INTRODUCTION:
An antioxidant is a molecule that inhibits the oxidant of other molecules. Oxidation is a chemical reaction that can produce free radicals leading to chain reactions that may damage cells. Antioxidant such as thiols terminates these chain reactions by removing free radical intermediates and inhibits other oxidation reactions. The term “antioxidant” is mainly used for two different groups of substances; industrial chemicals which are added to products to prevent oxidation, and natural chemicals found in food and body tissues which are said to have beneficial health effects1,2. To balance the oxidative state, plants and animals maintain complex systems of overlapping antioxidants, such as glutathione and enzymes produced internally3,4.
Antioxidant dietary supplements do not improve health nor are they effective in preventing diseases by randomized clinical trials including supplements of beta- Carotene. Supplementation with selenium does not reduce the risk of cardiovascular disease5,6. Oxidative stress can be considered as either a cause or consequence of some disease, an area of research stimulating drug development for antioxidant compounds for use as potential therapies7.
Relation to diet:
Although certain levels of antioxidant vitamins in the diet are required for good health, there is considerable debate on whether a whether antioxidant rich foods have anti-disease activity8,9,10. Some authors dispute the hypothesis that antioxidant vitamins could prevent chronic diseases11,12. Polyphenols, which often have antioxidant properties in vitro, are not necessarily antioxidants in vivo due to extensive metabolism13. Many polyphenols may have non - antioxidant roles in minute concentrations that affect cell-to-cell signaling, receptor sensitivity, inflammatory enzyme activity or gene regulation14,15,16,17. Although dietary antioxidants have been investigated for potential effects on neurodegenerative diseases such as Alzheimer’s disease, Parkinsons disease and amyotrophic lateral Sclerosis18,19 these studies have been inconclusive20,21,22. As of November 2014, other antioxidants are being studied as neuroprotectants23. Common properties may interface with the efficacy of certain anticancer meditation and radiation24,25.
The evolution of angiosperm plants between 50 and 200 million years ago resulted in the development of many antioxidant pigments. Particularly during the Jurassic period as chemical defenses against reactive oxygen species that are byproducts of photosynthesis. Originally the term antioxidant specially referred to a chemical that prevents the consumption of oxygen. In the late 19th and early 20th centuries, extensive study concentrated on the use of antioxidant in important industrial processes, such as the prevention of metal corrosion, the vulcanization of rubber, and the polymerization of fuels in the fouling of internal combustion engines26,27. Early research on the role of antioxidants in biology focused on the use in preventing the oxidation of unsaturated fats, which is the cause of rancidity. Antioxidant activity could be measured simply by placing the fat in a closed container with oxygen and measuring the rate of oxygen consumption. However it was the identification of vitamins A, C and E as antioxidants in the biochemistry of living organisms. The possible mechanisms of action of antioxidants were first explored when it was recognized that a substance with anti-oxidative activity is likely to be one that it if self readily oxidized. Research into have vitamins prevents the process of lipid per oxidation led to the identification of antioxidants as reducing agents that prevent oxidative reactions often by scavenging reactive oxygen spices before they can damage cells28,29.
Toxicity associated with high doses of water soluble antioxidants such as ascorbic acid are less of a concern, as these compounds can be excreted rapidly in wine. More seriously, very high doses of some antioxidants may have harmful long- term effects30. These harmful effects may also be seen in non-smokers, as a recent meta-analysis including data from approximately 230,000 patients showed that β-Carotene, Vitamin A supplementation is associated with increased mortality. While antioxidant supplementation is widely used in attempts to prevent the development of cancer, antioxidant may interface with cancer treatments31, since the environment of cancer cells causes high levels of oxidative stress, making these cells more susceptible to the further oxidative stress induced by treatments32. As a result by reducing the redox stress in cancer cells, antioxidant supplements could decrease the effectiveness of radiotherapy and chemotherapy33,34. On the other hand, other reviews have suggested that antioxidants could reduce side effects or increase survival times35.
Organisms contain a complex network of antioxidant metabolites and enzymes that work together to prevent oxidative damage to cellular compounds such as DNA, proteins and lipids36,37. In general, antioxidant systems either prevent these reactive species from being formed or remove them before they can damage vital components of the cell. However, reactive oxygen species also have useful cellular functions, such as redox signaling. Thus the function of antioxidant systems is not to remove oxidants entirely, but instead to keep them at an optimum level38. The reactive oxygen species produced in cells include hydrogen, peroxide, hypochlorous acid and free radical such as hydroxyl radical and the superoxide anion55. The hydroxyl radical is particularly unstable and will react rapidly and non- specifically with most biological molecules. This species is produced from hydrogen peroxide in metal catalyzed redox reactions such as the Fenton reaction39. These oxidants can damage cells by starting chemical chain reactions such as lipid per oxidation or by oxidizing DNA or proteins. Damage to DNA can cause mutation and possibly cancer if not reversed by DNA repair mechanisms, while damage to protein causes enzyme inhibition denaturation and protein degradation40,41,42. The use of oxygen as part of the process for generating metabolic energy produces reactive oxygen species43.
Metabolites:
Antioxidants are classified into two broad divisions, depending on whether they are soluble in water or in lipids. In general water soluble antioxidants react with oxidants in the cell cytosol and the blood plasma, while lipid soluble antioxidants protect cell membranes from lipid peroxidation44. These compounds may be synthesized in the body or obtained from the diet45. The different antioxidants are present at a wide range of concentrations in body fluids and tissues. Some antioxidants are only found in a few organisms and these compounds can be important in pathogens and can be virulence factors46. The relative importance and interactions between these different antioxidants is a very complex question, with the various metabolites and enzyme systems having synergistic and interdependent effects on one another47. The action of one antioxidant may therefore depend on the proper function of other members of the antioxidant system. The amount of protection provided by any one antioxidant will also depends on its concentration, its reactivity towards the particular reactive oxygen species being considered and the status of the antioxidants with which it interacts.
Some compounds contribute to antioxidant defense by chelating transition metals and preventing them from catalyzing the production of free radial in the cell. Particularly important is the ability to sequester iron, which is the function of iron-binding proteins such as transferring and ferritin. Selenium and Zinc are commonly referred to as antioxidant nutrients but these chemical elements have no antioxidant action themselves and are instead required for the activity of some antioxidant enzymes48. Glutathione is a cysteine containing peptide found in most forms of aerobic life49. Glutathione has antioxidant properties since the thiol group in its cysteine moiety is a reducing agent and can be reversibility oxidized and reduced. In cells, glutathione is maintained in the reduced from by the enzyme glutathione reductase and in turn reduces other metabolites and enzyme systems. Such as ascorbate in the glutathione, ascorbate cycle, glutathione peroxidases directly with oxidants50. Due to its high concentration and its central role in maintaining the cell’s redox state, glutathione is one of the most important cellular antioxidants51, 52. In some organisms glutathione is replaced by other thiols, such as by mycothil in the Actinomycetes, bacillithiol in some Gram-positive bacteria or by trypanothione in the Kinetoplastids53,54.
Melatonin is a powerful antioxidant55. Melatonin easily crosses cell membranes and the blood brain barrier56. Unlike other antioxidants, melatonin does not undergo redox cycling, which is the ability of the molecule to undergo reduction and oxidation. Redox cycling may allow other antioxidants to act as pro-oxidants and promote free radical formation. Melatonin, once oxidized cannot be reduced to its former state because it forms several stable end products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant57. Antioxidants that are reducing agents can also act as pro-oxidants58. For example, vitamin C has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide. However, it will also reduce metal irons that generate free radical through the Fenton reaction59.
2Fe3++ Ascorbate → 2Fe2+ + Dehydroascorbate
2Fe2+ + 2H2O2 → 2Fe3+ + 2OH. + 2OH-
Some antioxidant supplements may promote disease and increase mortality in humans under certain conditions60. Hypothetically, free radicals induce an endogenous response that protects against exogenous radicals (and possibly other toxic compounds). Free radicals may increase life span. This increase may be prevented by antioxidants, providing direct evidence that toxic radicals may mitohormetically exerts life extending and healthy promoting effects61. As with the chemical antioxidants cells are protected against oxidative stress by an interacting network of antioxidant enzymes. Here the superoxide released by processes such as oxidative phosphorylation is first converted to hydrogen peroxide and then further reduced to give water. This detoxification pathway is the result of multiple enzymes, with superoxide dismutases catalyzing the various peroxidases removing hydrogen peroxide. As with antioxidant metabolites, the contributions of these enzymes to antioxidant defenses can be hard to separate from one another62.
Antioxidants are used as food additives to help guard against food deterioration. Antioxidants are an especially important class of preservatives as, unlike bacterial or fungal spoilage, oxidation reactions still occur relatively rapidly in frozen or refrigerated food63. These preservatives include natural antioxidants such as ascorbic acid (AA, E300) and tocopherols (E306), as well as synthetic antioxidants such as propyl gallate (PG, E310), tertiary butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA,E320) and butylated hydroxytoluene (BHT,E321)64,65. The most important common molecules attacked by oxidation are unsaturated fats; oxidation causes them to turn rancid. Since oxidized lipids are often discolored and usually have unpleasant taste such as metallic or sulfurous flavours, it is important to avoid oxidation in fat-rich foods. Thus, these foods are rarely preserved by drying; instead they are preserved by smoking, salting or fermenting. Oxidation is often catalyzed by metals, which is why fats such as butter should never be wrapped in aluminium foil. Some fatty foods such as olive oil are partially protected from oxidation by their natural content of antioxidants, but remain sensitive to photo oxidation. Antioxidant preservatives are also added to fat based cosmetics such as lipstick and moisturizers to prevent rancidity. Substituted phenols and derivatives of phenylenediamine are common antioxidants used to inhibit gum formation in gasoline (petrol).
EXPERIMENT:
Measurement and invalidation of ORAC:
Measurement of antioxidant content in food is not a straight forward process, as antioxidants collectively are a diverse group of compounds with different reactivities to various reactive oxygen species. DPPH is a stable free radical due to delocalization of the spare electron over the whole molecule. The delocalization restricts from dimerising as would be the case with most other free radicals. The delocalization also gives rise to the deep violet colouration characterized by a strong absorption band at 517 nm. DPPH free radical can accept an electron or hydrogen radical and can be converted into a stable, diamagnetic molecule with a loss of the violet colour. This paired radical can undergo further reaction, which control the overall stoichiometry and the absorption decreases with respect to the number of electron take up.
DPPH 1mg in 10-5 mol methanol was prepared in 250ml standard flask (control 208ml of this solution +0.05ml methanol). Benzimidazole solutions of different concentrations (0.1, 0.25, 0.5, 0.75, 1mM) were prepared. BHA (standard) solutions of different concentrations (0.1, 0.25, 0.5, 0.75, 1mM) were prepared. The absorbance of the control and the test solutions were recorded out at 517nm. By following similar procedure the absorbance will be measured for BHA solutions. From the absorbance values, % of inhibition was calculated. Then the % of inhibition was plotted against concentrations for different samples as well as BHA. The % reduction and IC50 were calculated. The IC50 values indicate that less IC50 is a more antioxidant capacity. The standard BHA shows the IC50 values of 624µM.
Plot of % of inhibition Vs concentration of 2-(2-phenylaminothiozol-5-oyl)-N-methylbenzimidazole 1a
Plot of % of inhibition Vs concentration of 2-(2-chloroaminothiozol-5-oyl)-N-methylbenzimidazole 1b
Plot of % of inhibition Vs concentration of 2-(2-ethylaminothiozol-5-oyl)-N-methylbenzimidazole 2a
Plot of % of inhibition Vs concentration of 2-[2-(n-propylamino)thiozol-5-oyl]-N-methylbenzimidazole 2b
Plot of % of inhibition Vs concentration of 2-(2-phenylaminothiozol-5-oyl)-N-methyl-6-chlorobenzimidazole 3a
Plot of % of inhibition Vs concentration of 2-(2-chlorophenylaminothiozol-5-oyl)-N-methyl-6-chlorobenzimidazole 3b
Plot of % of inhibition Vs concentration of 2-(2-ethylaminothiozol-5-oyl)-N-methyl-6-chlorobenzimidazole 4a
Plot of % of inhibition Vs concentration of 2-[2-(n-propylamino)thiozol-5-oyl]-N-methyl-6-chlorobenzimidazole 4b
Plot of % of inhibition Vs concentration of 2-(2-phenylaminothiozol-5-oyl)-N-methyl-6-methylbenzimidazole 5a
Plot of % of inhibition Vs concentration of 2-(2-chlorophenylaminothiozol-5-oyl)-N-methyl-6-methylbenzimidazole 25b
Plot of % of inhibition Vs concentration of 2-(2-ethylaminothiozol-5-oyl)-N-methyl-6-methylbenzimidazole 6a
Plot of % of inhibition Vs concentration of 2-[2-(n-propylamino)thiozol-5-oyl]-N-methyl-6-methylbenzimidazole 6b
% inhibition=
The antioxidant properties of all new compounds were studied and the results were correlated to the nature of the heterocyclic moiety attached to the C-5 of the thiazole and the substituent present in C-5 of the thiazole and the substituent present in C-2 position.
RESULTS AND DISCUSSION:
Effect of C-2 substituents:
The compound containing unsubstituted phenylamino group 1a, exhibit an IC50 value 191 μM, 3a has an IC50 value of 406μM and 5a has 132 μM. The compounds containing 4-chlorophenyl ring 1b and 5b shows an IC50 value below the value of BHA (standard) and the compound 3b has an IC50 value 310μM. The compound, which consists of 4-methylphenyl group attached to the ring 1c, 3c, and5c shows an IC50 value below the value of BHA (standard). The compound with 4-methoxyphenyl group attached to the ring 1d has an IC50 value of 103 μM, but the compound 3d has an IC50 value of 124 μM. The compounds containing 4-ethoxyphenyl group 1e shows an IC50 value of 179 μM and the compound 3e exhibits an IC50 value of 528 μM.
The compound containing ethyl group 2a exhibits an IC50 value of 132 μM and the compound 4a exhibits an IC50 value 357 μM. The compound 6a exhibits an IC50 value at 520 μM. The compounds containing n-propylamino group 2b, 4b and 6b shows an IC50values of 521, 810 and 659 μM respectively. The compound containing isopropylamino group 2c and 4b shows an IC50 values of 570 and 810 μM respectively. The compounds with n-butylamino substituent 2d, 4d and 6d shows an IC50 values of 357, 241 and 524 μM. From these results we observed that the compounds with 4-chlorophenylamino group are more powerful antioxidants than those with 4-methylphenylamino group, which in turn more powerful than those with phenylamino group.
The benzimidazoles with aryl substituents are better antioxidants than those with alkyl substituents. Among the aryl series compounds compounds, the compounds with methoxyamino group is more powerful than with 4-methylphenylamino group than those with unsubstituted phenylamino group which is more powerful than with 4-chlorophenylamino group. In the alkyl series, the compounds with n-propylamino group are more powerful antioxidants than ethylamino group than butylamino group than isopropylamino group.
Table 1. Antioxidant activities of 2-(2-arylaminothiazole-5-oyl)-1-N-methylbenzimidazoles 1
|
Compound |
IC50 Value (µM) |
|
1a |
191 |
|
1b |
132 |
|
1c |
166 |
|
1d |
103 |
|
1e |
179 |
|
BHA (Standard) |
624 |
Table 2 Antioxidant activities of 2-(2-alkylaminothiazole-5-oyl)-N-methylbenzimidazoles 2
|
Compound |
IC50 Value (µM) |
|
2a |
132 |
|
2b |
521 |
|
2c |
570 |
|
2d |
357 |
|
BHA (Standard) |
624 |
Table 3 Antioxidant activities of 2-(2-arylaminothiazole-5-oyl)-N-methyl-6-chlorobenzimidazoles 3
|
Compound |
IC50 Value (µM) |
|
3a |
406 |
|
3b |
310 |
|
3c |
121 |
|
3d |
124 |
|
3e |
528 |
|
BHA (Standard) |
624 |
Table 4 Antioxidant activities of 2-(2-alkylaminothiazole-5-oyl)-N-methyl-6-chlorobenzimidazoles 4
|
Compound |
IC50 Value (µM) |
|
4a |
357 |
|
4b |
810 |
|
4c |
659 |
|
4d |
241 |
|
BHA (Standard) |
624 |
Table 5 Antioxidant activities of 2-(2-arylaminothiazole-5-oyl)-N-methyl-6-methylbenzimidazoles 5
|
Compound |
IC50 Value (µM) |
|
5a |
132 |
|
5b |
51 |
|
5c |
189 |
|
5d |
357 |
|
5e |
241 |
|
BHA (Standard) |
624 |
Table 6 Antioxidant activities of 2-(2-alkylaminothiazole-5-oyl)-N-methyl-6-methylbenzimidazoles 6
|
Compound |
IC50 Value (µM) |
|
6a |
520 |
|
6b |
659 |
|
6c |
810 |
|
6d |
524 |
|
BHA (Standard) |
624 |
Effect of the heterocyclic moiety:
CONCLUSION:
In the antioxidant results, the compounds containing phenylamino group 1d have low IC 50 value. The compounds 1b, 2a and 2d have intermediateIC50 value. The compound 1c have average IC50 value. The compound 1a have average IC50 value. The compounds containing 4-chlorophenylamino group 3c and 4d have very low IC50 value than that of BHA (standard). The compound 4d has low IC50 value. The compounds 3d and 4a have low IC50 values. The compounds containing 4-methylphenylamino group have very low IC50 values. The compound 5c have a low IC50 value. The compounds 6a and 6b have intermediate IC50 values.
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Received on 18.09.2018 Modified on 22.10.2018
Accepted on 12.11.2018 © AJRC All right reserved
Asian J. Research Chem. 2018; 11(6):835-842.
DOI: 10.5958/0974-4150.2018.00147.5