1. INTRODUCTION

Medicinal chemistry is the branch of science that deals mainly with the synthetic organic chemistry and pharmacology of the drugs with special references to structure including design, modifications and analysis of drugs or chemical synthesis of lead compounds to make them suitable for the mankind or animals with least toxicity and optimum response¹.

Heterocyclic chemistry is a very important branch of organic chemistry and most of the organic synthetic or semi synthetic compounds are heterocyclic in structural properties. Its structure can be described with carbon atoms in ring forming carbocyclic compound².

The most common heteroatoms are Nitrogen, oxygen and sulfur. But heterocyclic rings containing other hetero atoms are having in broad variety. Heterocyclic compounds can be classified as aliphatic and aromatic. The aliphatic heterocyclics are the cyclic similarities of amines, ethers, thio ethers, amides, etc.

Heterocyclic compounds are having importance in various medicinal formulations and are present in a large variety of drugs, most vitamins, natural products etc. In addition to this biologically active compounds, including antitumor, antibiotic, anti-inflammatory, antidepressant, antimalarial, anti-HIV, antimicrobial, antibacterial, antifungal, antiviral, antidiabetic, herbicidal, fungicidal, anticonvulsant, and insecticidal agents³.

1.1 Pyrimidine

Heterocyclic aromatic organic compound like benzene or pyridine, having two nitrogen atoms at positions 1 and 3 of the six-membered ring;they have isomers in the forms of diazine⁴

Figure 1

IUPAC Name: 1, 3-Diazine, m-Diazine

Formula: C₄H₄N₂

Molecular Mass: 80.088 g mol-1

Density: 1.016 g cm-3

Solublity: Alcohol, Water

Melting Point: 20-22 °C

1.2 Types of Pyrimidine

Three nucleobases found in nucleic acids, cytosine (C), thymine (T), and uracil (U), are pyrimidine derivatives: ^[4]

Figure 2

1.3 Hydrazones

An organic compounds having structure of R₁R₂C=NNH₂ and are associated to ketones and aldehydes by substitution of the oxygen by means of NNH₂ functional group. They are designed basically by the feat of hydrazine on ketones or aldehydes^5.

Figure 3

Hydrazones have antioxidant, antimicrobial, antimalarial, antiviral actions and if they are allowed to fuse with Pyrimidine they produce CNS activity too. Therefore the above data clearly showed that pyrimidine hydrazones are potent biologically active compounds.

1.4 Schiff base

A Schiff base, invented by Hugo Schiff, is a compound with a functional group that consists of a C=N double bond by means of nitrogen atom connected to an aryl or alkyl group and having general formula of R¹R²C=NR³, where R is an organic side chain. In this definition, Schiff base is identical to azomethine⁶_.

Figure 4

1.5 Some Compounds Having Pyrimidine Hydrazones

a). 4-methoxybenzaldehyde (5-bromopyrimidin-2-yl) hydrazone monohydrate⁷_. Pyrimidine and their derivatives possess biological and pharmacological activities such as antibacterial, antimicrobial, anti-inflammatory, analgesic, anticonvulsant and anti-aggressive properties

C₁₂H₁₁BrN₄O·H₂O

b). Novel thieno [2, 3-d] pyrimidin-4-yl Hydrazone-based Cyclin D1-CDK4 inhibitors⁸

2. CHEMICAL APPROACHES

2.1 Pyrimidine

2.1.1 Scheme-1: ZnCl₂-catalyzed three-component coupling reaction allows the synthesis of various 4, 5-disubstituted pyrimidine derivatives in a single step from functionalized enamines, triethylorthoformate, and ammonium acetate. The procedure can be successfully applied to the efficient synthesis of mono- and disubstituted pyrimidine derivatives, using methyl ketone derivatives instead of enamines⁹

2.1.3 Scheme-2: Synthesis of pyrimidines from ketones using microwave irradiation¹⁰

2.1.3 Scheme 3: Synthesis, analgesic and ulcerogenic activity of novel pyrimidine derivative of coumarin moiety: A novel series of 3-(2-amino-6-pyrimidin-4-yl)-6-bromo-2H-chromen-2-one (2a-2j) was synthesized from 3-acetyl-6-bromo-2H-chromen-2-one¹¹

2.2 Hydrazone

2.2.1 Scheme 4: Tosyl- and Boc-hydrazones were found to be effective nucleophiles in the Mitsunobu reaction. Tosyl hydrazones reacted cleanly with primary and secondary alcohols when co-administered to a cooled DBAD/PPh3 or DEAD/PPh3 complex¹²

2.2.2 Scheme-5: Central to an alternative source of substrates for Fischer indolizations was a palladium-catalyzed coupling to prepare N-aryl benzophenone hydrazones. Hydrolysis of the hydrazones in the presence of ketones produced enolizable hydrazones that underwent Fischer indolization¹²

3. BIOLOGICAL ACTIVITY APPROACHES

3.1 Pyrimidine

3.1.1 Biologically Active Pyridopyrimidines:

The compounds below have efficient analgesics, CNS depressant activity, and in spite of that it also exhibit antibacterial and antifungal activity¹³

3.1.2 Anti-cancer activity

A series of novel 2, 4, 5-substituted pyrimidine derivatives were synthesized and evaluated for inhibition against the human hepatocellular carcinoma BEL-7402 cancer cell line¹⁴

3.2 Hydrazone

There has been considerable interest in the development of novel compounds with anticonvulsant, antidepressant, analgesic, anti-inflammatory, antiplatelet, antimalarial, antimicrobial, antimycobacterial, antitumor, vasodilator, antiviral and antischistosomiasis activities¹⁵

Anti-tubercular

Antidiarrheal, Antibiotic,

3.2.1 Anti-Depressant Activity

New arylidenehydrazides which were synthesized by reacting 3-phenyl-5sulfonamidoindole-2-carboxylic acid hydrazide with various aldehydes, evaluated for their antidepressant activity¹⁵

3.2.2 Analgesic, anti-inflammatory and antiplatelet activity

Derivative 2-(2-formylfuryl) pyridylhydrazone presented a 79 % inhibition of pleurisy at a dose of 80.1 µmol/kg. The authors also described the results concerning the mechanism of the action of these series of N-heterocyclic derivatives in platelet aggregation that suggests a Ca2+ scavenger mechanism¹⁶

4. CONCLUSION:

Pyrimidine constitutes an important heterocyclic class in drug discovery and is very well known for their anticancer, antimicrobial, antioxidant and antiviral activities. Hydrazones is a class of organic compounds and have efficient CNS depressant, analgesics activity. In the same context, Schiff bases of pyrimidine hydrazones are a potent and efficient biological activities such as anticancer, antimicrobial, antioxidant, CNS depressant, analgesic and antiviral activities. There are various synthetic pathways in which various studies are made also to form a potent and efficient Schiff bases and product of pyrimidine hydrazones.

5. REFERENCES:

1. www.wikipedia.org/wiki/Medicinal chemistry, 2011

2. Katritzky. A. R. Handbook of Heterocyclic Chemistry, Pergamon Press, New York, 1985.

3. Stoll. A. Helvi. Chim. Acta. 28; 1283:1945.

4. http://en.wikipedia.org/wiki/Pyrimidine, 2011

5. http://en.wikipedia.org/wiki/Hydrazone, 2011

6. http://en.wikipedia.org/wiki/Schiff_base, 2011

7. Fun HK, Loh WS, Nayak SP, Methoxybenzaldehyde (5-bromopyrimidin-2-yl) Hydrazone monohydrate, Act.Crys. Sec. E struc. rep.; 2010, 66 (9): 2467

8. Horiuchi T, Chiba J, Uoto K, Soga T, Novel thieno [2, 3-d] pyrimidin-4-ylhydrazone-based Cyclin D1-CDK4 inhibitors, Bioorg. Med. Chem. Lett.; 2009, 19 (2): 305-308

9. http://www.organic-chemistry.org/synthesis/heterocycles/pyrimidines.shtm

10. Tyagarajan S, Chakravarty PK, Synthesis of pyrimidines from ketones using microwave irradiation, Tet. Lett; 2005, 46 (46): 7889-7891

11. Gupta J K, Sharma PK, Dudhe R, Anshu C, Verma PK, Synthesis, analgesic and ulcerogenic activity of novel pyrimidine derivative of coumarin moiety, Annals of Bucharest Univ. Chem; 2010, 19 (2): 9–21

12. http://www.organic-chemistry.org/synthesis/C1N/hydrazones. shtm

13. Kidwai M, Rastogi S, Saxena S, Base Catalyzed Pyrimidine Synthesis Using Microwave ,Bull Korean Chem Soc; 2003, 24 (11): 1575

14. Fuchun Xie, Hongbing Zhao, Lizhi Zhao, Liguang Lou, Youhong Hu, A series of novel 2,4,5-substituted pyrimidine derivatives, Bioorganic and Medicinal Chemistry Letters; 2009, 19 (1): 275-278

15. Sevim R, Guniz KS; Molecules 2007, Derivative 2-(2-formylfuryl) pyridylhydrazone; 12: 1910-1939

16. Takao Horiuchi, Motoko Nagata, Mayumi Kitagawa, Kouichi Akahane, Kouichi Uoto; Bioorganic and Medicinal Chemistry, 2009, 17 (23): 7850-7860.

Received on 02.10.2015 Accepted on 21.10.2015

Asian J. Pharm. Res. 5(3): July- Sept., 2015; Page 162-165

DOI: 10.5958/2231-5691.2015.00025.8