Review Article SYNTHETIC STRATEGIES AND PHARMACOLOGY OF 2-OXO-3-CYANOPYRIDINE DERIVATIVES: A REVIEW PARTHA SAKHA GHOSH 1 ,* KUNTAL MANNA 1 , UDAYAN BANIK 1 , MANIK DAS 1 , PRIYATOSH SARKAR 1 1 Department of pharmacy, Tripura University(A Central University) Agartala, Tripura, India, Pin 799022 Email: [email protected]Received: 5 March 2014 Revised and Accepted: 20 March 2014 ABSTRACT 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 has been a cause of concern for biologists’ and chemists’ for the last twenty years. Specifically 2-oxo-3-cyanopyridine scaffold demand importance due to their diverse, promising biological activities like anticancer, antibacterial, antifungal, sedative, cardiotonic agents, and HIV-1 non-nucleoside reverse transcriptase inhibitors. Due to high reactivity of this scaffold, it has been found asa reactive chemical intermediates invarious organic synthesis. In this short review we tried to focus on the recent development in synthesis of 2-oxo-3-cyanopyridine derivatives and all possible pharmacology reported for this compound. This review might be helpful for medicinal chemist in research regarding 2-oxo-3-cyanopyridine in future. Keywords: Cyanopyridines, PDEs, One Pot Synthesis, PIM-1, AMPK INTRODUCTION The Pyridine moiety has profound importance in the fields of chemistry and biology. Pyridine and its substructures are widely scattered and dominantly found in natural products, pharmaceuticals, vitamins and other functional as well as essential materials[1]. In fact the pyridine ring system forms the integral backbone of more than 7000 drugs which are already in existence[2]. Cyanopyridine, a pyridine derivativehas attracted considerable attention in the recent time due to its emergence as a derivative with diverse pharmacological activity. The cyanopyridine derivative is also employed in the industrial production of nicotinamide, nicotinic acid, isonicotinic acid and also as an intermediate for several organic synthesis. Cyanopyridines fused to several functional groups form fused cyanopyridines which have been proven to have a broad spectrum of pharmacological activity The derivative 2-oxo-3-cyanopyridine is one of the biodynamic cyanopyridinederivative. 2-oxo-3-cyanopyridine nucleus is analogous to the alkaloid Ricinine the first known alkaloid containing a cyano-group. The importance of 2-oxo-3-cyanopyridine as a pharmacologically as well as physiologically active potential molecule was highlighted with the synthesis and the study of the non glycosidiccardiotonic agent milrinone, inhibitor of dipyridinephosphodiesterase[3].Another derivative 3-Cyano-2- Pyridone has shown promising anticancer activity which might be due to the interference of the molecule with PDE3 [4], PIM1 [5] Kinase, and Survivin protein [6]. Therefore, the synthesis and pharmacological evaluation of these compounds is of great significance. SYNTHESIS OF 2-OXO-3-CYANOPYRIDINES There are many synthetic strategies for 2-oxo-3-cyanopyridine derivatives which already have been reported, we have mentioned the only the most efficient synthetic strategies. One-pot multi-component reaction [7] (SCHEME 1) Synthesis of 4-alkyl(aryl)-6-aryl-3-cyano-2(1H)-pyridinones through one-pot multi-component reaction of 3,4- dimethoxyacetophenone, malonitrile or ethyl cyanoacetate, an aldehyde and ammonium acetate in the presence of K2CO3. This reaction was carried out in various solvents such as water, DMF, chloroform, ethanol, CH2Cl2 and toluene. The best results in terms of yield and time were obtained in ethanol. By carrying out reactions with different amounts of ammonium acetate, it has been found that 8 mmol of the ammonium acetate furnished the maximum yield for 1 mmol of the reactants. COCH 3 OMe OMe 1-(3,4- dimethoxyphenyl) ethanone COOEt CN ethyl 2-cyanoacetate CHO CH 3 COONH 4 K 2 CO 3 Reflux MeO OMe N H CN O 1,2-dihydro-6-(3,4-dimethoxyphenyl)-2-oxopyridine-3- carbonitrile R benzaldehyde Scheme 1: Synthesis of 2-oxo-3-cyanopyridine derivative from substituted Aldehyde & Ketone. One-pot synthesis using piperidine[8] (SCHEME 2) The one-pot reaction of 2-cyanoacetohydrazide with aldehyde and an activated nitrile in ethanol containing a catalytic amount of piperidine yielded pyridine-2-one derivative. Scheme 2: Synthesis of 2-cyanoacetohydrazide using piperidine as catalyst O NH CN NH 2 2-isocyanoacetohydrazide X CN CHO benzaldehyde NH O CN X NH 2 CN N NH 2 NH 2 O CN X EtOH Piperidine X = CN, COPh, CO 2 Ph International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 6, Issue 4, 2014 Innovare Academic Sciences
Transcript
Review Article
SYNTHETIC STRATEGIES AND PHARMACOLOGY OF 2-OXO-3-CYANOPYRIDINE DERIVATIVES: A REVIEW
Received: 5 March 2014 Revised and Accepted: 20 March 2014
ABSTRACT
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 has been a cause of concern for biologists’ and chemists’ for the last twenty years. Specifically 2-oxo-3-cyanopyridine scaffold demand importance due to their diverse, promising biological activities like anticancer, antibacterial, antifungal, sedative, cardiotonic agents, and HIV-1 non-nucleoside reverse transcriptase inhibitors. Due to high reactivity of this scaffold, it has been found asa reactive chemical intermediates invarious organic synthesis. In this short review we tried to focus on the recent development in synthesis of 2-oxo-3-cyanopyridine derivatives and all possible pharmacology reported for this compound. This review might be helpful for medicinal chemist in research regarding 2-oxo-3-cyanopyridine in future.
Keywords: Cyanopyridines, PDEs, One Pot Synthesis, PIM-1, AMPK
INTRODUCTION
The Pyridine moiety has profound importance in the fields of chemistry and biology. Pyridine and its substructures are widely scattered and dominantly found in natural products, pharmaceuticals, vitamins and other functional as well as essential materials[1]. In fact the pyridine ring system forms the integral backbone of more than 7000 drugs which are already in existence[2].
Cyanopyridine, a pyridine derivativehas attracted considerable attention in the recent time due to its emergence as a derivative with diverse pharmacological activity. The cyanopyridine derivative is also employed in the industrial production of nicotinamide, nicotinic acid, isonicotinic acid and also as an intermediate for several organic synthesis. Cyanopyridines fused to several functional groups form fused cyanopyridines which have been proven to have a broad spectrum of pharmacological activity
The derivative 2-oxo-3-cyanopyridine is one of the biodynamic cyanopyridinederivative. 2-oxo-3-cyanopyridine nucleus is analogous to the alkaloid Ricinine the first known alkaloid containing a cyano-group. The importance of 2-oxo-3-cyanopyridine as a pharmacologically as well as physiologically active potential molecule was highlighted with the synthesis and the study of the non glycosidiccardiotonic agent milrinone, inhibitor of dipyridinephosphodiesterase[3].Another derivative 3-Cyano-2-Pyridone has shown promising anticancer activity which might be due to the interference of the molecule with PDE3 [4], PIM1 [5] Kinase, and Survivin protein [6]. Therefore, the synthesis and pharmacological evaluation of these compounds is of great significance.
SYNTHESIS OF 2-OXO-3-CYANOPYRIDINES
There are many synthetic strategies for 2-oxo-3-cyanopyridine derivatives which already have been reported, we have mentioned the only the most efficient synthetic strategies.
One-pot multi-component reaction [7] (SCHEME 1)
Synthesis of 4-alkyl(aryl)-6-aryl-3-cyano-2(1H)-pyridinones through one-pot multi-component reaction of 3,4-dimethoxyacetophenone, malonitrile or ethyl cyanoacetate, an aldehyde and ammonium acetate in the presence of K2CO3. This reaction was carried out in various solvents such as water, DMF,
chloroform, ethanol, CH2Cl2 and toluene. The best results in terms of yield and time were obtained in ethanol. By carrying out reactions with different amounts of ammonium acetate, it has been found that 8 mmol of the ammonium acetate furnished the maximum yield for 1 mmol of the reactants.
Scheme 1: Synthesis of 2-oxo-3-cyanopyridine derivative from substituted Aldehyde & Ketone.
One-pot synthesis using piperidine[8] (SCHEME 2)
The one-pot reaction of 2-cyanoacetohydrazide with aldehyde and an activated nitrile in ethanol containing a catalytic amount of piperidine yielded pyridine-2-one derivative.
Scheme 2: Synthesis of 2-cyanoacetohydrazide using piperidine as catalyst
O NH
CN
NH2
2-isocyanoacetohydrazide
X
CN
CHO
benzaldehydeNHO
CN X
NH2
CNN NH2
NH2
O
CN XEtOHPiperidine
X = CN, COPh, CO2Ph
International Journal of Pharmacy and Pharmaceutical Sciences
ISSN- 0975-1491 Vol 6, Issue 4, 2014
Innovare
Academic Sciences
Ghosh et al. Int J Pharm Pharm Sci, Vol 6, Issue 4, 39-42
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From α,β-unsaturated ketones[10] (SCHEME 3)
Condensation of ethyl cyanoacetate with α,β-unsaturated ketones in presence of excess ammonium acetate afforded 3-cyanopyridin-2-ones [9]. Also, a green chemistry approach describing reaction of α,β-unsaturated ketones with ethyl cyanoacetate using samarium iodide as catalyst has been reported recently.
SCHEME 3: Synthesis of 2-oxo-3-cyanopyridine from chalcones.
From β-dicarbonyl compound [11](SCHEME 4.)
A mixture of β-dicarbonyl (2 mmol), malononitrile (2 mmol) and triethylamine (0.2 ml) in ethanol (20 mL) was refluxed with stirring for 15 min (the progress of the reaction being monitored by TLC and used hexane/ethyl acetate as an eluent). When the reaction was completed as indicated by TLC, the crude product was precipitated from the reaction mixture by cooling, and the solid was filtered and recrystallized with ethanol to get the pure product.
Scheme 4: Synthesis of 2-oxo-3-cyanopyridine from β-dicarbonyl derivatives.
3. Pharmacology of 2-oxo-3-cyanopyridine
NH
N
O
NH
N
O
N
Dipyridine Phosphodiesterase F-III inhibitor
NH
O
NC
O OH
O
Cardiotonic
N
OCH2CONH2
OCH3
N
Antimicrobial
NH
N
O
NH
N
O
OH
Br
Cl
Cl
PIM-1 Kinase inhibitor
Survivin Inhibitor
NH
O
CN
OH
S
AMPK Activator
Biodynamic Activities of defferent derivatives of 2-oxo-3-cyanopyridine
The dominant role ofPyridone and its derivatives are well known in several biological processes as well as, its pharmacological and chemical importance [12]. The pharmacophore 2-Pyridone is prominent in various therapeutic agents which can be diversified into HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs)[13] (FIG 1.), antibacterials[14], antifungals[15], sedatives[16], cardio tonic agents[17] and has attracted attention due to their structural similarity to nucleosides [18]. Studies have also shown that they were found to be an important precursor in the building of complex natural products like nitro guanidine insecticide Imidacloprid[19] and subtype selective GABAA receptor agonists[20].Also, 2-pyridones were employed as ligands for the late 3d-metals[21].
Fig. 1: 2-oxo-3-cyanopyridine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors
Cardiovascular activity[17]
3-cyano-2-oxopyridine derivatives are proved to show potent cardiotonic activity. One of the 3-cyano-2-oxopyridine derivativeMilrinone (Fig 2) has been marketed for the treatment of congestive heart failure. Other derivatives which also have shown cardiotonicactivity(compound 1, 3, 4, 5) listed in (FIG 2) Its mechanism of action involves PDE3(Phosphodiesterase) inhibition, results in prevention of degradation of CAMP and consequently amount of PKA with in cells decreases.
NH
O
O
6,7-dihydro-1H-cyclopenta[b]pyridine-2,5-dione
1
NH
N
NC
H3C O
2
Milrinone
N
O
R
3
NR
O
4
MeO
O
O
HO OH
H O H
OH
5
Fig. 2: 2-oxo-3-cyanopyridine derivatives as non glycosidiccardiotonic activity
R1 R
O
CN
H2N
O NH4OAC
NH
R1 O
CN
R
Chalcone
2-cyanoacetamide 2-oxo-3-cyanopyridine
R R1
O O
CH2(CN)2
EtOH,Et3N
NH
O
CN
R1
R NH
O
CN
R
R1
reflux
-dicarbonylManonitrile
2-oxo-3-cyanopyridine
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ANTICANCER ACTIVITY
PDES (phosphodiesterases) inhibitor
Comparing with normal cells Phosphodiesterase, especially PDE3, PDE4 and PDE5 are over expressed in cancer cells. In addition, cross inhibition of PDE3 together with other PDEs may lead to inhibition of tumor cell growth and angiogenesis[22]. The inhibition of PDE3 was able to inhibit the growth and proliferation of the squamous cell carcinoma cell line HeLa, and in HSG cells and further studies revealed that the pyridone derivative, cilostamide a selective PDE3 inhibitor has synergism action to the anti-apoptotic action of PDE4 inhibitors in leukemia cells[23]. Also several groups have reported that PDE5 inhibitors can enhance the sensitivity of certain cancer cells to standard chemotherapeutic drugs[24].
PIM-1 inhibitor
PIM-1(Proto-oncogenic encodes for serine/ threonine kinase) kinase have been shown to be over expressed in a variety of cancer cell lines. 2-oxo-3-cyanopyridine derivative, 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles ( Fig.3.) has shown inhibition of the oncogenic serine/threonine kinase PIM-1, which plays a role in cancer cell survival, differentiation and proliferation[5].
2-oxo-3-cyanopyridine derivatives as PIM-1 inhibitor
Survivin, is a protein that is encoded by the BIRC5 gene in human. It is over expressed in cancer cells. Some derivatives of 2-oxo-3-cyanopyridine(Fig. 4.) with higher lipophilic properties can inhibit survivin which is a member of the inhibitor of apoptosis family (IAP)[26]. The level of expression ofsurvivin in tumor cells is often associated with poor prognosis and shorter patient survival rates. Survivin is highly expressed in most human tumors and fetal tissue but undetectable in most terminally differentiated adult tissues. This fact therefore makes survivingan ideal target for cancer therapy[26].
2-oxo-3-cyanopyridine derivatives as survivin inhibitor.
The thienopyridone (FIG 5.) agonist have shown moderate AMPK activity. AMPK (adenosine monophosphate-activated protein kinase), a heterotrimeric serine/ threonine kinase, is well established as a key sensor and regulator of intracellular and whole-body energy metabolism [27]. Activation of AMPK alters carbohydrate and lipid metabolism to increase fatty acid oxidation and glucose uptake and decrease fatty acid and cholesterol synthesis. Through its central role in the regulation of glucose and lipid metabolism, AMPK is emerging as an attractive molecular target for the treatment of diabetes, metabolic syndrome, and obesity[28].
2-oxo-3-cyanopyridine derivatives as an AMPK inhibitor.
2-oxo-3-cyanopyridine is a potential molecular scaffold for its diverse biological activities, as mentioned. Also it can be synthesized easily. But there is only one marketed drug is available, “Milrinone” as non glycosidiccardiotonic agent containing this scaffold. We thing that this valuable motif should be investigated according to its merits and we may get some novel anticancer agents or novel AMPK activator.
ACKNOWLEDGEMENTS
The authors express their sincere gratitude to The Department of Pharmacy, Tripura University for providing e – resources and facilities during the work.
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