Synthesis and antimicrobial activity of some pyridinyliminothiazoline derivatives

Article abstract of DOI:10.1016/S0014-827X(02)01250-8

The synthesis of some pyridinyliminothiazoline derivatives starting from N-pyridine-N′-phenyl thiourea and α-halogenoacetophenones is described. The chemical structures of the compounds were elucidated. The prepared compounds were tested for antimicrobial activity.

Full text of DOI:10.1016/S0014-827X(02)01250-8

Il Farmaco 57 (2002) 569–572
www.elsevier.com/locate/farmac
Synthesis and antimicrobial activity of some
pyridinyliminothiazoline derivatives
8
G. Turan-Zitouni*, D.M. Sıvacı, Z.A. Kaplancıklı, A. Ozdemir
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Uni6ersity of Anadolu, 26470 Eskis¸ehir, Turkey
Received 24 January 2002; accepted 27 January 2002
Abstract
The synthesis of some pyridinyliminothiazoline derivatives starting from N-pyridine-N%-phenyl thiourea and a-halogenoace-
tophenones is described. The chemical structures of the compounds were elucidated. The prepared compounds were tested for
´
antimicrobial activity. © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Pyridinyliminothiazoline; Antimicrobial activity
1. Introduction
Analytical and spectral data (IR, 1H NMR, MS-
(FAB+)) confirmed the structure of all compounds.
Thiazoline derivatives present some interesting bio-
logical activities. Among them the most important ef-
fects are; anticonvulsant [1,2], convulsant [2], local
anesthesic [3], fungicide [4], bactericide [5,6], herbicide
[6], insecticide [7], antituberculostatic [8], cardiotonic
[9], acaricid [6,7], antiulcer [10] and antineoplastic [11]
activities.
Some pyridine derivatives have been reported to pos-
sess analgesic [12], antibacterial [13], antituberculostatic
[14], uriner antiseptic [15], anesthesic [16], Vit B6 [17],
analeptic [18] activities.
3. Experimental
3.1. Chemistry
M.p.s were determined by using a Gallenkamp ap-
paratus. Spectroscopic data were recorded by the fol-
lowing instruments. IR: Shimadzu 435 spectro-
1
photometer; H NMR: Bruker 400 MHz spectrometer;
MS: VG Quattro mass spectrometer.
Therefore, we aimed the synthesis of new pyridinyl-
iminothiazoline derivatives.
3.1.1. General procedure for the synthesis of the
compounds
2. Chemistry
3.1.1.1. Preparation of N-(4-methyl-2-pyridinyl)-N%-
phenyl thiourea deri6ati6es (1) and N-(3-pyridinyl-
In this work; N-pyridinyl-N%-phenyl thioureas (1)
were prepared for the first time in accordance with the
method described in literature [19].
The reaction of thiourea (1 or 3) with a-halogenoace-
tophenone gave the pyridinyliminothiazoline derivatives
(2a–g, 4) (Scheme 1).
methyl)-N%-phenyl thiourea (3).
A
mixture of
aminopyridine (0.1 mol) and phenylisothiocyanate (0.1
mol) in EtOH was refluxed for 2 h. The solid separated
upon cooling was filtered, dried and recrystallized.
3.1.1.2. Preparation of pyridinyliminothiazoline deri6a-
ti6es (2a–g, 4). Thiourea (1 or 3) (0.001 mol) and
appropriate a-halogenoacetophenone (0.001 mol) in ab-
solute EtOH was refluxed for 4–5 h. The solid sepa-
rated was filtered and recrystallized (Table 1).
* Corresponding author
E-mail address: gzitouni@anadolu.edu.tr (G. Turan-Zitouni).
´
0014-827X/02/$ - see front matter © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S0014-827X(02)01250-8

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G. Turan-Zitouni et al. / Il Farmaco 57 (2002) 569–572
2.3 (3H, s, CH3), 6.8–8.0 (12H, m, aromatic protons),
8.2 (1H, s, thiazoline 5-H). MS (ES+): m/z: 423
[M+1].
2c: IR (KBr) wmaks (cm−1): 1635 (CꢀN), 1587 (CꢀC
1
aromatic) H NMR (400 MHz, DMSO-d6, l ppm): 2.4
(3H, s, CH3), 3.7 (3H, s, OCH3), 6.8 (2H, d (J=8.7
Hz), phenyl-2%-H, 6%-H), 7.1 (2H, d, J=8.65 Hz, phenyl
3%-H, 5%-H), 7.1–7.5 (8H, m, aromatic protons), 8.3
(1H, s, thiazoline 5-H). MS (ES+): m/z: 374 [M+1].
2d: IR (KBr) wmaks (cm−1): 1625 (CꢀN), 1587 (CꢀC
2a: IR (KBr) wmaks (cm−1): 1637 (CꢀN), 1592 (CꢀC
1
1
aromatic). H NMR (400 MHz, DMSO-d6, l ppm): 2.4
aromatic). H NMR (400 MHz, DMSO-d6, l ppm): 2.4
(3H, s, CH3), 7.2 (2H, d, J=6.77 Hz, phenyl 2%-H,
6%-H), 7.5 (2H, d (J=6.79 Hz), phenyl 3%-H, 5%-H),
7.0–7.6 (8H, m, aromatic protons), 8.2 (1H, s, thiazo-
line 5-H). MS (ES+): m/z: 378.2 [M+1].
(3H, s, CH3), 7.0–7.6 (13H, m, aromatic protons), 8.2
(1H, s, thiazoline 5-H). MS (ES+): m/z: 344.2 [M+1].
2b: IR (KBr) wmaks (cm−1): 1625 ( CꢀN), 1587 (CꢀC
aromatic). 1H NMR (400 MHz, DMSO-d6, l ppm):
Scheme 1.
Table 1
Comp.
R1
R2
R3
M.p. (°C)
Yield (%)
Molecular formula
C21H17N3S
2a
2b
2c
2d
2e
2f
H
Br
H
H
H
H
H
H
H
Cl
H
H
H
H
OCH3
Cl
Cl
298
142
220
210
197
162
227
85
78
83
81
83
79
88
C21H16BrN3S
C22H19N3OS
C21H16ClN3S
C21H15Cl2N3S
C21H17N3OS
OH
CH3
H
OH
2g
C22H19N3OS

G. Turan-Zitouni et al. / Il Farmaco 57 (2002) 569–572
571
Table 2
Antimicrobial activities of the compounds
Microorganizm
Strain
4
2a
2c
2d
2e
Control comp. 1
Control comp. 2
Escherichia coli
ATCC 25922
ATCC 6538
ATCC 27853
NRRL 3567
NRRL 123
31.25
62.5
62.5
250
31.25
125
15.62
62.5
62.5
125
125
62.5
62.5
31.25
125
62.5
31.25
31.25
31.25
250
31.25
250
250
31.25
31.25
62.5
62.5
31.25
31.25
31.25
15.62
62.5
7.81
250
62.5
31.25
62.5
Staphylococcus aureus
Pseudomonas aeruginosa
Entereobacter aerogenes
Proteus vulgaris
Salmonella typhimurium
Candida albicans
NRRL 4420
62.5
62.5
125
31.25
8
O.G.U. Tıp
125
*MIC (mg/ml); Control comp. 1, chloramphenicole; Control comp. 2, ketoconazole
2e: IR (KBr) wmaks (cm−1): 1631 (CꢀN), 1565 (CꢀC
IR spectra of all compounds CꢀN and CꢀC bands
1
aromatic). H NMR (400 MHz, DMSO-d6, l ppm): 2.4
were observed at about 1635 and 1580 cm−1
respectively.
,
(3H, s, CH3), 7.0–7.6 (11H, m, aromatic protons), 8.2
(1H, s, thiazoline 5-H). MS (ES+): m/z: 412.2 [M+1].
2f: IR (KBr) wmaks (cm−1): 1635 (CꢀN), 1585 (CꢀC
In the NMR spectra of 3-methyliminopyridine
derivatives the protons at methylene group resonated as
a singlet of 4.8 ppm, while the aromatic protons signal
appeared as multipled at 7.1–8.6 ppm.
In the NMR spectra of Pyridin-2-imino derivatives
the protons of methyl group in the pyridine were ob-
served at 2.3–2.4 ppm.
1
aromatic), 3490 (OꢁH). H NMR (400 MHz, DMSO-
d6, l ppm): 2.3 (3H, s, CH3), 6.8–8.1 (12H, m, aromatic
protons), 8.2 (1H, s, thiazoline 5-H), 11.3 (1H, s, OH).
MS (ES+): m/z: 360 [M+1].
2g: IR (KBr) wmaks (cm−1): 1638 (CꢀN), 1585 (CꢀC
1
aromatic), 3472 (OꢁH). H NMR (400 MHz, DMSO-
The proton of Thiazoline (C5) was observed at 8.2–
8.3 ppm.
d6, l ppm): 2.1 (3H, s, CH3), 2.3 (3H, s, CH3), 6.9–8.0
(11H, m, aromatic protons), 8.2 (1H, s, thiazoline 5-H),
11.5 (1H, s, OH). MS (ES+): m/z: 374 [M+1].
4: IR (KBr) wmaks (cm−1): 1642 (CꢀN), 1556 (CꢀC
An important antifungal activity was observed only
for compounds 2e (15.62 mg/ml) and 4 (15.62 mg/ml)
against C. albicans. The other compounds showed MIC
values \100 mg/ml against all the tested microbial
strains.
1
aromatic). H NMR (400 MHz, DMSO-d6, l ppm): 3.3
(3H, s, OCH3), 4.8 (2H, s, CH2), 7.1–8.6 (13H, m,
aromatic protons), 8.3 (1H, s, thiazoline 5-H). MS
(ES+): m/z: 374 [M+1].
References
3.2. Biological assay
[1] N. Ergenc¸, G. C¸ apan, Synthesis and anticonvulsant activity of
new 4-thiazolidone and 4-thiazoline derivatives, Farmaco 49
(1994) 449–451.
[2] E. Goeres, A. Faehndrich, Convulsive and anticonvulsive action
of aliphatic and alicyclic sulfonamides, Med. Ger. 20 (1968)
641–653.
[3] M. Engelmann, Synthesis of some 4-thiazolines from unsymmet-
rical thioureas and their fungicidal avtivity, US 2,027,030, Janu-
ary 7.
[4] B.C. Dash, B.B. Nandi, Synthesis of thiazoline compounds and
the use of their mercurated derivatives as fungicides and bacteri-
cides, Nippon Noyaku Gakkaishi 3 (1978) 427–431.
[5] G.N. Mahapatra, Synthesis of thiazoline compounds and the use
of their mercurated derivatives as fungicides and bactericides, J.
Proc. Inst. Chemists (India) 31 (1959) 113–117.
Antibacterial activities of compounds were deter-
mined using the tube dilution technique [20]. MIC
values were calculated as mg/ml (Table 2). Standard
bacteria strain used were: Esherichia coli (ATCC
25922), Staphylococcus aureus (ATCC 6538), Pseu-
domonas aeruginosa (ATCC 27853), Proteus 6ulgaris
(NRRL B-123), Enterobacter aerogenes (NRRL 3567),
Salmonella typhimurium (NRRL B-4420) and Candida
albicans (University of Osmangazi, Faculty of
Medicine, Eskis¸ehir).
[6] CIBA Ltd. S¸ti., Thiazolines., Belg. 627278, July 18, 1963; Swiss
Appl. January 9, 1962, 33 pp.
[7] N.N. Mel’nikov, A.F. Grapov, Insecticide and acaricide, USSR
524339 (Cl A01N9/36), 05 May 1978, Appl. 2,087,260, 25 De-
cember 1974. From Otkrytiya, Izobret, Prom. Obraztsy, To-
varnye Znaki 55 17 (1978) 183–185.
[8] R.H. Mizzoni, P.C. Eisman, Some thiazolines and thiazolidi-
nones with antituberculous activity, J. Am. Chem. Soc. 80 (1958)
3471–3475 Ciba Pharm. Products, Inc, Summit, NJ.
[9] A. Andreani, M. Rambaldi, Substituted 6-phenylimidazo[2,1-b]-
thiazoles and thiazolines as potential cardiotonic agents, Eur. J.
Med. Chem. —Chim. Ther. 19 (1984) 219–222.
4. Results and discussion
Scheme 1 illustrated the way used for the preparation
of target compounds. As a starting material, aminopy-
ridine and phenylisothiocyanates were used to produce
thiazolines.
The structure of the compounds was elucidated by
IR, 1H NMR, MASS spectral data and elemental
analysis.

572
G. Turan-Zitouni et al. / Il Farmaco 57 (2002) 569–572
[10] Y. Kiyotani, T. Yamaguchi, Preparation of thiazoles as antiulcer
agents and liver-disease therapeutics, Jpn. Kokai Tokkyo Koho
JP 63,203,672 [88,203,672] (Cl. C07D277/04). 23 August 1988,
Appl. 87/35,705, 20 February 1987, 45 pp.
[11] M. Sakuta, T. Yoneda, M. Nishimura, Potent antitumor agents
with low toxicity, Jpn. Kokai Tokkyo Koho JP 05 58,894 [93
58,894] (Cl. A61K31/425). 09 March 1993, Appl. 91/215,448, 27
August 1991; 26 pp.
[12] D.R. Jasinski, W.R. Martin, Dependence-producing properties
of GPA-1657, profadol and propiram in man, Clin. Pharmacol.
Ther. 12 (1971) 613–649.
[13] D. Liebermann, M. Moyeux, N. Rist, Preparation of new
thioamides of pyridine with antitubercular activty, Compt.
Rend. 242 (1956) 2409–2412.
[15] M. Dohrn, P. Diedrich, Therapeutic azo derivatives of
the heterocyclic series, June 7, See Ger. 543,288 (CA: 26,
2470).
[16] A.R. Johnston, The toxic effects of amines, J. Infectious Dis. 42
(1928) 473–484.
[17] E.T. Stiller, J.C. Keresztesy, The structure of Vitamin B6, J. Am.
Chem. Soc. 61 (1939) 1237–1239.
[18] C.H. Browning, J. Cohen, B.S. Ellingworth, Antiseptic action of
the styrylpyridines and styrylquinolines, Br. Med. J. II (1923)
326–329.
[19] G. Vasilev, P. Ionova, Synthesis, and herbicidal and growth
regulating activity of some N-alkyl- and N%-pyridylthioureas,
Fiziol. Rast. (Sofia) 10 (1984) 40–49.
[20] E.W. Koneman, S.D. Allen, W.M. Janda, W.C. Winn, Color
Atlas and Textbook of Diagnostic Microbiology, Lippincott-
Raven Pub, Philadelphia, 1997, pp. 785–856.
[14] E.M. Bavin, B. James, E. Kay, The antibacterial activty of
Mycobacterium tuberculosis of o-hydroxybenzalisonicotinoylhy-
drazone, J. Pharm. Pharmacol. 7 (1955) 1032–1037.