الفهرس 
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Abstract
English Summary
PART 1
Synthesis of Cyclic and Acyclic Nucleosides for 2-Pyridone Derivatives.
The pyridin-2(1H)-one ring system present in various natural active substances. The existence of a pyridin-2(1H)-one structural unit is a key to the pharmacological activities of many natural and synthetic drugs. A large number of compounds having pyridin-2(1H)-one ring system has been reported to possess different kind of biological activities like anti-tumor, cardiotonic, antituberculosis, antibacterial and antihepatitis B virus. Recently, pyridin-2(1H)-ones include 5-ethyl-1-phenyl-2-(1H)-pyridone, camptothecin and 3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-quinolin-2-one have been reported to show strong cytotoxicity against several human cancer cell lines.
In view of these reports and in continuation with the previous work, we therefore envisaged that integrating pyridin-2(1H)-one and based pyridine carrying cyclic and acyclic sugar moieties in one molecular platform could potentially produce novel compounds with significant synergistic antitumor and anti-oxidant properties. These new pyridin-2(1H)-ones analogues bearing cyclic, acyclic and alkyl moiety were prepared to verify their efficacy as potential antimicrobial, anti-oxidant and anticancer agents.
Recently, N-methylcytisine and (-)-cytisine containing on the substituent’s secondary N atom and in the 2-pyridone nucleoside analogue core has antiviral activity against hepatitis C (HCV), hepatitis B (HBV) Herps simplex 1 (HSV-1), anti-SARS-CoV and Influenza type A (H5N1 and H1N1) activities. Sulfonyl biscompounds carrying 2-pyridone moiety exhibited a good anticancer activity against human breast cell line (MCF7). In continuation of our efforts, we synthesyzed the new 2-pyridone derivatives containing a new substituents at position-4 and 6, which containing 3-methyl-2-thiophenecarboxaldehyde and 2-naphthyl moiety to evaluate the biological activity against antimicrobial, anti-cancer and antioxidant.
In the present work, we synthesized a new 2-pyridone derivatives 1a-c by four component system from the reaction of 2-acetylnaphthalene, 4-bromoacetophenone, aromatic aldehydes namely (p-tolualdehyde, 3-methyl-2-thiophenecarboxaldehyde and 4-chlorobenzaldehyde), ethyl cyanoacetate in the presence of excess from ammonium acetate as procedure reported in literature (Scheme 1).
Glycosylation of 6-(naphthalen-2-yl)-2-oxo-4-(p-tolyl)-1,2-dihydro-pyridine-3-carbonitrile (1a), and 4-(3-methylthien-2-yl)-6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (1b) with glucosyl/galactosyl bromides in the presence of dry DMF and KOH afforded the nucleosides 2a,b and 4a,b, respectively (Scheme 2, 3).
Deprotection of nucleosides 2a,b and 4a,b in the presence of TEA/MeOH and few drops of water at room temperature afforded the free nucleosides 3a,b and 5a,b in a high yield more than 80%, respectively (Scheme 2, 3).
Reaction of 6-(naphthalen-2-yl)-2-oxo-4-(p-tolyl)-1,2-dihydro-pyridine-3-carbonitrile (1a) and 4-(3-methylthien-2-yl)-6-(naphthalen-2-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (1b) with peracetylated ribose in domestic microwave irradiation supported in silica gel (200-400 mesh) for 5 minutes afforded the riboside 6a,b which deacetylated in the presence of TEA/MeOH and few drops of water afforded free riboside 7a,b in high yield 91% (Scheme 4).
Deportation of ribosied 6a,b in the presence of methanol/TEA and few drops of water afforded the depredated ribosied 7a,b, in high yields > 80% (Scheme 4).
The acyclic nucleosides 9 and 11a,b were obtained by the reaction of 2-pyridone derivatives 1a,b with acyclic sugar namely, 4-bromo butylacetate and 2-acetoxyethoxymethyl bromide, in the presence of dry DMF and anhydrous K2CO3 after deacetylation of protected acyclic nucleosides 8 and 10a,b (Scheme 5).
PART 2
Alkylation and Formation of 1,2,3-Triazole for 2-Pyridone Derivatives via Click Reaction.
Alkylation of 2-pyridone derivatives 1a-c with alkylating agents namely (allyl/propargyl bromides, chloroacetonitrile, ethylbromoacetate, acetic anhydride) in the presence of base catalysis as K2CO3 in presence of dry DMF as a solvent afforded the N-alkylated products 12a-c, 14b,c, 17a,b, 20a,b and O-alkylated product 13, 15 and 16a,b in case of allyl/propargyl bromides and chloroacetonitrile (Scheme 6, 7).
The hydrolyses of ester 17a,b using hydrazine hydrate (99%) in refluxing ethanol afforded the hydrazide 18a,b, while, the hydrolysis of the ester 17a,b (1.98 g, 5 mmol) in presence of sodium hydroxide (0.40 g, 10 mmol) in refluxing 20 mL methanol (60%) afforded free acids 19a,b (Scheme 7). Refluxing of 2-pyridone 1a,b with (5.0 mL) of acetic anhydride afforded N-acylating products 20a,b (Scheme 7).
Condensation of the hydraside 18a, b with acetylacetone and ethyl acetoacetate in refluxing methanol afforded the pyrazole 21a, b and acetohydrazide 27 (Scheme 8), while, the condensation with benzaldehyde, acetophenone, p-nitroacetophenone, 4-chloroacetophenone and 4-bromoacetophenone in the same above conditions afforded the acetohydrazide 22a, b - 26a, b, respectively (Scheme 8).
Synthesis of 1,2,3-triazole derivatives for 2-pyridone 28 and 29 were obtained via click reaction by formation of the ethyl 2-azidoacetate from ethyl bromoacetate with sodium azide as literature reported followed by reaction with alkylated 2-pyridone 15 and 14b in the presence of CuSO4.H2O/(+)sodium-L- ascorbate/DMF:H2O (7:3) at room temperature in a high yields between 82 and 76.5 %, respectively (Scheme 9). The newly synthesized compounds are characterized on the basis of elemental analyses, IR, 1H and 13C NMR. Mainly from the synthesized compounds have been screened for their antimicrobial activity against two types of G (+ve), G (-ve) and one type of Fungi, antitumor against two types Cell culture of RPE-1 (human normal Retina pigmented epithelium cells) and MCF-7 (human breast adenocarcinoma) cell lines and antioxidant agents. The results showed that all tested compounds have a high and significant activity against G (+ve) and G (-ve) bacteria and some of these compounds have moderate effect on Fungi comparison with the standard drugs. Also, the results for antitumor and antioxidant showed the compounds have a good and moderate effects.
Scheme 1: Synthesis of 2-pyridone derivatives (1a-c).
Scheme 2: Glycosylation of 2-pyridone derivatives.
Scheme 3: Glactosylation of 2-pyridone derivatives.
Scheme 4: Synthesis of ribonucleoside for 2-pyridone derivatives.
Scheme 5: Synthesis of acyclic nucleosides for 2-pyridone derivatives.
Scheme 6: Alkylation of 2-pyridone derivatives allyl, propargyl bromides and chloroacetonitrile.
Scheme 7: Alkylation, hydrazonolysis and hydrolysis of esters.
Scheme 8: Condensation of the hydrazine for 2-pyridone derivatives with different aldehydes and ketons.
Scheme 9: Formation of 1,2,3-triazole for 2- pyridone derivatives via click reaction.