Free radical scavenging properties of pyrimidine derivatives
© Bano et al.; licensee Springer. 2012
Received: 7 June 2012
Accepted: 7 September 2012
Published: 14 November 2012
Free radicals are well known for playing a dual role in our body- deleterious as well as beneficial. It includes a metabolic pathway for its generation. Oxidative stress in our body occurs due to excessive generation of free radicals and reduced level of antioxidants, but at low concentrations, these radicals help to perform normal physiological functions of the body. Scientific evidence suggests that antioxidants reduce the risk for chronic diseases including cancer and heart disease. This review shows current tendency in the pyrimidine synthesis and reveals the pyrimidine core to be a very potent moiety which can be a rich source for the synthesis of new compounds having desirable antioxidant activity.
KeywordsFree radical Antioxidant Pyrimidine Oxidative stress
Free radicals can be defined as the atoms, molecules, or ions with unpaired electrons in an open shell configuration. Sometimes, these free radicals may bear some charge, either positive, negative, or zero. They also play a significant role in combustion, atmospheric chemistry, polymerization, plasma chemistry, and many other chemical processes. Free radicals may generate different kinds of chemical and biological reactions in the body. Development of free radicals in the body is believed to involve in the development of various degenerative diseases; huge generation of free radicals particularly reactive oxygen species and their high activity may lead to progression of a number of pathological disturbances such as inflammation, atherosclerosis, cancer, Parkinson's disease, and Alzheimer's disease. This phenomenon of excessive production of free radicals is termed as oxidative stress. This oxidative stress has also been found to be implicated in many ailments such as heart disease and some age-related diseases. Thus, in a concise way, it can be said that excessive production of free radicals is harmful for the body.
Types of free radical reaction
Termination reaction 
Sources of free radical generation
Various sources lead to the generation of free radicals:
UV radiations, X-rays, gamma rays, and microwave radiation
Reaction catalyzed by metals
Oxygen free radicals in the atmosphere considered as pollutants
Inflammation that initiates neutrophils and macrophages to produce reactive oxygen species and reactive nitrogen species
In mitochondria-catalyzed electron transport reactions, oxygen free radicals produced as by-product
Reactive oxygen species (ROS) generated by the metabolism of arachidonic acid, platelets, macrophages and smooth muscle cells
Interaction with chemicals, automobile exhaust fumes, smoking of cigarettes and cigars
Burning of organic matter during cooking, forest fires, volcanic activities
Industrial effluents, excess chemicals, alcoholic intake, certain drugs, asbestos, certain pesticides and herbicides, some metal ions, fungal toxins, and xenobiotics
Generation of free radical by metabolic pathway
Free radicals are mainly generated by various metabolic pathways such as lipid and peroxidation, gluconeogenesis, and glucuronidation. Generation of free radicals is first converted to hydrogen peroxide which is further reduced to water. This detoxification occurs during oxidative stress, where in the oxygen generates inside the body. The superoxide released by the oxidative phosphorylation pathway is the result of multiple enzymes; superoxide dismutase catalyzes the first step, and then various peroxides help in removing the hydrogen peroxide.
Role of free radicals in our body
Diseases caused by the free radical generation in the human body
Oxygen is an element that is essential to life. Living systems have evolved to survive in the presence of molecular oxygen, which is also applicable to most biological systems. Oxidative properties of oxygen play a vital role in diverse biological systems. It includes the following:
Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, memory loss, and depression
Cardiovascular diseases such as atherosclerosis, ischemic heart disease, cardiac hypertrophy, hypertension, shock, and trauma
Pulmonary disorders such as inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease
Diseases associated with premature infants, including bronchopulmonary, dysplasia, periventricular leukomalacia, and intraventricular hemorrhage, retinopathy of prematurity, and necrotizing enterocolitis
Autoimmune disease such as rheumatoid arthritis
Renal disorders such as glomerulonephritis and tubulointerstitial nephritis, chronic renal failure, proteinuria, and uremia
Gastrointestinal diseases such as peptic ulcer, inflammatory bowel disease, and colitis
Tumors and cancer such as lung cancer, leukemia, and breast, ovary, and rectum cancers
Eye diseases such as cataract and age-related retinal maculopathy. Aging process, diabetes, skin lesions, immunodepression, liver disease, pancreatitis, AIDS, infertility 
General properties of antioxidants
The main characteristic of an antioxidant is its ability to trap free radicals. Scientific evidence suggests that antioxidants reduce the risk of chronic diseases including cancer and heart disease. Antioxidant activity was performed by DPPH free radical scavenging method using ascorbic acid as a standard drug.
Classification of antioxidants
Enzymes. Enzyme such as superoxide dismutase, catalase, and glutathione peroxidase (GPx) attenuate the generation of reactive oxygen species by removing potential oxidants or by transferring ROS/RNS into relatively stable compounds (Figure 3). GPx reduces lipid peroxides (ROOH), formed by the oxidation of polyunsaturated fatty acids, to a stable nontoxic molecule - hydroxyl fatty acid (ROH).
Lipid-soluble antioxidants. This group of antioxidants is supposed to act as highly efficient scavengers, against lipid peroxyl radical, which is formed within the lipoprotein as a consequence of free radical chain reaction of lipid peroxidation.
Water-soluble antioxidants. These antioxidants cannot enter the lipid moiety of low density lipoprotein (LDL); these will be less efficient as these are principally unable to encounter most of these lyophilic radicals.
Low molecular weight antioxidants. These are subdivided into lipid-soluble antioxidants (tocopherol, carotenoids, quinones, bilirubin, and some polyphenols) and water-soluble antioxidants (ascorbic acid, uric acid, and polyphenols). These delay or inhibit cellular damage mainly through their free radical scavenging property.
Various ROS and corresponding neutralizing antioxidants
Beta-carotene, flavonoids, vitamin E, ubiquinone, glutathione1 peroxidase
Flavonoids, vitamin C, glutathione
Vitamin E, vitamin C, glutathione, lipoic acid beta-carotene, flavonoids
Lipoic acid, vitamin C, glutathione, flavonoids
Chemistry of the pyrimidine ring
Leading compound as antioxidant templates
The present review is concentrating on the synthesis and antioxidant activity of the pyrimidine nucleus. Pyrimidine is a unique molecule that is associated with several other biological activities. Among the antioxidants, it has the ability to trap the free radicals which are responsible for the generation of different diseases such as inflammation, skin lesions, immune depression, liver disease, pancreatitis, AIDS, infertility. Mainly antioxidants having pyrimidine nucleus are not able to enter in the lipid moiety of low density lipoprotein, so the penetration power of these types of compounds is very low, and they are least effective. To rectify this problem, the substitution on pyrimidine nucleus was made by different substitutions of Cl, Br, CF3, and NO2, which increased the penetration of molecules into the lipid membrane so that they increase the antioxidant activity by combining with the reactive oxygen species, which is generated by the different disease conditions. By making these changes on the pyrimidine nucleus, we are able to find out the most potent pyrimidine-substituted antioxidant compounds.
The authors are highly thankful to NISCARE and NML, India for providing the necessary library and internet facilities to complete this article.
- Kumar SM, Pavani M, Bhalgat CM, Deepthi R, Mounika A, Mudshinge SR, Reas IJ, Ghomi JS, Ghasemzadeh MA: Novel pyrimidine and its triazole fused derivatives: synthesis and investigation of antioxidant and anti-inflammatory activity. J Serb Chem Soc 2011, 76: 679–684. 10.2298/JSC100212057SView ArticleGoogle Scholar
- Gayathri G, Nair BR, Babu V: Analysis of proximate and nutritional composition in the leaves of Azima tetracantha Lam. Pharma Bio Sci 2011, 2: 1568–1570.Google Scholar
- March J: Advanced organic chemistry reactions mechanism and structure. 3rd edition. Wiley, New York; 1985:165–179.Google Scholar
- Morrison RT, Boyd RN, Boyd RK: Organic Chemistry. 6th edition. Prentice Hall, Upper Saddle River; 1992:218–232.Google Scholar
- Acworth IN, Bailey B: Reactive oxygen species. In The handbook of oxidative metabolism. ESA Inc, Chelmsford; 1997:89–95.Google Scholar
- Alessio HM, Blasi ER: Physical activity as a natural antioxidant booster and its effect on a healthy lifestyle. Res Q Exerc Sport 1997,68(4):292–302.View ArticleGoogle Scholar
- Saikat S, Chakraborty R, Sridhar C, Reddy YS, Biplab D: Free radicals, antioxidants, diseases and phytomedicines: current status and future prospect. Int J Ph Sci R 2010,3(1):91–100.Google Scholar
- Butkovica VL, Bors KWJ: Kinetic study of flavonoid reactions with stable radicals. Agric Food Chem 2004, 52: 2816–2820. 10.1021/jf049880hView ArticleGoogle Scholar
- Singh RP, Sharad S, Kapur S: Free radicals and oxidative stress in neurodegenerative diseases, relevance of dietary antioxidants. JIACM 2004,5(3):218–225.Google Scholar
- Lonita P: Plasma polymerisation: study and application. Chem Pap 2005, 59: 11–16.Google Scholar
- Kumar SM, Pavani M, Bhalgat CM, Deepthi R, Mounika A, Mudshinge SR: In-vitro antioxidant studies of 4,6-bis aryl-pyrimidin- 2-amine derivatives. Inter JR Ph Bio Sci 2009, 2: 1568–1570.Google Scholar
- Mondal P, Jana S, Kanthal LK: Synthesis of novel mercapto-pyrimidine and amino-pyrimidine derivatives of indoline-2-one as potential antioxidant & antibacterial agent. T Ph Res 2010, 3: 17–26.Google Scholar
- Abu-Hashem AA, Youssef MM, Hoda AR: Synthesis, antioxidant, antituomer activities of some new thiazolopyrimidines, pyrrolothiazolopyrimidines and triazolopyrrolothiazolopyrimidines derivatives. J Chi Chem Soc 2011, 58: 41–48. 10.1002/jccs.201190056View ArticleGoogle Scholar
- Gressler V, Moura S, Flores AFC, Flores DC, Colepicolo P, Pinto E: Antioxidant and antimicrobial properties of 2-(4,5-dihydro-1H-pyrazol-1-yl)- pyrimidine and 1-carboxamidino-1H-pyrazole derivatives. J Braz Chem Soc 2010, 21: 1–7. 10.1590/S0103-50532010000100001View ArticleGoogle Scholar
- Bhalgat CM, Ali MI, Arsab GR: In-vitro antioxidant studies of 4,6-bis aryl-pyrimidin- 2-amine derivatives. J Chem 2011. (in press)Google Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.