Essential Oils: Chemistry and Pharmacological Activities.

In this review, we provide an overview of the current understanding of the main mechanisms of pharmacological action of essential oils and their components in various biological systems. A brief introduction on essential oil chemistry is presented to better understand the relationship of chemical aspects with the bioactivity of these products. Next, the antioxidant, anti-inflammatory, antitumor, and antimicrobial activities are discussed. The mechanisms of action against various types of viruses are also addressed. The data show that the multiplicity of pharmacological properties of essential oils occurs due to the chemical diversity in their composition and their ability to interfere with biological processes at cellular and multicellular levels via interaction with various biological targets. Therefore, these natural products can be a promising source for the development of new drugs.

Role of Sulphur and Heavier Chalcogens on the Antioxidant Power and Bioactivity of Natural Phenolic Compounds.

The activity of natural phenols is primarily associated to their antioxidant potential, but is ultimately expressed in a variety of biological effects. Molecular scaffold manipulation of this large variety of compounds is a currently pursued approach to boost or modulate their properties. Insertion of S/Se/Te containing substituents on phenols may increase/decrease their H-donor/acceptor ability by electronic and stereo-electronic effects related to the site of substitution and geometrical constrains. Oxygen to sulphur/selenium isosteric replacement in resveratrol or ferulic acid leads to an increase in the radical scavenging activity with respect to the parent phenol. Several chalcogen-substituted phenols inspired by Vitamin E and flavonoids have been prepared, which in some cases prove to be chain-breaking antioxidants, far better than the natural counterparts. Conjugation of catechols with biological thiols (cysteine, glutathione, dihydrolipoic acid) is easily achieved by addition to the corresponding ortho-quinones. Noticeable examples of compounds with potentiated antioxidant activities are the human metabolite 5-S-cysteinyldopa, with high iron-induced lipid peroxidation inhibitory activity, due to strong iron (III) binding, 5-S-glutathionylpiceatannol a most effective inhibitor of nitrosation processes, and 5-S-lipoylhydroxytyrosol, and its polysulfides that proved valuable oxidative-stress protective agents in various cellular models. Different methodologies have been used for evaluation of the antioxidant power of these compounds against the parent compounds. These include kinetics of inhibition of lipid peroxidation alkylperoxyl radicals, common chemical assays of radical scavenging, inhibition of the OH• mediated hydroxylation/oxidation of model systems, ferric- or copper-reducing power, scavenging of nitrosating species. In addition, computational methods allowed researchers to determine the Bond Dissociation Enthalpy values of the OH groups of chalcogen modified phenolics and predict the best performing derivative. Finally, the activity of Se and Te containing compounds as mimic of glutathione peroxidase has been evaluated, together with other biological activities including anticancer action and (neuro)protective effects in various cellular models. These and other achievements are discussed and rationalized to guide future development in the field.

Calibration of Squalene, p-Cymene, and Sunflower Oil as Standard Oxidizable Substrates for Quantitative Antioxidant Testing.

The autoxidation kinetics of stripped sunflower oil (SSO), squalene (SQ), and p-cymene ( p-C) initiated by 2,2'-azobis(isobutyronitrile) at 303 K were investigated under controlled conditions by differential oximetry in order to build reference model systems that are representative of the natural variability of oxidizable materials, for quantitative antioxidant testing. Rate constants for oxidative chain propagation ( kp) and chain termination (2 kt) and the oxidizability ( kp/√2 kt) were measured using 2,6-di- tert-butyl-4-methoxyphenol, 2,2,5,7,8-pentamethyl-6-chromanol, BHT, and 4-methoxyphenol as reference antioxidants. Measured values of kp (M-1 s-1)/2 kt (M-1 s-1)/oxidizability (M-1/2 s-1/2) at 303 K in chlorobenzene were 66.9/3.45 × 106/3.6 × 10-2, 68.0/7.40 × 106/2.5 × 10-2, and 0.83/2.87 × 106/4.9 × 10-4, respectively, for SSO, SQ, and p-C. Quercetin, magnolol, caffeic acid phenethyl ester, and 2,4,6-trimethylphenol were investigated to validate calibrations. The distinctive usefulness of the three substrates in testing antioxidants is discussed.

Methods To Measure the Antioxidant Activity of Phytochemicals and Plant Extracts.

Measurement of antioxidant properties in plant-derived compounds requires appropriate methods that address the mechanism of antioxidant activity and focus on the kinetics of the reactions involving the antioxidants. Methods based on inhibited autoxidations are the most suited for chain-breaking antioxidants and for termination-enhancing antioxidants, while different specific studies are needed for preventive antioxidants. A selection of chemical testing methods is critically reviewed, highlighting their advantages and limitations and discussing their usefulness to investigate both pure molecules and raw extracts. The influence of the reaction medium on antioxidants' performance is also addressed.

Explaining the antioxidant activity of some common non-phenolic components of essential oils.

Limonene, linalool and citral are common non-phenolic terpenoid components of essential oils, with attributed controversial antioxidant properties. The kinetics of their antioxidant activity was investigated using the inhibited autoxidation of a standard model substrate. Results indicate that antioxidant behavior of limonene, linalool and citral occurs by co-oxidation with the substrate, due to very fast self-termination and cross-termination of the oxidative chain. Rate constants kp and 2kt, (M-1s-1) at 30°C were 4.5 and 3.5×106 for limonene, 2.2 and 9.0×105 for linalool and 39 and 1.0×108 for citral. Behavior is bimodal antioxidant/pro-oxidant depending on the concentration. Calculations at the M05/6-311+g(2df,2p) level indicate that citral reacts selectively at the aldehyde C-H having activation enthalpy and energy respectively lower by 1.3 and 1.8kcal/mol compared to the most activated allyl position. Their termination-enhancing antioxidant chemistry might be relevant in food preservation and could be exploited under appropriate settings.

Antioxidant activity of essential oils.

Essential oils (EOs) are liquid mixtures of volatile compounds obtained from aromatic plants. Many EOs have antioxidant properties, and the use of EOs as natural antioxidants is a field of growing interest because some synthetic antioxidants such as BHA and BHT are now suspected to be potentially harmful to human health. Addition of EOs to edible products, either by direct mixing or in active packaging and edible coatings, may therefore represent a valid alternative to prevent autoxidation and prolong shelf life. The evaluation of the antioxidant performance of EOs is, however, a crucial issue, because many commonly used "tests" are inappropriate and give contradictory results that may mislead future research. The chemistry explaining EO antioxidant activity is discussed along with an analysis of the potential in food protection. Literature methods to assess EOs' antioxidant performance are critically reviewed.

The reaction of sulfenic acids with peroxyl radicals: insights into the radical-trapping antioxidant activity of plant-derived thiosulfinates.

Sulfenic acids play a prominent role in biology as key participants in cellular signaling relating to redox homeostasis, in the formation of protein-disulfide linkages, and as the central players in the fascinating organosulfur chemistry of the Allium species (e.g., garlic). Despite their relevance, direct measurements of their reaction kinetics have proven difficult owing to their high reactivity. Herein, we describe the results of hydrocarbon autoxidations inhibited by the persistent 9-triptycenesulfenic acid, which yields a second order rate constant of 3.0×10(6) M(-1) s(-1) for its reaction with peroxyl radicals in PhCl at 30 °C. This rate constant drops 19-fold in CH(3)CN, and is subject to a significant primary deuterium kinetic isotope effect, k(H)/k(D) = 6.1, supporting a formal H-atom transfer (HAT) mechanism. Analogous autoxidations inhibited by the Allium-derived (S)-benzyl phenylmethanethiosulfinate and a corresponding deuterium-labeled derivative unequivocally demonstrate the role of sulfenic acids in the radical-trapping antioxidant activity of thiosulfinates, through the rate-determining Cope elimination of phenylmethanesulfenic acid (k(H)/k(D) ≈ 4.5) and its subsequent formal HAT reaction with peroxyl radicals (k(H)/k(D) ≈ 3.5). The rate constant that we derived from these experiments for the reaction of phenylmethanesulfenic acid with peroxyl radicals was 2.8×10(7) M(-1) s(-1); a value 10-fold larger than that we measured for the reaction of 9-triptycenesulfenic acid with peroxyl radicals. We propose that whereas phenylmethanesulfenic acid can adopt the optimal syn geometry for a 5-centre proton-coupled electron-transfer reaction with a peroxyl radical, the 9-triptycenesulfenic is too sterically hindered, and undergoes the reaction instead through the less-energetically favorable anti geometry, which is reminiscent of a conventional HAT.

Do garlic-derived allyl sulfides scavenge peroxyl radicals?

The chain-breaking antioxidant activities of two garlic-derived allyl sulfides, i.e. diallyl disulfide (1), the main component of steam-distilled garlic oil, and allyl methyl sulfide (3) were evaluated by studying the thermally initiated autoxidation of cumene or styrene in their presence. Although the rate of cumene oxidation was reduced by addition of both 1 and 3, the dependence on the concentration of the two sulfides could not be explained on the basis of the classic antioxidant mechanism as with phenolic antioxidants. The rate of oxidation of styrene, on the other hand, did not show significant changes upon addition of either 1 or 3. This unusual behaviour was explained in terms of the co-oxidant effect, consisting in the decrease of the autoxidation rate of a substrate forming tertiary peroxyl radicals (i.e. cumene) upon addition of little amounts of a second oxidizable substrate giving rise instead to secondary peroxyl radicals. The relevant rate constants for the reaction of ROO(.) with 1 and 3 were measured as 1.6 and 1.0 M(-1) s(-1), respectively, fully consistent with the H-atom abstraction from substituted sulfides. It is therefore concluded that sulfides 1 and 3 do not scavenge peroxyl radicals and therefore cannot be considered chain-breaking antioxidants.

Antioxidant profile of ethoxyquin and some of its S, Se, and Te analogues.

6-(Ethylthio)-, 6-(ethylseleno)-, and 6-(ethyltelluro)-2,2,4-trimethyl-1,2-dihydroquinoline-three heavier chalcogen analogues of ethoxyquin-were prepared by dilithiation of the corresponding 6-bromodihydroquinoline followed either by treatment with the corresponding diethyl dichalcogenide (sulfur derivative) or by insertion of selenium/tellurium into the carbon-lithium bond, oxidation to a diaryl dichalcogenide, borohydride reduction, and finally alkylation of the resulting areneselenolate/arenetellurolate. Ethoxyquin, its heavier chalcogen analogues, and the corresponding 6-PhS, 6-PhSe, and 6-PhTe derivatives were assayed for both their chain-breaking antioxidative capacity and their ability to catalyze reduction of hydrogen peroxide in the presence of a stoichiometric amount of a thiol reducing agent (thiol peroxidase activity). Ethoxyquin itself turned out to be the best inhibitor of azo-initiated peroxidation of linoleic acid in a water/chlorobenzene two-phase system. In the absence of N-acetylcysteine as a coantioxidant in the aqueous phase, it inhibited peroxidation as efficiently as alpha-tocopherol but with a more than 2-fold longer inhibition time. In the presence of 0.25 mM coantioxidant in the aqueous phase, the inhibition time was further increased by almost a factor of 2. This is probably due to thiol-mediated regeneration of the active antioxidant across the lipid-aqueous interphase. The ethyltelluro analogue 1d of ethoxyquin was a similarly efficient quencher of peroxyl radicals compared to the parent in the two-phase system, but less regenerable. Ethoxyquin was found to inhibit azo-initiated oxidation of styrene in the homogeneous phase (chlorobenzene) almost as efficiently (kinh = (2.0 +/- 0.2) x 106 M-1 s-1) as alpha-tocopherol with a stoichiometric factor n = 2.2 +/- 0.1. At the end of the inhibition period, autoxidation was additionally retarded, probably by ethoxyquin nitroxide formed during the course of peroxidation. The N-H bond dissociation enthalpy of ethoxyquin (81.3 +/- 0.3 kcal/mol) was determined by a radical equilibration method using 2,6-dimethoxyphenol and 2,6-di-tert-butyl-4-methylphenol as equilibration partners. Among the investigated compounds, only the tellurium analogues 1d and, less efficiently, 1g had a capacity to catalyze reduction of hydrogen peroxide in the presence of thiophenol. Therefore, analogue 1d is the only antioxidant which is multifunctional (chain-breaking and preventive) in character and which can act in a truly catalytic fashion to decompose both peroxyl radicals and organic hydroperoxides in the presence of suitable thiol reducing agents.