BIOLOGICAL AND MEDICINAL SIGNIFICANCE OF PYRIMIDINES: A REVIEW

BIOLOGICAL AND MEDICINAL SIGNIFICANCE OF PYRIMIDINES: A REVIEW    

Sharanabasappa B. Patil

Department of Chemistry, Ramaiah Institute of Technology, Bangalore - 560054, Karnataka, India.

ABSTRACT: Pyrimidine is a 5-membered heterocyclic ring which is versatile lead compound for designing potent bioactive agents. This interesting group of compound has diverse biological activities such as antimicrobial, CNS depressant, anti-inflammatory, analgesic, anti-convulsant, anticancer, antihelmentic, antioxidant and herbicidal. Available data represents that pyrimidine being heterocyclic planar five membered ring systems has various pharmacological actions and Synthesis of various pyrimidine derivatives and their pharmacological actions discussed below. These derivatives of pyrimidine are analysed in this article for varying pharmacological activities. This review describes various Pyrimidine derivatives have potent biological and pharmacological applications.

Pyrimidine derivatives, Pharmacological Significance

INTRODUCTION: Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring. It is isomeric with two other forms of diazine Fig. 1.

FIG. 1: PYRIMIDINE

Whereas purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring.

Purines and pyrimidines make up the two groups of nitrogenous bases. These bases make up a crucial part of both deoxyribonucleotides and ribo-nucleotides, and the basis for the universal genetic code. The general term purine also refers to substituted purines and their tautomers. The purine is the most widely distributed nitrogen-containing heterocycle in nature notable purines. The quantity of naturally occurring purines produced on earth is enormous, as 50% of the bases in nucleic acids, adenine and guanine are purines. In DNA, these bases form hydrogen bonds with their complementary pyrimidines thymine and cytosine. This is called complementary base pairing. The beginning of the pyrimidine chemistry may be traced back to the isolation of alloxan ¹.

1. Purines:

FIG. 2: ADENINE

FIG. 3: GUANINE

2. Pyrimidines:

FIG. 4: CYTOSINE       

FIG. 5: URACIL

FIG. 6: THYMINE

In DNA and RNA, these bases form hydrogen bonds with their complementary purines. Thus the purines adenine (A) and guanine (G) pair up with the pyrimidines thymine (T) and cytosine (C), respectively. In RNA, the complement of A is U instead of T and the pairs that form are adenine: uracil and guanine: cytosine. These hydrogen bonding modes are for classical Watson-Crick base pairing. Other hydrogen bonding modes ("wobble pairings") are available in both DNA and RNA, although the additional 2'-hydroxyl group of RNA expands the configurations through which RNA can form hydrogen bonds. Pyrimidines can also be prepared in the laboratory by synthesis. The classical method for the synthesis of pyrimidine is the Biginelli reaction ².

Chemical Properties: A pyrimidine has many properties in common with pyridine, as the number of nitrogen atoms in the ring increases the ring pi electrons become less energetic and electrophilic aromatic substitution gets more difficult while nucleophilic aromatic substitution gets easier. An example of the displacement of the amino group in 2-aminopyrimidine by chlorine and its reverse. Reduction in resonance stabilization of pyrimidines may lead to addition and ring cleavage reactions rather than substitutions. One such manifestation is observed in the Dimroth rearrangement. Compared to pyridine, N-alkylation and N-oxidation is more difficult, and pyrimidines are also less basic. ThePk_a value for protonated pyrimidine is 1.23 compared to 5.30 for pyridine.

Organic Synthesis: Pyrimidines can also be prepared in the laboratory by organic synthesis. One method is the classic Biginelli reaction. Many other methods rely on condensation of carbonyls with amines for instance the synthesis of 2-thio-6-methyluracil from thiourea and ethyl acetoacetate or the synthesis of 4-methylpyrimidine from 4, 4-dimethoxy-2-butanone and formamide.

Pyrimidine ring is found in Vitamins like thiamine, riboflavinand folic acid. Pyrimidine derivatives have been found to be possessed diverse biological activities including antiviral, anticancer, antifungal, antimalarial, sedative, hypnotic, anticonvulsant, anthelmintics and antithyroid activities.

FIG. 7: FOLIC ACID

Further some hetero-fused pyrimidines are known to exhibit promising antiviral, ³ antibacterial, ⁴ anti-AIDS ⁵ activities. It is found that fused pyrimidines are selective inhibitors for multidrug resistance (MDR) ^{6, 7}. Folate metabolism as antitumor agents ⁸. Atherothrombotic coronary artery disease, giving rise to a number of cardio circulatory disorders such as myocardial infarction (MI), unstable angina (UA), or acute stroke associated with deep vein thrombosis (DVT), is one of the most important causes of death worldwide. The relevance of fused pyrimidines as anti-platelet and antithrombotic drugs ⁹ has been firmly established by clinical trials.

FIG. 8: THIAMINE                                            

FIG. 9: RIBOFLAVIN

2.1.2. Medicinal Significance of Pyrimidines: In medicinal chemistry pyrimidine derivatives have been very well known for their therapeutic applications. During the last two decades, several pyrimidine derivatives have been developed as chemotherapeutic agents and have found wide clinical applications, which are as follows.

2.1.2.1 Pyrimidines as Antineoplastic (Anticancer) Agents: Cancer is not just one disease, but a large group of almost one hundred diseases. Its two main characteristics are uncontrolled growth of the cells in the human body and the ability of these cells to migrate from the original site and spread to distant sites. If the spread is not controlled, cancer can result in death.

The main target of anti-tumor chemotherapies is DNA^{10, 11}_. Alteration of DNA structure affects its synthesis and function which usually leads to disruption of cell proliferation and can eventually elicit cell death via apoptosis. These effects are currently being exploited to develop novel biologically active drugs with potential applications as anti-proliferative therapies, e.g. ligands that will form ternary complexes with DNA and the enzyme(s) topoisomerase. These enzymes are responsible for DNA unfolding within the nucleus, which may not be possible when the nucleotide has been structurally modified. As DNA unfolding is a preliminary step in cell replication, a ligand capable of inducing structural alterations to DNA could be used as a chemotherapeutic ^{12, 13}.

In addition tegafur ¹⁴ and 5-thiouracil ¹⁵ are also shown to exhibit some useful antineoplastic activity. Gemitabine a cytosine nucleoside analogue possess anticancer activity against murine solid tumor.

FIG. 10: 5-THIOURACIL     

FIG. 11: 5-FLUOROURACIL

FIG. 12: TEGAFUR

2.1.2.2 Pyrimidine as Anti-inflammatory and Analgesic Agents: There are large numbers of pyrimidine derivatives found to exhibit anti-inflammatory and analgesic activity. Some of them are as follows. New lipid soluble forms of thiamine (Vitamin-B₁) such as Acetamine, ¹⁶ bentamine ¹⁶ and fursultiamine ¹⁷ are used for beriberi, polyneuritis, encephalopathy and pain.

FIG. 13: 3A-B

3A: ACETAMINE                  3B: BENTAMINE

 Pirisino et al., ¹⁸ have studied 2-phenylpyrazolo-4-ethyl-4, 7-dihydro [1, 5-a] pyrimidine-5-one for its analgesic, antipyretic and anti-inflammatory activities.

FIG. 14: PHENYLPYRAZOLO[1,5-A]PYRIMIDIN-7(4H)-ONE

Modica et al., ¹⁹ synthesized some new thiazolidazolothieno pyrimidinones and tested them for anti-inflammatory activities and obtained encouraging results.

Cenicola et al., ²⁰ evaluated some imidazolo [1, 2-c] pyrimidines for antipyretic, analgesic and anti-inflammatory.

FIG. 15: A-B

3.6-a. R₁ = Cl, OCH₃, CH₃

3.6-b R2 = COOH, CH₂COOH

2.1.2.3 Pyrimidine Analogues as Antibiotics: Pyrimidine derivatives are also known for antibiotic properties.  Pyrimidine analogs which acts as antibiotic are bacimethrin (5-hydroxymethyl-2-methoxypyrimidin-4-amine) Fig. 16, which is found to be effective against several staphylococcal infections ²¹. Gourgetin Fig. 17 a cytosine derivative is active against mycobacteria as well as several Gram-positive and Gram-negative bacteria ²².

Wide-spectrum antibiotics aminoglycoside antibiotics, phleomycin, bleomycin are some other example of pyrimidine analogues. Further bleomycin is used for the treatment of certin tumors like Hodgkin’s lymphoma and disseminated testicular cancer ²³.

Natural occurring exocyclic nucleoside clitocine is isolated from the mushromm Clitocybeinversa possess strong insecticidal activities and potent cytostatic effects against several leukemia cell lines through inhibition of adenosine kinase ²⁴. Nikkomycins were the first nucleoside antibiotics found to inhibit fungal cell wall chitin biosynthesis ²⁵.

FIG. 16: BACIMETHRIN

2.1.2.4 Pyrimidine as Anti- HIV Agents: Human immunodeficiency virus (HIV-1) the causative agent of the acquired immune deficiency syndrome (AIDS), utilizes a reverse transcriptase (RT) that plays a central role in the replicative life cycle of the virus. This enzyme to date has been one of the main chemotherapeutic targets in efforts to control infections. A large number of molecules have been designed and synthesized to target various active sites on this enzyme. Among these chain terminators, the nucleoside analogs, 3'-azidothymidine (AZT), 2', 3'-dideoxycytidine (DDC), 2', 3'-didehydro-3'-deoxythymidine (d4T), Although approved for clinical use for patients with AIDS, the toxicity associated with these drugs together with the emergence of resistance strains of the virus has raised the need for molecules with a different mode of action.

FIG. 17: GOURGITIN                   

FIG. 18: FURAN-2-YL)-2-OXOPYRIMIDIN-4-YL)-4-METHOXYBENZAMIDE

FIG. 19: DDC                                      

FIG. 20: (D4T)

Cidofovir, ²⁶ an antimetabolite for deoxycytosine triphosphate is used for treatment of cytomegalo virus (CMV) in AIDS patients.

In addition HEPT analogs viz., EPT and BPT having terminal ethoxymethyl and benzyloxy-methyl groups respectively are more potent inhibitor of HIV-1 replication than HEPT ²⁷. HEPT is a potent and selective inhibitor of HIV–1 but not HIV-2. Hence, N. M. Goudgaon et al., ^28-29 synthesized selenium related analogs of HEPT (6-(phenylselenenyl) pyrimidine nucleoside analogs).

FIG. 21: HEPT

These compounds exhibited selective antiviral activity against both HIV-1 and HIV-2 in primary human lymphocytes. Bai-Chuan et al., ³⁰ have synthesized 6-arylthio and 6-arylselenoacyclo-nucleosides and tested for anti HIV-1 activity.

FIG. 22: A, B

6.9a Arylthio (Z= S) and

6.9b Arylseleno (Z= Se) acyclonuleoside

2.1.2.5 Pyrimidine Analogs as Anesthetics Agents: Thimylal ^{31, 32} is a short acting general anesthetic drug, which is a pyrimidine analogue. Saxitoxin ³¹ is naturally occurring pyrimidine containing anesthetic drug, however it is too much toxic to be used as clinical drug.

FIG. 22: THIMYLAL

FIG. 23: SAXITOXIN

2.1.2.6 Pyrimidine as Cardiac agents: Fused pyrimidines, quinoazolines are used as antihypertensive agents ^{33, 34}. For example prazosin ³⁵ is a selective α_1-adernergic antagonist. It is related to bunazosin ³⁶,

FIG. 24: BUNAZOSIN

Terazosin ³⁷ and triazosin ³⁸ which are potent antihypertensive agents. Ketarasin ³⁹ is another example of this kind which is antagonist of both α_1-adernergic and serotonin-S₂ receptor.

FIG. 25: PRAZOSIN

2.1.2.7 Pyrimidine as Antibacterial Agents (Sulfa Drugs): A number of pyrimidine derivatives have been found to be useful as chemotherapeutic agent. The antibacterial profile of sulfonamide is well. Among the sulfonamide, sulfadiazine, sulfamerazine and sulfadimidine are pyrimidine analogues of sulfa drugs which are more superior clinically antibacterial agent and are also used in the treatment of acute UT infections, cerebrerospinal meningitis and for patients allergic to penicillins ⁴⁰.

FIG. 26: SULFA DRUGS

However combination of sulfonamide and trimethoprim is used for the treatment of AIDS ⁴¹. Whereas Sulfadoxine ⁴² having half life of 7-9 days used for malarial prophylaxis and sulfisomidine with life of 7 hours used as veterinary medicine ⁴³. In 1959, sulfamethoxine ⁴⁴ was introduced with a half-life of 40 hr. The related 4-sulfon-amidopyrimidine such as sulfamethoxine⁴⁴ has the half-life of about 150 hr.

Verma et al., reported the synthesis and antibacterial activity of 2-amino-4, 6-diaryl pyrimidine derivatives ⁴⁵.

Certain pyrano [2, 3-d] pyrimidine have been synthesized and screened for antibacterial activity, antifungal and antitubercular activities ⁴⁶.

Dave et al., synthesized several 2-thiopyrido [2, 3-d] pyrimidin-4(3H)-one for antibacterial and antihistaminic activity ⁴⁷.

Kim et al., ⁴⁸ reported a series of novel cephalosporin which have 3-[(aminopyrimidnium-yl) thio] methyl substituent have been synthesized. The compounds exhibited significant antimicrobial activity against various bacterial species.

FIG. 27: SULFADIMETHOXINE

FIG. 28: SULFAMETHOXINE

2.1.2.8 Pyrimidine as Antifungal Agents: Pyrimidines also known to exhibit antifungal properties. Flucytosin, ⁴⁹ a pyrimidine derivative is useful in the case of infection due to candida taalbicans and Cryptococcus neoformans ⁵⁰. Another pyrimidine analogue hexitidine is also used for aphthous ulceration ⁵¹.

FIG. 29: FLUCYTOCINE

FIG. 30: HEXITIDINE

Nizamuddin et al., reported 1-aroyl-4-oxo-5-substitutedphenylpyrazole [3, 4-d] pyrimidine-6-thionone synthesis and their antifungal activity ⁵². Also 4, 6-disubstituted-2-(cyanamino) pyrimidines reported for fungistatic and nemotodial activity ⁵³.

2.1.2.9 Pyrimidne Analogs as Metabolic Electrolytes: A simple pyrimidine analogue and its mineral forms, orotic acid ⁵⁴ is used in the metabolic therapy, as orate is needed as key intermediate in the biosynthesis of pyrimidine nucleotides which are the building block of DNA and RNA required for the final protein synthesis. Especially it is used in the cardiovascular patients to prevent heart failure.

FIG. 31: OROTIC ACID

2.1.2.10 Pyrimidine Analogues as Cardiotonic / Bronchodilators: Astmizole and Terfenadine are two examples of pyrimidine analogs which exhibit good bronchodilator activity. However its affinity towards H₁-hitamine-binding site is about ten less then the potent pyrimidine analogue taziphylline ⁵⁵. Another pyrimidine containing antihistaminic drug, temelastine is comparable to mepyramine ⁵⁶. Pemirolast, ⁵⁷ a new oral non bronchodilators antihistaminic agent also a pyrimidine analogue.

FIG. 32: A, B

7.8 a, R1 = Br, R2 = CH₃; temelastine

7.8 b, R1 = H, R2 = OCH₃; icotidine

FIG. 33: TAZIPHYLLINE

FIG. 34: PEMIROLAST

CONCLUSION: Pyrimidine’s showed diverse biological activities such as antimicrobial, CNS depressant, anti-inflammatory, analgesic, anti-convulsant, anticancer, antihelmentic, antioxidant and herbicidal. This review describes various Pyrimidine derivatives have potent biological and pharmacological applications.

ACKNOWLEDGEMENT: The authors are highly thankful to Dr. N. M. Goudgaon, Professor, Department of Chemistry, Gulbarga University Kalburgi, Karnataka for the needful support.

CONFLICT OF INTEREST: The authors declared no competing interests.

REFERENCES:

1. Eussell JA: Annu. Rev. Biochem., 1945; 17: 309.
2. Cox RA: Quart. Rev., 1968; 22: 499.
3. Hossain N, Rzewski J, Clercq ED and Herdewijn P: J. Org. Chem., 1997; 62: 2442.
4. Sabnis RW and Rangnekar DW: Indian J. Technol., 1990; 28: 54.
5. Joseph S and Burke JM: J. Biol. Chem., 1993; 268: 24515.
6. Bookser BC, Ugarkar BG, Matelich MC, Lemus RH, Allan M, Tsuchiya M, Nakane M, Nagahisa A, Wiesner JB and Erion MD: J. Med. Chem., 2005; 48: 7808.
7. Wang S, Folkes A, Chuckowree I, Cockcroft X, Sohal S, Miller W, kilton J, Wren SP, Vicker N, Depledge P, Scott J, Smith L, Jones H, Mistry P, Faint R, Thompson D and Cocks SJ: Med. Chem., 2004; 47: 1329.
8. Gangjee A, Jain HD, Phan J, Lin X, Song X, McGuire JJ and Kisliuk RL: J.  Chem., 2006; 49: 1055.
9. Bruno O, Brullo C, Schenone S, Bondavalli F, Ranise A, Tognolini M, Impicciatore M, Ballabeni V and Barocelli E: Bioorg. Med. Chem., 2006; 14: 121.
10. Neidle S and Thurston DE: Nat. Rev. Cancer., 2005; 5: 285.
11. Wright WE, Tesmer VM, Huffman KE, Levene SD and Shay WJ: Genes Dev., 1997; 11: 2801.
12. Larsen AK, Escargueil AE and Skladanowski A: Pharmacol. Ther., 2003; 99: 167.
13. Marco E, Laine W, Tardy C, Lansiaux A, Iwao M, Ishibashi F, Bailly C and Gago F: J. Med. Chem., 2005; 48: 3796.
14. Giller SA, Zhuk RA and Lidak MI: Dokl. Akad. Nauk. SSR. 1967; 176: 332.
15. Al Safarjalani ON, Zhou XJ, Ras RH, Shi J, Schinazi RF, Naguib FN and El Kouni MH: Cancer Chemother. Pharmacol., 2005; 55: 541.
16. Gauthier B: Ann. Pharm. Fr., 1963; 21: 655.
17. Takeda, US Patent, 1962; 3 016 380.
18. Pirisino R, Bainchini G, Ignesti G and Ramondi L: Pharmocol. Res. Comm., 1996; 18: 241.
19. Modica M, Santagati A, Cutuli V, Mangano N and Caruso A: Pharmazie. 2000; 55: 500.
20. Cenicola ML, Donnali D, Stella L, Paola CD, Constanatio M, Anignwente E, Arena F, Luraschi E and Saturnino C: Pharmacol. Res., 1990; 22: 80.
21. Reddick JJ, Saha S, Lee J, Melnick JS, Perkins and J and Begley TP: Bioorg. Med. Chem. Lett., 2001; 11: 2245.
22. Singh P, Kumar R and Sharma BK: J. Enzyme Inhib. Med. Chem., 2003; 18: 395.
23. Wakelin LP and Waring MJ: DNA intercalating agents. In Comprehensive Medicinal Chemistry, Drug Compendium (ed. Sammers, P.G.), Pergamon Press 1990; 2: 731.
24. Bacchelli C, Condom R, Patino N and Aubertin AM: Nucleosides Nucleotides and Nucleic Acids. 2000; 19: 567.
25. Barett AG and Lebold SA: J. Org. Chem., 1990; 55: 5818.
26. Van Leeuwen R: J. Infect. Dis., 1995; 171: 1161.
27. Pontikis R and Monneret C: Tetrahedron Letters. 1994; 35: 4351.
28. Goudgaon NM and Schinazi RF: J. Med. Chem., 1991; 34: 3305.
29. Goudgaon NM, McMillan A and Schinazi RF: Antiviral Chemother, 1992; 3: 263.
30. Bai-Chuan P, Zhi-Hao C, Giovanna P, Ginger E, Datschman, Elizabeth CR, Yung-Chi C and Shih-His C: J. Heterocyclic. Chem., 1994; 31: 177.
31. Abott, US Patent, 1939; 2 153 729.
32. Abott, US Patent, 1934; 2 153 729.
33. Arnaud MJ: Products of metabolism of caffeine. In Caffein, Perspectives from Recent Research (ed. Dews, P. B.), Springer-Verlag, New York 1984; 3.
34. Pfizer, US Patent, 1970; 3 511 836.
35. Koshy MM and Mickey D: Circulation. 1977; 55: 533.
36. Hara H, Ichikawa M, Oku H, Shimazawa M and Araie M: Cardiovasc. Drug Rev., 2005; 23: 43.
37. Honkanen E, Pipuri A, Kairisalo P, Nore P, Karppaness H and Paakari I: J. Med. Chem., 1983; 26: 143.
38. Meredith PA, Scott PJ, Kelman AW, Hughes DM and Reid JL: Am. J. Ther., 1995; 2: 541.
39. Ganzevoort W, Bonsel GJ, de Vries JI and Wolf H: Hypertension. 2004; 22: 1235.
40. Shinogi, US Patent, 1959; 2 888 455.
41. MacDonald L and Kazanijan P: Formulary, 1996; 31: 470.
42. White NJN: Engl. J. Med., 1996; 335: 800.
43. Von Zabern I, Nolte R, Przyklenk H and Vogt W. Int. Arch. Allergy Appl. Immunol., 1985; 76: 205.
44. Huges J, Roberts LC and Coppridge AJ: J. Urol., 1975; 114: 912.
45. Verma BL, Hussain KF and Ashawa A: Asian. J. Chem., 1997; 9(1): 86.
46. Ahluwalia VK and Madhu B: Indian. J. Chem., 1996; 35(B): 742.
47. Dave CG, Shah PR, Desai RB and Srinivasan S: Indian. J. Chem., 1982; 21B: 750.
48. Kim YZ, Lim JC, Yeo JH, Bamg CS, Kim WS, Kim SS, Woo YM, Yang DH, Nahm K: J. Med. Chem., 1994; 37(22): 3828.
49. Polak A and Scholer H: J. Chemotherapy., 1975; 21: 113.
50. Hunter PA, Darby KG and Russel N: Fifty years of antimicrobials: Past perspectives and future trends. In Symposia of the society for General Microbiology (ed. Collins, M), Cambridge University Press, Cambridge, 1995; 12.
51. Chadwick B, Addy M and Walker DM: Br. Dent. J., 1991; 71: 83.
52. Nizamuddin, Giri S and Shukla RP: Indian J. Chem., 1990; 29(B): 153.
53. Kreutzberger A and Sellheim MA: J. Heterocyclic. Chem., 1985; 22(3): 721.
54. Jones ME: Annu. Rev. Biochem. 1980; 49: 233.
55. Gane’s Chem Works, US Patent, 1955; 2715: 125.
56. Brown EA, Griffith R, Harvey CA and Owen DD: Brit. J. Pharmacol. 1986; 87: 569.
57. Bristol-Myer, US Patent, 1978; 4 122 274.
    

    ---

    How to cite this article:

    Patil SB: Biological and medicinal significance of pyrimidines: A review. Int J Pharm Sci Res 2018; 9(1): 44-52.doi: 10.13040/ IJPSR. 0975-8232.9(1).44-52.       

    ---

    All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

    ---