preservative in halothane, an anaesthetic, and as an antiseptic in mouthwash. When used to reduce plaque and gingivitis, thymol has been found to be more effective when used in combination with chlorhexidine than when used purely by itself.[17] Thymol is also the active antiseptic ingredient in some toothpastes, such as Euthymol.

There is evidence supporting the belief that thymol, when applied two to three times daily, can eliminate certain kinds of fungal infections that affect fingernails and toenails in humans.[citation needed] Regular application to the affected nail over periods of about three months has been shown to eliminate the affliction by effectively preventing further progress;[citation needed] by simply cutting the nail as one normally would, all infected material is eventually eliminated.[18] The antifungal nature of thymol is caused by thymol's ability to alter in the hyphal morphology and cause hyphal aggregates, resulting in reduced hyphal diameters and lyses of hyphal wall.[19] Additionally, thymol is lipophilic, enabling it to interact with the cell membrane of fungus cells, altering cell membrane permeability permitting the loss of macromolecules.[20]

Recent medical research on rats concludes that "Thyme extract had relaxing effects on organs possessing β2-receptors (uterus and trachea)."[21]

In a 1994 report released by five major cigarette companies, thymol was listed as one of 599 additives to cigarettes.[22]

Thymol has been used to successfully control varroa mites and prevent fermentation and the growth of mold in bee colonies, methods developed by beekeeper R.O.B. Manley.[23]

Thymol is also used as a rapidly degrading, non-persisting pesticide.[24]

Derivatives of thymol and carvacrol with increased antimicrobial activities have been developed.[25] The preparation of methacrylic and p-styrenesulfonic acid esters of thymol could lead to less toxic macromolecular biocides, which can be attached to a polymeric backbone.[26]

A minor use of thymol is in book and paper conservation: Paper with mold damage can be sealed in bags with thymol crystals to kill fungal spores. However, this practice is not currently recommended due to apparent accelerated degradation suffered by these objects.[citation needed]

Thymol—named after the herb itself—is the primary volatile oil constituent of thyme, and its health-supporting effects are well documented. In studies on aging in rats, thymol has been found to protect and significantly increase the percentage of healthy fats found in cell membranes and other cell structures. In particular, the amount of DHA (docosahexaenoic acid, an omega-3 fatty acid) in brain, kidney, and heart cell membranes was increased after dietary supplementation with thyme. In other studies looking more closely at changes in the brains cells themselves, researchers found that the maximum benefits of thyme occurred when the food was introduced very early in the lifecycle of the rats, but was less effective in offsetting the problems in brain cell aging when introduced late in the aging process.

Thyme also contains a variety of flavonoids, including apigenin, naringenin, luteolin, and thymonin. These flavonoids increase thyme's antioxidant capacity, and combined with its status as a very good source of manganese, give thyme a high standing on the list of anti-oxidant foods.

List of plants that contain thymol [edit]

Toxicology and environmental impacts [edit]

The U.S. Environmental Protection Agency (EPA) reviewed the literature and published research on the toxicology and environmental impact of thymol in 2009 and concluded that "Thymol has minimal potential toxicity and poses minimal risk"[37][38]

However, in 2011 the U.S. Food and Drug Administration published a graph of the top adverse events for Thymol over time.[39] Data gathered by their Adverse Event Reporting System (AERS) shows a total of 303 adverse events from 2004 to 2011 in the categories of: oral soft tissue, psychiatric (malaise), neurological, gastrointestinal, dermal, and respiratory symptoms.

Environmental breakdown and use as a pesticide [edit]

Studies have shown that hydrocarbon monoterpenes and thymol in particular degrade rapidly (DT50 16 days in water, 5 days in soil[24]) in the environment and are, thus, low risks because of rapid dissipation and low bound residues,[24] supporting the use of thymol as a pesticide agent that offers a safe alternative to other more persistent chemical pesticides that can be dispersed in runoff and produce subsequent contamination.

Compendial status [edit]

See also [edit]

Thymohydroquinone
Thymoquinone
Thymohydroquinone dimethyl ether
Nigella sativa
Water hemp

Notes and references [edit]

  1. ^ CRC Handbook of Chemistry and Physics, 1977
  2. ^ a b Palaniappan, K. and Holley, R.A. Use of natural antimicrobials to increase antibiotic susceptibility of drug resistant bacteria doi:10.1016/j.ijfoodmicro.2010.04.001.
  3. ^ Ü. Ündeg˘er a, A. Bas�aran b, G.H. Degen c, N. Bas�aran a Antioxidant activities of major thyme ingredients and lack of (oxidative)DNA damage in V79 Chinese hamster lung fibroblast cells at low levels of carvacrol and thymol doi:10.1016/j.fct.2009.05.020
  4. ^ Ahmad A, et al, Proton translocating ATPase mediated fungicidal activity of eugenol and thymol,Fitoterapia (2010), doi:10.1016/j.fitote.2010.07.020
  5. ^ N. Mezzouga et. al Investigation of the mutagenic and antimutagenic effects of Origanum compactum essential oil and some of its constituents doi:10.1016/j.mrgentox.2007.01.011
  6. ^ Andersen A, Final report on the safety assessment of sodium p-chloro-mcresol,p-chloro-m-cresol, chlorothymol, mixed cresols, mcresol,o-cresol, p-cresol, isopropyl cresols, thymol, o-cymen-5-ol, and carvacrol.Int J Toxicol. 2006;25 Suppl 1:29-127
  7. ^ D. Trombetta et. al, Mechanisms of Antibacterial Action of Three Monoterpenes, doi:10.1128/AAC.49.6.2474–2478.2005
  8. ^ Webster's 1913 dictionary
  9. ^ CAS Registry: Data were obtained from SciFinder
  10. ^ Mndzhoyan, A. L. Thymol from Thymus kotschyanus. Sbornik Trudov Armyanskogo Filial. Akad. Nauk. 1940, 25-28.
  11. ^ CAS Registry: Data were obtained from SciFinder
  12. ^ Norwitz, G.; Nataro, N.; Keliher, P. N. (1986). "Study of the Steam Distillation of Phenolic Compounds Using Ultraviolent Spectrometry". Anal. Chem 58 (639-640): 641. 
  13. ^ Edible and Medicinal Plants of the West, Gregory L. Tilford, ISBN 0-87842-359-1
  14. ^ Dorman, H.J.D.; Deans, S.G. (2000). "Antimicrobial agents from plants: antibacterial activity of plant volatile oils". J. Appl. Microbiol 88: 308–316. 
  15. ^ Evans, J.; Evans, J. D. (2000). "Effects of thymol on ruminal microorganisms". Curr. Microbiol 41: 336. 
  16. ^ The Rural School and Hookworm Disease. Jno A Ferrell, 1914 http://books.google.com/books?id=omYAAAAAYAAJ&dq=THE+RURAL+SCHOOL+AND+hookworm+disease&printsec=frontcover&source=bl&ots=MzB2Qc83MN&sig=XuzEewv27ty90cJ3IxS8fhyh0A4&hl=en&ei=KHKUSsOVKY_QsQOmnNnZBg&sa=X&oi=book_result&ct=result&resnum=1#v=onepage&q=&f=true
  17. ^ Filoche, S.K.; Soma, K.; Sissons, C.H. (2005). "Antimicrobial effects of essential oils in combination with chlorhexidine digluconate". Oral Microbiol Immunol 20: 221–225. 
  18. ^ "Toenail Fungus". The New York Times. 
  19. ^ Numpaque, M. A.; Oviedo, L. A.; Gil, J. H.; Garcia, C. M.; Durango, D. L. (2011). "Thymol and carvacrol: biotransformation and antifungal activity against the plant pathogenic fungi Colletotrichum acutatum and Botryodiplodia theobromae". Trop. Plant Pathol 36: 3–13. 
  20. ^ Segvic Klaric, M.; Kosalec, I.; Mastelic, J.; Pieckova, E.; Pepeljnak, S. Antifungal activity of thyme (Thymus vulgaris L.) essential oil and thymol against moulds from damp dwellings Lett. Appl. Microbiol. 2007, 44, 36-42.
  21. ^ Wienkötter, N.; F. Begrow, U. Kinzinger, D. Schierstedt, E.J. Verspohl (2007). "The Effect of Thyme Extract on β2-Receptors and Mucociliary Clearance". Planta Medica 73 (7): 629–635. doi:10.1055/s-2007-981535. PMID 17564943. 
  22. ^ List of 599 Cigarette additives
  23. ^ Almond farmers seek healthy bees
  24. ^ a b c D. Hu and J. Coats, Evaluation of the environmental fate of thymol and phenethyl propionate in the laboratory, Pest Manag Sci 64:775–779 (2008) doi:10.1002/ps.1555
  25. ^ Mathela, CS; Singh, KK; Gupta, VK (2010). "Synthesis and in-vitro antibacterial activity of thymol and carvacrol derivatives" (PDF). Acta Poloniae Pharmaceutica 67 (4): 375–380. 
  26. ^ N. Moszner, U. Salz, V. Rheinberger (1994) "Synthesis and polymerization of unsaturated derivatives of thymol". Polymer Bulletin 33 (1): 7-12. doi:10.1007/BF00313467
  27. ^ V. A. Zamureenko, N. A. Klyuev, B. V. Bocharov, V. S. Kabanov and A. M. Zakharov, "An investigation of the component composition of the essential oil of Monarda fistulosa", Chemistry of Natural Compounds, Vol. 25, No. 5, Sep. 1989.
  28. ^ a b Bouchra, Chebli et al.; Achouri, Mohamed; Idrissi Hassani, L.M; Hmamouchi, Mohamed (2003). "Chemical composition and antifungal activity of essential oils of seven Moroccan Labiatae against Botrytis cinerea Pers: Fr". Journal of Ethnopharmacology 89 (1): 165–169. doi:10.1016/S0378-8741(03)00275-7. PMID 14522450. 
  29. ^ Liolios, C.C. et al.; Gortzi, O; Lalas, S; Tsaknis, J; Chinou, I (2009). "Liposomal incorporation of carvacrol and thymol isolated from the essential oil of Origanum dictamnus L. and in vitro antimicrobial activity". Food Chemistry (Elsevier) 112 (1): 77–83. doi:10.1016/j.foodchem.2008.05.060. 
  30. ^ Ozkan, Gulcan et al.; Baydar, H; Erbas, S (2009). "The influence of harvest time on essential oil composition, phenolic constituents and antioxidant properties of Turkish oregano (Origanum onites L.)". Journal of the Science of Food and Agriculture 90 (2): 205–209. doi:10.1002/jsfa.3788. PMID 20355032. 
  31. ^ Lagouri, Vasiliki et al.; Blekas, George; Tsimidou, Maria; Kokkini, Stella; Boskou, Dimitrios (1993). "Composition and antioxidant activity of essential oils from Oregano plants grown wild in Greece". Zeitschrift für Lebensmitteluntersuchung und -Forschung A 197 (1): 1431–4630. doi:10.1007/BF01202694. 
  32. ^ Kanias, G. D. et al.; Souleles, C.; Loukis, A.; Philotheou-Panou, E. (1998). "Trace elements and essential oil composition in chemotypes of the aromatic plant Origanum vulgare". Journal of Radioanalytical and Nuclear Chemistry 227 (1 – 2): 23–31. doi:10.1007/BF02386426. 
  33. ^ Figiel, Adam et al.; Szumny, Antoni; Gutiérrez-Ortíz, Antonio; Carbonell-Barrachina, ÁNgel A. (2010). "Composition of oregano essential oil (Origanum vulgare) as affected by drying method". Journal of Food Engineering 98 (2): 240–247. doi:10.1016/j.jfoodeng.2010.01.002. 
  34. ^ a b Goodner, K.L. et al.; Mahattanatawee, K; Plotto, A; Sotomayor, J; Jordan, M (2006). "Aromatic profiles of Thymus hyemalis and Spanish T. vulgaris essential oils by GC–MS/GC–O". Industrial Crops and Products 24 (3): 264–268. doi:10.1016/j.indcrop.2006.06.006. 
  35. ^ Lee, Seung-Joo et al.; Umano, K; Shibamoto, T; Lee, K (2005). "Identification of volatile components in basil (Ocimum basilicum L.) and thyme leaves (Thymus vulgaris L.) and their antioxidant properties". Food Chemistry 91 (1): 131–137. doi:10.1016/j.foodchem.2004.05.056. 
  36. ^ Moldão-Martins, M. et al.; Palavra, A; Beiraodacosta, M; Bernardogil, M (2000). "Supercritical CO2 extraction of Thymus zygis L. subsp. sylvestris aroma". The Journal of Supercritical Fluids 18 (1): 25–34. doi:10.1016/S0896-8446(00)00047-4. 
  37. ^ 40 CFR part 180, volume 74, 3-25-2009 page 12613
  38. ^ http://www.epa.gov/fedrgstr/EPA-PEST/2009/March/Day-25/p6262.pdf
  39. ^ http://www.drugcite.com/?q=thymol&a=&s=
  40. ^ Xu, J. et al.; Zhou, F; Ji, BP; Pei, RS; Xu, N (2005). "The antibacterial mechanism of carvacrol and thymol against Escherichia coli". Letters in Applied Microbiology (John Wiley & Sons) 47 (3): 174–179. doi:10.1111/j.1472-765X.2008.02407.x. PMID 19552781. 
  41. ^ Rivas, Lucia et al.; McDonnell, MJ; Burgess, CM; O'Brien, M; Navarro-Villa, A; Fanning, S; Duffy, G (2010). "Inhibition of verocytotoxigenic Escherichia coli in model broth and rumen systems by carvacrol and thymol". International Journal of Food Microbiology (Elsevier) 139 (1 – 2): 70–78. doi:10.1016/j.ijfoodmicro.2010.01.029. PMID 20153068. 
  42. ^ a b Ettayebi, Khalil et al.; El Yamani, Jamal; Rossi-Hassani, Badr-Din (2006). "Synergistic effects of nisin and thymol on antimicrobial activities in Listeria monocytogenes and Bacillus subtilis". FEMS Microbiology Letters (John Wiley & Sons) 183 (1): 191–195. doi:10.1111/j.1574-6968.2000.tb08956.x. PMID 10650225. 
  43. ^ The British Pharmacopoeia Secretariat (2009). "Index, BP 2009". Retrieved 5 July 2009. 
  44. ^ "Japanese Pharmacopoeia". Retrieved 21 April 2010. 

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