Antimycobacterial and antimicrobial study of new 1,2,4-triazoles with benzothiazoles

Article abstract of DOI:10.1002/ardp.201000061

In this study, we report the antimycobacterial and antimicrobial evaluation of newly synthesized 3-(3-pyridyl)-5-(4-methoxyphenyl)-4-(N-substituted-1,3- benzothiazol-2-amino)-4H-1,2,4-triazole 6a-j in good yields. All the synthesized compounds have been established by elemental analysis, IR, ¹H NMR, ¹³C-NMR and Mass spectral data. In-vitro antimycobacterial activity was carried out against (Mycobacterium tuberculosis) H₃₇Rv strain using Lowenstein-Jensen medium and antimicrobial activity against two Gram positive bacteria (Staphylococcus aureus, Streptococcus pyogenes), two Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and three fungal species (Candida albicans, Aspergillus niger, Aspergillus clavatus) using the broth microdilution method. Compounds 2e, 6a, 6g, 6h, and 6j exhibited promising antimicrobial activity whereas compound 6j showed very good antimycobacterial activity. The antimycobacterial and antimicrobial evaluation of newly synthesized 3-(3-pyridyl)-5-(4-methoxyphenyl)-4-(N-substituted-1,3-benzothiazol- 2-amino)-4H-1,2,4-triazoles is reported in detail. Compounds 2e, 6a, 6g, 6h, and 6j exhibited promising antimicrobial activity whereas compound 6j showed very good antimycobacterial activity. Copyright

Full text of DOI:10.1002/ardp.201000061

692
Arch. Pharm. Chem. Life Sci. 2010, 10, 692–699
Full Paper
Antimycobacterial and antimicrobial study of
new 1,2,4-triazoles with benzothiazoles
Navin B. Patel1, Imran H. Khan1 and Smita D. Rajani2
1 Department of Chemistry, Veer Narmad South Gujarat University, Gujarat, India
2 Microcare Laboratory, Gujarat, India
In this study, we report the antimycobacterial and antimicrobial evaluation of newly synthesized 3-(3-
pyridyl)-5-(4-methoxyphenyl)-4-(N-substituted-1,3-benzothiazol-2-amino)-4H-1,2,4-triazole 6a–j in good
yields. All the synthesized compounds have been established by elemental analysis, IR, 1H NMR, 13C-
NMR and Mass spectral data. In-vitro antimycobacterial activity was carried out against (Mycobacterium
tuberculosis) H37Rv strain using Lowenstein-Jensen medium and antimicrobial activity against two
Gram positive bacteria (Staphylococcus aureus, Streptococcus pyogenes), two Gram negative bacteria
(Escherichia coli, Pseudomonas aeruginosa) and three fungal species (Candida albicans, Aspergillus niger,
Aspergillus clavatus) using the broth microdilution method. Compounds 2e, 6a, 6g, 6h, and
6j exhibited promising antimicrobial activity whereas compound 6j showed very good
antimycobacterial activity.
Keywords: 1,2,4-Triazole / Antimycobacterial activity / Antimicrobial activity
Received: February 27, 2010; Revised: May 3, 2010; Accepted: May 7, 2010
DOI 10.1002/ardp.201000061
Introduction
possesses a wide range of biological activities [21–26]. After
extensive literature survey, it was observed that, till date
enough effort have not been to combine this two moieties
as a single scaffold and to identify new candidates that may
be value in designing new, potent, selective and less toxic
antimycobacterial and antimicrobial agents. We reported
here the synthesis of new 1,2,4-triazoles incorporated with
benzothiazole at N-4 and pyridine at C-3 position encourag-
ing antimycobacterial activity against Mycobacterium
tuberculosis H37Rv and antimicrobial activity.
Among infectious diseases, tuberculosis (TB) is the leading
killer with over two million casualties annually worldwide.
The WHO considers tuberculosis to be the most dangerous
chronic communicable disease in the world [1]. The emer-
gence of AIDS, decline of socioeconomic standards and a
reduced emphasis on tuberculosis control programs contrib-
ute to the disease’s resurgence in industrialized countries [2].
Resistance of Mycobacterium tuberculosis strains to anti-
mycobacterial agents is an increasing problem worldwide
[3–6]. In spite of severe toxicity on repeated dosing of iso-
niazid (INH), it is still considered to be a first line drug for the
chemotherapy of tuberculosis. The azole antitubercular may
be regarded as a new class providing truly effective drugs,
which is reported to inhibit the bacteria by blocking the
biosynthesis of certain bacterial lipids and/or by additional
mechanism [7–9]. 1,2,4-Triazole derivatives are active against
many mycobacteria [10–13] and also possess wide variety of
biological activity [14–18]. Benzothiazole moiety has already
been reported for its mycobacterial activity [19, 20] and also
Result and discussion
Chemistry
2-Amino-6-flouro-1,3-benzothiazole 1a on treatment of hydra-
zine hydrate, concentrated hydrochloric acid and ethylene
glycol yields 2-hydrazino-6-fluoro-1,3-benzothiazole 2a. IR
spectra of 2a showed broad stretching band around 3425
and 3200 cmꢀ1 for NH and NH2. 1H-NMR spectrum showed a
singlet at d 4.83 and d 8.93 which were accounted for NH2 and
NH which vanished on D2O exchange. Ethyl nicotinoate 3 on
treatment with hydrazine hydrate yields nicotinoyl hydra-
zide 4, the IR spectra of 4 showed stretching band around
3335 and 3278 cmꢀ1 where due to amine/amide NH while
strong stretching band at 1610 cmꢀ1 was attributed to amide
Correspondence: Navin B. Patel, Department of Chemistry, Veer
Narmad South Gujarat University, Surat 395007, Gujarat, India.
E-mail: drnavin@satyam.net.in
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2010, 10, 692–699
Antimycobacterial and antimicrobial activity of 1,2,4-triazoles
693
carbonyl. 1H-NMR spectrum showed a singlet at d 4.51 and d
9.81 which were accounted for NH2 and NH which vanished
on D2O exchange. Intermolecular cyclization of nicotinoyl
hydrazide 4 with 4-methoxybenzoic acid in presence of phos-
phorous oxy chloride affords 2-(3-pyridyl)-5-(4-methoxy-
phenyl)-1,3,4-oxadiazole 5. Disappearance of 1H-NMR
Pharmacology
Antimycobacterial activity of all the synthesized compounds
were accessed by L.J.-method and antimicrobial activity were
assessed by broth microdilution method.
The minimum inhibitory concentrations (MICs) of antibac-
terial screening are shown in Table 1. All the compounds
were tested for in-vitro antibacterial activity against two Gram
positive (Staphylococcus aureus MTCC 96, Streptococcus pyogenes
MTCC 442) and two Gram negative (Escherichia coli MTCC 443,
Pseudomonas aeruginosa MTCC 2488) bacteria. Ampicillin was
used as a standard drug. The results revealed that substituted
2-hydrazino benzothiazoles were moderately active against
bacteria except 2e, which showed good activity as compared
with ampicillin against S. aureus and E. coli while 1,3,4-oxa-
diazole 5 exhibited quite good activity to some extent. Most of
1,2,4-triazole derivative were found good activity (100–
250 mg/mL) against S. aureus. Compounds 6a, 6g, and 6h
possessed very good activity (100–200 mg/mL) against
S. aureus. Most of the compounds exhibited moderate activity
(150–250 mg/mL) S. pyogenes. Compounds 6a, 6h, and 6j pos-
sessed good activity (100–125 mg/mL) while others displayed
moderate activity against E. coli. Compounds 6a, 6g, and 6j
showed good activity (62.5–125 mg/mL) except 6h showed
very good activity (25 mg/mL) while others possessed
1
resonances observed with NH and NH2 functions in the H-
NMR spectrum of 5 proved that ring closure starting from 4
resulted in the formation of 1,3,4-oxadiazole ring. This was
further substantiated by the 13C-NMR data of 5 which showed
a peak at d 157.30 and d 157.19 due to C2 and C5 of oxadiazole.
Mass spectrum of 5 displayed a molecular ion peak at m/z 253
which confirmed its molecular weight. Condensation of 5
with various substituted 2-hydrazino-1,3-benzothiazole 2a–j
in pyridine results in 3-(3-pyridyl)-5-(4-methoxyphenyl)-4-(N-
substituted-1,3-benzothiazol-2-amino)-4H-1,2,4-triazole 6a–j.
1
Absence of H-NMR resonances observed with NH2 function
of 2a and appearance of signal at d 7.82 for NH was observed
in 1H-NMR of 6a proved the condensation of 2 and 5 resulted
in the formation of 1,2,4-triazole ring. This was substantiated
by 13C-NMR data of 6a which showed a peak at d 162.58 and d
161.97 due to C3 and C5 of triazole. Mass spectrum of 6
displayed a molecular ion at m/z 418 which confirmed its
molecular weight.
Table 1. Antibacterial activtiy of compounds 2a–j, 5, 6a–j.
Compound
R
Minimum Inhibitory Concentration (MIC) (mg/mL)
Gram positive bacteria Gram negative bacteria
S. aureus
S. pyogenes
E. coli
P. aeruginosa
MTCC-96
MTCC-442
MTCC-443
MTCC-2488
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
5
6a
6b
6c
6d
6e
6f
6g
6h
6i
6-F
6-Br
6-NO2
6-CH3
6-OCH3
6-Cl
4-CH3
4-NO2
5-Cl, 6-Cl
4-Cl
500
250
500
250
200
500
500
500
250
500
500
125
500
500
250
500
250
100
200
500
250
250
250
500
500
250
250
500
500
250
500
500
500
250
500
200
250
500
250
250
250
250
500
100
250
500
250
100
62.5
100
250
500
100
250
100
100
500
250
500
500
1000
500
125
500
100
100
250
500
250
500
125
125
250
250
125
250
50
62.5
500
250
500
250
500
125
25
–
6-F
6-Br
6-NO2
6-CH3
6-OCH3
6-Cl
4-CH3
4-NO2
5-Cl, 6-Cl
4-Cl
250
62.5
100
6j
Ampicillin
–
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N. B. Patel et al.
Arch. Pharm. Chem. Life Sci. 2010, 10, 692–699
moderate activity against P. aeruginosa. Compounds 6a, 6g,
and 6h exhibited very good activity against Gram positive
bacteria whereas 6a, 6h, and 6j showed very good activity
towards Gram negative bacteria. Compound 2e was found to
be active against Gram positive and Gram negative bacteria.
The MICs of antifungal results are shown in Table 2.
All the compounds were screened for antifungal activity
against three fungal species Candida albicans, Aspergillus niger
and Aspergillus clavatus. The results showed that 2-hydrazino
benzothiazoles 2a–j possessed good activity (250–500 mg/mL)
compared to greseofulvin against C. albicans, except 2j
(1000 mg/mL). Compounds 2a–j displayed moderate to
poor activity (250–500 mg/mL) against A. niger and
A. clavatus compared with greseofluvin while 1,3,4-oxadiazole
5 exhibited good activity (250 mg/mL) weak activity against
A. niger and A. clavatus. Compounds 6a, 6c, 6d, 6e, 6g, 6i,
and 6j showed very good activity (200–500 mg/mL)
whereas 6b, 6f, and 6h exhibited pronounced activity
(100 mg/mL) against C. albicans. Compounds 6g and 6i
exhibited moderate activity (200–250 mg/mL) while remain-
ing compounds showed weak activity against A. niger.
Compounds 6f, 6g, and 6i displayed moderate activity
(200–250 mg/mL) while rest of the compounds showed
weak activity against A. clavatus. Compounds 2f, 2g, 2h, 6g,
and 6i were found to be active against all the three fungal
species.
From first preliminary examination of the antimycobacte-
rial activity results are summarized in Table 3. Compound 2e
containing hydrazide group, shows better activity (50 mg/mL)
against M. tuberculosis and compounds 6b, 6d, 6e, and 6h
showed good activity (50–62.5 mg/mL) whereas compound
6j showed pronounced activity (25 mg/mL). Due to the better
activity against tested microorganisms and mycobacteria,
compound 6j has been selected for further development
and studies to acquire more information about structure–
activity relationships are in progress in our laboratories.
MICs of tested compounds showed that 2-hydrazino ben-
zothiazoles possessed poor to good activity but when 2-hydra-
zino benzothiazoles were introduced to 1,3,4-oxadiazole to
form 1,2,4-triazole, the activity increased or decreased
depending upon the substituents. Flouro and chloro
containing 1,2,4-triazoles were found with good activity
towards bacterial and fungal species. Moreover methyl group
containing 1,2,4-triazoles also showed good bacterial and
fungal activity, whereas nitro containing 1,2,4-triazole com-
pounds showed good bacterial activity.
Bromo, chloro, nitro, methoxy, and methyl containing
1,2,4-triazoles showed good activity against M. tuberculosis.
Table 2. Antifungal activtiy of compounds 2a–j, 5, 6a–j.
Compound
R
Minimum Inhibitory Concentration (MIC) (mg/mL)
Fungal species
C. albicans
A. niger
A. clavatus
MTCC-227
MTCC-282
MTCC-323
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
5
6a
6b
6c
6d
6e
6f
6g
6h
6i
6-F
6-Br
6-NO2
6-CH3
6-OCH3
6-Cl
4-CH3
4-NO2
5-Cl, 6-Cl
4-Cl
250
500
500
250
500
250
500
200
500
1000
500
200
100
250
500
250
100
200
100
200
200
500
>1000
500
500
1000
500
200
250
250
500
500
1000
500
500
500
1000
500
500
250
500
250
500
100
>1000
500
1000
>1000
250
250
200
200
1000
500
–
6-F
6-Br
1000
1000
500
6-NO2
6-CH3
6-OCH3
6-Cl
4-CH3
4-NO2
5-Cl, 6-Cl
4-Cl
500
>1000
1000
250
200
500
250
1000
100
6j
Greseofulvin
–
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Arch. Pharm. Chem. Life Sci. 2010, 10, 692–699
Antimycobacterial and antimicrobial activity of 1,2,4-triazoles
695
Table 3. Antimycobacterial activtiy of compounds 2a–j, 5, 6a–j.
2-Hydrazino-6-fluoro-1,3-benzothiazole 2a
Yield 70%; m.p. 204-2068C; IR (KBr, gmax, cmꢀ1): 3435 (NH2), 3200
Compound
R1
MIC values (mg/mL)
of M. tuberculosis
% Inhibition
1
–
(NH), 1631 (C N), 1442 (thiazole); H-NMR (CDCl , d, ppm): 4.83 (s,
–
3
2H, NH2, disappeared on D2O exchange), 8.94 (s, 1H, NH, disappeared
on D2O exchange), 7.28–7.64 (m, 3H, 3 CH); Anal. calcd. for C7H6N3FS:
C, 45.89; H, 3.30; N, 22.94. Found: C, 45.91; H, 3.31; N, 22.98.
H
37Rv
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
5
6a
6b
6c
6d
6e
6f
6g
6h
6i
6-F
6-Br
6-NO2
6-CH3
6-OCH3
6-Cl
4-CH3
4-NO2
5-Cl, 6-Cl
4-Cl
250
500
250
1000
50
200
500
500
250
100
1000
200
50
250
62.5
62.5
250
500
50
98%
97%
99%
98%
99%
99%
98%
98%
99%
98%
99%
98%
99%
96%
98%
92%
94%
90%
99%
98%
99%
98%
2-Hydrazino-6-bromo-1,3-benzothiazole 2b
Yield 61%; m.p. 200–2028C; IR (KBr, gmax, cmꢀ1): 3449 (NH2), 3212
1
–
(NH), 1623 (C N), 1451 (thiazole); H-NMR (CDCl , d, ppm): 4.83 (s,
–
3
2H, NH2, disappeared on D2O exchange), 8.90 (s, 1H, NH, disap-
peared on D2O exchange), 7.63–7.93 (m, 3H, 3 CH); Anal. calcd.
for C7H6N3SBr: C, 34.44; H, 2.48; N, 17.21. Found: C, 34.40; H,
2.45; N, 17.19.
–
6-F
6-Br
2-Hydrazino-6-nitro-1,3-benzothiazole 2c
Yield 67%; m.p. 210–2128C; IR (KBr, gmax, cmꢀ1): 3445 (NH2), 3220
1
–
6-NO2
6-CH3
6-OCH3
6-Cl
4-CH3
4-NO2
5-Cl, 6-Cl
4-Cl
(NH), 1640 (C N), 1448 (thiazole); H-NMR (CDCl , d, ppm): 4.81 (s,
–
3
2H, NH2, disappeared on D2O exchange), 8.92 (s, 1H, NH, disap-
peared on D2O exchange), 7.04–7.79 (m, 3H, 3 CH); Anal. calcd.
for C7H6N4O2S: C, 40.00; H, 2.88; N, 26.65. Found: C, 39.97; H,
2.90; N, 26.68.
200
25
40
2-Hydrazino-6-methyl-1,3-benzothiazole 2d
Yield 62%; m.p. 198–2008C; IR (KBr, gmax, cmꢀ1): 3449 (NH2), 3222
6j
Rifampicin
–
1
–
(NH), 1620 (C N), 1439 (thiazole); H-NMR (CDCl , d, ppm): 4.82 (s,
–
3
2H, NH2, disappeared on D2O exchange), 8.94 (s, 1H, NH, disap-
peared on D2O exchange), 2.45 (s, 3H, CH3), 7.26–7.71 (m, 3H, 3
CH); Anal. calcd. for C8H9N3S: C, 53.61; H, 5.06; N, 23.44. Found: C,
53.57; H, 5.08; N, 23.47.
Experimental
Chemistry
2-Hydrazino-6-methoxy-1,3-benzothiazole 2e
Yield 65%; m.p. 193–1958C; IR (KBr, gmax, cmꢀ1): 3439 (NH2), 3208
All chemical were of analytical grade and used directly. Melting
points were determined in PMP-DM scientific melting point
apparatus and are uncorrected. The purities of compounds were
checked by TLC using Merck silica gel 60 F254. IR spectra were
recorded on Perkin-Elmer RX 1 FTIR spectrophotometer in KBr
(gmax in cmꢀ1). 1H- and 13C-NMR spectra were measured with
Bruker Avance II 400 NMR spectrometer (400 MHz) in CDCl3
using TMS as internal standard (d in ppm). The microanalyses
were performed on a Heraeus Carlo Erba 1180 CHN analyzer.
The mass spectra were obtained with micromass Q-T of micro
(TOF MS ESþ).
1
–
(NH), 1628 (C N), 1448 (thiazole); H-NMR (CDCl , d, ppm): 4.80 (s,
–
3
2H, NH2, disappeared on D2O exchange), 8.94 (s, 1H, NH, disap-
peared on D2O exchange), 3.86 (s, 3H, OCH3), 7.16–7.65 (m, 3H, 3
CH); Anal. calcd. for C8H9N3OS: C, 49.21; H, 4.65; N, 21.52. Found:
C, 49.25; H, 4.62; N, 21.48.
2-Hydrazino-6-chloro-1,3-benzothiazole 2f
Yield 68%; m.p. 198–2008C; IR (KBr, gmax, cmꢀ1): 3445 (NH2), 3218
1
–
(NH), 1624 (C N), 1428 (thiazole); H-NMR (CDCl , d, ppm): 4.79 (s,
–
3
2H, NH2, disappeared on D2O exchange), 8.90 (s, 1H, NH, disap-
peared on D2O exchange), 7.82–8.21 (m, 3H, 3 CH); Anal. calcd.
for C7H6N3ClS: C, 42.11; H, 3.03; N, 17.76. Found: C, 42.15; H, 3.07;
N, 17.79.
Substituted 2-amino-1,3-benzothiazole 2a–j were prepared
accordant to literature [27, 28].
General procedure for synthesis of 2-hydrazino
benzothiazoles 2a–j
2-Hydrazino-4-methyl-1,3-benzothiazole 2g
Yield 69%; m.p. 167–1698C; IR (KBr, gmax, cmꢀ1): 3439 (NH2), 3220
Concentrated hydrochloric acid (0.067 M) was added drop wise
with stirring to hydrazine hydrate (0.12 M) at 5–68C followed
by ethylene glycol (30 mL). Thereafter, 6-fluoro-2-amino-1,3-
benzothiazole 1a (20 mmol) was added in portions and the
resultant mixture was refluxed for 2–3 h and cooled at room
temperature. The reaction progress was monitored by TLC using
toluene/ethylacetate (75:25) as mobile phase. The reaction
mixture was filtered and resulting precipitate was washed
with distilled water. The resulting crude was crystallized from
ethanol. The other compounds of the series were prepared by
similar procedure.
1
–
(NH), 1638 (C N), 1435 (thiazole); H-NMR (CDCl , d, ppm): 4.83 (s,
–
3
2H, NH2, disappeared on D2O exchange), 8.92 (s, 1H, NH, disap-
peared on D2O exchange), 2.83 (s, 3H, CH3), 7.31–7.69 (m, 3H, 3
CH); Anal. calcd. for C8H9N3S: C, 53.61; H, 5.06; N, 23.44. Found: C,
53.65; H, 5.01; N, 23.38.
2-Hydrazino-4-nitro -1,3-benzothiazole 2h
Yield 60%; m.p. 199–2018C; IR (KBr, gmax, cmꢀ1): 3440 (NH2), 3200
1
–
(NH), 1631 (C N), 1445 (thiazole); H-NMR (CDCl , d, ppm): 4.88 (s,
–
2H, NH2, disappeared on D2O exchange), 8.95 (s, 1H, NH,
3
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696
N. B. Patel et al.
Arch. Pharm. Chem. Life Sci. 2010, 10, 692–699
Scheme 1. Synthetic protocol for the compounds 6a–j.
disappeared on D2O exchange), 7.06–8.82 (m, 3H, 3 CH); Anal.
calcd. for C7H6N4O2S: C, 40.00; H, 2.88; N, 26.65. Found: C, 40.04;
H, 2.85; N, 26.61.
2H, NH2, disappeared on D2O exchange), 8.92 (s, 1H, NH, disappeared
on D2O exchange), 7.55–7.87 (m, 3H, 3 CH); Anal. calcd. for C7H6N3ClS:
C, 42.11; H, 3.03; N, 17.76. Found: C, 42.07; H, 3.01; N, 18.00.
2-Hydrazino-(5,6-dichloro)-1,3-benzothiazole 2i
Yield 68%; m.p. 248–2508C; IR (KBr, gmax, cmꢀ1): 3449 (NH2), 3212
2-(3-Pyridyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole 5
A mixture of nicotinoyl hydrazide 4 (5 mmol) and 4-methoxy
benzoic acid (5 mmol) in phosphorus oxychloride (5 mL) was
refluxed on water bath for 9 h. The progress of the reaction
was monitored by TLC using toluene/ethylacetate/methanol
(70:20:10) as mobile phase. After the completion of reaction, it
was cooled and poured onto crushed ice with continuous stir-
ring. The solid mass separated was neutralized with sodium
bicarbonate solution (10% w/v). The resulting solid thus obtained
was collected by filtration, washed well with cold water, dried
and crystallized from absolute ethanol.
1
–
(NH), 1640 (C N), 1439 (thiazole); H-NMR (CDCl , d, ppm): 4.86 (s,
–
3
2H, NH2, disappeared on D2O exchange), 8.94 (s, 1H, NH, disap-
peared on D2O exchange), 7.81 (s, 1H, CH), 7.98 (s, 1H, CH); Anal.
calcd. for C7H5N3Cl2S: C, 35.91; H, 2.15; N, 17.95. Found: C, 35.88;
H, 2.19; N, 17.92.
2-Hydrazino-4-chloro-1,3-benzothiazole 2j
Yield 63%; m.p. 239–2418C; IR (KBr, gmax, cmꢀ1): 3449 (NH2), 3220
1
–
(NH), 1640 (C N), 1445 (thiazole); H-NMR (CDCl , d, ppm): 4.82 (s,
–
3
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Arch. Pharm. Chem. Life Sci. 2010, 10, 692–699
Antimycobacterial and antimicrobial activity of 1,2,4-triazoles
697
Yield 67%; m.p. 111–1138C; IR (KBr, gmax, cmꢀ1): 1667 (C N),
(d, 1H, J ¼ 7.84 Hz, CH), 8.74 (s, 1H, CH); 13C-NMR (CDCl3, d, ppm):
162.38 (C3-triazole), 161.79 (C5-triazole), 55.41 (OCH3), 163.01,
152.38, 147.28, 142.91, 139.21, 134.21, 129.38, 128.65, 126.29,
124.17, 121.75, 119.84, 118.58, 117.72, 116.32, 115.19; (m/z): 445
(Mþ); Anal. calcd. for C21H15N7O3S: C, 56.62; H, 3.39; N, 22.01.
Found: C, 52.65; H, 3.43; N, 21.98.
–
–
1287, 1073 (C–O–C) cmꢀ1 1H-NMR (CDCl3, d, ppm): 3.86 (s, 3H,
;
OCH3), 9.32 (s, 1H, CH), 8.77 (dd, 1H, J ¼ 3.48 Hz, CH), 8.40 (d, 1H,
J ¼ 8.08 Hz, CH), 7.48 (t, 1H, CH), 8.06 (d, 2H, J ¼ 8.16 Hz, 2 CH),
7.02 (d, 2H, J ¼ 8.04 Hz, 2 CH); 13C-NMR (CDCl3, d, ppm): 157.30
(C5-oxadiazole), 157.19 (C2-oxadiazole), 50.71 (OCH3), 160.25,
147.37, 142.88, 129.31, 127.16, 124.06, 115.83, 119.11, 109.84
(aromatic ring); MS (m/z): 253 (Mþ); Anal. calcd. for C14H11N3O2: C,
60.40; H, 4.84; N. 16.59; Found: C, 60.35; H, 4.91; N, 16.51.
3-(3-Pyridyl)-5-(4-methoxyphenyl)-4-(N-6-methyl-1,3-
benzothiazol-2-amino)-4H-1,2,4-triazole 6d
Yield 59%; m.p. 162–1658C; IR (KBr, gmax, cmꢀ1): 3438 (NH), 1661
(C N); 1H-NMR (CDCl3, d, ppm): 3.85 (s, 3H, OCH3), 2.33 (s, 3H,
–
–
General procedure for the synthesis of 3-(3-pyridyl)-5-(4-
methoxyphenyl)-4-(N-substituted-1,3-benzothiazol-2-
amino)-4H-1,2,4-triazole 6a–j
A mixture of 2-(3-pyridyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole 5
(5 mmol)
(5 mmol) in dry pyridine (10 mL) was refluxed for 18–24 h.
The reaction was monitored by TLC on silica gel using ethyl
acetate/toluene (2.5:7.5). It was then cooled and poured on to
crushed ice. The reaction mass was neutralized by dilute hydro-
chloric acid and resulting solid was washed with cold water,
dried and crystallized from absolute ethanol.
CH3), 7.86 (s, 1H, NH), 9.34 (s, 1H, CH), 8.80 (dd, 1H, J ¼ 3.8 Hz,
CH), 8.42 (d, 1H, J ¼ 8.38 Hz, CH), 7.54 (t, 1H, CH), 8.03 (d, 2H,
J ¼ 8.04 Hz, 2 CH), 7.01 (d, 2H, J ¼ 8.16 Hz, 2 CH), 7.05–7.48 (m,
3H, benzothiazole-H); 13C-NMR (CDCl3, d, ppm): 162.97 (C3-
triazole), 162.31 (C5-triazole), 55.49 (OCH3), 22.91 (CH3), 162.86,
152.38, 147.29, 142.83, 134.32, 129.24, 128.33, 128.63, 127.85,
123.53, 122.30, 120.58, 120.69, 119.93, 116.21, 114.98; (m/z): 414
(Mþ); Anal. calcd. for C22H18N6OS: C, 63.75; H, 4.38; N, 20.28.
Found: C, 63.72; H, 4.44; N, 20.32.
and
2-hydrazino-6-fluoro-1,3-benzothiazole
2a
3-(3-Pyridyl)-5-(4-methoxyphenyl)-4-(N-6-methoxy-1,3-
benzothiazol-2-amino)-4H-1,2,4-triazole 6e
The other compounds of the series were prepared by similar
procedure.
Yield 64%; m.p. 229–2318C; IR (KBr, gmax, cmꢀ1): 3449 (NH), 1649
(C N); 1H-NMR (CDCl3, d, ppm): 3.85 (s, 3H, OCH3), 3.80 (s, 3H,
–
–
3-(3-Pyridyl)-5-(4-methoxyphenyl)-4-(N-6-fluoro-1,3-
benzothiazol-2-amino)-4H-1,2,4-triazole 6a
OCH3), 7.86 (s, 1H, NH), 9.36 (s, 1H, CH), 8.80 (dd, 1H, J ¼ 4.0 Hz,
CH), 8.43 (d, 1H, J ¼ 8.24 Hz, CH), 7.48 (t, 1H, CH), 8.03 (d, 2H,
J ¼ 8.08 Hz, 2 CH), 7.01 (d, 2H, J ¼ 8.04 Hz, 2 CH), 7.05–7.28 (m,
3H, benzothiazole-H); 13C-NMR (CDCl3, d, ppm): 162.36 (C3-
triazole), 162.02 (C5-triazole), 55.43 (OCH3), 52.69 (OCH3),
162.78, 152.91, 147.35, 147.32, 144.96, 142.88, 131.13, 129.24,
128.68, 123.78, 120.21, 119.15, 115.52, 114.65, 113.98, 106.25;
(m/z): 430 (Mþ); Anal. calcd. for C22H18N6O2S: C, 61.38; H, 4.21; N,
19.52. Found: C, 61.42; H, 4.24; N, 19.49.
Yield 65%; m.p. 168–1708C; IR (KBr, gmax, cmꢀ1): 3434 (NH),1649
(C N); 1H-NMR (CDCl3, d, ppm): 3.88 (s, 3H, OCH3), 7.82 (s, 1H,
–
–
NH), 9.32 (s, 1H, CH), 8.78 (dd, 1H, J ¼ 4.0 Hz, CH), 8.41 (d, 1H,
J ¼ 8.35 Hz, CH), 7.52 (t, 1H, CH), 8.05 (d, 2H, J ¼ 8.16 Hz, 2 CH),
6.98 (d, 2H, J ¼ 8.04 Hz, 2 CH), 7.07–7.24 (m, 3H, benzothiazole-
H); 13C-NMR (CDCl3, d, ppm): 162.58 (C3-triazole), 161.97 (C5-
triazole), 55.53 (OCH3), 162.94, 152.22, 147.37, 146.54, 142.91,
133.96, 129.33, 128.78, 125.78, 123.94, 121.88, 120.18, 115.78,
114.65, 112.01, 108.21; (m/z): 418 (Mþ); Anal. calcd. for
C21H15N6OFS: C, 60.28; H, 3.61; N, 20.08. Found: C, 60.32; H,
3.63; N, 20.11.
3-(3-Pyridyl)-5-(4-methoxyphenyl)-4-(N-6-chloro-1,3-
benzothiazol-2-amino)-4H-1,2,4-triazole 6f
Yield 72%; m.p. 241–2438C; IR (KBr, gmax, cmꢀ1): 3442 (NH), 1659
(C N); 1H-NMR (CDCl3, d, ppm): 3.85 (s, 3H, OCH3), 7.89 (s, 1H,
–
–
3-(3-Pyridyl)-5-(4-methoxyphenyl)-4-(N-6-bromo-1,3-
benzothiazol-2-amino)-4H-1,2,4-triazole 6b
NH), 9.32 (s, 1H, CH), 8.74 (dd, 1H, J ¼ 3.8 Hz, CH), 8.42 (d, 1H,
J ¼ 8.40 Hz, CH), 7.49 (t, 1H, CH), 8.05 (d, 2H, J ¼ 8.04 Hz, 2 CH),
7.09 (d, 2H, J ¼ 8.28 Hz, 2 CH), 7.59–7.80 (m, 3H, benzothiazole-
H); 13C-NMR (CDCl3, d, ppm): 162.12 (C3-triazole), 161.99
(C5-triazole), 55.46 (OCH3), 162.85, 152.16, 147.32, 144.44,
142.69, 132.96, 129.31, 128.63, 126.85, 123.84, 125.47, 121.95,
120.24, 119.52, 115.65, 114.58; (m/z): 434 (Mþ), 436 (M þ 2); Anal.
calcd. for C21H15N6OClS: C, 58.00; H, 3.48; N, 19.32. Found: C,
57.96; H, 3.51; N, 19.36.
Yield 62%; m.p. 153–1558C; IR (KBr, gmax, cmꢀ1): 3432 (NH), 1646
(C N); 1H-NMR (CDCl3, d, ppm): 3.85 (s, 3H, OCH3), 7.86 (s, 1H,
–
–
NH), 9.35 (s, 1H, CH), 8.80 (dd, 1H, J ¼ 3.8 Hz, CH), 8.45 (d, 1H,
J ¼ 8.35 Hz, CH), 7.50 (t, 1H, CH), 8.05 (d, 2H, J ¼ 8.04 Hz, 2 CH),
7.02 (d, 2H, J ¼ 8.16 Hz, 2 CH), 7.61–7.76 (m, 3H, benzothiazole-
H); 13C-NMR (CDCl3, d, ppm): 162.37 (C3-triazole), 161.85
(C5-triazole), 55.48 (OCH3), 162.31, 152.54, 147.32, 142.91,
133.85, 129.33, 128.78, 126.58, 125.91, 124.01, 121.09, 120.18,
116.99, 115.78, 114.88, 109.79; (m/z): 479 (Mþ), 481 (M þ 2); Anal.
calcd. for C21H15N6OBrS: C, 52.62; H, 3.15; N, 17.53. Found: C,
52.59; H, 3.18; N, 17.49.
3-(3-Pyridyl)-5-(4-methoxyphenyl)-4-(N-4-methyl-1,3-
benzothiazol-2-amino)-4H-1,2,4-triazole 6g
Yield 62%; m.p. 167–1698C; IR (KBr, gmax, cmꢀ1): 3435 (NH), 1660
(C N); 1H-NMR (CDCl3, d, ppm): 2.61 (s, 3H, CH3), 3.85 (s, 3H,
–
–
3-(3-Pyridyl)-5-(4-methoxyphenyl)-4-(N-6-nitro-1,3-
benzothiazol-2-amino)-4H-1,2,4-triazole 6c
OCH3), 7.87 (s, 1H, NH), 9.36 (s, 1H, CH), 8.81 (dd, 1H, J ¼ 4.0 Hz,
CH), 8.43 (d, 1H, J ¼ 8.02 Hz, CH), 7.54 (t, 1H, CH), 8.07 (d, 2H,
J ¼ 8.34 Hz, 2 CH), 7.02 (d, 2H, J ¼ 8.24 Hz, 2 CH), 7.09–7.28 (m,
3H, benzothiazole-H); 13C-NMR (CDCl3, d, ppm): 161.98 (C3-
triazole), 161.53 (C5-triazole), 20.49 (CH3), 55.43 (OCH3), 162.89,
152.12, 147.34, 143.47, 142.87, 132.87, 129.29, 128.82, 128.64,
127.57, 123.59, 122.04, 120.96, 119.98, 115.78, 114.65; (m/z): 414
Yield 68%; m.p. 159–1618C; IR (KBr, gmax, cmꢀ1): 3445 (NH), 1652
(C N); 1H-NMR (CDCl3, d, ppm): 3.82 (s, 3H, OCH3), 7.88 (s, 1H,
–
–
NH), 9.36 (s, 1H, CH), 8.81 (dd, 1H, J ¼ 4.0 Hz, CH), 8.44 (d, 1H,
J ¼ 8.38 Hz, CH), 7.54 (t, 1H, CH), 8.03 (d, 2H, J ¼ 8.20 Hz, 2 CH),
7.04 (d, 2H, J ¼ 8.16 Hz, 2 CH), 7.63 (d, 1H, J ¼ 8.04 Hz, CH), 8.12
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

698
N. B. Patel et al.
Arch. Pharm. Chem. Life Sci. 2010, 10, 692–699
(Mþ); Anal. calcd. for C22H18N6OS: C, 63.75; H, 4.38; N, 20.28.
Found: C, 63.79; H, 4.35; N, 20.24.
described above) was sub cultured and incubated overnight at
378C. The amount of growth from the control tube before incu-
bation (which represents the original inoculum) was compared.
Subcultures might show similar number of colonies indicating
bacteriostatic; a reduced number of colonies indicating a partial
or slow bactericidal activity and no growth if the whole inocu-
lum has been killed. The test must include a second set of the
same dilutions inoculated with an organism of known sensi-
tivity. Each synthesized drug was diluted obtaining 2000 mg/mL
concentration, as a stock solution. In primary screening 500, 250,
and 125 mg/mL concentrations of the synthesized drugs were
taken. The active synthesized drugs found in this primary screen-
ing were further tested in a second set of dilution against all
microorganisms. The drugs found active in primary screening
were similarly diluted to obtain 100, 50, 25, 12.5, 6.250, 3.125,
and 1.5625 mg/mL concentrations. The highest dilution showing
at least 99% inhibition is taken as MIC.
3-(3-Pyridyl)-5-(4-methoxyphenyl)-4-(N-4-nitro-1,3-
benzothiazol-2-amino)-4H-1,2,4-triazole 6h
Yield 65%; m.p. 198–2008C; IR (KBr, gmax, cmꢀ1): 3442 (NH), 1657
(C N); 1H-NMR (CDCl3, d, ppm): 3.84 (s, 3H, OCH3), 7.88 (s, 1H,
–
–
NH), 9.34 (s, 1H, CH), 8.80 (dd, 1H, J ¼ 3.8 Hz, CH), 8.43 (d, 1H,
J ¼ 8.08 Hz, CH), 7.50 (t, 1H, CH), 8.03 (d, 2H, J ¼ 8.16 Hz, 2 CH),
7.01 (d, 2H, J ¼ 8.34 Hz, 2 CH), 6.63 (t, 1H, CH), 8.22 (d, 1H,
J ¼ 8.24 Hz, CH), 8.56 (d, 1H, J ¼ 8.24 Hz, CH); 13C-NMR
(CDCl3, d, ppm): 162.45 (C3-triazole), 161.99 (C5-triazole), 55.40
(OCH3), 162.83, 152.22, 147.41, 144.36, 142.93, 138.06, 132.10,
129.37, 128.82, 128.07, 123.85, 122.55, 120.65, 119.97, 115.82,
114.74; (m/z): 445 (Mþ); Anal. calcd. for C21H15N7O3S: C, 56.62; H,
3.39; N, 22.01. Found: C, 56.59; H, 3.44; N, 22.05.
3-(3-Pyridyl)-5-(4-methoxyphenyl)-4-(N-(5,6-dichloro)-1,3-
benzothiazol-2-amino)-4H-1,2,4-triazole 6i
In-vitro evaluation of antimycobacterial activity
Yield 69%; m.p. 176–1788C; IR (KBr, gmax, cmꢀ1): 3449 (NH), 1655
Drug susceptibility and determination of MIC of the test com-
pounds against M. tuberculosis H37Rv were performed by
Lowenstein-Jensen (LJ) MIC method [29–32] where primary
1000, 500, 250, and secondary 200, 100, 62.5, 50, 25, 12.5,
6.25, 3.25 mg/mL dilutions of each test compound were added
liquid Lowenstein-Jensen Medium and then media were steri-
lized by inspissation method. A culture of M. tuberculosis
H37Rv growing on Lowenstein-Jensen Medium was harvested
in 0.85% saline in bijou bottles. All test compound make first
stock solution of 2000 mg/mL concentration of compounds was
prepared in DMSO. These tubes were then incubated at 378C for
24 h followed by streaking of M. tuberculosis H37Rv (5 ꢁ 104 bacilli
per tube). These tubes were then incubated at 378C. Growth of
bacilli was seen after 12, 22, and finally 28 days of incubation.
Tubes having the compounds were compared with control tubes
where medium alone was incubated with M. tuberculosis H37Rv.
The concentration at which no development of colonies occurred
or <20 colonies was taken as MIC concentration of test com-
pound. The standard strain M. tuberculosis H37Rv was tested with
known drug rifampicin.
(C N); 1H-NMR (CDCl3, d, ppm): 3.82 (s, 3H, OCH3), 7.85 (s, 1H,
–
–
NH), 9.36 (s, 1H, CH), 8.82 (dd, 1H, J ¼ 4.0 Hz, CH), 8.45 (d, 1H,
J ¼ 8.48 Hz, CH), 7.54 (t, 1H, CH), 8.06 (d, 2H, J ¼ 8.38 Hz, 2 CH),
7.03 (d, 2H, J ¼ 8.16 Hz, 2 CH), 7.59 (s, 1H, CH), 7.66 (s, 1H, CH);
13C-NMR (CDCl3, d, ppm): 162.58 (C3-triazole), 161.97 (C5-triazole),
55.53 (OCH3), 162.86, 152.35, 147.32, 144.86, 142.84, 133.96,
129.35, 128.02, 128.75, 128.69, 123.86, 123.78, 123.37, 121.74,
119.89, 115.78, 114.65, 112.01, 108.21; (m/z): 469 (Mþ), 471
(M þ 2), 473 (M þ 4); Anal. calcd. for C21H14N6OCl2S: C, 53.74;
H, 3.01; N, 17.91. Found: C, 53.79; H, 3.05; N, 17.87.
3-(3-Pyridyl)-5-(4-methoxyphenyl)-4-(N-4-chloro-1,3-
benzothiazol-2-amino)-4H-1,2,4-triazole 6j
Yield 64%; m.p. 192–1948C; IR (KBr, gmax, cmꢀ1): 3447 (NH), 1661
(C N); 1H-NMR (CDCl3, d, ppm): 3.85 (s, 3H, OCH3), 7.88 (s, 1H,
–
–
NH), 9.36 (s, 1H, CH), 8.82 (dd, 1H, J ¼ 3.4 Hz, CH), 8.45 (d, 1H,
J ¼ 8.08 Hz, CH), 7.53 (t, 1H, CH), 8.07 (d, 2H, J ¼ 8.24 Hz, 2 CH),
6.96 (d, 2H, J ¼ 8.04 Hz, 2 CH), 7.03–7.35 (m, 3H, benzothiazole-
H); 13C-NMR (CDCl3, d, ppm): 162.12 (C3-triazole), 161.57
(C5-triazole), 55.45 (OCH3), 162.85, 152.59, 147.36, 144.86,
142.88, 132.96, 129.28, 128.71, 123.94, 123.18, 121.52, 119.98,
118.79, 115.82, 114.78; (m/z): 434 (Mþ), 436 (M þ 2); Anal. calcd.
for C21H15N6OClS: C, 58.00; H, 3.48; N, 19.32. Found: C, 58.04; H,
3.45; N, 19.37.
The authors have declared no conflict of interest.
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