Synthesis and pharmacological evaluation of clubbed isopropylthiazole derived triazolothiadiazoles, triazolothiadiazines and mannich bases as potential antimicrobial and antitubercular agents

Article abstract of DOI:10.1016/j.ejmech.2010.08.023

A series of novel clubbed Isopropylthiazole derivatives triazolothiadiazines 2a-g, dihydro triazolothiadiazoles 3a-g, thioxotriazoles 4a-d, triazolothiadiazole 5, arylideneamino triazolethiones 7a-h and oxadiazolethiones 11a-b were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, elemental and mass spectral analysis. These compounds were evaluated for their preliminary in vitro antibacterial, antifungal and antitubercular activity against Mycobacterium tuberculosis H₃₇Rv strain by broth dilution assay method. All the compounds exhibited moderate to significant antibacterial and antifungal activities. Results of the antitubercular screening against M. tuberculosis H₃₇Rv showed compounds 7c and 7d exhibited good antitubercular activity (MIC 4 and 8 μg/mL) respectively, when compared with first line drug such as isoniazid (0.25 μg/mL).

Full text of DOI:10.1016/j.ejmech.2010.08.023

European Journal of Medicinal Chemistry 45 (2010) 5120e5129
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and pharmacological evaluation of clubbed isopropylthiazole derived
triazolothiadiazoles, triazolothiadiazines and mannich bases as potential
antimicrobial and antitubercular agents
,
b
c
d
G.V. Suresh Kumar a , Y. Rajendra Prasad , B.P. Mallikarjuna , S.M. Chandrashekar
*
a St Johns Pharmacy College, Department of Medicinal Chemistry, 6, 2nd stage Vijaynagar, R.P.C. Layout, Bangalore 560040, Karnataka, India
b University College of Pharmaceutical Sciences, Andhra University, Visakhapatnam 530003, Andhra Pradesh, India
c PES College of Pharmacy, Department of Medicinal Chemistry, 50 feet road, Hanumantha nagar, B.S.K. Ist stage, Bangalore 560050, Karnataka, India
d St Johns Pharmacy College, Department of Medicinal Chemistry, 6, 2nd stage Vijaynagar, R.P.C. Layout, Bangalore 560040, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A
series of novel clubbed Isopropylthiazole derivatives triazolothiadiazines 2aeg, dihydro tri-
Received 3 April 2010
Received in revised form
1 August 2010
Accepted 9 August 2010
Available online 14 August 2010
azolothiadiazoles 3aeg, thioxotriazoles 4aed, triazolothiadiazole 5, arylideneamino triazolethiones 7aeh
and oxadiazolethiones 11aeb were synthesized and characterized by IR, 1H NMR, 13C NMR, elemental and
mass spectral analysis. These compounds were evaluated for their preliminary in vitro antibacterial, anti-
fungal and antitubercular activity against Mycobacterium tuberculosis H37Rv strain by broth dilution assay
method.
All the compounds exhibited moderate to significant antibacterial and antifungal activities. Results of
the antitubercular screening against M. tuberculosis H37Rv showed compounds 7c and 7d exhibited good
Keywords:
4-Isopropylthiazole
Triazolothiadiazoles
Triazolothiadiazines
Mannich bases
Cytotoxicity
antitubercular activity (MIC 4 and 8
isoniazid (0.25 g/mL).
m
g/mL) respectively, when compared with first line drug such as
m
Ó 2010 Elsevier Masson SAS. All rights reserved.
Antitubercular
1. Introduction
target by transmembrane diffusion because of its lipophilic prop-
erty and target the sterol demthylase, a mixed function oxidase
involved in sterol synthesis in eukaryotic organism [6,7]. Iso-
propylthiazole moiety has already been identified for its antimi-
crobial activity and its coupling with other heterocyclic rings
furnishes novel biologically active compounds [8].
Tuberculosis (TB) still remains a major public health threat and
recent world health organization (WHO) reports show that TB is
responsible for more than three million deaths annually worldwide
[1]. The raise is attributed to increase in emergence of drug-resistant
strains ofMycobacterium tuberculosis, multi drug-resistant (MDR)TB
and extensively drug-resistant (XDR) TB. For this reason it is critical
to discover new drugs acting with different mechanism from those
drugs used in current therapy [2,3].
One of the important strategies for designing effective antitu-
bercular agents is to develop inhibitors of Mycobacterial cell-wall
biosynthesis. The cell-wall of Mycobacteria consists of a wide array
of complex fatty acids, such as mycocerosic acid, mycolic acid,
arabinogalactans and peptidoglycans [4,5]. Azole derivatives have
demonstrated interesting antimycobacterial activity in addition to
antimicrobial activity. It is established that these compounds reach
Multi-component reactions (MCRs) constitute a major part in the
present day organic synthesis with advantages ranging from lower
reaction times, increased reaction rates to higher yields and repro-
ducibility [22,9]. Mannich reaction is a three-component condensa-
tion reaction involving active hydrogen containing compound,
formaldehyde and a secondary amine [10]. The aminoalkylation of
aromatic substrates by Mannich reaction is of considerable impor-
tance for the synthesis and modification of biologically active
compounds [11,12]. Considering above facts and in continuation of
our research on thiazoles [13e17], it was contemplated to synthesize
a series of clubbed isopropylthiazole derivatives triazolothiadiazoles,
triazolothiadiazines and mannich bases, study their cytotoxicity,
antimicrobial (bacterial and fungal) and antitubercular activity
against H37Rv strain. The synthetic route and the sequence of reac-
tions are depicted in Schemes 1 and 2.
* Corresponding author. Tel.: þ91 80 23190191, þ91 9886104039 (Mobile);
fax: þ91 80 23350035.
E-mail address: gvsureshkumar@yahoo.com (G.V. Suresh Kumar).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.08.023

G.V. Suresh Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 5120e5129
5121
N
N
N
S
N
N
S
2a-g
N
N
N
N
N
N
N
S
I
Ar
3a-g
S
N
S
HN
S
8
VII
N
NH
N
N
Ar
CH3
N
S
S
V
1
H2N
N
I
I
NH
I
N
N
N
IV
NH
S
N
S
S
6a-d
4a-d
N
N
N
N
N
S
HN
VI
Ar
N
O
S
S
R
5
Ar
N
N
N
N
SH
S
N
S
7a-h
N
Ar
Scheme 1. Synthesis of 3-(4-isopropylthiazol-2-yl)-6-substituted triazolothiadiazines, triazolothiadiazoles and substituted benzylideneamino-triazole derivatives.
2. Chemistry
component mannich reaction in presence of formaldehyde and
morpholine or N-methylpiperazine in ethanol-dioxane medium.
The synthesis of 3-(4-isopropylthiazol-2-yl)-6-methyl-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazole 8 was achieved by reacting (4-
amino-5-(4-isopropyl-1,3-thiazol-2-yl)-4H-1,2,4-triazole-3-thiol)
triazole 1 with phosphorus oxychloride and acetic acid.
The reaction sequences employed for synthesis of target
compounds are shown in Schemes 1 and 2, and their physical
properties are depicted in Table 1. The key intermediates in the
present study 4-amino-5-(4-isopropyl-1,3-thiazol-2-yl)-4H-1,2,4-
triazole-3-thiol 1, 4-arylideneamino-1,2,4-triazol-3(2H)-thione
derivatives 6aed, 4-isopropylthiazole-2-carbohydrazide 9 and 5-
(4-isopropylthiazol-2-yl)-1,3,4-oxadiazole-2(3H)-thione 10 were
prepared as per the literature [18,19].
The Scheme 2 depicts synthesis of 5-(4-isopropylthiazol-2-yl)-
3-(4-methylpiperazin-1-yl)-1,3,4-oxadiazole-2(3H)-thione
11a
and 5-(4-isopropylthiazol-2-yl)-3-(morpholinomethyl)-1,3,4-oxa-
diazole-2(3H)-thione 11b by reacting compound 10 with appro-
priate cyclic amines.
Condensation of triazole 1 with phenacyl bromides in presence of
anhydrous sodium acetate and absolute ethanol produced a series of
3-(4-isopropylthiazol-2-yl)-6-substituted phenyl-7H-[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazines 2aeg, condensation of compound 1 with
appropriate substituted aldehydes in presence of p-toluenesulphonic
acid produced a series of 5,6-dihydro fused triazolothiadiazoles
3aeg. Triazole 1 when treated with substituted benzoyl chloride at
3. Biological activity
The standard strains were procured from the American Type
Culture Collection (ATCC) and Gene Bank, Institute of Microbial
Technology, Chandigarh, India. The antibacterial activity of the
synthesized compounds (2aeg, 3aeg, 4aed, 5, 7aeh, 8 and 11aeb)
was performed by broth dilution method [20,21] against the
following standard bacterial strains Staphylococcus aureus (ATCC
11632), Streptococcus faecalis (ATCC 14506), Bacillus subtilis (ATCC
60511), Klebsiella pneumoniae (ATCC 10031), Escherichia and Pseu-
domonas aeruginosa (ATCC 10145) and antifungal activity against
Yeasts: Saccharomyces cerevisiae (ATCC 9763, Sc) and Candida tro-
picalis (ATCC 1369, CT), mould: Aspergillus niger (ATCC 6275). MIC of
compounds was determined against M. tuberculosis H37Rv strain by
using broth dilution assay method. The cytotoxicity of the synthe-
sized compounds were evaluated for their cytotoxic potential using
A549 (lung adenocarcinoma) cell lines in the presence of fetal
bovine serum.
0
ꢀC provided compounds 4aed in good yields. Chemical trans-
formation of compound 1 to 5 was achieved by treating it with
carbon disulfide and potassium hydroxide. Compounds 7aeh was
synthesized by reacting Schiff bases 6aed in one pot multi-
Scheme 2. Synthesis of 5-(4-isopropylthiazol-2-yl)-3-substituted-1,3,4-oxadiazole-2
(3H)-thiones.

Table 1
Analytical and physico-chemical data of synthesized compounds 2aeg, 3aeg, 4aed, 5, 7aeh and 11aeb.
Compound
X
R
Molecular Formula M.W.a
M.p. (ꢀC)b/crystallization solvent
Yield (%) % Analysis of C, H, N found (Calc.)c
C
H
N
2a
2b
2c
2d
2e
2f
2g
3a
3b
3c
3d
3e
3f
3g
4a
4b
4c
4d
5
7a
7b
7c
7d
7e
7f
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
C
16H15N5S2
341.45 224e227 Ethanol
81
75
72
83
80
75
89
74
83
71
69
74
70
87
74
75
79
72
82
65
68
65
67
64
68
70
67
56.28 (56.24) 4.43 (4.42) 20.51 (20.54)
4-CH3
4-OCH3
4-OH
4-Cl
4-NO2
4-Br
2-Cl
4-CH3
4-N(CH3)2
C17H17N5S2
355.48 232e235 Ethanol
371.48 216e219 Ethanol
357.45 208e210 Ethanol
57.44 (57.43)
54.96 (54.98)
53.76 (53.78)
51.12 (51.15)
49.73 (49.76)
45.72 (45.70)
4.82(4.87)
19.70(19.71)
C17H17N5OS2
C16H15N5OS2
C16H14ClN5S2
C16H14N6O2S2
C16H14BrN5S2
C15H14ClN5S2
C16H17N5OS2
C17H20N6S2
4.61(4.65) 18.85 (18.82)
4.23(4.25) 19.59 (19.62)
3.75(3.77) 18.63 (18.65)
3.65(3.67) 21.75 (21.78)
3.36(3.38) 16.66 (16.67)
375.9
202e205 Ethanol
386.45 229e231 Ethanol
420.35 224e226 Ethanol
363.04 238e240 Ethanol
359.09 222e225 Ethanol
372.12 230e234 Ethanol
419.52 218e221 Ethanol
365.06 254e257 Ethanol
345.44 221e225 Ethanol
374.44 234e236 Ethanol
345.07 281e285 Ethanol
359.47 265e268 Ethanol
361.44 254e256 Ethanol
375.47 248e250 Ethanol
49.51 (49.08) 3.88 (3.91) 19.25 (19.28)
53.46 (53.48) 4.77 (4.76) 19.48 (19.44)
54.81 (54.84) 5.41 (5.44) 22.56 (22.59)
51.53 (51.55) 5.05 (5.08) 16.69 (16.67)
49.30 (49.34) 3.59 (3.58) 10.40 (10.42)
52.15 (52.09) 4.38 (4.34) 20.27 (20.29)
48.11 (48.16) 3.77 (3.75) 22.44 (22.47)
52.15 (52.16) 4.38 (4.36) 20.27 (20.31)
53.46(53.44) 4.77 (4.79) 19.48 (19.51)
49.84 (49.88) 4.18 (4.19) 19.38 (19.37)
51.18 (51.14) 4.56 (4.19) 18.65 (18.66)
38.14 (38.13) 3.20 (3.21) 24.71 (24.75)
52.98 (52.94) 5.50 (5.53) 20.60 (20.66)
56.02 (56.08) 6.20 (6.24) 20.79 (20.81)
57.00 (57.03) 6.65 (6.66) 23.12 (23.10)
54.21 (54.25) 6.26 (6.24) 18.44 (18.45)
51.88 (51.89) 5.01 (5.09) 18.15 (18.10)
55.00 (55.05) 5.71 (5.78) 18.33 (18.39)
56.02 (56.09) 6.20 (6.23) 20.79 (20.80)
53.26 (53.28) 5.83 (5.88) 16.20 (16.18)
3,4,5-OCH3 C18H21N5O3S2
2,4-F
4-OH
4-NO2
e
C15H13F2N5S2
C15H15N5OS2
C15H14N6O2S2
C15H15N5OS2
C16H17N5OS2
C15H15N5O2S2
C16H17N5O2S2
C9H9N5S3
4-CH3
4-OH
4-OCH3
e
283.4
212e214 Ethanol
NeCH3 2-Cl
NeCH3 4-OCH3
NeCH3 4-N(CH3)2
NeCH3 3,4,5-OCH3 C24H33N7O3S2
O
O
O
O
e
C21H26ClN7S2
C22H29N7OS2
C23H32N8S2
476.06 156e158 Ethanol: dioxane (2:1)
471.19 173e175 Ethanol: dioxane (2:1)
484.68 150e152 Ethanol: dioxane (2:1)
531.69 161e163 Ethanol: dioxane (2:1)
463.02 148e150 Ethanol: dioxane (2:1)
2-Cl
4-OCH3
4-N(CH3)2
C20H23ClN6OS2
C21H26N6O2S2
C22H29N7OS2
458.6
154e157 Ethanol: dioxane (2:1)
7g
7h
8
11a
11b
471.64 157e159 Ethanol: dioxane (2:1)
518.65 159e161 Ethanol: dioxane (2:1)
265.05 255e258 Dimethylsulfoxide/water (1:1)
3,4,5-OCH3 C23H30N6O4S2
e
e
e
C10H11N5S2
C13H19N5OS2
C13H18N4O2S2
45.26 (45.28)
4.18(4.19)
26.39(26.35)
NeCH3
O
325.1
218e220 Ethanol: dioxane (2:1)
81
83
47.98 (47.89) 5.88 (5.87) 21.52 (21.57)
47.83 (47.86) 5.56 (5.59) 17.16 (17.19)
326.09 226e229 Ethanol: dioxane (2:1)
a
Molecular weight of the compound.
Melting point of the compound at their decomposition.
Elelmental analysis of C, H, and N were with in ꢁ0.4% of theoretical value.
b
c
Table 2
Antibacterial and antifungal activity of compounds 2aeg, 3aeg, 4aed, 5, 7aeh and 11aeb expressed as MIC (
m
g/mL).
Pa
Compounds
Gram-positive organismsa
Gram-negative organismsb
Fungic
Sa
Sf
Bs
Kp
Ec
Sc
Ct
An
2a
2b
2c
2d
2e
2f
2g
3a
3b
3c
3d
3e
3f
3g
4a
4b
4c
4d
5
7a
7b
7c
7d
7e
7f
7g
7h
8
125
16
8
62.5
125
125
125
31.25
31.25
16
31.25
8
62.5
125
16
62.5
125
62.5
125
16
31.25
31.25
16
125
31.25
4
31.25
8
125
31.25
31.25
16
31.25
31.25
4
62.5
125
31.25
125
62.5
125
31.25
31.25
16
62.5
31.25
8
31.25
8
125
8
16
16
16
125
8
16
62.5
8
8
62.5
16
62.5
62.5
16
16
16
125
31.25
31.25
31.25
62.5
31.25
31.25
16
125
31.25
16
125
125
8
62.5
31.25
16
31.25
125
16
31.25
62.5
125
62.5
125
16
62.5
62.5
31.25
62.5
31.25
8
62.5
125
31.25
16
31.25
31.25
62.5
125
31.25
125
31.25
31.25
31.25
125
8
16
31.25
16
125
62.5
62.5
62.5
62.5
31.25
16
62.5
125
16
125
31.25
8
31.25
31.25
16
31.25
31.25
62.5
16
31.25
62.5
62.5
16
16
31.25
125
62.5
62.5
31.25
4
31.25
62.5
31.25
62.5
31.25
62.5
16
62.5
125
62.5
31.25
16
62.5
62.5
16
62.5
62.5
31.25
4
31.25
250
125
62.5
31.25
62.5
31.25
125
62.5
31.25
16
31.25
16
31.25
4
16
16
31.25
125
125
8
16
62.5
125
16
16
125
16
8
16
125
8
8
125
31.25
31.25
62.5
125
31.25
31.25
62.5
31.25
31.25
31.25
e
62.5
31.25
8
16
31.25
16
4
8
16
4
8
125
125
62.5
62.5
125
62.5
62.5
31.25
e
31.25
125
16
62.5
62.5
31.25
62.5
31.25
31.25
16
125
125
16
62.5
31.25
31.25
16
62.5
125
31.25
125
125
31.25
31.25
ꢂ1
31.25
31.25
16
16
16
16
125
62.5
62.5
31.25
ꢂ5
62.5
31.25
16
62.5
e
11a
11b
Ciprofloxacin
Norfloxacin
Flucanozole
31.25
ꢂ1
16
ꢂ5
ꢂ1
ꢂ5
ꢂ5
ꢂ5
ꢂ1
ꢂ1
ꢂ1
ꢂ5
e
e
e
e
e
e
e
e
e
ꢂ1
ꢂ1
ꢂ1
a
The screening organisms. Gram-positive bacteria: Staphylococcus aureus (ATCC 11632, Sa), Streptococus faecalis (ATCC 14506, Sf), and Bacillus subtilis (ATCC 60511, Bs).
The screening organisms. Gram-negative bacteria: Klebsiella penumoniae (ATCC 10031, Kp), Escherichia coli (ATCC 10536, Ec), and Pseudomonas aeruginosa (ATCC 10145,
b
Pa).
c
The screening organisms. Yeasts: Saccharomyces cerevisiae (ATCC 9763, Sc) and Candida tropicalis (ATCC 1369, Ct), mould: Aspergillus niger (ATCC 6275, An).

G.V. Suresh Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 5120e5129
5123
4. Results and discussion
4
250µM
200µM
150µM
100µM
50µM
The results of antimicrobial testing of synthesized compounds
against selected gram þve, gram ꢃve bacteria, yeasts, moulds and
M. tuberculosis H37Rv are illustrated in Tables 2 and 3 respectively.
The prepared compounds 2aeg, 3aeg, 4aed, 5, 8 and 11aeb
exhibited interesting trends in Structure Activity Relationship (SAR)
studies. The linkage between NH2 and SH groups depicted
moderate antimicrobial activity (3aeg), whereas the aforemen-
tioned moieties linked through methylene spacer (2aeg) exhibited
significant activity against both Gram-positive and gram-negative
strains. Interestingly, compound 2c comprising p-methoxy substi-
tution demonstrated improved antimicrobial activity against tested
bacterial and fungal species and excellent activity against
3
2
1
0
Treatment
M. tuberculosis H37Rv at MIC 4 mg/mL.
Fig. 1. Cytotoxic activity of compounds 2c, 3e, 4d, 7c and 7d tested in A549 cells by MTT
assay. The bars reflect the viable cells in each treatment. Cells represents, cells alone
without any treatment, DMSO denote the vehicle control. The experiment was done in
duplicate with triplicate readings of each experiment.
The SAR studies and antimicrobial activity of thiadiazole series
3aeg illustrate compound 3e comprising di fluoro substitution
exhibited excellent inhibition against M. tuberculosis H37Rv
compared to its antifungal inhibition, this increased activity is
attributed to presence of fluorine atoms (highly electro negative) in
the molecule which increases the lipophilicity and affects the par-
titioning of a molecule into membranes and facilitates hydrophobic
interactions of the molecule with specific binding sites on either
receptor or enzymes [22e24]. Compound 3g comprising electron
withdrawing nitro group showed increased antifungal inhibition,
but loss of activity against tested bacterial species. Although,
compounds 3a and 3f which are having inductively electron
withdrawing but mesomerically electron donating substituent’s on
phenyl group were found to be less active compounds against the
tested microorganisms.
substituted benzamide derivatives 4aed, it was ascertained that
the compounds were more effective against tested gram -ve
bacteria and antifungal species compared to gram þve bacteria.
Particularly, compound 4d comprising para-methoxy (electron
withdrawing) substitution exhibited excellent inhibition at MIC
4e16
m
g/mL against tested gram ꢃve bacteria. This excellent inhi-
bition of compound 4d is attributed to participation of the free
electron pairs on the oxygen by resonance and increased electron
density in the aromatic system. In contrarily compound 4b con-
taining electron donating para-methyl substitution exhibited loss of
activity.
The Mannich bases 7aeh exhibited varying degrees of inhibition
against the tested microorganisms. The presence of N-methyl-
piperazine moiety was found instrumental in contributing to the
net biological activity of system and to increase antimicrobial
activity of parent compound. Compounds 7c and 7d showed
comparatively good activity against all tested microbial strains and
excellent inhibition towards M. tuberculosis H37Rv at MIC 4 and
Comparing the antimicrobial activity of the synthesized 3-(4-
isopropylthiazol-2-yl)-5-thioxo-1H-1,2,4-triazol-4(5H)-yl
Table 3
Comparison of in vitro antimycobacterial activity of compounds
2aeg, 3aeg, 4aed, 5, 7aeh and 11aeb against drug-sensitive
Mycobacterium tuberculosis H37Rv strain.
8
m
g/mL respectively. Compounds 7b and 7g possessing para-
methoxy and para-di methyl amino substitution exhibited moderate
activity at MIC 8e31.25 g/mL. Compounds having oxadiazole rings
11a and 11b exhibited good to moderate antimicrobial activity at
16e62.5 g/mL.
The most active antitubercular compounds 2c, 3e, 4d, 7c and 7d
were tested for their cytotoxic potential using A549 (lung adeno-
carcinoma) cell lines in the presence of fetal bovine serum. As
shown in Fig. 1 compound 3e showed maximum cytotoxicity at the
Compound
MIC values (mg/mL) of
M. tuberculosis H37Rv
m
2a
2b
2c
2d
2e
2f
2g
3a
3b
3c
3d
3e
3f
3g
4a
4b
4c
4d
5
7a
7b
7c
7d
7e
7f
125
16
4
125
16
31.25
62.5
62.5
31.25
4
62.5
4
125
62.5
16
m
concentration of 250
mM. The other compounds 2c, 4d, 7c and 7d
showed appreciable cytotoxicity of about 50% of the vehicle control
at a concentration of 250 mM.
5. Conclusion
31.25
62.5
16
31.25
31.25
16
In conclusion, this work demonstrates the synthesis of series of
novel clubbed Isopropylthiazole derivatives triazolothiadiazines,
dihydro triazolothiadiazoles, thioxotriazoles, triazolothiadiazoles,
arylideneamino triazolethiones, oxadiazolethiones and in vitro
evaluation of antimicrobial (bacterial and fungal) and antituber-
cular activity against H37Rv strain. Antimicrobial study revealed
that compounds 2c, 4d and 7b demonstrated significant activity
against tested gram þve and gram ꢃve bacteria and fungal species.
The in vitro antituberculosis screening of these series showed that
all compounds were active, in particular compounds 7c and 7d
4
8
31.25
31,25
16
31.25
31.25
16
7g
7h
8
11a
11b
Isoniazid
exhibited excellent antitubercular activity at MIC 4 and 8 mg/mL
respectively, when compared with first line drug such as Isoniazid.
The promising in vitro antimicrobial activity and low-toxicity
31.25
0.25

5124
G.V. Suresh Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 5120e5129
profile of clubbed Isopropylthiazole class of compounds make them
certain promising molecules for further lead optimization in the
development of novel antimycobacterial agents.
1H NMR (DMSO-d6, 300 MHz)
d: 7.4e7.9 (4H, Ar-H), 7.31 (s, 1H,
thiazole-C5), 3.74 (s, 3H, OCH3 at C4-phenyl), 3.25 (m, 1H, iso-
propyl), 3.11(s, 2H, C6 thiadiazine), 1.12 (d, J ¼ 8.5 Hz, 6H, terminal
2CH3 of isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 165.58 (C5-thiadiazine), 163.54
6. Experimental
(thiazole-C5), 142.44 (triazole-C5), 133.81 (C4-phenyl), 133.25 (C1-
phenyl),128.25 (phenyl C3 and C5), 126.87 (phenyl C2 and C6),111.34
(thiazole-C2), 55.94 (OCH3 at C4-phenyl), 35.25 (C6-thiadiazine),
32.11 (tertiary-1C-isopropyl), 21.55 (terminal 2CH3-isopropyl) ppm.
MS (%) 371.48 (100.0%), 372.09 (20.2%), 373.08 (9.1%), 374.09
(1.8%).
6.1. Chemical protocols
Melting points were determined in open capillary tubes in
a Thomas Hoover melting point apparatus and are uncorrected.
Infrared spectra were recorded on Shimadzu FT-IR 157, 1H NMR and
13C NMR spectra were recorded (in CDCl3/DMSO-d6) on a Bruker
spectrometer at 300/400 MHz using TMS as an internal standard.
Mass spectra (EI) on (AMD-604) mass spectrometer operating at
70 eV. Elemental analysis was performed on Thermo Finnigan Flash
(EA 1112 CHNS Analyzer).
Thin layer chromatography (TLC) was performed throughout the
reaction on Merck silica gel GF254 aluminium sheets using mixture
of different polar and nonpolar solvents in varying proportions and
spots were observed using iodine as visualizing agent.
6.1.1.4. 4-(3-(4-Isopropylthiazol-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazin-6-yl)phenol (2d). IR (KBr)
CeH), 1616 (C]N), 1274 (NeN]C), 677 (CeSeC).
1H NMR (DMSO-d6, 300 MHz)
: 7.4e7.9 (4H, Ar-H), 7.25 (s, 1H,
n
max, cmꢃ1: 3078 (aromatic
d
thiazole-C5), 5.02 (s, OH at C4-phenyl) 3.91 (s, 2H, C6 thiadiazine),
3.40 (m, 1H, isopropyl), 1.39 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of
isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 165.21 (C5-thiadiazine), 163.54
(thiazole-C5), 143.02 (triazole-C5), 133.58 (C4-phenyl), 133.51 (C1-
phenyl), 128.58 (phenyl C3 and C5), 126.11 (phenyl C2 and C6), 111.02
(thiazole-C2), 35.64 (C6-thiadiazine), 32.45 (tertiary-1C-isopropyl),
21.79 (terminal 2CH3-isopropyl)ppm.
6.1.1. General procedure for the synthesis of 3-(4-isopropylthiazol-
2-yl)-6-substituted-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines
(2aeg)
MS (%) 357.45 (100.0%), 238.02 (17.5%), 152.05 (1.7%).
A mixture of triazole 1 (1.0 mmol) and substituted phenacyl
bromide (1.2 mmol) in 15 ml of absolute ethanol and sodium
acetate was refluxed for 6e7 h. The reaction mixture was cooled
and slowly quenched onto crushed ice with stirring and neutralized
with solid sodium bicarbonate. The solid which separated after
standing overnight was filtered, washed with cold water, dried and
recrystallized.
6.1.1.5. 6-(4-chlorophenyl)-3-(4-isopropylthiazol-2-yl)-7H-[1,2,4]tri-
azolo[3,4-b][1,3,4]thiadiazine (2e). IR (KBr)
(aromatic CeH), 1613 (C]N), 1232 (NeN]C), 674 (CeSeC).
1H NMR (DMSO-d6, 300 MHz)
: 8.4e7.9 (4H, Ar-H), 7.02 (s, 1H,
n
max, cmꢃ1: 3085
d
thiazole-C5), 3.97 (s, 2H, C6 thiadiazine), 3.25 (m, 1H, isopropyl),
1.25 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 165.74 (C5-thiadiazine), 163.24
6.1.1.1. 3-(4-Isopropylthiazol-2-yl)-6-phenyl-7H-[1,2,4]triazolo[3,4-
(thiazole-C5), 143.09 (triazole-C5), 133.24 (C4-phenyl), 131.51 (C1-
phenyl),128.26 (phenyl C3 and C5), 126.58 (phenyl C2 and C6),111.02
(thiazole-C2), 32.56 (tertiary-1C-isopropyl), 35.21 (C6-thiadiazine),
21.11 (terminal 2CH3-isopropyl) ppm.
b][1,3,4]thiadiazine (2a). IR (KBr)
CeH), 1619 (C]N), 1237 (NeN]C), 684 (CeSeC).
1H NMR (DMSO-d6, 300 MHz)
: 7.4e7.9 (5H, Ar-H), 7.71 (s, 1H,
n
max, cmꢃ1: 3087 (aromatic
d
thiazole-C5), 3.26 (m, 1H, isopropyl), 3.06 (s, 2H, C6 thiadiazine),
MS (%) 375.9 (100.0%), 377.03 (41.0%), 376.03 (3.2%), 376.03
(1.8%), 378.03 (1.3%).
1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 165.43 (C5-thiadiazine), 162.48
(thiazole-C5),145.24 (triazole-C5),135.76 (C6-thiadiazine),133.65 (C4-
phenyl),131.76 (C1-phenyl), 129.11 (phenyl C3 and C5),127.87 (phenyl
C2 and C6), 112.20 (thiazole-C2), 32.49 (tertiary-1C-isopropyl), 21.34
(terminal 2CH3-isopropyl) ppm.
6.1.1.6. 3-(4-Isopropylthiazol-2-yl)-6-(4-nitrophenyl)-7H-[1,2,4]tri-
azolo[3,4-b][1,3,4]thiadiazine (2f). IR (KBr)
(aromatic CeH), 1614 (C]N), 1236 (NeN]C), 674 (CeSeC).
1H NMR (DMSO-d6, 300 MHz)
: 7.4e7.9 (4H, Ar-H), 7.58 (s, 1H,
n
max, cmꢃ1: 3097
d
MS (%) 341.45 (100.0%), 342.08 (19.1%), 343.07 (9.1%), 342.07
(1.8%), 344.08 (1.6%).
thiazole-C5), 3.43 (m, 1H, isopropyl), 3.31 (s, 2H, C6 thiadiazine),
1.25 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 164.35 (C5-thiadiazine), 163.11
6.1.1.2. 3-(4-Isopropylthiazol-2-yl)-6-p-tolyl-7H-[1,2,4]triazolo[3,4-
(thiazole-C5), 143.12 (triazole-C5), 133.58 (C1-phenyl), 133.26 (C4-
phenyl), 128.14 (phenyl C3 and C5), 126.00 (phenyl C2 and C6), 111.18
(thiazole-C2), 38.61 (C6-thiadiazine), 32.55 (tertiary-1C-isopropyl),
21.21 (terminal 2CH3-isopropyl), ppm.
b][1,3,4]thiadiazine (2b). IR (KBr)
CeH), 1617 (C]N), 1266 (NeN]C), 689 (CeSeC).
1H NMR (DMSO-d6, 300 MHz)
: 7.4e7.9 (4H, Ar-H), 7.23 (s, 1H,
n
max, cmꢃ1: 3075 (aromatic
d
thiazole-C5), 3.26 (m, 1H, isopropyl), 3.11 (s, 2H, C6 thiadiazine),
2.56 (s, 3H, CH3 at C4-phenyl), 1.24 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3
of isopropyl) ppm.
MS (%) 386.4 (100.0%), 377.03 (41.0%), 378.04 (7.2%), 379.03
(3.2%).
13C NMR (DMSO-d6, 300 MHz)
d: 165.43 (C5-thiadiazine), 163.43
6.1.1.7. 6-(4-bromophenyl)-3-(4-isopropylthiazol-2-yl)-7H-[1,2,4]tri-
(thiazole-C5), 144.43 (triazole-C5), 135.76 (C1-phenyl), 133.63 (C4-
phenyl), 128.43 (phenyl C3 and C5), 126.11 (phenyl C2 and C6), 111.48
(thiazole-C2), 35.43 (C6-thiadiazine), 32.43 (tertiary-1C-isopropyl),
24.16 (CH3 at C4-phenyl), 21.43 (terminal 2CH3-isopropyl) ppm.
MS (%) 355.48 (100.0%), 356.10 (18.6%), 357.09 (9.4%), 356.09
(3.4%).
azolo[3,4-b][1,3,4]thiadiazine (2g). IR (KBr)
(aromatic CeH), 1613 (C]N), 1233 (N-N]C), 679 (CeSeC).
1H NMR (DMSO-d6, 300 MHz)
: 7.4e7.9 (4H, Ar-H), 7.65 (s, 1H,
n
max, cmꢃ1: 3092
d
thiazole-C5), 3.43 (s, 2H, C6 thiadiazine), 3.22 (m, 1H, isopropyl),
1.22 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 165.74 (C5-thiadiazine), 163.11
(thiazole-C5), 143.05 (triazole-C5), 111.17 (thiazole-C2), 128.24
(phenyl C3 and C5), 126.54 (phenyl C2 and C6), 133.24 (C4-phenyl),
131.51 (C1-phenyl), 32.95 (tertiary-1C-isopropyl), 35.21 (C6-thia-
diazine), 21.11 (terminal 2CH3-isopropyl), ppm.
6.1.1.3. 3-(4-Isopropylthiazol-2-yl)-6-(4-methoxyphenyl)-7H-[1,2,4]
triazolo[3,4-b][1,3,4] thiadiazine (2c). IR (KBr)
(aromatic CeH), 1615 (C]N), 1268 (NeN]C), 683 (CeSeC).
n
max, cmꢃ1: 3086

G.V. Suresh Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 5120e5129
5125
MS (%) 418.99 (100.0%), 420.99 (99.3%), 422.98 (9.1%), 423.98
(1.8%).
cmꢃ1: 3370 (NH stretching), 3052 (aromatic CH stretching), 1612
(C]N stretching), 1589, 1536 (C]C ring stretch).
1H NMR (DMSO-d6, 300 MHz)
d: 7.71 (s, 1H, thiazole-C5), 6.1 (2H,
6.1.2. General procedure for the synthesis of 3-(4-isopropylthiazol-
2-yl)-6-substituted 5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazoles (3aeg)
Ar-H), 4.91(s, 1H, NHeCHeS), 3.81(s, 9H, 3OCH3), 3.26 (m, 1H,
isopropyl), 2.11(s, 1H, NeNH), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3
of isopropyl) ppm.
An equimolecular mixture of triazole (0.02 mol) 1 and appro-
priate aldehyde (0.02 M), dry DMF (30 ml) and a catalytic amount
of p-toluenesulphonic acid (10 mg) was taken in a round bottom
flask. The mixture was refluxed for about 10e12 h, concentrated to
half of its volume and cooled to room temperature. The cooled
mixture was poured gradually onto crushed ice cubes with stirring.
The mixture was allowed to stand and solid was separated. It was
filtered, washed thoroughly with cold water, dried and
recrystallized.
13C NMR (DMSO-d6, 300 MHz)
d: 165.48 (thiazole-C4), 152.20
(thiazole-C2), 148.27(C3 of triazole), 145.24 (triazole-C5), 115e135
(phenyl C1 to C6), 115.48 (thiazole-C5), 56.83(3OCH3), 53.4
(NHeCeS), 32.49 (tertiary-1C-isopropyl), 21.34 (terminal 2CH3-
isopropyl) ppm.
MS (%) 419.51 (100.0%), 420.11 (23.3%), 421.10 (9.1%), 422.11
(1.9%).
6.1.2.5. 6-(2,4-difluorophenyl)-3-(4-isopropylthiazol-2-yl)-5,6-dihy-
dro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (3e). IR (KBr)
n max,
6.1.2.1. 3-(4-Isopropylthiazol-2-yl)-6-(2-chlorophenyl)-5,6-dihydro-
cmꢃ1: 3370 (NH stretching), 3055 (aromatic CH stretching), 1619
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (3a). IR (KBr)
n
max, cmꢃ1
:
(C]N stretching), 1589, 1539 (C]C ring stretch).
3370 (NH stretching), 3056 (aromatic CH stretching), 1618 (C]N
stretching), 1580, 1535 (C]C ring stretch).
1H NMR (DMSO-d6, 300 MHz)
d: 7.71 (s,1H, thiazole-C5), 6.6e6.9
(3H, Ar-H), 4.91(s, 1H, NHeCHeS), 3.26 (m, 1H, isopropyl), 2.11(s,
1H, NeNH), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of isopropyl) ppm.
1H NMR (DMSO-d6, 300 MHz)
d: 7.71e7.78 (4H, Ar-H), 7.71 (s,
1H, thiazole-C5), 4.91(s, 1H, NHeCHeS), 3.26 (m, 1H, isopropyl),
2.11(s, 1H, NeNH), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of iso-
propyl)ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 165.48 (thiazole-C4), 152.20
(thiazole-C2), 148.25(C3 of triazole), 145.24 (triazole-C5), 115e135
(phenyl C1 to C6), 115.48 (thiazole-C5), 53.42(NHeCeS), 32.49
(tertiary-1C-isopropyl), 21.34 (terminal 2CH3-isopropyl) ppm.
MS (%) 365.06 (100.0%), 366.06 (19.8%), 367.05 (9.1%), 368.06
(1.5%).
13C NMR (DMSO-d6, 300 MHz)
d: 165.48 (thiazole-C4), 152.20
(thiazole-C2), 141e105 (phenyl C1 to C6), 148.2 (C3 of triazole),
145.24 (triazole-C5), 115.48 (thiazole-C5), 53.4(NHeCeS), 32.49
(tertiary-1C-isopropyl), 21.34 (terminal 2CH3-isopropyl) ppm.
MS (%) 363.04 (100.0%), 365.03 (41.0%), 364.04 (18.0%), 366.04
(6.8%), 367.03 (3.2%).
6.1.2.6. 3-(3-(4-Isopropylthiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazol-6-yl)phenol (3f). IR (KBr) n
max, cmꢃ1: 3377
(NH stretching), 3053 (aromatic CH stretching), 1612 (C]N
stretching), 1586, 1532 (C]C ring stretch).
6.1.2.2. 3-(4-Isopropylthiazol-2-yl)-6-(4-methoxyphenyl)-5,6-dihy-
dro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (3b). IR (KBr)
n
max,
1H NMR (DMSO-d6, 300 MHz)
d: 7.71 (s, 1H, thiazole-C5), 6.6e7.9
cmꢃ1: 3374 (NH stretching), 3052 (aromatic CH stretching), 1612
(4H, Ar-H), 5.11(s, 1H, OH), 4.91(s, 1H, NHeCHeS), 3.26 (m, 1H,
isopropyl), 2.11(s, 1H, NeNH), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3
of isopropyl) ppm.
(C]N stretching), 1578, 1531 (C]C ring stretch).
1H NMR (DMSO-d6, 300 MHz)
d: 7.71e7.78 (4H, Ar-H), 7.71
(s, 1H, thiazole-C5), 4.91(s, 1H, NHeCHeS), 3.73(s, 3H, OCH3), 3.26
(m, 1H, isopropyl), 2.15(s, 1H, NeNH), 1.27 (d, J ¼ 8.5 Hz, 6H,
terminal 2CH3 of isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 165.48 (thiazole-C4), 152.20
(thiazole-C2), 148.2 (C3 of triazole), 145.24 (triazole-C5), 115e135
(phenyl C1 to C6), 115.48 (thiazole-C5), 53.43(NHeCeS), 32.49
(tertiary-1C-isopropyl), 21.34 (terminal 2CH3-isopropyl), ppm.
MS (%) 345.44 (100.0%), 347.07 (9.6%), 348.07 (1.6%).
13C NMR (DMSO-d6, 300 MHz)
d: 165.48 (thiazole-C4), 152.20
(thiazole-C2), 148.2(C3 of triazole), 145.44 (triazole-C5), 115e135
(phenyl C1 to C6), 115.48 (thiazole-C5), 55.82(OCH3), 53.9(NHeCeS),
32.49 (tertiary-1C-isopropyl), 21.34 (terminal 2CH3-isopropyl),
ppm.
6.1.2.7. 3-(4-Isopropylthiazol-2-yl)-6-(4-nitrophenyl)-5,6-dihydro-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (3g). IR (KBr)
n :
max, cmꢃ1
MS (%) 359.09 (100.0%), 360.09 (19.1%), 361.08 (9.1%), 362.09
(1.6%).
3375 (NH stretching), 3057 (aromatic CH stretching), 1613 (C]N
stretching), 1586, 1530 (C]C ring stretch).
1H NMR (DMSO-d6, 300 MHz)
d: 7.3e8.4 (4H, Ar-H), 7.71 (s, 1H,
6.1.2.3. 4-(3-(4-Isopropylthiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo
thiazole-C5), 4.91(s, 1H, NHeCHeS), 3.26 (m, 1H, isopropyl), 2.11(s,
1H, NeNH), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of isopropyl),
ppm.
[3,4-b][1,3,4]thiadiazol-6-yl)-N,N-dimethylbenzenamine
(KBr)
max, cmꢃ1: 3377 (NH stretching), 3058 (aromatic CH
stretching), 1615 (C]N stretching), 1582, 1537 (C]C ring stretch).
1H NMR (DMSO-d6, 300 MHz)
: 7.71 (s,1H, thiazole-C5), 6.3e6.8
(3c). IR
n
13C NMR (DMSO-d6, 300 MHz)
d: 165.48 (thiazole-C4), 152.20
d
(thiazole-C2), 148.2(C3 of triazole), 145.24 (triazole-C5), 115e135
(phenyl C1 to C6), 115.48 (thiazole-C5), 53.4(NHeCeS), 32.49
(tertiary-1C-isopropyl), 21.34 (terminal 2CH3-isopropyl) ppm.
MS (%) 374.44 (100.0%), 375.07 (16.5%), 376.06 (9.7%), 377.06
(1.6%).
(4H, Ar-H), 4.91(s, 1H, NHeCHeS), 3.26 (m, 1H, isopropyl), 2.81(s,
6H, Ne(CH3)2), 2.13(s, 1H, NeNH), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal
2CH3 of isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 165.48 (thiazole-C4), 152.20
(thiazole-C2), 148.24 (C3 of triazole), 145.24 (triazole-C5), 115e135
(phenyl C1 to C6), 115.48 (thiazole-C5), 53.42(NHeCeS), 40.34
(N-(CH3)2), 32.49 (tertiary-1C-isopropyl), 21.34 (terminal 2CH3-
isopropyl) ppm.
6.1.3. General procedure for the synthesis of 3-(4-isopropylthiazol-
2-yl)-5-thioxo-1H-(1,2,4-triazol-4(5H)-yl) substituted benzamides
(4aed)
MS (%) 372.12 (100.0%), 373.12 (22.2%), 374.11 (9.1%), 375.12
(1.7%).
The triazole 1 (0.01 mol) in 20 mL of 10% NaOH was treated
dropwise with an equimolar amount of the substituted benzoyl
chloride at 0 ꢀC, which was stirred for 30e45 min. At the end of
stirring, obtained precipitate was filtered, washed thoroughly with
water and recrystallized.
6.1.2.4. 3-(4-Isopropylthiazol-2-yl)-6-(3,4,5-trimethoxyphenyl)-5,6-
dihydro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (3d). IR (KBr) n max,

5126
G.V. Suresh Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 5120e5129
6.1.3.1. 3-(4-Isopropylthiazol-2-yl)-5-thioxo-1H-(1,2,4-triazol-4
(5H)-yl)benzamide (4a). IR (KBr)
max, cmꢃ1: 3049 (aromatic CH
stretching), 3257 (NH), 1694 (C]O).
1H NMR (DMSO-d6, 300 MHz)
: 13.59 (s, 1H, N]CeSH), 8.23 (s,
IR (KBr)
1587, 1543 and 1432 (C]N stretching).
1H NMR (DMSO-d6, 300 MHz)
: 13.50 (s, eSH), 7.71 (s, 1H,
n
max, cmꢃ1: 3375 (NH stretching), 2598 (eSH), 1608,
n
d
d
thiazole-C5), 3.26 (m, 1H, isopropyl), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal
1H, NeNH), 7.7e7.8 (5H, Ar-H), 7.71 (s, 1H, thiazole-C5), 3.26 (m, 1H,
isopropyl), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of isopropyl) ppm.
2CH3 of isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 223.4(CeSH), 165.48 (thiazole-
13C NMR (DMSO-d6, 300 MHz)
d: 184.12 (C]S of triazole),
C4), 152.20 (thiazole-C2), 148.2(C3 of triazole), 145.24 (triazole-C5),
115.48 (thiazole-C5), 32.49 (tertiary-1C-isopropyl), 21.34 (terminal
2CH3-isopropyl) ppm.
165.48 (thiazole-C4), 164.12 (C]O), 120e140 (phenyl C1 to C6),
115.48 (thiazole-C5), 152.20 (thiazole-C2), 145.24 (triazole-C5),
32.49 (tertiary-1C-isopropyl), 21.34 (terminal 2CH3-isopropyl)
ppm.
MS (%) 283.00 (100.0%), 285.00 (14.0%), 284.01 (9.8%).
MS (%) 345.07 (100.0%), 346.08 (15.1%), 348.07 (1.6%), 347.08
(1.5%).
6.1.5. General procedure for the synthesis of 4-(substituted
benzylideneamino)-5-(4-isopropylthiazol-2-yl)-2-substituted-2H-
1,2,4-triazole-3(4H)-thione (7aeh)
The appropriate compounds 6aed (10 mmol) was dissolved in
a mixture of ethanol and dioxane (2:1). Then, formaldehyde (40%,
1.5 ml) and suitable cyclic amine (10 mmol) in ethanol was added to
the solution. The mixture was stirred for 2e3 h and kept overnight
at room temperature. The resulting solid that separated was
collected by filtration, washed with ethanol and recrystalised.
6.1.3.2. 3-(4-Isopropylthiazol-2-yl)-5-thioxo-1H-(1,2,4-triazol-4
(5H)-yl)-4-methylbenzamide (4b). IR (KBr)
(aromatic CH stretching), 3248 (NH), 1691 (C]O).
1H NMR (DMSO-d6, 300 MHz)
: 13.59 (s, 1H, N]CeSH), 8.23 (s,
n
max, cmꢃ1: 3040
d
1H, NeNH), 7.7e7.8 (4H, Ar-H), 7.71 (s, 1H, thiazole-C5), 3.26 (m, 1H,
isopropyl), 2.32 (m, 3H, eCH3), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3
of isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 184.12 (C]S of triazole),
6.1.5.1. 4-(2-chlorobenzylideneamino)-5-(4-isopropylthiazol-2-yl)-2-
((4-methylpiperazin-1-yl)methyl)-2H-1,2,4-triazole-3(4H)-thione
165.48 (thiazole-C4), 164.12 (C]O), 152.20 (thiazole-C2), 145.24
(triazole-C5), 120e140 (phenyl C1 to C6), 115.48 (thiazole-C5), 32.49
(tertiary-1C-isopropyl), 24.15 (CH3), 21.34 (terminal 2CH3-iso-
propyl) ppm.
MS (%) 359.09 (100.0%), 360.09 (16.1%), 361.08 (7.1%), 362.09
(1.4%).
(7a). IR (KBr) n
max, cmꢃ1: 3087 (aromatic CeH), 2949 (CH2), 1618
(CH]N), 1243 (C]S), 1179 (NeCH2eN), 1065 (CH2eOeCH2), 1042
(NeN).
1H NMR (DMSO-d6, 300 MHz)
d: 10.12 (s, 1H, N]CH), 7.4e7.9
(4H, Ar-H), 7.71 (s, 1H, thiazole-C5), 4.52 (s, 2H, NeCH2eN), 3.26 (m,
1H, isopropyl), 3.00 (t, 4H, CH2eNeCH2), 2.68 (t, 4H, CH2eNeCH2),
2.46 (s, 3H, NeCH3 of piperazine), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal
2CH3 of isopropyl), ppm.
6.1.3.3. 4-Hydroxy-N-(3-(4-isopropylthiazol-2-yl)-5-thioxo-1H-
1,2,4-triazol-4(5H)-yl)benzamide (4c). IR (KBr)
(aromatic CH stretching), 3251 (NH), 1696 (C]O).
1H NMR (DMSO-d6, 300 MHz)
: 13.59 (s, 1H, N]CeSH), 7.62 (s,
n
max, cmꢃ1: 3043
13C NMR (DMSO-d6, 300 MHz)
d: 184.12 (C]S of triazole),
d
165.48 (thiazole C4), 152.20 (thiazole-C2), 145.24 (triazole-C5),
134.12 (s, 1H, N]CH), 120e140 (phenyl C1 to C6), 115.48 (thiazole-
C5), 61.1 (NeCH2eN), 54.9 (piperazine C3 and C5), 50.4 (piperazine
C2 and C6), 44.9 (piperazine NeCH3), 32.49 (tertiary-1C-isopropyl),
21.34 (terminal 2CH3-isopropyl) ppm.
1H, thiazole-C5), 8.23 (s, 1H, NeNH), 7.7e7.8 (4H, Ar-H), 5.21 (s, 1H,
eOH), 3.26 (m, 1H, isopropyl), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3
of isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 184.12 (C]S of triazole),
165.48 (thiazole-C4), 164.12 (C]O), 152.20 (thiazole-C2), 145.24
(triazole-C5), 120e140 (phenyl C1 to C6), 115.48 (thiazole-C5), 32.49
(tertiary-1C-isopropyl), 21.34 (terminal 2CH3-isopropyl) ppm.
MS (%) 361.44 (100.0%), 362.07 (18.1%), 363.07 (2.2%), 364.07
(1.6%).
MS (%) 475.14 (100.0%), 477.14 (35.4%), 113.04 (9.6%), 479.13
(3.2%), 478.13 (1.6%).
6.1.5.2. 4-(4-methoxybenzylideneamino)-5-(4-isopropylthiazol-2-
yl)-2-((4-methylpiperazin-1-yl)methyl)-2H-1,2,4-triazole-3(4H)-thi-
one (7b). IR (KBr)
n
max, cmꢃ1: 3092 (aromatic CeH), 2954 (CH2),
6.1.3.4. 3-(4-Isopropylthiazol-2-yl)-5-thioxo-1H-(1,2,4-triazol-4
1608 (CH]N), 1227 (C]S), 1179 (NeCH2eN), 1072 (CH2eOeCH2),
1022 (NeN).
(5H)-yl)-4-methoxybenzamide (4d). IR (KBr)
(aromatic CH stretching), 3255 (NH), 1692 (C]O).
1H NMR (DMSO-d6, 300 MHz)
: 13.59 (s, 1H, N]CeSH), 8.23 (s,
n
max, cmꢃ1: 3045
1H NMR (DMSO-d6, 300 MHz)
d: 8.12 (s,1H, N]CH), 7.4e7.9 (4H,
d
Ar-H), 7.71 (s, 1H, thiazole-C5), 4.56 (s, 1H, NeCH2eN), 3.74 (s, 3H,
OCH3 at C4-phenyl), 3.26 (m, 1H, isopropyl), 3.12 (t, 4H,
CH2eNeCH2), 2.74 (t, 4H, CH2eNeCH2), 2.46 (s, 3H, NeCH3 of
piperazine),1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of isopropyl) ppm.
1H, NeNH), 7.7e7.8 (4H, Ar-H), 7.71 (s, 1H, thiazole-C5), 3.71 (s, 1H,
eOCH3), 13.26 (m, 1H, isopropyl), 21.7 (d, J ¼ 8.5 Hz, 6H, terminal
2CH3 of isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 184.12 (C]S of triazole),
13C NMR (DMSO-d6, 300 MHz)
d: 184.12 (C]S of triazole),
165.48 (thiazole-C4), 164.12 (C]O), 115.48 (thiazole-C5), 152.20
(thiazole-C2), 145.24 (triazole-C5), 120e140 (phenyl C1 to C6), 55.15
(eOCH3), 32.49 (tertiary-1C-isopropyl), 21.34 (terminal 2CH3-iso-
propyl) ppm.
MS (%) 375.08 (100.0%), 376.09 (14.6%), 377.08 (7.4%), 377.09
(1.1%).
165.48 (thiazole-C4), 152.20 (thiazole-C2), 145.24 (triazole-C5),
120e140 (phenyl C1 to C6), 134.12 (s, 1H, N]CH), 115.48 (thiazole-
C5), 63.1 (NeCH2eN), 55.9 (OCH3 at C4-phenyl), 50.4 (piperazine C2
and C6), 44.9 (piperazine NeCH3), 44.1 (piperazine C3 and C5), 32.49
(tertiary-1C-isopropyl), 21.34 (terminal 2CH3-isopropyl) ppm.
MS (%) 471.19 (100.0%), 472.19 (25.8%), 113.0 (9.6%), 473.19
(3.9%), 472.18 (2.6%), 474.19 (2.3%).
6.1.4. General preparation of 3-(4-isopropylthiazol-2-yl)-[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazole-6(5H)-thione (5)
6.1.5.3. 4-(4-(dimethylamino)benzylideneamino)-5-(4-iso-
Carbon disulfide (0.015 mol) was added dropwise with constant
stirring to the solution of 1 (0.01 mol) in methanolic potassium
hydroxide. Refluxed for 6-7h, mixture was cooled and then product
was extracted with dry methanol, which was then poured onto ice
and acidified with dil. hydrochloric acid and recrystalized.
propylthiazol-2-yl)-2-((4-methylpiperazin-1-yl)methyl)-2H-1,2,4-tri-
azole-3(4H)-thione (7c). IR (KBr)
n
max, cmꢃ1: 3092 (aromatic
CeH), 2954 (CH2), 1608 (CH]N), 1227 (C]S), 1179 (NeCH2eN),
1072 (CH2eOeCH2), 1022 (NeN).

G.V. Suresh Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 5120e5129
5127
1H NMR (DMSO-d6, 300 MHz)
d
: 8.12 (s, 1H, N]CH), 7.4e7.9 (4H,
MS (%) 458.16 (100.0%), 459.16 (24.7%), 460.15 (9.1%), 459.15
(2.2%).
Ar-H), 7.71 (s, 1H, thiazole-C5), 4.55 (s, 2H, NeCH2eN), 3.26 (m, 1H,
isopropyl), 3.15 (t, 4H, CH2eNeCH2), 2.84(s, 6H, N(CH3)2 at C4-
phenyl), 2.65 (t, 4H, CH2eNeCH2), 2.46 (s, 3H, NeCH3 of pipera-
zine), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of isopropyl) ppm.
6.1.5.7. 4-(4-(dimethylamino)benzylideneamino)-5-(4-iso-
propylthiazol-2-yl)-2-morpholinomethyl-2H-1,2,4-triazole-3(4H)-
13C NMR (DMSO-d6, 300 MHz)
d
: 184.12 (C]S of triazole),165.48
thione (7g). IR (KBr) n
max, cmꢃ1: 3082 (aromatic CeH), 2963
(thiazole-C4),152.20 (thiazole-C2),145.24 (triazole-C5),134.12 (s,1H,
N]CH), 120e140 (phenyl C1 to C6), 115.48 (thiazole-C5), 62.8
(NeCH2eN), 50.4 (piperazine C2 and C6), 44.9 (piperazine NeCH3),
43.9 (piperazine C3 and C5), 40.5 (N(CH3)2 at C4-phenyl), 32.49
(tertiary-1C-isopropyl), 21.34 (terminal 2CH3-isopropyl) ppm.
MS (%) 484.22 (100.0%), 485.22 (29.4%), 113.02 (9.1%), 486.21
(9.1%).
(CH2), 1610 (CH]N), 1224 (C]S), 1173 (NeCH2eN), 1076
(CH2eOeCH2), 1027 (NeN).
1H NMR (DMSO-d6, 300 MHz)
d: 10.12 (s, 1H, N]CH), 7.71 (s, 1H,
thiazole-C5), 7.4e7.9 (4H, Ar-H), 4.25 (s, 2H, NeCH2eN), 3.67 (t,
J ¼ 4.5 Hz, 4H, morpholine residue), 3.26 (m, 1H, isopropyl), 2.84 (s,
6H, N(CH3)2 at C4-phenyl), 2.42 (t, J ¼ 4.5 Hz, 4H, morpholine
residue), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 173.72 (C]S of triazole),
6.1.5.4. 4-(3,4,5-trimethoxybenzylideneamino)-5-(4-iso-
165.48 (thiazole-C4), 152.20 (thiazole-C2), 145.24 (triazole-C5),
120e140 (phenyl C1 to C6), 134.12 (s, 1H, N]CH), 115.48 (thiazole-
C5), 66.8 (NeCH2eN), 50.1, 66.9 (morpholine residue), 40.5 (N
(CH3)2 at C4-phenyl), 32.49 (tertiary-1C-isopropyl), 21.34 (terminal
2CH3-isopropyl) ppm.
propylthiazol-2-yl)-2-((4-methylpiperazin-1-yl)methyl)-2H-1,2,4-tri-
azole-3(4H)-thione (7d). IR (KBr)
n
max, cmꢃ1: 3092 (aromatic
CeH), 2954 (CH2), 1608 (CH]N), 1227 (C]S), 1179 (NeCH2eN),
1072 (CH2eOeCH2), 1022 (NeN).
1H NMR (DMSO-d6, 300 MHz)
d
: 1.27 (d, J ¼ 8.5 Hz, 6H, terminal
MS (%) 471.19 (100.0%), 472.19 (25.8%), 473.18 (9.1%), 474.19
(2.3%).
2CH3 of isopropyl), 3.26 (m, 1H, isopropyl), 8.12 (s, 1H, N]CH), 7.71
(s, 1H, thiazole-C5), 7.4e7.9 (2H, Ar-H), 4.58 (s, 2H, NeCH2eN), 3.84
(s, 3H, 3OCH3 at C3,4,5-phenyl), 3.62 (t, 4H, CH2eNeCH2), 3.03 (t, 4H,
CH2eNeCH2), 2.46 (s, 3H, NeCH3 of piperazine) ppm.
6.1.5.8. 4-(3,4,5-trimethoxybenzylideneamino)-5-(4-iso-
propylthiazol-2-yl)-2-(morpholinomethyl)-2H-1,2,4-triazole-3(4H)-
13C NMR (DMSO-d6, 300 MHz)
d
: 184.12 (C]S of triazole),165.48
thione (7h). IR (KBr) n
max, cmꢃ1: 3082 (aromatic CeH), 2963
(thiazole-C4), 152.20 (thiazole-C2), 145.24 (triazole-C5), 120e140
(phenyl C1 to C6), 115.48 (thiazole-C5), 134.12 (s, 1H, N]CH), 62.3
(NeCH2eN), 56.5 (3OCH3 at C3,4,5-phenyl), 50.4 (piperazine C2 and
C6), 47.2 (piperazine C3 and C5), 44.9 (piperazine NeCH3), 32.49
(tertiary-1C-isopropyl), 21.34 (terminal 2CH3-isopropyl) ppm.
MS (%) 531.21 (100.0%), 532.21 (30.6%), 113.03 (9.3%), 533.22
(3.4%), 534.21 (2.6%), 533.21 (1.8%).
(CH2), 1610 (CH]N), 1224 (C]S), 1173 (NeCH2eN), 1076
(CH2eOeCH2), 1027 (NeN).
1H NMR (DMSO-d6, 300 MHz)
d: 10.12 (s, 1H, N]CH), 7.4e7.9
(4H, Ar-H), 7.71 (s, 1H, thiazole-C5), 4.52 (s, 2H, NeCH2eN), 3.84(s,
9H, 3OCH3 at C3,4,5-phenyl), 3.67 (t, J ¼ 4.5 Hz, 4H, morpholine
residue), 3.26 (m, 1H, isopropyl), 2.42 (t, J ¼ 4.5 Hz, 4H, morpholine
residue), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 184.12 (C]S of triazole),
6.1.5.5. 4-(2-chlorobenzylideneamino)-5-(4-isopropylthiazol-2-yl)-
165.48 (thiazole-C4), 152.20 (thiazole-C2), 145.24 (triazole-C5),
120e140 (phenyl C1 to C6), 134.12 (s, 1H, N]CH), 115.48 (thiazole-
C5), 59.8 (NeCH2eN), 56.5 (3OCH3 at C3,4,5-phenyl), 50.2, 66.3
(morpholine residue), 32.49 (tertiary-1C-isopropyl), 21.34
(terminal 2CH3-isopropyl) ppm.
2-(morpholinomethyl)-2H-1,2,4-triazole-3(4H)-thione (7e). IR (KBr)
n
max, cmꢃ1: 3092 (aromatic CeH), 2954 (CH2), 1608 (CH]N), 1227
(C]S), 1179 (NeCH2eN), 1072 (CH2eOeCH2), 1022 (NeN).
1H NMR (DMSO-d6, 300 MHz)
d
: 10.12 (s, 1H, N]CH), 7.4e7.9
(4H, Ar-H), 7.71 (s, 1H, thiazole-C5), 4.12 (s, 2H, NeCH2eN), 3.65 (t,
J ¼ 4.5 Hz, 4H, morpholine residue), 3.26 (m, 1H, isopropyl), 2.46 (t,
J ¼ 4.5 Hz, 4H, morpholine residue), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal
2CH3 of isopropyl) ppm.
MS (%) 518.18 (100.0%), 519.18 (27.0%), 520.17 (9.1%), 520.18
(4.8%), 521.18 (2.7%), 519.17 (2.2%).
6.1.6. General method for the synthesis of 3-(4-isopropylthiazol-2-
yl)-6-methyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (8)
13C NMR (DMSO-d6, 300 MHz)
d: 174.12 (C]S of triazole),165.48
(thiazole-C4), 152.20 (thiazole-C2), 120e140 (phenyl C1 to C6),
145.24 (triazole-C5), 144.12 (N]CH), 115.48 (thiazole-C5), 65.4
(NeCH2eN), 50.4, 66.3 (morpholine residue), 32.49 (tertiary-1C-
isopropyl), 21.34 (terminal 2CH3-isopropyl)ppm.
MS (%) 462.11 (100.0%), 464.10 (41.1%), 113.1 (9.3%), 463.10
(2.2%).
To a mixture of compound 1 (0.01 mol) and acetic acid
(0.01 mol), phosphorus oxychloride (10 mL) was added and the
reaction contents were refluxed for 2 h on a water bath. After
removing the excess of phosphorus oxychloride under reduced
pressure, ice water was added to residue with vigorous stirring. The
precipitate was filtered off and washed with 20% sodium bicar-
bonate solution and water and recrystalized.
6.1.5.6. 4-(4-methoxybenzylideneamino)-5-(4-isopropylthiazol-2-
IR (KBr)
n
max, cmꢃ1: 1603, 1595, 1557 and 1446 (C]N).
: 7.71 (s, 1H, thiazole-C5), 3.26
yl)-2-(morpholinomethyl)-2H-1,2,4-triazole-3(4H)-thione
(KBr)
max, cmꢃ1: 3090 (aromatic CeH), 2954 (CH2), 1610 (CH]N),
1224 (C]S), 1173 (NeCH2eN), 1076 (CH2eOeCH2), 1027 (NeN).
1H NMR (DMSO-d6, 300 MHz)
: 10.12 (s, 1H, N]CH), 7.4e7.9
(7f). IR
1H NMR (DMSO-d6, 300 MHz)
d
n
(m, 1H, isopropyl), 2.62 (s, eCH3), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal
2CH3 of isopropyl), ppm.
d
13C NMR (DMSO-d6, 300 MHz)
d: 165.48 (thiazole-C4), 152.20
(4H, Ar-H), 7.71 (s, 1H, thiazole-C5), 4.17 (s, 2H, NeCH2eN), 3.67 (t,
J ¼ 4.5 Hz, 4H, morpholine residue), 3.74(s, 3H, OCH3 at C4-phenyl),
3.26 (m, 1H, isopropyl), 2.42 (t, J ¼ 4.5 Hz, 4H, morpholine residue),
1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of isopropyl) ppm.
(thiazole-C2), 148.2(C3 of triazole), 145.24 (triazole-C5), 115.48
(thiazole-C5), 32.49 (tertiary-1C-isopropyl), 21.34 (terminal 2CH3-
isopropyl), 13.55 (CH3) ppm.
MS (%) 265.05 (100.0%), 266.05 (10.9%), 267.04 (9.1%).
13C NMR (DMSO-d6, 300 MHz)
d: 171.12 (C]S of triazole), 164.48
(thiazole-C4), 152.20 (thiazole-C2), 139.42 (s, 1H, N]CH), 120e140
(phenyl C1 to C6), 145.24 (triazole-C5), 62.8 (NeCH2eN), 113.48
(thiazole-C5), 55.9 (OCH3 at C4-phenyl), 50.2, 66.5 (morpholine
residue), 32.49 (tertiary-1C-isopropyl), 21.14 (terminal 2CH3-iso-
propyl) ppm.
6.1.7. General procedure for the synthesis of 5-(4-isopropylthiazol-
2-yl)-3-(4-substituted)-1,3,4-oxadiazole-2(3H)-thione (11aeb)
The compound 10 (10 mmol) was dissolved in a mixture of
ethanol and dioxane (2:1). Then, formaldehyde (40%, 1.5 ml) and
suitable secondary amine (10 mmol) in ethanol was added to the

5128
G.V. Suresh Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 5120e5129
solution. The mixture was stirred for 2e3 h and kept overnight at
room temperature and resulting solid is washed with ethanol and
recrystalized.
0.2%glycerolwas thawed anddiluted inbrothto 105 cfu mLꢃ1 (colony
forming unit/mL) dilutions. Each test compound was dissolved in
DMSO and then diluted in broth twice at the desired concentration.
The final concentration of DMSO in the assay medium was 1.3%. Each
U-tubewas then inoculated with 0.05 mL ofstandardizedculture and
then incubated at 37 ꢀC for 21 days. The growth in the U-tubes was
compared with visibility against positive control (without drug),
negative control (without drug and inoculum) and with standard
isoniazid.
6.1.7.1. 5-(4-Isopropylthiazol-2-yl)-3-(4-methylpiperazin-1-yl)-1,3,4-
oxadiazole-2(3H)-thione (11a). IR (KBr)
(aromatic CeH), 2954 (CH2), 1227 (C]S), 1179 (NeCH2eN).
1H NMR (DMSO-d6, 300 MHz)
: 7.71 (s, 1H, thiazole-C5), 4.52 (s,
n : 3092
max, cmꢃ1
d
2H, NeCH2eN), 3.26 (m, 1H, isopropyl), 2.46 (s, 8H, of piperazine),
2.26 (s, 3H, NeCH3 of piperazine), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal
2CH3 of isopropyl), ppm.
6.2.3. MTT assay for cell viability
13C NMR (DMSO-d6, 300 MHz)
d
: 174.12 (C]S of oxadiazole),
The toxicity of most active antitubercular compounds 2c, 3e, 4d,
7c and 7d in A549 cell lines in the presence of 10% and 0.2% FBS,
respectively, was determined using 3-(4,5-dimethylthiazole-2-yl)-
2,5-diphenyltetrazolium bromide reduction assay [30,31]. The
compounds were dissolved in DMSO at 10 mM concentration and
stored at ꢃ20ꢀ. The dilutions were made in culture medium before
treatment.
165.48 (thiazole-C4), 152.20 (thiazole-C2), 115.48 (thiazole-C5), 72.8
(NeCH2eN), 54.9 (piperazineC3 and C5), 50.4 (piperazineC2 and C6),
44.9 (piperazine NeCH3), 32.49 (tertiary-1C-isopropyl), 21.34
(terminal 2CH3-isopropyl) ppm.
MS (%) 325.10 (100.0%), 326.11 (14.3%),113.1 (9.3%), 327.11 (1.4%).
6.1.7.2. 5-(4-Isopropylthiazol-2-yl)-3-(morpholinomethyl)-1,3,4-oxa-
diazole-2(3H)-thione (11b). IR (KBr)
(C]S), 1171 (NeCH2eN), 1072 (CH2eOeCH2).
1H NMR (DMSO-d6, 300 MHz)
: 7.71 (s, 1H, thiazole-C5), 3.72 (s,
n
max, cmꢃ1: 2961 (CH2), 1222
Acknowledgements
d
We thank management of St. Johns Pharmacy College, Banga-
lore, for providing necessary facilities. We are grateful to Dr. K.G.
Bhat, Maratha Mandal’s Dental College, Hospital and Research
Centre, Belgaum, India, for providing the facilities to determine the
antibacterial and antitubercular activities. We also wish to thank
IISC, Bangalore, India for providing IR, NMR, mass spectra and
elemental analysis data.
2H, NeCH2eN), 3.26 (m, 1H, isopropyl), 2.46 (s, 4H of morpholine),
3.31 (s, 4H of morpholine), 1.27 (d, J ¼ 8.5 Hz, 6H, terminal 2CH3 of
isopropyl) ppm.
13C NMR (DMSO-d6, 300 MHz)
d: 174.12 (C]S of oxadiazole),
165.48 (thiazole-C4), 152.20 (thiazole-C2), 115.48 (thiazole-C5), 66.1
(NeCH2eN), 66.4 (morpholine C2 and C6), 50.9 (morpholine C3 and
C5), 44.9 (piperazine NeCH3), 32.49 (tertiary-1C-isopropyl), 21.34
(terminal 2CH3-isopropyl)ppm.
MS (%) 326.09 (100.0%), 327.09 (15.9%), 328.08 (9.1%).
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