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M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
International Journal of ChemTech Research
CODEN( USA): IJCRGG ISSN : 0974-4290
Vol.2, No.4, pp 1980-1986, Oct-Dec 2010
Synthesis of 7-[4-(4-(6-Phenyl pyrimidin-4-yl-amino) phenyl)-6-arylpyrimidine-2-thio-2-yl]-amino-4-methyl-1,8-naphthyridin-2-ols as antibacterial activity
E.Laxminarayana2, M.Ranadheer Kumar3 , D.Ramesh 4
and M.Thirumala Chary1*
1Jawaharlal Nehru Technological University College of Engineering, Jagityala, 505 327 India
2Sreenidhi Institute of Science and Technology, HYDERABAD-501301(A.P.) India
3Kakatiya Institute of technology & Science-Warangal-506015-India.
4Mahatma Gandhi University, NALGONDA-508 001(A.P.) India
*Corres.author:
Abstract: 2,4-Dichloro-6-phenylpyrimidine 1,on reaction with 4-aminoacetophenone 2 to afford 1-(4-(2-chloro-6-phenylpyrimidin-4-ylamino)phenyl)ethanone 3. Compound 3 on heating with different aromatic aldehydes 4 to furnish the chalcones 5a-e. Chalcones 5a-e on treated with 7-amino-4-methyl-1,8-naphthyridin-2-ol 6 to yield 3-phenyl prop-2-en-1-one phenyl)-6-phenylpyrimidin-4-yl-amino)-2-yl]-amino-4-methyl-1,8-naphthyridin-2-ols 7a-e which underwent cyclisation with thiourea 8 to yield title compounds 7-[4-(4-(6-phenylpyrimidin-4-yl-amino)phenyl)-6-arylpyrimidine-2-thio-2-yl]-amino-4-methyl-1,8-naphthyridin-2-ol 9a-e. They have been screened for their antibacterial activity.
Keywords: Pyrazolines, Chalcones, Aminopyrimidinethione, Antibacterial activity.
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Introduction:
Among the wide variety of heterocycles that have been explored for developing pharmaceutically important molecules, such as chalcones, pyrazolines and amino pyrimidines have played an important role in medicinal chemistry. The presence of reactive α, β-unsaturated carbonyl function in chalcones is found to be responsible for their antibacterial and anti fungal activity. Chalcones1 constitute an important group of natural products and some of them possess wide range of biological activity such as antibacterial,2, 3 antitumer,4anticancer,5, 6 antitubercular,7 antiviral8, 9 etc. Pyrazoline derivatives have been found to possess wide range of therapeutic activity such as anticonvulsant,10 analgesic,11 antibacterial,12, 13
antifungal,14 anticancer15etc. Some of pyrimidine derivatives have been found to possess antiulser,16 anti-inflammatory,17, 18 physiological,19 antitumor,20 antibacterial21, 22 and anticancer23 activity. Pyrimidine thiones have also been known to exhibit a broad spectrum of biological activity such as antiparasitic,24 hypoglycemic,25 antiviral,26 antibacterail,27,28 antifungal,29,30 antituberculat31 etc.
Compound 1 is prepared by arylation of halogenated pyrimidines via a suzuki coupling reaction.32 A series of pyrazolines was prepared by reacting hydrazine or its derivatives with α,β-unsaturated carbonyl compounds in the present of microwave irradiation.33 A series pyrazoline derivatives bearing chloro quinolines have been synthesized from chalcones and
evaluated for antimicrobial activity.34 A series of new bis-1,8-naphthyriidines, 1,8-naphthyriidinyl-2-pyrazolines and 2-thioxopyrimidines have been synthesized.35 Anjani et al reported the reaction of 2-phenylamino-4-(3`-flourophenylamino)-o-(4`-acetylphenyamino-s-triazene with different aromatic aldehydes to form chalcones. Chalcones are cyclised with hydrazine hydrate, and thiourea to form pyrazolines and aminopyrimidinethione respectively.36 A novel and efficient synthesis of pyrimidine from β-formyl enamide involves samarium chloride catalysed cyclisation of β-formyl enamides using urea as source of ammonia under microwave irradiation.37 A single-step conversion of various N-vinyl and N-aryl amides to the corresponding pyrimidine and quinazoline derivatives involves amide activation with 2-chloropyridine and trifluoromethanesulfonic anhydride followed by nitrile addition into the reactive intermediate and cycloisomerization.38 A photochemically induced Fries rearrangement of anilides gave several ortho-aminoacylbenzene derivatives that were acylated. These acylamides underwent rapid microwave-assited cyclization to 2,4-disubstituted quinazolines (and benzoquinazolines) in the presence of ammonium formate.39 In view of this, we now report the synthesis of 7-[4-(4-(6-phenylpyrimidin-4-yl-amino)phenyl)-6-aryl pyrimidine-2-thio-2-yl]-amino-4-methyl-1,8-naphthyridin-2-ol and their antibacterial activity.
Experimental:
Chemicals and solvents were reagent grade and used without further purification. Melting points were determined on a capillary melting point apparatus and are uncorrected. The 1H NMR were recorded in the indicated solvent on a Varian 500 MHz and 200 MHz spectrometer with TMS as internal standard. All chemical shifts (δ) were reported in ppm from internal TMS. Mass spectra were measured on a Jeol JMS D-300 spectrometer. Infrared spectra were recorded in KBr on Brucher-IFS-66 FTIR spectrophotometer. The homogeneity of the compounds was checked using precoated TLC plates (E.Merk Kieselgel 60 F254).
Procedure for the preparation of 1-(4-(2-chloro-6-phenylpyrimidin-4-yl-amino) phenyl)ethanone 3
To a solution of 1 µ moles of 2,4-dichloro-6-phenylpyrimidine,1 µ moles of 4-aminoacetophenone,5 µL of ethyl alcohol and 5 µL dioxane : hydrochloride were heated under reflux for 12 hrs. After completion of the reaction as indicated by T.L.C. The alcohol and dioxane was completely evaporated and the residue was poured into ice cold sodium carbonate solution to neutralize the reaction mixture. The precipitated solid was collected by filtration. The solid thus obtained was recrystalized from ethanol (Scheme 1).
General procedure for the preparation of 1-(4-(2-chloro-6-phenylpyrimidin-4-ylamino)phenyl)-3-phenylprop-2-en-1-ones 5a-e
To a solution of 1 µ moles of compound 3, 1 µ moles of different substituted aromatic aldehydes (4a-e),5 µL of dimethyl formamide and 40% potassium hydroxide were stirred at room temperature for 18 hrs. After completion of the reaction as indicated by T.L.C. The reaction mixture was completely concentrated and the residue was poured into ice cold hydrochloric acid to neutralize the reaction mixture. The precipitated solid was collected by filtration. The solid thus obtained was recrystalized from ethanol (Scheme 1). The chemical, spectral data and biological data of the compounds (5a-e) are in Table 1, 2, 3 and 4.
General procedure for the preparation of 3-phenyl-prop-2-en-1-one phenyl)-6-phenylpyrimidin-4-yl-amino)-2-yl)-amino-4-methyl-1,8-naphthyridin-2-ols 7a-e
To a solution of 1 µ moles of compound 5a-e, 1 µ moles of 7-amino-4-methyl-1,8-naphthyridin-2-ol and 5 µL methanol : hydrochloride were heated under reflux for 2 hrs. After completion of the reaction as indicated by T.L.C. The alcohol was completely evaporated and the residue was poured into ice cold sodium carbonate solution to neutralize the reaction mixture. The precipitated solid was collected by filtration. The solid thus obtained was recrystalized from ethanol (Scheme 1). The chemical, spectral data and biological data of the compounds (7a-e) are in Table 1, 2, 3 and 4.
General procedure for the preparation of 7-[4-(4-(6-phenylpyrimidin-4-yl-amino)phenyl)-6-arylpyrimidine-2-thio-2-yl]-amino-4-methyl-1,8-naphthyridin-2-ol 9a-e
To a solution of 1 µ moles of compound 7a-e, 1 µ moles of thiourea (8), 5 µL of dry dimethyl formamide and 40% of potassium hydroxide solution were heated under reflux for 18 hrs. After completion of the reaction as indicated by T.L.C. The residue was poured into chilled dilute hydrochloric acid to neutralize the reaction mixture. The precipitated solid was collected by filtration. The solid thus obtained was recrystalized from ethanol (Scheme 1). The chemical, spectral data and biological data of the compounds (9a-e) are in Table 1, 2, 3 and 4.
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M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
Scheme 1
Table 1: Characterization data of compounds (5a-e), (7a-e) and (9a-e)
Compd R* Yield m.p. Mol.
(%) (C) formula
5a C6H5 75 215 C25H18N3OCl
5b 4-Br-C6H4 72 221 C25H17N3OClBr
5c 4-Cl-C6H4 69 203 C25H17N3OCl2
5d 4-OMe-C6H4 85 211 C26H20N3O2Cl
5e 4-OH-C6H4 79 217 C25H18N3O2Cl
7a C6H5 65 222 C34H26N6O2
7b 4-Br-C6H4 80 202 C34H25N6O2Br
7c 4-Cl-C6H4 72 240 C34H25N6O2Cl
7d 4-OMe-C6H4 69 232 C35H28N6O3
7e 4-OH-C6H4 75 228 C34H26N6O3
7a C6H5 65 222 C34H26N6O2
7b 4-Br-C6H4 80 202 C34H25N6O2Br
7c 4-Cl-C6H4 72 240 C34H25N6O2Cl
7d 4-OMe-C6H4 69 232 C35H28N6O3
7e 4-OH-C6H4 75 228 C34H26N6O3
9a C6H5 65 249 C35H26N8OS
9b 4-Br-C6H4 68 257 C35H25N8OSBr
9c 4-Cl-C6H4 59 232 C35H25N8OSCl
9d 4-OMe-C6H4 61 241 C36H28N8O2S
9e 4-OH-C6H4 55 239 C35H26N8O2S
Elemental analyses for C,H,N are within ± 0.4% of the theoretical values.
*Solvent for crystallization: Ethanol for (5a-e); (7a-e) and (9a-e).
Table 2. Spectral data of the compounds (5a-e), (7a-e) and (9a-e)
Compd. 1H-NMR (DMSO-d6, ppm)
5a 6.31-6.72(3H,m,Ar-H), 7.10 -7.55(12H,m,Ar-H), 7.58(1H,d,-CH-),
7.90 (1H,d,-CH-), 8.25 (1H,brs,-NH-)
5b 6.35-6.65(3H,m,Ar-H), 7.19 -7.56(11H,m,Ar-H), 7.66(1H,d,-CH-),
7.92 (1H,d,-CH-), 8.35 (1H,brs,-NH-)
5c 6.35-6.65(3H,m,Ar-H), 7.19 -7.56(11H,m,Ar-H), 7.66(1H,d,-CH-),
7.92 (1H,d,-CH-), 8.35 (1H,brs,-NH-)
5d 3.75 (3H,s,-OCH3), 6.32-6.75(5H,m,Ar-H), 7.19 -7.56(9H,m,Ar-H),
7.66(1H,d,-CH-), 7.92 (1H,d,-CH-), 8.35 (1H,brs,-NH-)
5e 6.32-6.75(5H,m,Ar-H), 7.19 -7.56(9H,m,Ar-H), 7.66(1H,d,-CH-),
7.92 (1H,d,-CH-), 8.35 (1H,brs,-NH-), 9.12(1H,brs,-OH)
7a 2.37 (3H,s,-CH3),5.82-6.77(5H,m,Ar-H), 7.14 -7.82(13H,m,Ar-H),
7.58(1H,d,-CH-),7.90 (1H,d,-CH-), 8.25(2H,brs,-NH-), 9.12(1H,brs,-OH)
7b 2.37 (3H,s,-CH3),5.82-6.77(5H,m,Ar-H), 7.14 -7.82(12H,m,Ar-H),
7.58(1H,d,-CH-),7.90 (1H,d,-CH-), 8.25(2H,brs,-NH-), 9.12(1H,brs,-OH)
7c 2.37 (3H,s,-CH3),5.82-6.77(5H,m,Ar-H), 7.14 -7.82(12H,m,Ar-H),
7.58(1H,d,-CH-),7.90 (1H,d,-CH-), 8.25(2H,brs,-NH-), 9.12(1H,brs,-OH)
7d 2.37 (3H,s,-CH3), 3.75 (3H,s,-OCH3), 5.82-6.77(7H,m,Ar-H), 7.14 –7.82
(10H,m,Ar-H),7.58(1H,d,-CH-),7.90 (1H,d,-CH-), 8.25(2H,brs,-NH-),
9.12(1H,brs,-OH)
7e 2.37 (3H,s,-CH3), 5.82-6.77(7H,m,Ar-H), 7.14 –7.82 (10H,m,Ar-H),7.58
(1H,d,-CH-),7.90 (1H,d,-CH-), 8.25(2H,brs,-NH-), 9.12(2H,brs,-OH)
9a 2.37 (3H,s,-CH3), 3.21(1H,brs,-SH),5.82-6.77(5H,m,Ar-H)
7.12 -7.86(14H,m,Ar-H), 8.25(2H,brs,-NH-), 9.12(1H,brs,-OH)
9b 2.37 (3H,s,-CH3), 3.21(1H,brs,-SH), 5.82-6.77(5H,m,Ar-H),
7.12 -7.86(13H,m,Ar-H), 8.25(2H,brs,-NH-), 9.12(1H,brs,-OH)
9c 2.37 (3H,s,-CH3), 3.21(1H,brs,-SH),5.82-6.77(5H,m,Ar-H),
7.12 -7.86(13H,m,Ar-H), 8.25(2H,brs,-NH-), 9.12(1H,brs,-OH)
9d 2.37 (3H,s,-CH3), 3.21(1H,brs,-SH),3.61 (3H,s,-OCH3),
5.82-6.77(7H,m,Ar-H), 7.12 -7.86(11H,m,Ar-H), 8.25(2H,brs,-NH-),
9.12(1H,brs,-OH)
9e 2.37 (3H,s,-CH3), 3.21(1H,brs,-SH),5.82-6.77(7H,m,Ar-H),
7.12 -7.86(11H,m,Ar-H), 8.25(2H,brs,-NH-), 9.12(2H,brs,-OH)
S, singlet; d, doublet ; dd, doublet of doublets; m, multiplet.
Table 3. Spectral data of the compounds (5a-e), (7a-e) and (9a-e)
Compd. IR ( KBr, cm-1)
5 a-e 1589 (C=N), 1776 (C=O), 3265 (N-H), 3118 (C-H aromatic)
7 a-e 1589 (C=N), 1776 (C=O), 3118 (C-H aromatic),3265 (N-H),
3400 (OH)
9 a-e 1591 (C=N), 2993 (C-H aromatic), 3390 (OH), 3468 (N-H)
Table 4. Antibacterial screening data of the compounds (5a-e), (7a-e) and (9a-e)
Compound / Staphylococcus aureus / E.coli / Salmonella typhi / Bacillus subtilis5a / 4 / 3 / 1 / 2
5b / 19 / 15 / 9 / 8
5c / 10 / 11 / 5 / 4
5d / 18 / 15 / 7 / 9
5e / 10 / 17 / 8 / 9
7 a / 9 / - / - / 1
7 b / 10 / 9 / - / 1
7 c / 5 / 4 / 1 / 2
7 d / 8 / 7 / 1 / 1
7 e / 12 / 11 / 2 / 3
9 a / 6 / 4 / 1 / 2
9b / 10 / - / 3 / 2
9c / 8 / 5 / 12 / 2
9 d / 10 / 8 / 2 / 3
9e / 12 / 11 / 10 / 4
Control
Chloramphenicol / 19 / 23 / 24 / 18
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M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
Results and Discussion:
The antibacterial activity of all the substituted 1,8-naphthyridine derivatives were determined against four bacteria strains. The newly prepared compounds for antibacterial activity were screened through agar-cup method. Their antibacterial activities are reported in Table-4. Perusal of the above Table-4 reveals that the derivatives were growth inhibitory towards all the bacteria. In the synthesized compounds some compounds showed moderate to good activity while some were found to be inactive. 5b and 5d were as good as the standard drug chloramphenicol towards S.aureus. Similarly, 5e was effective against E.coli while 7a and 9b were not growth inhibitory. 9c and 9e were effective against S.typhi but most derivatives did not show good inhibitory activity against this bacterium. Compounds 5d and 5e were the most potent for inhibition of B.subtilis.
Acknowledgements:
Authors are thankful to management, Director, Principal and Head, Department of Bio-Technology Head, Department of Science and Humanities of SNIST & Management and Principal of KITS for providing research facilities, grants and for their encouragement.
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M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
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