Convenient synthesis of some thiadiazolotriazinones carrying 4-methylthiobenzyl moieties as possible antimicrobial agents

Article abstract of DOI:10.1080/10426500601088853

4-amino-6-(4-methylthiobenzyl)-3-mercapto-1,2,4-triazin-5(4H)-one was condensed with various substituted benzoic acids/aryloxyacetic acids in the presence of phosphorus oxychloride to afford a series of 7-(substituted aryl/aryloxymethyl)-3-(4-methylthiobenzyl)-4H-1,3,4-thiadiazolo[2,3-c]-1,2, 4-triazin-4-ones in good yields. The structures of the newly synthesized compounds were confirmed on the basis of elemental analysis, IR, 1H NMR, and mass spectral studies. All the newly synthesized compounds were tested for their antibacterial and antifungal activity against a variety of microorganisms.

Full text of DOI:10.1080/10426500601088853

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Phosphorus, Sulfur, and Silicon
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Convenient Synthesis of Some
Thiadiazolotriazinones Carrying
4-Methylthiobenzyl Moieties as
Possible Antimicrobial Agents
Mithun Ashok a & B. Shivarama Holla a
a Department of Chemistry, Mangalore University,
Mangalagangothri, India
Published online: 20 Apr 2007.
To cite this article: Mithun Ashok & B. Shivarama Holla (2007) Convenient Synthesis
of Some Thiadiazolotriazinones Carrying 4-Methylthiobenzyl Moieties as Possible
Antimicrobial Agents, Phosphorus, Sulfur, and Silicon and the Related Elements,
182:5, 981-991, DOI: 10.1080/10426500601088853
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Phosphorus, Sulfur, and Silicon, 182:981–991, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601088853
Convenient Synthesis of Some Thiadiazolotriazinones
Carrying 4-Methylthiobenzyl Moieties as Possible
Antimicrobial Agents
Mithun Ashok
B. Shivarama Holla
Department of Chemistry, Mangalore University, Mangalagangothri,
India
4-amino-6-(4-methylthiobenzyl)-3-mercapto-1,2,4-triazin-5(4H)-one was con-
densed with various substituted benzoic acids/aryloxyacetic acids in the presence
of phosphorus oxychloride to afford a series of 7-(substituted aryl/aryloxymethyl)-
3-(4-methylthiobenzyl)-4H-1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-4-ones in good
yields. The structures of the newly synthesized compounds were confirmed on the
1
basis of elemental analysis, IR, H NMR, and mass spectral studies. All the newly
synthesized compounds were tested for their antibacterial and antifungal activity
against a variety of microorganisms.
Keywords 1,3,4-Thiadiazole; 1,2,4-triazin-5(4H)-one; antibacterial; antifungal
INTRODUCTION
Various substituted 1,2,4-triazines and their derivatives are im-
portant biological agents, and a significant amount of research ac-
tivity has been directed toward this class of compounds. Triazi-
nones and their condensation products find important applications in
medicinal and agricultural fields.1−7 Some 1,2,4-triazinone derivatives
are reported to possess antidiuretic, neurodepressant, and herbicidal
properties.8,9 A large number of 1,3,4-thiadiazoles are reported to pos-
sess antibacterial properties similar to those of well-known sulfon-
amide drugs.10 Similarly, the 1,3,4-thiadiazole nucleus is associated
Received July 30, 2006; accepted October 6, 2006.
The authors are thankful to the head of CDRI, Lucknow, and the head of SAIF, IISc,
Bangalore, for providing the mass and 1H NMR spectral data. The authors are also
grateful to Dr. Suchetha Kumari N, Department of Biochemistry, K.S. Hegde Medical
Academy, Deralakatte, Mangalore, for providing antimicrobial activity data for the newly
synthesized compounds.
Address correspondence to B. Shivarama Holla, Department of Chemistry, Mangalore
University, Mangalagangothri, 574 199 India. E-mail: mithun4l@rediffmail.com
981

982
M. Ashok and B. S. Holla
with a wide range of biological activities, namely anticancer, antimy-
cobacterial, antitrypanosomal, antihypertensive, anesthetic, and car-
diotonic activities.11−16 It is also known that the thiadiazole nucleus,
due to its pharmacophoric N-C-S linkage exhibits a large number of
biological activities.17 In view of the possible pharmacological activ-
ity of new heterocyclic systems containing 1,3,4-thiadiazoles, a series
of [1,3,4]-thiadiazolo[2,3-c][1,2,4]-triazines were synthesized and re-
ported in the literature.18−20 As a part of our research program to
find potent biologically active molecules,21 we have herein synthesized
some new 7-(substituted aryl/aryloxymethyl)-3-(4-methylthiobenzyl)-
4H-1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-4-ones and studied their an-
tibacterial and antifungal properties.
RESULTS AND DISCUSSION
In the present investigation, some new 7-(substituted aryl/aryloxy-
methyl)-3-(4-methylthiobenzyl)-4H-1,3,4-thiadiazolo[2,3-c]-1,2,4-tria-
zin-4-ones (6a–d) and (7a–d) were prepared by reacting 4-amino-
6-(4-methylthiobenzyl)-3-mercapto-1,2,4-triazin-5(4H)-one (5) with
substituted benzoic acids/aryloxyacetic acids in the presence of
phosphorus oxychloride (Scheme 1). 4-amino-6-(4-methylthiobenzyl)-
3-mercapto-1,2,4-triazin-5(4H)-one (5) was prepared by reacting
4-(4-methylthiobenzylidene)-2-methyl-oxazol-5-one (3) with thiocar-
bohydrazide (4) in refluxing aqueous ethanol. Some of the newly
synthesized compounds were well characterized by their elemental
analysis, IR, 1H NMR, and mass spectral studies.
The IR spectrum of oxazolone (3) showed characteristic absorption
bands at 1694 cm−1 and 1598 cm−1, which are due to the C O and
1
C N functional groups, respectively. The H NMR (CDCl3) spectrum
of (3) showed two singlets at δ 2.40 and δ 2.52, which are due to the
CH3 and SCH3 protons, respectively. Another singlet at δ 7.08 is due
to the olefinic proton. The four protons of the 4-methylthiophenyl ring
resonated as a pair of doublets centred at δ 7.76 and δ 7.99 with a
coupling constant of J = 8.36 Hz each. The mass spectrum of (3) showed
a protonated molecular ion peak (M++ 1) at m/z 234 along with the
molecular ion peak (M+) at m/z 233 in accordance with its molecular
formula C12H11NO2S.
The IR spectrum of triazinone (5) showed characteristic absorption
bands at 3290 cm−1 and 3161 cm−1, which are due to the free amino
group present. Absorption bands at 1160 cm−1 and 1527 cm−1 are due to
C O and C N functional groups, respectively. The 1H NMR (DMSO-d6)
spectrum of (5) showed two singlets at δ 2.43 and δ 3.86, which are due to
SCH3 and CH2 protons. Another set of singlets at δ 6.47 and δ 13.86 that

4-Methylthiobenzyl Moieties
983
SCHEME 1
are exchangeable with D2O are due to NH2 and SH protons. The four
protons of 4-methylthiophenyl ring resonated as a multiplet at δ 7.17–
7.22. The 13C NMR (DMSO-d6) spectrum of (5) showed peaks at 15, 35,
126, 130, 133, 136, 147, 148, and 168, which account for nine different

984
M. Ashok and B. S. Holla
carbon atoms present in the molecule. The mass spectrum of (5) showed
the presence of a molecular ion peak (M+) at m/z 280 in accordance with
its molecular formula C11H12N4OS2, thereby confirming its formation.
IR spectra of the cyclized products 6a–d and 7a–d showed the ab-
sence of absorption bands above 3100, thereby indicating the absence of
a free NH2 group, which is involved in the cyclization process. Also their
1H NMR spectrum showed the absence of two singlets corresponding to
NH2 and SH protons, thereby further confirming the cyclization. The
IR spectrum of (6a) exhibited absorption bands at 1705 cm−1 and 1598
cm−1, which are due to C O and C N functional groups, respectively.
The 1H NMR spectrum of (6a) showed two singlets at δ 2.46 and δ 4.30,
which are due to the SCH3 and CH2 protons, respectively. The four
protons of the 4-methylthiophenyl ring resonated as a pair of doublets
centred at δ 7.21 and δ 7.42. The five protons of the phenyl ring ap-
peared as a multiplet at δ 7.55–7.96. The mass spectrum of (6a) showed
a molecular ion peak (M+) at m/z 366 in accordance with its molecular
formula C18H14N4OS2. The experimental data of all the newly synthe-
sized compounds are presented in Table I. The spectral details of some
of the compounds have also been discussed herein.
An antibacterial and antifungal study carried out for the newly syn-
thesized compounds 6a–d and 7a–d reveals that the all the compounds
possess moderate to good antibacterial and antifungal activity. How-
ever, compounds 7c and 7d showed the maximum activity against
all the tested organisms. The presence of a potential fused triazino-
thiadiazole ring system along with multiple halogen atoms may be the
reason for their increased activity. In addition to this the presence of
an aryloxyalkyl moiety in a molecule is also known to enhance its bio-
logical property.22 The antibacterial and antifungal activity data of the
newly synthesized compounds are given in Tables II and III.
Antibacterial Activity
We investigated the newly synthesized 7-(substituted aryl/aryloxy-
methyl)-3-(4-methylthiobenzyl)-4H-1,3,4-thiadiazolo[2,3-c]-1,2,4-triaz-
in-4-ones (6a–d) and (7a–d) for their antibacterial activity against
Escherichia coli (ATCC-25922), Staphylococcus aureus (ATCC-25923),
Psuedomonas aeruginosa (ATCC-27853), and Klebsiella pneumoniae
(recultured) bacterial stains by the disc diffusion method.23−25 The
discs, measuring 6.25 mm in diameter, were punched from Whatman
No. 1 filter paper. Batches of 100 discs were dispensed in each
screw-capped bottle and sterilized by dry heat at 140◦C for an hour.
The test compounds were prepared in different concentrations using
DMF. Exactly 1 mL containing 100 times the amount of chemical

4-Methylthiobenzyl Moieties
985
TABLE I Characterization Data of Thiadiazolotriazinones (6a–d and
7a–d)
Elemental Analysis
Found (Calcd.)
Compound
no.
Molecular
formula
Yield
Ar/Arꢀ
M.P. (◦C) (%)
C
H
N
6a
C18H14N4OS2
196–198 72 59.06 3.81 15.20
(59.00) (3.85) (15.29)
6b
C19H16N4O2S2 188–190 76 57.61 4.09 14.20
(57.56) (4.07) (14.13)
6c
6d
7a
C18H13ClN4OS2 202–204 79 53.92 3.29 13.91
(53.93) (3.27) (13.97)
C18H12Cl2N4OS2 170–172 80 49.56 2.76 12.88
(49.66) (2.78) (12.87)
C19H16N4O2S2 164–166 73 58.61 4.02 14.18
(58.56) (4.07) (14.13)
7b
7c
7d
C20H18N4O2S2 166–168 73 58.57 4.43 13.69
(58.52) (4.42) (13.65)
C19H15ClN4O2S2 172–174 78 52.98 3.57 13.06
(52.96) (3.51) (13.00)
C19H14Cl2N4O2S2 154–156 82 49.08 3.02 12.07
(49.04) (3.03) (12.04)
in each disc was added to each bottle, which contained 100 discs.
The discs of each concentration were placed separately in nutrient
agar medium inoculated with fresh bacterial strains. The plates were
incubated at 37◦C for 24 h. Ciprofloxacin was used as the standard
drug. Ciprofloxacin has an inhibition length of 19–29 mm for S. aureus,
25–33 mm for P. aeruginosa, 20–25 mm for K. pneumoniae, and 18–26
mm for E. coli at 10 µg/mL concentration. Solvent and growth controls

986
M. Ashok and B. S. Holla
TABLE II Antibacterial Activity of the Newly Synthesized
Compounds (6a–d) and (7a–d)
Diameter of the inhibition zone (in mm) (MIC)∗
Compound no.
S. aureus
P. aeruginosa
K. pneumoniae
E. coli
6a
12
(25)
12
(25)
15
(12.5)
15
(12.5)
10
(25)
12
(25)
18
(12.5)
16
10
(12.5)
10
(12.5)
20
(12.5)
20
(6)
13
(12.5)
12
(12.5)
22
(6)
10
(12.5)
10
(12.5)
15
(6)
18
(6)
10
(12.5)
10
(12.5)
20
(6)
19
10
(25)
10
(25)
13
(12.5)
16
(12.5)
12
(25)
10
(25)
17
(12.5)
17
6b
6c
6d
7a
7b
7c
7d
24
(12.5)
19–29
(12.5)
(6)
25–33
(6)
(6)
20–25
(6)
(12.5)
18–26
(12.5)
Standard
(Ciprofloxacin)
12 mm or less: resistant or no inhibition.
13–17 mm, intermediate or moderate inhibition.
18 mm or more, sensitive or maximum inhibition.
∗The values within the parentheses indicate MIC, which is defined as the
lowest concentration of an antibacterial that considerably inhibits growth of the
organism as visually detected.
were kept separately and the diameter of the inhibition zone, and MIC
were noted. The results of such studies are given in Table II.
Antifungal Activity
The newly synthesized 7-(substituted aryl/aryloxymethyl)-3-(4-methyl-
thiobenzyl)-4H-1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-4-ones (6a–d) and
(7a–d) were screened for their antifungal activity against Aspergillus
flavus (NCIM No. 524), Aspergillus fumigatus (NCIM No. 902), Candida
albicans (NCIM No. 3100), and Penicillium marneffei (recultured) in
DMSO by the serial plate dilution method.23−25 Sabourands agar media
(prepared by dissolving peptone [1 g], D-glucose [4 g] and agar [2 g] in
distilled water [100 mL] and adjusting the pH to 5.7) was used as the
medium for fungal growth. Normal saline was used to make the spore

4-Methylthiobenzyl Moieties
987
TABLE III Antifungal Activity of Newly Synthesized Compounds
(6a–d) and (7a–d)
Diameter of the inhibition zone (in mm)
(MIC)∗
Compound no.
A. fumigatus A. flavus C. albicans P. marneffei
6a
10
(12.5)
12
(12.5)
20
(6)
20
(6)
10
(12.5)
10
(12.5)
22
(6)
20
10
(25)
10
(25)
15
(12.5)
16
(12.5)
10
(25)
10
(25)
16
(12.5)
18
10
(12.5)
10
(12.5)
17
(6)
17
(6)
10
(12.5)
10
(12.5)
18
(6)
19
10
(12.5)
10
(12.5)
15
(6)
18
(6)
10
(12.5)
10
(12.5)
20
(6)
19
6b
6c
6d
7a
7b
7c
7d
(6)
22–30
(6)
(12.5)
18–26
(12.5)
(6)
20–25
(6)
(6)
20–25
(6)
Standard
(Ciclopiroxolamine)
12 mm or less, resistant or no inhibition.
13–17 mm, intermediate or moderate inhibition.
18 mm or more, sensitive or maximum inhibition.
∗The values within the parentheses indicate MIC, which is defined as the lowest
concentration of an antifungal that considerably inhibits growth of the organism as
visually detected.
suspension of the fungal strains (i.e., a loopful of particular fungal strain
was transferred to 3 mL saline to get a suspension of the corresponding
species). Then 20 mL of the previously discussed prepared agar media
was poured into each of the petridishes. Excess media was decanted,
and the plates were dried by placing them in an incubator at 37◦C for
1 h. Wells were made on these seeded agar plates using an agar punch. A
10 µg/mL solution of the test compounds in DMSO was then added into
each of these labeled wells. A control was also prepared in the same way
using DMSO. The petridishes were then incubated at 37◦C for 3–4 days.
Ciclopiroxolamine was used as the standard drug. Ciclopiroxolamine
has an inhibition length of 22–30 mm for A. fumigatus, 18–26 mm for
A. flavus, 20–25 mm each for C. albicans and P. marneffei at 10 µg/mL
concentration. The antifungal activity was determined by measuring

988
M. Ashok and B. S. Holla
the diameter of the inhibition zone and the MIC. The results of such
studies are given in Table III.
EXPERIMENTAL
Melting points were determined by an open capillary method and
are uncorrected. The IR spectra (in KBr pellets) were recorded on
a Shimadzu FT-IR 157 spectrophotometer. 1H NMR spectra were
recorded on a Bruker AMX-400 (400 MHz) spectrophotometer using
TMS as an internal standard. Mass spectra were recorded on a Jeol
JMS-D 300 spectrometer operating at 70 eV. The purity of the com-
pounds was checked by TLC on a silica gel plate using n-hexane and
ethyl acetate (4:1, v/v).
Procedure for the Preparation of
4-(4-Methylthiobenzylidene)-2-methyl-oxazol-5-one (3)
A mixture of acetyl glycine 1 (11.70 g, 100 mmol), 4-methylthio-
benzaldehyde 2 (15.20 g, 100 mmol), anhydrous sodium acetate (4.1
g, 50 mmol), and 95% acetic anhydride (25 mL) were heated on a wa-
ter bath for 3 h. The reaction mixture was then allowed to cool and
left overnight in a refrigerator. The solid mass thus obtained was fil-
tered, washed with cold water, and dried. It was then recrystallized
from ethanol. Yield 85%, m.p. 150–152◦C.
Procedure for the Preparation of 4-Amino-6-(4-
methylthiobenzyl)-3-mercapto-1,2,4-triazin-5(4H)-one (5)
To a solution of thiocarbohydrazide 4 (11.65 g, 50 mmol) in warm
water, a solution of 3 (5.3 g, 50 mmol) in ethanol was added drop-
wise with stirring. The resulting reaction mixture was then refluxed
for 3 h and allowed to cool to r.t. The solid thus obtained was fil-
tered, washed thoroughly with water, and dried. It was then recrys-
tallized from ethanol to obtain the pure triazinone. Yield: 81%, m.p.
206–208◦C.
General Procedure for the Preparation of 7-(substituted
aryl/aryloxymethyl)-3-(4-methylthiobenzyl)-4H-1,3,4-
thiadiazolo[2,3-c]-1,2,4-triazin-4-ones (6a–d) and
(7a–d)
A mixture of triazinone 5 (2.80 g, 10 mmol), substituted ben-
zoic acids/aryloxyacetic acids (10 mmol), and phosphorus oxychloride

4-Methylthiobenzyl Moieties
989
(10 mL) was heated on a water bath for 8 h. Excess of phosphorus
oxychloride was removed under reduced pressure. The resulting reac-
tion mass was cooled and poured into crushed ice with vigorous stirring.
The solid product thus obtained was filtered and washed thoroughly
with diluted sodium bicarbonate solution to remove any unreacted acid
left. It was then washed well with cold water, dried, and recrystallized
from ethanol. The characterization data of these compounds are given
in the Table I.
6b: IR (KBr, cm−1): 2919 (Aliph.CH), 1701 (C O), 1589 (C N),
1H-NMR (CDCl3) δ: 2.48 (s, 3H, SCH3), 3.91 (s, 3H, OCH3), 4.28
(s, 2H, CH2) 7.02 (d, 2H, J = 8.52 Hz, 4-methoxyphenyl), 7.21 (d,
2H, J = 8.36Hz, 4-methylthiophenyl), 7.42 (d, 2H, J = 8.32 Hz, 4-
methylthiophenyl), 7.89 (d, 2H, J = 8.56 Hz, 4-methoxyphenyl), MS
(m/z, %): 397(M++ 1, 80), 396(M+, 40) 391(50), 369(10), 307(70),
289(30), 273(5), 167(5), 154(100), 137(70), 136(70), 120(10), 107(20),
105(5)
6c: IR (KBr, cm−1): 2918 (Aliph.CH), 1703 (C O), 1593 (C N), 833
1
(C Cl), H-NMR (CDCl3) δ: 2.44 (s, 3H, SCH3), 4.27 (s, 2H, CH2) 7.19
(d, 2H, J = 8.28 Hz, 4-methylthiophenyl), 7.39 (d, 2H, J = 8.28 Hz,
4-methylthiophenyl), 7.53 (d, 2H, J = 8.64 Hz, 4-chlorophenyl), 7.88
(d, 2H, J = 8.60 Hz, 4-chlorophenyl), MS (m/z, %): 401(M++ 1, 20),
399(M+, 20) 391(30), 308(10), 307(50), 289(25), 279(5), 242(5), 209(5),
178(5), 167(10), 154(100), 149(30), 137(65), 136(70), 120(10), 107(20),
90(10), 88(10).
7b: IR (KBr, cm−1): 2917, 2859 (Aliph.CH), 1710 (C O), 1589 (C N),
1
1064 (C-O), H-NMR (CDCl3) δ: 2.30 (s, 3H, CH3), 2.44 (s, 3H, SCH3),
4.26 (s, 2H, CH2), 5.33 (s, 2H, OCH2), 6.86 (d, 2H, J = 8.60 Hz, 4-
methylphenoxy), 7.12 (d, 2H, J = 8.36 Hz, 4-methylphenoxy), 7.18 (d,
2H, J = 8.28 Hz, 4-methylthiophenyl), 7.38 (d, 2H, J = 8.24 Hz, 4-
methylthiophenyl), MS (m/z, %): 412(M++ 2, 15), 410(M+, 30), 391(5),
307(30), 289(20), 279(5), 242(5), 180(2), 165(5), 154(100), 137(55),
136(60), 120(10), 107(15), 88(10), 76(5).
7d: IR (KBr, cm−1): 2921, 2852 (Aliph.CH), 1709 (C O), 1588
(C N), 1071 (C O), 800 (C Cl), 1H-NMR (CDCl3) δ: 2.43 (s,
3H, SCH3), 4.25 (s, 2H, CH2), 5.38 (s, 2H, OCH2), 6.93 (d, 1H,
Jo= 8.76 Hz, 2,4-dichlorophenoxy), 7.17 (d, 2H, J = 8.24 Hz, 4-
methylthiophenyl), 7.23 (dd, 1H, Jo/m = 8.76 Hz, 2.44 Hz, 2,4-
dichlorophenoxy) 7.36 (d, 2H, J = 8.20 Hz, 4-methylthiophenyl), 7.44
(d, 1H, Jm = 2.44 Hz, 2,4-dichlorophenoxy), MS (m/z, %): 467(M++
2, 40), 465(M+, 60), 391(2), 307(25), 304(20), 289(25), 234(10), 209(2),
165(10), 154(100), 137(55), 136(70), 120(10), 107(25), 91(10), 89(15),
77(10).

990
M. Ashok and B. S. Holla
CONCLUSION
Some new 7-(substituted aryl/aryloxymethyl)-3-(4-methylthiobenzyl)-
4H-1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-4-ones (6a–d) and (7a–d) were
synthesized and screened for their antibacterial and antifungal activity.
The antimicrobial study revealed that compounds 7c and 7d showed
excellent antibacterial and antifungal activity against all the tested
organisms. This enhanced activity could be attributed to the presence of
potential 1,2,4-triazine functionality along with aryloxymethyl moiety
carrying one or more chlorine atoms.
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