2-AMINO-3-CYANOPYRIDINE: A BIOACTIVE SCAFFOLD
HTML Full Text2-AMINO-3-CYANOPYRIDINE: A BIOACTIVE SCAFFOLD
Kuntal Manna, Partha Sakha Ghosh*, Manik Das, Udayan Banik and Ashish Das
Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, Agartala, Tripura (West), India
ABSTRACT:One of the most fascinating branches of pharmaceutical field is the chemistry of heterocyclic molecules. Heterocyclic compounds are widely distributed in nature and have biological and industrial significance. Already most of the drugs available in the market are heterocyclic in nature. Cyanopyridine, a structural motif is a cause of concern for biologist and chemist in last twenty years. Specifically 2-amino-3-cyanopyridine scaffolds demand importance due to their diverse biological activity like antiviral, antibacterial, and fungicidal activities, novel IKK-β inhibitors, A2A adenosine receptor antagonists, potent inhibitor of HIV-1 integrase. Due to high reactivity of this scaffold, it has been found as reactive chemical intermediates in organic synthesis like, commercial production of nicotinamide, and pharmaceuticals such as Ridogrel and Pirenzepine. In this short review we have focused on the recent development in synthesis of 2-amino-3-cyanopyridine derivatives and all possible pharmacology reported for this compound. This review may helpful for medicinal chemist in research regarding 2-amino-3-cyanopyridine in future
Keywords: |
Cyanopyridines, One pot synthesis, IKK-β, A2A, Solvent free synthesis.
INTRODUCTION: Molecules containing pyridine always have grave importance in chemistry as well as in biology. The pyridine substructure is one of the most prevalent heterocyclic molecular frameworks found in natural products, pharmaceuticals, vitamins and functional materials 1–4.
The pyridine ring systems have emerged as integral backbones of over 7000 existing drugs 5, 6.
Cyanopyridines a pyridine derivative attract attention as its many derivative having different pharmacological activities, used in the industrial production of nicotinamide, nicotinic acid and isonicotinic acid,intermediates to pharmaceuticals such as Ridogrel and Pirenzepine, also serves as the intermediate in many organic synthesis. Fused cyanopyridines also have wide range of pharmacological activity. Among these compounds, 2-amino-3-cyanopyridine derivatives have been reported to possess antiviral, antibacterial, and fungicidal activities 7, 8. 2-Amino-3-cyanopyridine derivatives were also reported as novel IKK-β inhibitors 9, A2A adenosine receptor antagonists10, potent inhibitor of HIV-1 integrase11, and so on. 2-Amino-3-cyanopyridines are important and useful intermediates in preparing variety of heterocyclic compounds 12, 13.
A complete review on this compound is hard to find, that’s why we have tried to accumulate all the synthetic work, and biological evaluation regarding this compound up to present time which will be useful to find a new lead compound in the pharmaceutical arena and may also useful to the chemist.
Structure of 2-amino-3-cyanopyridine:
FIGURE 1:
White to tan crystals or lumps having characteristic odour, and easily soluble in water and gives a clear solution at around 40oC. Melting range is 48-50oC. Due to the presence of lone pair, it has the ability to form significant additive complexes. X-Ray crystallographic studies have shown that it has two isomers. Both isomers are planar in nature, with the characteristic deformation of the aromatic ring due to the presence of lone pair and the ideal symmetrical hexagon form, especially around the pyridine nitrogen atom. The internal angles C – N – C are significantly smaller than 120o and two angles N – C – C within the rings are greater than 120o 32.
Synthesis of 2-amino-3-cyanopyridine: Various preparation methods of 2-amino-3-carbonitrile have been reported. The common method used in the preparation of 2-amino-3-cyanopyridine is the condensation of chalcone or carbonyl compound with malononitrile and ammonium acetate by conventional heating up-to 5 to 6 hours in the presence of ethyl alcohol as a solvent. The same method was repeated by using microwave irradiation 14, ultrasound irradiation 15, 16. To enhance the yield, lowering the reaction time, hexadecyldimethyl benzyl ammonium bromide 17, triethylamine 17, 18, DMF 19 and acetic acid 20 are also used as Catalyst or solvent. These reported methods suffered from severaldrawbacks like prolonged reaction times, low yields, harsh reaction conditions, critical isolation procedures, and expensive catalysts.
In recent years few synthetic methods were published which overcomes the drawbacks of the conventional methods.
Method (A) 21: Reaction of Chalcone with Malononitrile and Ammonium acetate in presence of ethylammoniumnitrate at 60oC gave corresponding 2-amino-3-cyanopyridine. Material used, the ionic liquid EAN (2mL), chalcones (1 mmol), malononitrile, (1 mmol, 0.066 g), and ammonium acetate (8 mmol, 0.601 g). This process gives a good yield.
Method (B) 22: Four-component condensation of benzaldehyde, acetophenone, malononitrile, and ammonium acetate in trifluoroethanol at refluxing temperature for 6 h results in the formation of 2-amino-3-cyanopyridine.
SCHEME 1: SYNTHESIS OF 2-AMINO-3-CYANOPYRIDINE FROM CHALCONES
SCHEME 2: SYNTHESIS OF 2-AMINO-3-CYANOPYRIDINE FROM ALDEHYDE & KETONE USING TRIFLUORO ETHANOL AS CATALYST
Method (C) 23: The one-pot reaction of synthesis of 2-amino-3-carbonitrile was done by taking a mixture of benzaldehyde, acetophenone, malononitrile, ammonium acetate, and of Yb(PFO)3, in ethanol at refluxing temperature for 12 h yielded the crude product in 92%.
SCHEME 3: ONE POT SYNTHESIS OF 2-AMINO-3-CYANOPYRIDINE FROM ALDEHYDE & KETONE USING YTTERBIUM PERFIUOROOCTANOATE
Method (D) 24: A mixture of aldehyde, substituted acetophenone, malononitrile, ammonium acetate and TBBDA (Tetra-bromobenzene-1, 3-disulfonamide) or PBBS (Poly(N-bromo-N-ethylbenzene-1,3-dis-ulfonamide)) was heated under stirring at 100◦C for appropriate times yielded the final product.
SCHEME 4: SOLVENT FREE SYNTHESIS OF 2-AMINO-3-CYANOPYRIDINE USING TBBDA OR PBBS
Pharmacology of 2-amino-3-cyanopyridine: Heteroaromatic rings containing nitrogen atoms often play important roles as the scaffolds of bioactive substances. The pyridine ring system is one of the most popular N-heteroaromatics incorporated into the structure of many pharmaceuticals.
Anti-inflammatory activity 25: Kumar et al has reported eight derivatives of 2- amino-4,6-diphenylpyridine-3-carbonitrile and carried out anti-inflammatory screening in healthy rats using indomethacin as standard. Among them, three derivatives have shown potential anti-inflammatory activity.
Antimicrobial activity 26: Vyas et al reported the synthesis of some new cyanopyridine derivatives and their screening against M. tuberculosis and other microorganism. Anti-tubercular data was compared to the rifampin. Antimicrobial activities of the compounds were compared with norfloxacin, griseofulvin, benzyl penicillin, amoxicillin and ampicillin against various bacterial strain, Bacillus subtillis, Bacillus megaterium, E. coli, Proteus Vulgaris, and Aspergillus niger.
Few derivatives have shown promising Antimicrobial and Antitubercular activity.
FIGURE 2:
A2A Adenosin receptor antagonist 10: Mantri et al reported the synthesis of 2-Amino-6-furan-2-yl-4-substituted Nicotinonitriles as A2A Adenosine Receptor Antagonists. A molecular super-imposition model was constructed using previously published antagonist ligands having high affinity and selectivity for the A2A adenosine receptor. All these molecules were selected with the criteria of having diverse scaffolds based on the heterocyclic aromatic core of each molecule. The actual ligand taken from a specific scaffold class was the one that had a combination of high affinity and selectivity for the A2A adenosine receptor.
IKK-β inhibitory activity: Murata et al reported the novel IKK-β inhibitory activity of 2-amino-3-cyanopyridine derivative. IKK-β inhibition helps the brain cell to stay alive in harsh condition. 9
FIGURE 3:
FIGURE 4:
Other activity: 2-amino-3- cyanopyridine derivatives are known to have multiple biological activities, such cardiotonic 27, antiparkinsonism 10, aurora a kinase inhibitor 28, Herbicidal 29 and anti-tumor properties 30 and potent inhibitor of HIV-1 integrase 11.
CONCLUSION: It is found that 2-amino-3-cyanopyridine is an important bioactive scaffold having diverse biological activities. Unfortunately there are no marketed drugs at present having 2-amino-3-cyanopyridine in there structure. For further research it can be proposed that 2-amino-3-cyanopyridine molecular skeleton can be conjugated with drugs, like antibiotics, antitumor, to suppress their adverse effect or to alter the physiochemical property.
ACKNOWLEDGEMENT: The authors are thankful to Department of Pharmacy, Tripura University for providing e – resources.
REFERENCE:
- Jones G: Comprehensive Heterocyclic Chemistry II. Pyridines and their Benzo Derivatives Synthesis. ELSEVIER, Vol. 5.05, 1996: 167-243.
- Henry GD: De novo synthesis of substituted pyridines. Tetrahedron, 2004; 60 (29): 6043-6061.
- Joseph PM: Quinoline, quinazoline and acridone alkaloids. Natural Product Reports, 2005; 22 (5): 627-646.
- Movassaghi M, Hill MD and Ahmad OK: Direct Synthesis of Pyridine Derivatives. Journal of the American Chemical Society, 2007; 129: 10096–10097.
- Li AH, Moro S, Forsyth N, Melman N, Ji X and Jacobson KA: Synthesis, CoMFA Analysis, and Receptor Docking of 3,5-Diacyl-2,4-Dialkylpyridine Derivatives as Selective A3 Adenosine Receptor Antagonists. Journal of Medicinal Chemistry, 1999; 42: 706-721.
- Vacher B, Bonnaud B, Funes P, Jubault N, Koek W, Assie MB, Cosi C and Kleven M: Novel Derivatives of 2-Pyridinemethylamine as Selective, Potent, and Orally Active Agonists at 5-HT1A Receptors.Journal of Medicinal Chemistry 1999; 42(9):1648-1660.
- Ibrahima ES, Elgemeieabe GEH, Abbasic MM, Abbasd YA, Elbadawic MA and Attiad AME: Synthesis of N-Glycosylated Pyridines as New Antiviral Agents. Nucleosides and Nucleotides 2006; 14(6): 1415-1423.
- Prakash L, Verma SS, Shaihla, Tyagi E and Mital RL: A novel synthesis of flourinated pyrido [2,3-d] pyrimidine derivatives. Journal of Fluorine Chemistry 1988; 41(3): 303-310.
- Murata T, Shimada M, Sakakibara S, Yoshino T, Kadono H, Masuda T, Shimazaki M, Shintani T, Fuchikami K, Sakai K, Inbe H, Takeshita K, Niki T, Umeda M, Bacon KB, Ziegelbauer KB and Lowinger TB: Discovery of novel and selective IKK-β serine-threonine protein kinase inhibitors. Bioorganic & Medicinal Chemistry Letters 2003; 13(5): 913-918.
- Mantri M, De Graaf O, Van Veldhoven J, Go¨blyo¨s A, Von Frijtag Drabbe Ku¨nzel JK, Mulder-Krieger T, Link R, De Vries H, Beukers MW, Brussee J, and IJzerman AP: 2-Amino-6-furan-2-yl-4-substituted Nicotinonitriles as A2A Adenosine Receptor Antagonists. Journal of Medicinal Chemistry 2008; 51: 4449–4455.
- Deng J, Sanchez T, Al-Mawsawi LQ, Dayam R, Yunes RA, Garofalo A, Bolger MB and Neamati N: Discovery of structurally diverse HIV-1 integrase inhibitors based on a chalcone pharmacophore. Bioorganic & Medicinal Chemistry 2007; 15: 4985-5002.
- Al-Haiza M, Mostafa M and El-Kady: Synthesis and Biological Evaluation of Some New Coumarin Derivatives. Molecules 2003; 8: 275-286.
- Girgis AS, Kalmouch A and Hosni HM: Synthesis of novel 3-pyridinecarbonitriles with amino acid function and their fluorescence properties. Amino Acids 2004; 26: 139–146.
- Shi F, Tu S, Fang F and Li T: One-pot synthesis of 2-amino-3-cyanopyridine derivatives under microwave irradiation without solvent. ARKIVOC 2005; (i): 137-142.
- Shujiang T, Hong J, Qiya Z, Chunbao M, Daqing S, Xiangshan W and Yuan G: One-Pot Synthesis of 2-Amimo-3-cyano-4-aryl-7,7-dimethyl-5-oxo-5,6, 7,8-tetrahydro-4H-benzo[b]pyran under Ultrasonic Irradiation without Catalyst. Chinese Journal of organic Chemistry 2003; 23(5): 488-490.
- Zhou WJ, Ji SJ and Shen ZL: An efficient synthesis of ferrocenyl substituted 3-cyanopyridine derivatives under ultrasound irradiation. Journal of Organometallic Chemistry 2006; 691(7): 1356-1360.
- Jin TS, Wang AQ, Shi F, Han LS, Liu LB and Li TS: Hexadecyldimethyl benzyl ammonium bromide: an efficient catalystfor a clean one-pot synthesis of tetrahydrobenzopyran derivatives in water. ARKIVOC 2006; (xiv): 78-86.
- Tret’yakova EV, Flekhter OB, Galin FZ, Spirikhin LV and Tolstikov GA: Synthesis of 2-amino-4-aryl-3-cyano-4Hpyrano and 2-amino-3-cyanothieno derivatives of cyclopentanonopimaric acid. Russian Journal of Organic Chemistry 2002; 39: 1811-1813.
- Shestopalov AM and Naumov OA: Synthesis of substituted 2-amino-3-cyano-7,9-dimethyl-4H pyrano[2´,3´:4,5]thieno[2,3b]pyridines. Russian Chemical Bulletin, International Edition 2003; 52(6): 1380—1385.
- Vasiliev AN, Kayukov YS, Nasakin OE, Lyshchikov AN, Nesterov VN, Kayukova OV and Poulkherovskaya OV: Synthesis of alkyl 5,6-dialkyl-2-amino-3-cyanopyridine-4-carboxylates. Chemistry of Heterocyclic Compounds 2001; 37(3): 309–314.
- Sarda SR, Kale JD, Wasmatkar SK, Kadam VS, Ingole PG, Jadhav WN and Pawar RP: An efficient protocol for the synthesis of 2-amino-4,6-diphenylpyridine-3-carbonitrile using ionic liquid ethylammonium nitrate. Molecular Diversity 2009; 13: 545–549.
- Khaksar S and Yaghoobi M: A concise and versatile synthesis of 2-amino-3-cyanopyridine derivatives in 2,2,2-trifluoroethanol. Journal of Fluorine Chemistry 2012; 142: 41-44.
- Tang J, Wang L, Yao Y, Zhang L and Wanga W: One-pot synthesis of 2-amino-3-cyanopyridine derivatives catalyzed by ytterbium perfluorooctanoate [Yb(PFO)3]. Tetrahedron Letters 2011; 52: 509–511.
- Ghorbani-Vaghei R, Toghraei-Semiromi Z and Karimi-Nami R: One-pot synthesis of 2-amino-3-cyanopyridine derivatives under solvent-free conditions. Comptes Rendus Chimie 2013;16(12): 1111–1117.
- Kumar N, Chauhan A and Drabu S: Synthesis of cyanopyridine and pyrimidine analogues as new anti-inflammatory and antimicrobial agents. Biomedicine & Pharmacotherapy 2011; 65: 375–380.
- Vyas DH, Tala SD, Akbari JD, Dhaduk MF, Joshi KA and Joshi HS: Synthesis and antimicrobial activity of some new cyanopyridines and cyanopyrans towards mycobacterium tuberculosis and other microorganism, Indian journal of chemistry 2009; 48B: 833-839.
- Bekhit AA and Baraka AM: Novel milrinone analogs of pyridine-3-carbonitrile derivatives as promising cardiotonic agents. European Journal of Medicinal Chemistry 2005; 40(12): 1405-1413.
- Ando R, Ikegami H, Sakiyama M, Ooike S, Hayashi M, Fujino Y, Abe D, Nakamura H, Mishina T, Kato H, Iwase Y, Tomozane H and Morioka M: 3-Cyano-6-(5-methyl-3-pyrazoloamino)pyridines: Selective Aurora A kinase inhibitors. Bioorganic and Medicinal Chemistry Letters 2010; 20(15): 4709-4711.
- Ren Q, Mo W, Gao L, He H and Gu Y: Facile synthesis and herbicidal activity of novel multisubstituted pyridine derivatives. Journal of Heterocyclic Chemistry 2010; 47(1): 171–178.
- Zhang F, Zhao Y, Sun L, Ding L, Gu Y and Gong P: Synthesis and anti-tumor activity of 2-amino-3-cyano-6-(1H-indol-3-yl)-4-phenylpyridine derivatives in vitro. European Journal of Medicinal Chemistry 2011; 46(7): 3149-3157.
- Murata T, Shimada M, Sakakibara S, Yoshino T, Masuda T, Shintani T, Sato H, Koriyama Y, Fukushima K, Nunami N, Yamauchi M, Fuchikami K, Komura H, Watanabe A, Ziegelbauer KB, Bacon KB and Lowinger TB: Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 3: Orally active anti-inflammatory agents. Bioorganic Medicinal Chemistry Letter 2004; 14(15): 4019-4022.
- Kubiak R, Janczak J and Sledz M, Crystal structures of 2 – and 3 – cyanopyridines, Journal of Molecular Structure 2002; 610: 59 – 64.
How to cite this article:
Manna K, Ghosh PS, Das M, Banik U and Das A: 2-amino-3-cyanopyridine:a bioactive scaffold. Int J Pharm Sci Res 2014; 5(6): 2158-63.doi: 10.13040/IJPSR.0975-8232.5 (6).2158-63
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
Article Information
6
2158-2163
386KB
2911
English
IJPSR
Kuntal Manna, Partha Sakha Ghosh*, Manik Das, Udayan Banik and Ashish Das
Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, Agartala, Tripura (West), India
ghoshpartha.tu@gmail.com
08 December, 2013
11 January, 2014
09 April, 2014
http://dx.doi.org/10.13040/IJPSR.0975-8232.5(6).2158-63
01, June 2014