Synthesis of some new 4-{2-[(aryl)amino]-1,3-thiazol-4-yl}benzene-1,2-diols as possible antibacterial and antifungal agents

Article abstract of DOI:10.1080/10426500500327071

Some new 4-{2-[(aryl) amino]-1,3-thiazol-4-yl}benzene-1,2-diols are prepared and characterized by spectral analysis. The newly prepared compounds are studied for their antibacterial and antifungal activity. Interestingly, almost all the compounds are found to possess promising antibacterial and antifungal activity against all tested microorganisms. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500500327071

This article was downloaded by: [New York University]
On: 18 May 2015, At: 03:01
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Synthesis of Some New 4-{2-
[(Aryl)amino]-1,3-thiazol4-
yl}benzene-1,2-diols as
Possible Antibacterial and
Antifungal Agents
B. Narayana a , B. V. Ashalatha a , K. K. Vijaya Raj a
& N. Suchetha Kumari b
a Department of Post-Graduate Studies and
Research in Chemistry , Mangalore University ,
Mangalagangothri, India
b Department of Biochemistry , K. S. Hegde Medical
Academy , Deralakatte, India
Published online: 01 Feb 2007.
To cite this article: B. Narayana , B. V. Ashalatha , K. K. Vijaya Raj & N. Suchetha
Kumari (2006) Synthesis of Some New 4-{2-[(Aryl)amino]-1,3-thiazol4-yl}benzene-1,2-
diols as Possible Antibacterial and Antifungal Agents, Phosphorus, Sulfur, and Silicon
and the Related Elements, 181:6, 1381-1389, DOI: 10.1080/10426500500327071
To link to this article: http://dx.doi.org/10.1080/10426500500327071
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and

are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 181:1381–1389, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500327071
Synthesis of Some New 4-{2-[(Aryl)amino]-1,3-thiazol-
4-yl}benzene-1,2-diols as Possible Antibacterial and
Antifungal Agents
B. Narayana
B. V. Ashalatha
K. K. Vijaya Raj
Department of Post-Graduate Studies and Research in Chemistry,
Mangalore University, Mangalagangothri, India
N. Suchetha Kumari
Department of Biochemistry, K. S. Hegde Medical Academy,
Deralakatte, India
Some new 4-{2-[(aryl) amino]-1,3-thiazol-4-yl}benzene-1,2-diols are prepared and
characterized by spectral analysis. The newly prepared compounds are studied for
their antibacterial and antifungal activity. Interestingly, almost all the compounds
are found to possess promising antibacterial and antifungal activity against all
tested microorganisms.
Keywords Antibacterial; antifungal; thiazole
Heterocycle containing a thiazole ring system are found to exhibit a
wide spectrum of biological activities, including antibacterial and an-
tifungal activities and many thiazole-containing compounds are re-
ported to have herbicidal, fungicidal, antitubercular, antiallergic, an-
tianaphylactic, antiarthritic antibiotic, antiviral, anti-inflammatory,
analgesic and psychotropic agents.1−14 4-(chloroacetyl)-catechol is an
important moiety in broncho-plasmolytic agents such as Adrenaline,
Nor-adrenaline, Isoprenaline and Cobefrin.15,16 As a part of our
research program to find potent thiazole-containing antimicrobial
agents,17 we aimed at synthesizing new thiazoles starting from 4-
(chloroacetyl) catechol and to study their antimicrobial activity.
Received June 1, 2005; accepted July 14, 2005.
The authors are thankful to the Director, RSIC, Punjab University, and The Head,
RSIC, IIT, Chennai for Mass and NMR analysis.
Address correspondence to B. Narayana, Mangalore University, Department of Post-
Graduate Studies and Research in Chemistry, Mangalagangothri, 574 199 India. E-mail:
nbadiadka@yahoo.co.uk
1381

1382
B. Narayana et al.
RESULTS AND DISCUSSION
In the present investigation, some new 4-{2-[(aryl) amino]-1,3-thiazol-
4-yl}benzene-1,2-diol (3a–i) are prepared by reacting 4-(chloroacetyl)
catechol (1) with thiourea (2a), thioacetamide (2b), and various N-aryl
substituted thioureas (2c–i) by following the classical Hantzsch syn-
thesis (Scheme 1). 4-(chloroacetyl)-catechol (1) is prepared by reacting
catechol with chloroacetyl chloride.18 Substituted thioureas are syn-
thesized according to the standard literature procedure.19 We have at-
tempted to synthesize mono and bis-ethers 3a–i by reacting with alkyl
iodide and dimethylsulphate. In both cases, we ended up with impure
products. Mass analysis revealed that along with a hydroxy-protected
product, an amino-protected product also formed. We have not further
attempted to get pure products. For this reason, this limited our study
in the synthesis and antimicrobial evaluation of 4-{2-[(aryl) amino]-1,3-
thiazol-4-yl}benzene-1,2-diols only.
The IR spectrum of 3i exhibited absorption bands at 3757.1 cm−1
,
and 3679.9 cm−1 is due to two phenolic OH groups. Absorption bands
1604.7 cm−1, 1523.7 cm−1, and 1323.1 cm−1 are due to C O, C N-,
1
and C S-functional groups, respectively. The H-NMR spectrum of
SCHEME 1

Possible Antibacterial and Antifungal Agents
1383
3i showed two singlets at δ 6.8 and δ 6.9 that are due to two phenolic
−OH protons, a singlet at δ 8.06 is due to an aromatic proton, and
one doublet of a doublet at δ 7.89 is due to an aromatic protons. A
multiplet at δ7.41–7.31 due to the aromatic protons on the benzene
ring bearing bromine. A singlet at δ 8.16 due to an aromatic proton
on the thiazole ring. A singlet at 4.8 is due to a NH-proton. The mass
spectrum of 3i showed m/z 363 in accordance with its molecular formula
C15H11BrN2O2. The 13C NMR (DMSO-d6) of 3f showed peaks at 22.41,
103.85, 108.87, 113.43, 115.84, 116.14, 117.21, 124.64, 140.34, 145.42,
145.85, 146.95, 149.75, and 160.16, which accounts for 15 carbon atoms
present in the molecule. The experimental data of other compounds are
presented in Table I. The spectral data are presented in Table II.
An antibacterial study carried out for 3a–i reveals that except for
3c and 3d, all other compounds possess excellent antibacterial activ-
ity against all tested organisms. Even though the observed antibacte-
rial activity cannot be related to the variation in the N-substitution
at thiazole moiety, the combination of potential thiaz moiety with
catechol may be the reason for the excellent antibacterial activity.
However, antifungal study results reveal that compound 3c is most
active amongst all. A known antifungal agent N-[4-(4-chlorophenyl)-
2-thiazolyl salicylamide20 contains the 4-chlorophenyl moiety. The
compound 3g that contains the 4-chlorophenyl moiety has also shown
good antifungal activity. Hence, we can conclude that the higher activ-
ity of compound 3c may be attributed to the N- (3-chorophenyl) moiety.
The higher antifungal activity of 3e may be due to the presence of a
potent pyridine moiety. The compounds 3a, 3f, and 3i are found to be
least active. Other compounds have shown good to moderate antifungal
activity.
Antibacterial Activity
We investigated the newly synthesized 4-{2-[(aryl) amino]-1,3-thiazol-
5-yl} benzene-1,2-diol (3a–i) for their antibacterial activity against
Escherichia coli (ATTC-25922), Staphyllococcus aureus (ATTC-25923),
Psuedomonus aeruginosa (ATTC-27853), and Klebsiella pneumoniae
(Recultered) bacterial strains by the disc diffusion method.21−23 The
discs measuring 6.25 mm in diameter were punched from Whatman no.
1 filter paper. Batches of 100 discs were dispensed to each screw-capped
bottle and sterilized by dry heat at 140◦C for an hour. The test com-
pounds were prepared with different concentrations using Dimethyl-
formamide (DMF). One mL containing 100 times the amount of chemi-
cal in each disc was added to each bottle, which contains 100 discs. The
discs of each concentration were placed in triplicate in a nutrient agar

1384
B. Narayana et al.
TABLE I Characterization Data of 4-{2-[(Aryl)amino]-1,3-thiazol-
4-yl}benzene-1, 2-diol (3a–i)
% Nitrogen
Compound
no.
R, AR
M.p. (◦C) Yield (%)
Mol. formula
Found Calcd.
3a
3b
R = NH2
R = CH3
235–236
230–232
78
82
C9H8N2O2S
C9H9NO2S
13.25
6.68
13.45
6.78
3c
3d
200–202
248–250
90
86
C15H11ClN2O2S
C16H14N2O2S
8.81
9.39
8.79
9.28
3e
3f
260–262
78
72
C14H11N3O2S
C15H13N3O2S
14.78
14.10
14.73
14.04
>260
3g
223–225
80
C15H11ClN2O2S
8.80
8.79
3h
3i
220–222
210–212
80
52
C16H13ClN2O2S
C15H11BrN2O2S
8.48
7.68
8.42
7.71
aCompounds showed satisfactory microanalysis.
bReported yields are after recrystallisation.
cThe compounds were crystallized form ethanol/dimethylformamide.
medium separately seeded with fresh bacteria. The incubation was car-
ried out at 37◦C for 24 h. Ampicillin was used as standard drug. Ampi-
cillin has 16–22 mm inhibition length for Escherichia coli and 27–35
mm inhibition length for Staphyllococcus aureus at the concentration
of 10 µg/mL. Solvent and growth controls were kept, and the zones of
inhibition and minimum inhibitory Concentrations (MIC) were noted.

1385

1386
B. Narayana et al.
Results of such studies are given in Table II. All compounds need fur-
ther evaluation at different concentrations and with different known
antifungal agents.
Antifungal Study
Newly prepared compounds 4-{2-[(aryl)amino]-1,3-thiazol-4-yl}
benzene-1,2-diol (3a–i) were screened for their antifungal activity
against Aspergilus flavus (NCIM No. 524), Aspergilus fumigatus (NCIM
No. 902), Candida albicans (NCIM No. 3100), Penicillium marneffei
(Recultered) and Trichophyton mentagrophytes (Recultered) in DMSO
by the serial plate dilution methodm.21−23 Sabourands agar media was
prepared by dissolving peptone (1 g), D-glucose (4 g) and agar (2 g) in
distilled water (100 mL) and the pH was adjusted to 5.7. Normal saline
was use to make a suspension of spores of fungal strain for lawning.
A loopful of particular fungal strain was transferred to 3 mL of saline
to get a suspension of corresponding species. Agar media of 20 mL was
poured into each petridish. An excess of suspension was decanted, and
the plates were dried by placing them in an incubator at 37◦C for 1 h.
Using an agar, punch wells were made on these seeded agar plates, and
10 µg/mL–100 µg/mL of the test compounds in DMSO were added into
each well labeled. A control was also prepared for plates in the same way
using solvent DMSO. The petridishes were prepared in triplicate and
maintained at 37◦C for 3–4 days. Antifungal activity was determined by
measuring the diameter of the inhibition zone. Results of such studies
are given in Table III. The activity of each compound was compared
with Itraconozole as a standard drug. The MIC for the Itraconazole
in DMSO was 0.03–16 µg/mL against the tested species.21 We found
that Itraconazole exhibited maximum inhibition at the concentration
≤0.125 µg/mL and no inhibition at the concentration ≤1.0 µg/mL which
is well in agreement with the literature.21
EXPERIMENTAL
Preparation of 4-(Chloroacetyl) Catechol (1)
This compound was prepared as per the literature procedure.19 Yield
60%, off-white needles, m.p. 173◦C dec.
General Procedure for the Synthesis of N-Substituted
Thioureas (2c–i)20
Benzoylchloride (0.01 mol) was added over 5 min to a freshly prepared
solution of ammonium thiocyanate (0.012 mol) in dry acetone, and the

Possible Antibacterial and Antifungal Agents
1387
TABLE III Antibacterial Activity of the Newly Synthesized
Compounds 3a–i at the Concentration 10 µg/mL–100 µg/mL
Compound
no.
Escherichia
coli
Staphyllococcus
aureus
Psuedomonus
aeruginosa
Klebsiella
pneumoniae
3a
3b
3c
3d
3e
3f
3g
3h
3i
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
—
—
+ + +
+ + +
+ + +
+ + +
+ + +
Standard drug: Ampicillin, which has a 16–22 mm inhibition length for Escherichia
coli and 27–35 mm inhibition length for Staphyllococcus aureus at the concentration of
10 µg/mL.
—, <8 mm, no inhibition (for any concentration).
+, 8–10 mm, minimum inhibition (100 µg/mL).
++, 10–15 mm, moderate inhibition (60 µg/mL).
+ + +, 15–20 mm, maximum inhibition (10 µg/mL).
mixture was heated under reflux for about 15 min. Heating was stopped,
and an appropriate aniline in acetone was added over a period of 15
min. The mixture was heated under reflux for 30 min and then poured
to crushed ice. The resulting solid was collected, washed with water and
TABLE IV Antifungal Activity of Newly Synthesized Compounds
(3a–i)
Compound
no.
Aspergilus
flavus
Aspergilus
fumigatus
Penicillium Candida
Trichophyton
mentagrophytes
marneffei
albicans
3a
3b
3c
3d
3e
3f
3g
3h
3i
—
—
—
—
—
+ + +
—
+ + +
+ + +
—
—
—
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
—
—
—
+ + +
—
+ + +
+ + +
—
+ + +
—
+ + +
—
+ + +
+ + +
—
—
—
+ + +
—
+
—
—
Standard drug, Itraconazole
+ + +
≤0.125 µg/mL
—
≤1.0 µg/mL
—, <8 mm, no inhibition (for any concentration).
++, 10–15 mm, moderate inhibition (100 µg/mL).
+ + +, 15–20 mm, maximum inhibition (10 µg/mL).

1388
B. Narayana et al.
followed by cold mixture of water and methanol (1:1). Suitably substi-
tuted benzoylthioureas were added to a preheated solution of aqueous
sodium hydroxide (5%) and stirred. The mixture was then poured into
crushed ice containing hydrochloric acid (5%). The benzoic acid sepa-
rated was removed by treating the reaction mixture with sodium car-
bonate. The product was collected, washed with water, and then dried.
All products were isolated in a yield varying from 80–90% and were
taken directly for the next reaction without further purification.
General Procedure for the Synthesis of 4-{2-[(Aryl)
amino]-1,3-thiazol-4-yl}benzene-1,2-diol (3a–i)
4-(chloroacetyl) catechol (0.01 mol) and an appropriate alkylthio-
mide/thiourea/substituted thiourea (0.01 mol) in absolute ethanol was
refluxed for 6 h and allowed to stand overnight. The solid separated
on cooling was filtered and recrystallized in a mixture of ethanol and
dimethylformamide mixture (5–10% of dimethylformamide in ethanol).
CONCLUSION
Some new 4-{2-[(4-aryl) amino]-1,3-thiazol-4-yl} benzene-1,2-diols (3a–
i) were synthesized and screened for their antibacterial and antifungal
activity. Antibacterial study carried out for 3a–i revealed that for ex-
cept 3c and 3d, all compounds possess excellent antibacterial activ-
ity against all tested organisms. However, antifungal study results re-
vealed that compound 3c is most active amongst all. Compounds 3a, 3f,
and 3i are found to be least active. Other compounds have shown good-
to-moderate antifungal activity. The combination of potential thiazole
moiety with catechol may be the reason for the excellent antibacterial
activity. Since we have limited our antimicrobial study in 4-{2-[(4-aryl)
amino]-1,3-thiazol-4-yl}benzene-1,2-diol only, there is more scope to in-
vestigate antimicrobial activity modifying the structure with mono and
bis substitution at hydroxy function.
REFERENCES
[1] G. Beck and H. Heitzer, U.S. 4,748,243 (1998); Bayer Akleingesellschaft.
[2] H. Ul. Osaka, N. H. Matubara, and I. M. Kawabe, U.S. 5180833 (1993), Takela
Chemical industries Ltd.
[3] K. Schule, F. Ritchur, R. Seishiet, R. Krause, and M. Mahlstadt, J. Prakt. Chemie,
332, 629 (1980).
[4] R. Murugan and E. F. V. Scriven, WO 9845179 (1998) Reilly Industries Inc.; Chem.
Abstr., 129, 3026633v (1998).

Possible Antibacterial and Antifungal Agents
1389
[5] A. Jackson, G. Heys, J. I. Grayson, and R. Calrke, U.S. 5,705,652 (1998), Fine Or-
ganics Ltd.
[6] R. M. Leanna and H. E. Morton, WO 9616050 (1996) Abott Laborataories, USA;
Chem. Abstr., 125, 114603d (1996).
[7] H. Tripathy and D. G. Pradhan, Agricult. Biol. Chem., 37, 1375 (1973).
[8] J. L. Bayer, J. P. Denonte, and G. Mourioux, EP 508901 (1992).
[9] M. Q. Zhang, A. Haemers, D. Vaden Berghe, S. R. Pattyn, and W. Bolaert, J. Hete-
rocycl. Chem., 28, 673 (1991).
[10] J. A. Parvate, V. S. Bhagwat, and S. N. Redkar., Indian Drugs, 26, 172 (1989).
[11] R. Khan and R. C. Rastogi, Ind. J. Chem., 27B, 501 (1988).
[12] Y. Katsura, S. Nishino, M. Ohno, K. Sakane, Y. Matsumoto, C. Morinaga,
H. Ishikawa, and H. Takasugi, J. Med. Chem., 42, 2920 (1999).
[13] X. Y. Yu, J. M. Hill, G. Yu, W. Wang, A. F. Kluge, P. Wendler, P. Gallant, Bioorg. Med.
Chem. Lett., 9, 375 (1999).
[14] S. Demirayak, K. Benkli, C. Sezer, and H. Erdeniz, Acta Pharmaceutica Turcica, 39,
133 (1997).
[15] C. Stolz, Ber, 37, 4152 (1904).
[16] K. R. Payne, Industrial Chemist, Nov., 523 (1991).
[17] B. Narayana, K. K. Vijaya Raj, B. V. Ashalatha, N. Suchetha Kumari, and B. K.
Sarojini, Eur. J. Med. Chem., 39, 867 (2004).
[18] L. Nathan and H. H. Walter, J. Org. Chem., 7, 408 (1942).
[19] B. S. Holla, K. V. Malini, B. Sooryanarayana Rao, B. K. Sarojini, and N. Suchetha
Kumari, Eur. J. Med. Chem., 38, 313 (2003).
[20] H. Tripathy and D. G. Pradhan, Agricult. and Biol. Chem., 37, 1375 (1973).
[21] R. Cruickshank, J. P. Duguid, B. P. Marmion, and R. H. A. Swain, Medicinal Micro-
biology, 12th ed., Vol. 2, p. 196 (Churchil Livingstone, London, 1975).
[22] A. H. Collins, Ed., Microbiological Methods, 2nd ed., (Butterworth, London, 1976).
[23] B. A. Arthington, M. Motley, D. W. Warnock, and C. J. Morrison, J. Clin. Microbiology,
38, 2254 (2000).