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-4yl-amino) phenyl)-6-arylpyrimidine-2-thio-2yl]-amino-4-methyl-1,8-naphthyridin-2-ols as
antibacterial activity
E.Laxminarayana2, M.Ranadheer Kumar3 , D.Ramesh 4
and M.Thirumala Chary1*
1Jawaharlal
2Sreenidhi
Nehru Technological University College of Engineering, Jagityala, 505 327
India
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: mtcharya@yahoo.com
Abstract: 2,4-Dichloro-6-phenylpyrimidine 1,on reaction with 4-aminoacetophenone 2 to afford 1-(4-(2-chloro-6phenylpyrimidin-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-2en-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-arylpyrimidine2-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.
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, βunsaturated 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
29,30
31
antifungal,
antituberculat 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
M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
evaluated for antimicrobial activity.34 A series of new
bis-1,8-naphthyriidines,
1,8-naphthyriidinyl-2pyrazolines and 2-thioxopyrimidines have been
synthesized.35 Anjani et al reported the reaction of 2phenylamino-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 βformyl enamide involves samarium chloride catalysed
cyclisation of β-formyl enamides using urea as source
of ammonia under microwave irradiation.37 A singlestep conversion of various N-vinyl and N-aryl amides
to the corresponding pyrimidine and quinazoline
derivatives involves amide activation with 2chloropyridine 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 2,4disubstituted quinazolines (and benzoquinazolines) in
the presence of ammonium formate.39 In view of this,
we now report the synthesis of 7-[4-(4-(6phenylpyrimidin-4-yl-amino)phenyl)-6-aryl
pyrimidine-2-thio-2-yl]-amino-4-methyl-1,8naphthyridin-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 D300 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-6phenylpyrimidin-4-yl-amino) phenyl)ethanone 3
To a solution of 1 µ moles of 2,4-dichloro-6phenylpyrimidine,1
µ
moles
of
4aminoacetophenone,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
1981
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-(2chloro-6-phenylpyrimidin-4-ylamino)phenyl)-3phenylprop-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-phenylprop-2-en-1-one phenyl)-6-phenylpyrimidin-4-ylamino)-2-yl)-amino-4-methyl-1,8-naphthyridin-2ols 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)-6arylpyrimidine-2-thio-2-yl]-amino-4-methyl-1,8naphthyridin-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.
M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
1982
Ar
Cl
O
HN
Cl
HN
O
N
ArCHO
O
N
N
Dioxane.HCl
Ethyl alcohol
Cl
N
4 a-e
N
Cl
N
NH2
5a-e
3
2
1
Methanol.HCl
HO
Ar
N
SH
HO
N
N
H
N
N
HN
H2N
O
NH2
8
N
HO
N
N
N
N
H
9a-e
7a-e
Scheme 1
Table 1: Characterization data of compounds (5a-e), (7a-e) and (9a-e)
Compd
R*
NH2
S
N
N
N
6
Ar
HN
N
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
M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
1983
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.
5a
1
H-NMR (DMSO-d6, ppm)
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)
M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
1984
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)
IR ( KBr, cm-1)
Compd.
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
5a
5b
5c
5d
5e
7a
7b
7c
7d
7e
9a
9b
9c
Staphylococcus aureus
4
19
10
18
10
9
10
5
8
12
6
10
8
E.coli
3
15
11
15
17
9
4
7
11
4
5
Salmonella typhi
1
9
5
7
8
1
1
2
1
3
12
Bacillus subtilis
2
8
4
9
9
1
1
2
1
3
2
2
2
9d
9e
10
12
8
11
2
10
3
4
Control
Chloramphenicol
19
23
24
18
M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
Results and Discussion:
The antibacterial activity of all the substituted 1,8naphthyridine 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
References:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Ishidia S. Matsuda A, Kawamura Y and
Yamanaka, Chemotheraqpy, 1960, 8, 146;
Chem Abstr, 1960, 54, 22844c.
Hogale MB, Dhore NP, Shelar AR and Pawar
PK, Orient J Che, 1986, 2,55: Chem Abstr,
1987, 106, 32503a.
Methew J. Subba Rao AV and Rambhav S,
Curr Sci, 1984, 53, 576.
Vibhute YB and Wadje SS, Indian J Exptl
Biol, 1976, 14,739.
Yamakawa T, Kagechika H, Kawachi E,
Hashimoto Y and Shudo K J Med Chem,
1990, 33, 1430.
Ahluwalia VK, Nayal L, Kaila N, Bala S and
Tahim AK, Indian J Chem 1987, 26B, 384.
Bhatt AK, Bhamaria RP, Mrs Patel MR,
Bellare RA and Deliwala CV, Indian J Chem,
1972, 10, 694, Chem Abstr, 1973, 78,
119650n.
Ishitsuka H, Ninomiyo Y, Ohsawa C, Fujiu M
and Suhara Y, Antimicrob Agents Chemother,
1982, 22, 617.
Niomiya Y, Shimma N and Ishitsuka H,
Antiviral Res, 1990, 13, 61.
Parmar SS, Pandey BR and DiwediC, J Pharm
Sci 1974, 63, 1152, Chem Abstr, 1975, 82,
259660u.
Brozozowsk Z, and Pomarnacka E, Acta Pol
Pharm, 1980, 37,1378.
El-Kerdawy MM and El-Emam AA, J Chem
Soc Pak, 1987, 9, 285; Chem Abstr 1987, 107,
198165b.
Regaila Hassan AA, Latif N and Ibrahim I H, J
Pham Sci, 1989, 30, 179; Chem Abstr, 1990,
112, 216775k.
Safak Cihat, Tayhan Ayla, Saracselma and
Yulug Nuran, J Indian ChemSoc, 1990, 67,
571.
Jolly VS, Arora GD and Talwar Preeti, J
Indian Chem Soc, 1990, 67, 1001.
1985
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.
16. Kuki Masakatsu, Sakamoto Yasuhiko and Ota
Yoichiro, Chem Abstr, 1992, 117, 131220d.
17. Menozzi G, Falciani M and Filippell W ,
Farmaco, 1994, 49, 115, Chem Abstr, 1994,
121, 205269h.
18. Manna F, Chimenti F, Bolasco A, Cenicola
ML, Rossi CF and Marmo E, Chem Abstr,
118, 1993, 80902p
19. Weinherdt KK and Marn M, Chem Abstr,
1981, 95, 97837.
20. Zidermane A, Duburs G, Zibere A, Verpele R
and Uldrikis J, Chem Abstr; 1971, 75,
47266e.
21. Chanaban I, Ashur FA and Maharan MA, Sci
Pharma, 1984, 52, 75677a.
22. Gunar VI, Ovechkina LF, Arutyunyan EA,
Mikhailopulo IA and Kulaeva ON, Chem
Abstr, 1970, 72, 78969d.
23. Ghiya BJ and Rohatgaonker AM, Asian J
Chem, 1998, 10, 958.
24. Batra Sonika and SharmaSatyavan, Indian J
Chem, 1990, 29B, 1051, Chem Abstr, 1991,
114, 143320n.
25. Bancer Victor J, Dalalian HarryP, and Safir
SR, J Med Chem, 1969, 11, 4009c.
26. Kuchar Miroslav, Strof J and Vachek J, Colin
Czech Commun, 1969, 34(8), 2278; Chem
Abstr, 1969, 71, 91415u.
27. Sammour Abdel-Moged A, NorEl-Deen MM
and Abd-El Halim M, J ChemU AR, 1970, 13,
7; Chem Abstr, 1971, 75, 5840 g.
28. Novinson T, Hanon R, Dimitt MK, Simon I.N,
Robins RK and Obrien DE, J Med Chem,
1974, 17, 645.
29. Shephard Margaret C, Chem Abstr, 1970, 72,
99506r.
30. Gage C, J Chem Soc, 1949, 469.
31. Sokolova VN, Modnikova GA, Magidson O
Yu, Sheherbakova L I, Pershin GN and
Zykova TN, Khim Geterotsikl Soedin, 1970,
3, 422, Chem Abstr, 1970, 73, 25398f.
M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
32. Jennifer M. Schomaker and Thomas J. Delia,
J. Org. Chem., 2001, 66 (21), 7125.
33. Azarifar,D and Ghasemnejad, H. Molecules,
2003, 8, 642.
34. Dobaria.A.V, Patel.J.R and Parekh.H.H.,
Indian J Chem., 2003, 42B, 2019.
35. Mogilaiah.K., Rama Sudhakar.G, Indian J
Chem., 2003, 42B, 636.
*****
1986
36. Anjani solankee and Jayesh Patel, Indian J
Chem., 2004, 43B, 1580.
37. Barthakur M. G., Borthakur M., Devi P.,
Saikia C. J., Saikia A., Bora U., A. Chetia, and
Boruah R. C., Synlett, 2007, 223.
38. Movassaghi M., Hill M. D., J. Am. Chem.
Soc., 2006, 128, 14254.
39. Ferrini S., Ponticelli F., Taddei M., Org. Lett.
2007, 9, 69.