Syntheses of 2-(6'-Fluorobenzothiazol-2'-ylamino)-4, 6-(disubstituted thiouriedo)-1,3-pyrimidine derivatives as antimicrobial agents

Article abstract of DOI:10.1155/2011/820718

A new series of 1,3-pyrimidine derivatives (3a-f) have been synthesized by reacting 2,4,6-Trichloropyrimidine with nucleophilic reagents 2-amino-6-fluorobenzothiazole (1) in the presence of acetone. The (4,6- dichloropyrimidin-2-yl)-amine (2) so produced was then reacted to two moles of phenylthiourea derivatives to yield title compounds (3a-f). The structural assessment of the compounds (3a-f) was made on the basis of spectral data. The synthesized compounds were screened for their in vitro growth inhibiting activity against different strains of bacteria viz., B. subtilis, E. coli, P. aeruginosa and S. aureus using agar diffusion technique. Compounds 3c and 3f exhibited highest antibacterial activity.

Full text of DOI:10.1155/2011/820718

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(1), 240-244
http://www.e-journals.net
Syntheses of 2-(6’-Fluorobenzothiazol-2’-ylamino)
-4, 6-(disubstituted thiouriedo)-1,3-pyrimidine
Derivatives as Antimicrobial Agents
ANOOP K. PATHAK, VINEY CHAWLA and SHAILENDRA K. SARAF*
Faculty of Pharmacy, Northern India Engineering College
Sector-2, Dr. Akhilesh Das Nagar, Faizabad Road, Lucknow- 227105
dirpharmniec@gmail.com
Received 29 April 2010; Accepted 17 July 2010
Abstract: A new series of 1,3-pyrimidine derivatives (3a-f) have been
synthesized by reacting 2,4,6-Trichloropyrimidine with nucleophilic reagents 2-
amino-6-fluorobenzothiazole (1) in the presence of acetone. The (4,6- dichloro-
pyrimidin-2-yl)-amine (2) so produced was then reacted to two moles of
phenylthiourea derivatives to yield title compounds (3a-f). The structural
assessment of the compounds (3a-f) was made on the basis of spectral data. The
synthesized compounds were screened for their in vitro growth inhibiting
activity against different strains of bacteria viz., B. subtilis, E. coli, P.
aeruginosa and S. aureus using agar diffusion technique. Compounds 3c and 3f
exhibited highest antibacterial activity.
Keywords: Fluorobenzothiazole, Pyrimidine derivatives, Phenyl thiourea derivatives, Antimicrobial
activity.
Introduction
Pyrimidine is the most important member of all the diazines as this ring system occurs
widely in living organisms. Purines, uric acid, alloxan, barbituric acid and a number of
antimalarial and antibacterial drugs also contain the pyrimidine ring1,2. Thiazole ring system
is quite common in natural products, since it can be produced by cyclization of cysteine
residues in peptides3,4. The most important of these is Vitamin B1 (thiamine), which contains
both a pyrimidine and a thiazole ring system. The bleomycin antibiotics, which have anti-
tumour properties, are complex aminoglycosidic structures containing thiazole units. Several
semi-synthetic beta lactams contain 2-aminothiazole units in the side chain5,6.
Since benzothiazoles, pyrimidines and thioureas all possess diverse biological
activities7-11; the aim of this study was to synthesize some new derivatives incorporating
these nuclei and evaluate the prepared compounds for antibacterial activity.

Syntheses of Substituted Pyrimidine Derivatives
241
Experimental
To 2,4,6 trichloropyrimidine (18.3 g,0.1 mole) dissolved in acetone (100 mL) cooled at 0 °C,
2-amino-6 fluorobenzothiazole (16.8 g,0.1 mole) dissolved in acetone (100 mL) was added
with stirring at 0–5 °C followed by drop wise addition of sodium hydroxide (4.0 g,0.1 mole)
in water (50 mL). Contents were stirred for 3 h and poured into ice water, acidified with
dilute hydrochloric acid, filtered, washed, dried and recrystallized from ethanol, melting range
was 265-270 °C, yield was 53.94%, IR (KBr, cm-1): (3388>NH) and MS (m/z): 315 (M+ ).
General procedure for synthesis of 2-(6’-fluorobenzothiazol-2’-ylamino)-4,6-
(disubstituted thiouriedo)-1,3-pyrimidines (3a-f)
Compound 2 (31.5 g, 0.1 mole) (Scheme 1) dissolved in acetone (100 mL) was added to
substituted thiourea (0.2 mole) in acetone (100 mL), slowly with constant stirring followed
by addition of sodium hydroxide (4 g, 0.1 mole) in water (50 mL) and contents were
°
refluxed for 2 h at 85-95 C. The mixture was poured into ice water, acidified with dilute
HCl, filtered, washed and recrystallized from ethanol and melting range was determined.
195-200 °C, yield 39.83%, IR (KBr, cm-1): (3446>NH); 1120 (thioureido CS); and MS (m/z):
547 (M+1).
Spectral data of compound 3a
IR: (KBr cm-1): 3230 (secondary amine N-H str), 1569 (secondary amine N-H ben), 3085
(Aromatic C-H str), 1622 (Aromatic C=C str) 1282 (Aromatic amine C-N str), 1120
(Aromatic C-F str); MS (FAB) m/z: 391(M-3). Yield 73.63%, Melting range: 265-270 °C.
Compounds 3b-f were prepared by the aforesaid procedure12. The quantity of phenylthiourea
derivatives was changed as per Table 1.
Table 1. Quantities of different thiourea
Name of substituent at R
Phenylthiourea
Quantity
Compd..
30.4 g, 0.2 mole
34.0 g, 0.2 mole
37.2 g, 0.2 mole
46.2 g, 0.2 mole
39.4g, 0.2 mole
3b
3c
3d
3e
3f
4-fluorophenyl thiourea
4-chlorophenyl thiourea
4-bromophenyl thiourea
4-nitrophenyl thiourea
Compound 3b
IR: (KBr cm-1): 3446 (secondary amine N-H str), 1569 (secondary amine N-H ben), 3072
(Aromatic C-H str), 1627 (Aromatic C=C str), 1253 (Aromatic amine C-N str), 1012
(Aromatic C-F str) MS (FAB) m/z: 547(M+1).
Compound 3c
IR: (KBr cm-1): 3446 (secondary amine N-H str), 1568 (secondary amine N-H ben), 3087
(Aromatic C-H str), 1620 (Aromatic C=C str), 1255 (Aromatic amine C-N str), 1014
(Aromatic C-F str); MS (FAB) m/z: 582 (M+).
Compound 3d
IR: (KBr cm-1): 3434 (secondary amine N-H str), 1569 (secondary amine N-H ben), 3085
(Aromatic C-H str), 1623 (Aromatic C=C str), 1255 and 1120 (Aromatic amine C-N str),
1014 (Aromatic C-F str), 804 (Aromatic C-Cl str); MS (FAB) m/z: 615 (M+11).

242
SHAILENDRA K. SARAF et al.
Cl
Step 1
N
N
+
H2N
S
N
Cl
Cl
F
2,4,6-Trichloro-pyrimidine
6-Fluoro-benzothiazol-2-ylamine
1. Acetone
2. NaOH
3. Stirring For 3 hrs at 0-5 oC
Cl
N
N
HN
N
Cl
S
F
(4,6-Dichloro-pyrimidin-2-yl)-(6-fluoro-benzothiazol-2-yl)-amine
Step 2
Cl
N
N
NH2CSNHR
+
HN
N
Cl
S
F
(4,6-Dichloro-pyrimidin-2-yl)-(6-fluoro-benz
othiazol-2-yl)-amine
1. Acetone
2. NaOH
3. Refluxed For 2 hrs at 85-90 oC
R= -H
-C6H5
NHCSNHR
-4 FC6H4
-4 ClC6H
-4 BrC6H
-4 NO2C6H
N
N
HN
N
RHNSCHN
S
3
F
Scheme 1. Synthetic procedure for preparation of 2-(6’-fluorobenzothiazol-2’-ylamino)-4,6-
(disubstituted thiouriedo)-1,3-pyrimidine derivatives
Compound 3e
IR: (KBr cm-1): 3446 (secondary amine N-H str), 1568 (secondary amine N-H ben), 3087
(Aromatic C-H str), 1620 (Aromatic C=C str), 1255 (Aromatic amine C-N str), 1014
(Aromatic C-F str); MS (FAB) m/z: 703 (M-1).

Syntheses of Substituted Pyrimidine Derivatives
243
Compound 3f
IR: (KBr cm-1): 3253 (secondary amine N-H str), 1569 (secondary amine N-H ben), 3070
(Aromatic C-H str), 1623 (Aromatic C=C str), 1255 and 1120 (Aromatic amine C-N str), 1014
(Aromatic C-F str), 1521 and 1353 (symmetrical and asymmetrical aromatic NO str); MS
(FAB) m/z: 637 (M+1).
Purity of all the compounds was checked on silica gel G plates using iodine vapour and UV
lamp (at short and long wavelength) as the detecting agent. Thin layer chromatography was used
for monitoring the progress of reaction and product formation. Melting points of the synthesized
compounds were taken by open capillary method and are uncorrected. The infra-red spectra of
the synthesized compounds were recorded on a SHIMADZU FTIR 8400 spectrophotometer
using potassium bromide pellets. The FAB mass spectra were recorded on a JEOL SX 102/DA-
6000 mass spectrometer/ data system using Argon/Xenon (6 kV, 10 m A) as the FAB gas. The
accelerating voltage was 10 kV and the spectra were recorded at room temperature. The physical
and analytical data of synthesized compounds is summarized in Table 2.
Table 2. Physical and analytical data of the synthesized compounds (3a -f)
Mol
Wt
Calculated
N
Melting Yield,
Compd.
R
Mol. formula
Range, °C
%
74
40
38
16
17
60
C
H
S
H
C6H5
4FC6H4
C13H11FN8S3 394 39.6 2.8 28.4 24.4 260-265
C25H19FN8S3 546 54.9 3.5 20.5 17.6 195-200
C25H17F3N8S3 582 51.5 2.9 19.2 16.5 260-265
3a
3b
3c
3d
3e
3f
4ClC6H4 C25H17Cl2FN8S3 626 48.8 2.8 18.2 15.6 245-250
4BrC6H4 C25H17Br2FN8S3 704 42.6 2.4 15.9 13.7 240-245
4NO2C6H4 C25H17FN10O4S3 636 47.2 2.7 22.0 15.1 235-240
Antibacterial activity
Compounds 3a-f were screened for antibacterial activity against strains of Bacillus subtilis
(MTCC 441), Pseudomonas aeruginosa (MTCC 424), Escherichia coli (MTCC 1573) and
Staphylococcus aureus (MTCC 1430) using cylinder-plate method13. Culture media were
prepared using aseptic and sterilization techniques14. Incubation period was 24 h at 37 °C in
order to activate the bacterial strain. All the solutions of test compounds were prepared by
dissolving 1 mg of testing sample in 1 mL of DMF (N, N-Dimethylformamide). This gives
the conc. of sample 1000 µg/mL or 1000 ppm. Different dilutions such as 200 µg/mL and
100 µg/mL were prepared from the sample solution. A solution of DMF (10%) was used as
control. Pure cultures of Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli and
Staphylococcus aureus were procured from Institute of Microbial Technology (IMTECH),
Chandigarh, India and raised in conical flask (100 mL) containing potato dextrose agar
(PDA). The evaluation of the antibacterial activity was done by measuring the zone of
inhibition in different petri plates and taking average for each strain.
Results and Discussion
The compounds (3a-f) were synthesized by reacting 2,4,6-trichloropyrimidine with 2-amino-
6-fluorobenzothiazole yielding (4,6-dichloropyrimidin-2-yl-6-fluorobenzothiazol-2-yl)-
amine followed by reaction with two moles of phenylthiourea. The physical and analytical
data of the compounds are presented in Table 2.
The yields of compounds fall in the range of 16% to 74%. The spectral data (IR and
MS) are in good agreement with their structures. Scanning results of antimicrobial activity
(Table 3) reveal that the known standard antibiotic produced a zone of inhibition of the order

244
SHAILENDRA K. SARAF et al.
of 20-23 mm. Compounds 3c and 3f displayed good activity against E. coli, P. aeruginosa,
B. subtilis and S. aureus. This could be due to the presence of fluoro and nitro groups. Other
compounds (3a, 3b, 3d and 3f) exhibited less pronounced activity against the tested strains.
Table 3. Antibacterial screening data of compounds 3a-f
Average diameter of zone of inhibition, in mm
Compound
E. coli
15
18
P. aeruginosa
B. subtilis
S. aureus
15
16
20
15
16
19
21
00
14
13
18
12
14
15
20
00
16
16
19
16
15
15
21
00
3a
3b
19
14
3c
3d
16
19
3e
3f
Standard (Ciprofloxacin)
Control (DMF)
23
00
Conclusion
A series of 1,3 pyrimidine derivatives have been synthesized and characterized on the basis
of IR and MS spectral data. The compounds exhibited antibacterial activity with two
compounds showing good activity against selected strains.
Acknowledgment
The authors are thankful to Central Drug Research Institute (CDRI), Lucknow for providing
library facilities and spectral data.
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