Synthesis and antimicrobial evaluation of halogen-containing arylidene thiazolo triazinediones

Article abstract of DOI:10.1080/10426500902979917

A series of 7-substituted arylidene-1,3-thiazolo[2,3-c]-1,2,4-triazine-4,6- diones were synthesized in an one-pot multicomponent reaction of 6-arylmethyl-3-mercapto-1,2,4-triazin-5-ones with substituted benzaldehydes and monochloroacetic acid in the presence of acetic anhydride, acetic acid, and sodium acetate. The structures of the new compounds were supported by IR, ¹H NMR, MS, and analytical data. All the new compounds were tested for their antibacterial and antifungal activity. Arylidene thiazolo triazinediones with 1,3-benzodioxolo substituent at seventh and p-chlorophenyl or 2,4-dichlorophenyl substituents at third displayed good antibacterial and antifungal activity. And also compound bearing 2,3,5-trimethoxyphenyl substituent at seventh and 2,4-dichlorophenyl substituent at third displayed good activity.

Full text of DOI:10.1080/10426500902979917

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Synthesis and Antimicrobial
Evaluation of Halogen-
Containing Arylidene Thiazolo
Triazinediones
Mari Sithambaram Karthikeyan a , Manjathuru
Mahalinga a , Prakash Karegoundar a , Boja Poojary a
& Bantwal Shivarama Holla a
a Department of Chemistry, Mangalore University,
Mangalagangothri, India
Published online: 18 Nov 2009.
To cite this article: Mari Sithambaram Karthikeyan , Manjathuru Mahalinga ,
Prakash Karegoundar , Boja Poojary & Bantwal Shivarama Holla (2009) Synthesis and
Antimicrobial Evaluation of Halogen-Containing Arylidene Thiazolo Triazinediones,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:12, 3231-3240, DOI:
10.1080/10426500902979917
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Phosphorus, Sulfur, and Silicon, 184:3231–3240, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902979917
Synthesis and Antimicrobial Evaluation of
Halogen-Containing Arylidene Thiazolo Triazinediones
Mari Sithambaram Karthikeyan, Manjathuru Mahalinga,
Prakash Karegoundar, Boja Poojary, and Bantwal
Shivarama Holla
Department of Chemistry, Mangalore University, Mangalagangothri,
India
A series of 7-substituted arylidene-1,3-thiazolo[2,3-c]-1,2,4-triazine-4,6-diones were
synthesized in an one-pot multicomponent reaction of 6-arylmethyl-3-mercapto-
1,2,4-triazin-5-ones with substituted benzaldehydes and monochloroacetic acid in
the presence of acetic anhydride, acetic acid, and sodium acetate. The structures
of the new compounds were supported by IR, 1H NMR, MS, and analytical data.
All the new compounds were tested for their antibacterial and antifungal activity.
Arylidene thiazolo triazinediones with 1,3-benzodioxolo substituent at seventh and
p-chlorophenyl or 2,4-dichlorophenyl substituents at third displayed good antibac-
terial and antifungal activity. And also compound bearing 2,3,5-trimethoxyphenyl
substituent at seventh and 2,4-dichlorophenyl substituent at third displayed good
activity.
Keywords Antibacterial; antifungal activity; arylidene thiazolo triazinediones; one pot;
1,2,4-triazin-5-ones
INTRODUCTION
Triazinones and their condensation products find important applica-
tions in the fields of medicine and agriculture.1 Thioaza-uracils and
their thioalkyl derivatives have been reported to possess antidiuretic
and neurodepressant activities.2 Some of the S-alkylated mercap-
totriazinones such as 4-amino-3-methylthio-6-tert-butyl-1,2,4-triazin-
5(4H)-one (Sencor or Metribuzin, C8H14N4OS) are used as commercial
herbicides.3–5
Received 4 March 2008; accepted 20 April 2009.
The authors are thankful to the Head, NMR Research Center, IISc-Bangalore, and
CDRI, Lucknow, for providing 1H NMR and mass spectral data. M.S.K. is grateful to
CSIR New Delhi for providing Senior Research Fellowship.
Address correspondence to (present address) Mari Sithambaram Karthikeyan, Syn-
gene International Limited, Plot No. 2 & 3 C Unit-II, Bommansandra Industrial Area,
Bangalore- 560099, India. E-mail: karthims02@rediffmail.com
3231

3232
M. S. Karthikeyan et al.
Thiazolidin-4-one derivatives constitute an important class of het-
erocyclic compounds. (–)2-(5-Carboxypentyl)thiazolidin-4-one, (i.e., ac-
tithiazic acid, C9H15NO3), which is isolated from Streptomyces strains,
contains a thiazolidin-4-one ring system and displays highly specific
activity against Mycobacterium tuberculosis.6
Considerable interest has been shown towards the chemistry of
the thiazolidin-4-one ring system, which is a key structure in vari-
ous synthetic pharmaceuticals displaying various biological activities.7
Thiazolidin-4-one derivatives are known to exhibit diverse bioactivi-
ties such as anticonvulsant,8 antimicrobial,9 antitubercular,10 antidia-
betic,11 cycloxygenase inhibitory,12 Ca2+ channel blocker,13 anticancer,14
and anti-HIV.15
Prompted by these observations, we planned to synthesize a
new series of 7-substituted arylidene-1,3-thiazolo[2,3-c]-1,2,4-triazine-
4,6-diones and to screen them for their in vitro antimicrobial
properties. The results of these studies are presented in this
article.
RESULTS AND DISCUSSION
6-Arylmethyl-3-mercapto-1,2,4-triazin-5-ones (6) were synthesized ac-
cording to the reported method.16 7-Arylidene-1,3-thiazolo[2,3-c]-1,2,4-
triazine-4,6-diones (8) were obtained by a one-pot reaction of 6-
arylmethyl-3-mercapto-1,2,4-triazin-5-ones (6) with monochloroacetic
acid and substituted benzaldehydes (7) in the presence of anhydrous
sodium acetate, acetic anhydride, and acetic acid. The reaction se-
quence is outlined in Scheme 1.
Compound 8b was taken as representative. The IR spectrum shows
an absorption band at 3090 cm−1 indicating the presence of Ar-H. Other
prominent absorption bands are observed at 1730 cm−1(C = O), 1545
cm−1 (C = N), and 821 cm−1 (C-Cl).
The 400 MHz 1H NMR spectrum of compound 8b shows a singlet at δ
= 3.87 integrating for two protons, which is attributed to the methylene
protons of the p-chlorobenzyl group. The protons of the OCH3 group
resonate as a singlet at δ = 4.01. The signal due to the exocyclic vinylic
proton appears as a singlet at δ = 8.21. The signal of the aromatic
protons of the p-anisyl ring are observed as two doublets at δ = 7.17
and 7.46 (J = 8.7 Hz). The corresponding signals for the aromatic
protons of the p-chlorophenyl ring are found as two doublets at δ = 7.62
and 7.76 (J = 9 Hz).
Further evidence for the formation of compound 8b was obtained
from its mass spectrum. The mass spectrum of compound 8b showed a

Halogen-Containing Arylidene Thiazolo Triazinediones
3233
NH2-CH2-COOH
(CH3CO)2O
CH3CO-NH-CH2-COOH
+
1
2
R
Ac2O, NaOAc
OHC
3
N
R
CH3
O
O
4
aq. KOH
H2N-NH-CS-NH2
5
O
H
N
R
N
N
SH
6
ClCH2COOH, NaOAc,
AcOH, Ac2O
R1
OHC
7
O
O
N
R
N
S
N
8
R1
R = 4-Cl, 2,4-Cl2; R1 = 4-OCH3, 4-Cl, 2,4-Cl2, 3,4-(OCH3)2, 3,4-(OCH2O), 2,4,5(OCH3)3
SCHEME 1
molecular ion peak at m/z 416 along with (M+2) and (M+4) peaks at
m/z 418 and m/z 420 respectively, which is consistent with its molec-
ular formula C20H14ClN3O3S. Yields and analytical data of arylidene
thiazolo triazinediones 8a–l are given in Table I.

3234

Halogen-Containing Arylidene Thiazolo Triazinediones
3235
TABLE II Antibacterial Activity of Arylidene Thiazolo Triazine-
diones 8a–l
Staphylococcus Escherichia Pseudomonas Klebsiella Streptococcus
8
aureus
coli
aeruginosa
pneumoniae
pyogenes
a
b
c
d
e
f
g
h
i
j
k
l
18 (6.25)
–
20 (6.25)
23 (6.25)
14 (12.5)
–
20 (6.25)
12 (12.5)
21 (6.25)
23 (6.25)
–
23 (6.25)
10 (25)
–
25 (6.25)
–
29 (6.25)
11 (12.5)
–
30 (6.25)
10 (25)
25(6.25)
27 (6.25)
–
29 (6.25)
27 (6.25)
12 (12.5)
28 (6.25)
30 (6.25)
21 (6.25)
13 (12.5)
9 (25)
19 (6.25)
15 (12.5)
18 (6.25)
–
20 (6.25)
10 (25)
14 (12.5)
18 (6.25)
–
19 (6.25)
17 (6.25)
8 (25)
19 (6.250
18 (6.25)
–
20 (6.25)
20 (6.25)
–
15 (12.5)
22 (6.25)
20 (6.25)
24 (6.25)
14 (12.5)
25(6.25)
25 (6.25)
–
20 (6.25)
18 (6.25)
8 (25)
21 (6.25)
22 (6.25)
23 (6.25)
23 (6.25)
Standard
– Indicates bacteria resistant to the compounds at >100 µg /mL, MIC values
are given in brackets. MIC (µg/mL) = minimum inhibitory concentration, i.e., low-
est concentration to completely inhibit bacterial growth. Zone of inhibition in mm.
Ciprofloxacin was used as standard.
BIOLOGICAL ACTIVITY
Antibacterial Activity
The new compounds were screened for their antibacterial activity
against Escherichia coli (ATCC-25922), Staphylococcus aureus (ATCC-
25923), Pseudomonas aeruginosa (ATCC-27853), Streptococcus pyo-
genes, and Klebsiella pneumoniae (recultured) bacterial strains by disc
diffusion method and microdilution methods.1718 The results of the an-
tibacterial studies are given in the Table II.
The antibacterial screening data reveal that all tested compounds
show moderate to good bacterial inhibition. Compounds 8a, 8d, 8g, 8i,
8j, and 8l were active against Staphylococcus aureus, Escherichia coli,
Pseudomonas aeruginosa, and Streptococcus pyogenes at 6.25 µg/mL
concentrations. Compounds 8a, 8d, 8i, 8j, and 8l showed very good
activity against all the bacterial strains tested.
Antifungal Activity
The newly synthesized compounds were screened for their antifungal
activity against Aspergillus Flavus (NCIM No. 524), Aspergillus fumi-
gatus (NCIM No. 902), Candida albicans (NCIM No. 300), Penicillium

3236
M. S. Karthikeyan et al.
TABLE III Antifungal Activity of Arylidene Thiazolo Triazinediones
8a–l
Aspergillus
fumigatus
Aspergillus Trichophyton
flavus mentagrophytes marneffei
Penicillium
Candida
albicans
8
A
B
C
D
E
F
G
H
I
J
K
L
28 (6.25)
–
–
15 (12.5)
–
11 (12.5)
28 (6.25)
9 (25)
–
17 (6.25)
13 (12.5)
–
18 (6.25)
7 (25)
8 (25)
–
27 (6.25)
14 (12.5)
–
29 (6.25)
–
12 (12.5)
30 (6.25)
8 (25)
14 (12.5)
8 (25)
21 (6.25)
–
10 (25)
–
9 (25)
12 (12.5)
20 (6.25)
–
22 (6.25)
23 (6.25)
–
29 (6.25)
–
26 (6.25)
12 (12.5)
27 (6.25)
–
26 (6.25)
–
27 (6.25)
29 (6.25)
–
–
12 (12.5)
25 (6.25)
–
27 (6.25)
8 (25)
10 (25)
17 (6.25)
–
20 (6.25)
10 (25)
19 (6.25)
20 (6.25)
28 (6.25)
30 (6.25)
26 (6.25)
28 (6.25)
Standard
– Indicates fungus resistant to the compounds at >100 µg /mL, MIC values are given
in brackets. MIC (µg/mL) = minimum inhibitory concentration, i.e., lowest concentra-
tion to completely inhibit fungal growth. Zone of inhibition in mm. Griesofluvin was
used as standard.
marneffei, and Trichophyton mentagrophytes (recultured) in DMSO by
the serial plate dilution method.19,20 The results of the antifungal stud-
ies are given in Table III.
The antifungal screening data show moderate to good activity. Com-
pounds 8a, 8d, 8j, and 8l were active against A. fumigatus and
C. albicans. Compounds 8d, 8j, and 8l were revealed as very active
against all the fungal strains tested.
CONCLUSION
The antibacterial screening data reveal that among the 12 com-
pounds screened, five compounds show good bacterial inhibition al-
most equivalent to that of the standard. The antifungal screening
results show that only three of the compounds display good ac-
tivity. Arylidene thiazolo triazinediones with 1,3-benzodioxolo sub-
stituent at seventh with p-chlorophenyl and 2,4-dichlorophenyl sub-
stituents at third displayed good antibacterial and antifungal activity.
In addition, compounds bearing 2,3,5-trimethoxyphenyl substituent at
seventh and 2,4-dichlorophenyl substituent at third displayed good
activity.

Halogen-Containing Arylidene Thiazolo Triazinediones
3237
EXPERIMENTAL
Chemistry
Melting points were determined in a Thomas-Hoover melting appara-
tus by open capillary method and are uncorrected. The IR spectra (in
KBr pellets) were recorded with a Shimadzu FT-IR 157 spectropho-
tometer. 1H NMR spectra were recorded with a Bruker 400 MHz NMR
spectrometer using TMS as internal standard. The mass spectra were
recorded with a MASPEC low resolution mass spectrometer operating
at 70 eV. The purity of the compounds was checked by thin layer chro-
matography (TLC) on silica gel plates using petroleum ether and ethyl
acetate (6:4).
Preparation of 6-Arylmethyl-3-mercapto-triazin-5(4H)-ones (6)
6-Arylmethyl-3-mercapto-triazin-5-(4H)-ones (6) were synthesized ac-
cording to the reported method.16
Preparation of 7-Substituted Arylidene-1,3-thiazolo[2,3-c]-1,2,
4-triazine-4,6-diones (8): General Procedure
A mixture of the appropriate mercaptotriazinone 6, (0.01 mol),
monochloroacetic acid (0.015 mol), anhydrous sodium acetate (0.002
mol), glacial acetic acid (20 mL), acetic anhydride (15 mL), and the
substituted benzaldehyde 7, (0.01 mol) was heated to reflux for 5 h.
The reaction mixture was cooled and poured into crushed ice with vig-
orous stirring. The solid obtained was filtered, washed with excess of
water, dried, and recrystallized from a mixture of ethanol and dimethyl-
formamide (2:1).
1
8a: IR (KBr) ν/cm−1: 3089 (Ar-H), 1735 (C = O), 1535 (C = N); H
NMR (400 MHz, CDCl3) : δ = 4.01 (s, 2H, CH2), 7.45 (d, J = 8.2Hz, 2H,
Ar-H), 7.60 (d, J = 8.4 Hz, 2H, Ar-H), 7.66 (d, J = 8.4 Hz, 2H, Ar-H),
7.79 (d, J = 8.2 Hz, 2H, Ar-H), 8.25 (s, 1H, CH); MS (m/z,%): 412 (M+,
20).
8c: IR (KBr) ν/cm−1: 3092 (Ar-H), 1740 (C = O), 1527 (C = N), 812
1
(C-Cl); H NMR (400 MHz, CDCl3) : δ = 4.05 (s, 2H, CH2), 7.32- 7.39
(m, 4H, Ar-H), 7.65–7.73 (m, 4H, Ar-H), 8.20 (s, 1H, CH); MS (m/z,%):
451 (M+1, 25).
8d: IR (KBr) ν/cm−1: 3098 (Ar-H), 1753 (C = O), 1537 (C = N), 792
(C-Cl); 1H NMR (400 MHz, CDCl3) : δ = 4.00 (s, 2H, CH2), 6.18 (s, 2H,
OCH2O), 7.15–7.62 (m, 6H, Ar-H), 8.16 (s, 1H, CH); MS (m/z,%): 426
(M+1, 35).

3238
M. S. Karthikeyan et al.
8f: IR (KBr) ν/cm−1: 3082 (Ar-H), 1745 (C = O), 1528 (C = N), 787
1
(C-Cl); H NMR (400 MHz, CDCl3) : δ = 3.89 (s, 2H, CH2), 3.91–4.05
(3s, 3H, OCH3), 7.15 (s, 1H, Ar-H), 7.28 (s, 1H, Ar-H), 7.61 (d, J = 8.5
Hz, 2H, Ar-H), 7.87 (d, J = 8.5 Hz, 2H, Ar-H), 8.36 (s, 1H, CH); MS
(m/z,%): 471 (M+1, 27).
8g: IR (KBr) ν/cm−1: 3090 (Ar-H), 1731 (C = O), 1536 (C = N), 732
1
(C-Cl); H NMR (400 MHz, CDCl3) : δ = 4.14 (s, 2H, CH2), 7.58 (d, J
= 8.4 Hz, 2H, Ar-H), 7.79 (d, J = 8.4 Hz 2H, Ar-H), 7.65–7.67 (m, 2H,
Ar-H) 7.41–7.46 (m, 2H, Ar-H), 8.20 (s,1H, CH); MS (m/z,%): 486 (M+1,
31).
8h: IR (KBr) ν/cm−1: 3085 (Ar-H), 1740 (C = O), 1545 (C = N), 792
(C-Cl); 1H NMR (400 MHz, CDCl3) : δ = 3.87 (s, 2H, CH2), 4.13 (s, 3H,
OCH3), 7.58 (d, J = 8.5 Hz, 2H, Ar-H), 7.74 (d, J = 8.5Hz, 2H, Ar-H),
7.70 (m, J = 1.4Hz, 1H, Ar-H) 7.40–7.46 (m, 2H, Ar-H), 8.18 (s, 1H,
CH).
8i: IR (KBr) ν/cm−1: 3090 (Ar-H), 1745 (C = O), 1529 (C = N), 810
1
(C-Cl); H NMR (400 MHz, CDCl3) : δ = 3.95 (s, 2H, CH2), 7.32–7.39
(m, 4H, Ar-H), 7.61–7.67 (m, 2H, Ar-H), 8.37 (s, 1H, CH); MS (m/z,%):
485 (M+1, 15).
8k: IR (KBr) ν/cm−1: 3099 (Ar-H), 1715 (C = O), 1527 (C = N), 721
(C-Cl); 1H NMR (400 MHz, CDCl3) : δ = 3.93 (s, 2H, CH2), 4.12 (s, 3H,
OCH3), 4.14 (s, 3H, OCH3), 7.06 (s, 1H, Ar-H), 7.42–7.70 (m, 5H, Ar-H),
8.15 (s,1H, CH); MS (m/z,%): 477 (M+1, 20).
Microbiological Assay
Antibacterial Assay
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 bottles and sterilized by dry heat at 140 ◦C for 1 h. The test com-
pounds were prepared with different concentrations using dimethyl-
formamide. 1 mL containing 100 times the amount of chemical in each
disc was added to each bottle, which contains 100 discs. The discs of
each concentration were placed in triplicate in nutrient agar medium
seeded with fresh bacteria separately. The incubation was carried out
◦
at 37 C for 24 h. Ciprofloxacin was used as a standard drug. Solvent
and growth controls were kept and zones of inhibition and minimum
inhibitory concentrations (MIC) were noted.
Antifungal Assay
Sabourands agar medium was prepared by dissolving peptone (1 g),
D-glucose (4 g), and agar (2 g) in distilled water (100 mL) and adjusting

Halogen-Containing Arylidene Thiazolo Triazinediones
3239
pH to 5.7. Normal saline was used to make a suspension of spores of
the fungal strain for lawning. A loopful of a particular fungal strain
was transferred to 3 mL saline to get a suspension of corresponding
species. 20 mL of agar medium was poured into each petric dish. Ex-
cess of suspension was decanted, and the plates were dried by placing
in an incubator at 37◦C for 1 h. Each well was labeled. A control was
also prepared in triplicate and kept at 37◦C for 3–4 days. Zone of in-
hibition and minimum inhibitory concentration (MIC) were noted. The
activity of each compound was compared with Griesofluvin as standard
drug.
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