Synthesis and pharmacological evaluation of some novel 4-isopropyl thiazole-based sulfonyl derivatives as potent antimicrobial and antitubercular agents

Article abstract of DOI:10.1007/s00044-012-0431-1

A series of novel sulfonyl derivatives 3-(substituted benzylsulfonyl)-5-(4- isopropylthiazol-2-yl)-4-phenyl-4H-1,2,4-triazoles 4a-4e, isopropyl thiazole-derived schiff bases 8a-8l, and 2-(substituted benzylsulfonyl)-5-(4- isopropylthiazol-2-yl)-1,3,4-oxadiazoles 11a-11e were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, elemental, and mass spectral analysis. All the compounds exhibited moderate to significant antibacterial and antifungal activities. Results of the antitubercular screening against Mycobacterium tuberculosis H37Rv ascertain compounds 4e, 8b, and 8f as excellent antitubercular molecules, when compared with first line drug isoniazid (0.25 μg/mL).

Full text of DOI:10.1007/s00044-012-0431-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:4239–4252
DOI 10.1007/s00044-012-0431-1
ORIGINAL RESEARCH
Synthesis and pharmacological evaluation of some novel
4-isopropyl thiazole-based sulfonyl derivatives as potent
antimicrobial and antitubercular agents
•
G. V. Suresh Kumar Y. Rajendra Prasad
•
S. M. Chandrashekar
Received: 27 June 2012 / Accepted: 15 December 2012 / Published online: 3 January 2013
Ó Springer Science+Business Media New York 2012
Abstract A series of novel sulfonyl derivatives 3-(substi-
tuted benzylsulfonyl)-5-(4-isopropylthiazol-2-yl)-4-phenyl-
4H-1,2,4-triazoles 4a–4e, isopropyl thiazole-derived schiff
bases 8a–8l, and 2-(substituted benzylsulfonyl)-5-(4-iso-
propylthiazol-2-yl)-1,3,4-oxadiazoles 11a–11e were syn-
thesized and characterized by IR, 1H NMR, 13C NMR,
elemental, and mass spectral analysis. All the compounds
exhibited moderate to significant antibacterial and antifungal
activities. Results of the antitubercular screening against
Mycobacterium tuberculosis H37Rv ascertain compounds
4e, 8b, and 8f as excellent antitubercular molecules, when
compared with first line drug isoniazid (0.25 lg/mL).
Introduction
Despite current multidrug therapy and ongoing drug devel-
opment, tuberculosis (TB) continues to be a major health
concern today. With more than 1.6 million deaths and 9.2
million new cases being reported each year, it is a leading
infectious disease claiming millions of death globally
Mycobacterium tuberculosis has ability to survive for
extended periods of time in human host and thus requires
prolonged drug treatment (6–9 months) and resulting in low
compliance. Moreover, the evolution of multidrug-resistant
(MDR), extremely drug-resistant (XDR) tuberculosis, and
the AIDS epidemic further makes the situation more wors-
ening (Goulding et al., 2002). In M. tuberculosis, drug
resistance is not due to a common mechanism for all drugs,
but different mechanisms for different class of drugs. Almost
all conventional targets and drugs became inadequate to
control resistant TB infection and therefore the discovery of
novel, sensitive, and selective targets or new chemical entity
is needed for the development of new generation of antitu-
bercular drugs(Ballell et al., 2005); (Neu, 1992).
Keywords: 4-Isopropylthiazole Á Cytotoxicity Á
Antibacterial Á Antifungal Á Antitubercular activity
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-012-0431-1) contains supplementary
material, which is available to authorized users.
The development of inhibitors of Mycobacterial cell wall
biosynthesis is one of the key strategies for designing
effective antitubercular agents. The cell wall of Mycobac-
teria consists of a wide array of complex fatty acids, such as
mycocerosic acid, mycolic acid, arabinogalactans (AGs),
and peptidoglycans (PGs) (Spigelman, 2007); (Cegielski
et al., 2002). Azole derivatives possess interesting antimy-
cobacterial activity in addition to antimicrobial activity. It is
established that these compounds reach target by trans-
membrane diffusion because of their lipophilic property.
Azole derivatives target the sterol 14a-demethylase, a
mixed-function oxidase involved in sterol synthesis in
eukaryotic organisms (Walczak et al., 2004); (Babaoglu
et al., 2003); (Khalaf et al., 2004).
G. V. Suresh Kumar (&)
Department of Medicinal Chemistry, St. Johns Pharmacy
College, 6, 2nd Stage Vijaynagar, R.P.C.Layout,
Bangalore 560040, Karnataka, India
e-mail: gvsureshkumar@yahoo.com
Y. Rajendra Prasad
AU College of Pharmaceutical Sciences, Andhra University,
Visakhapatnam 530003, Andhra Pradesh, India
e-mail: dryrp_au@rediffmail.com
S. M. Chandrashekar
Poornaprajna Institute of Scientific Research (PPISR),
Poornaprajnapura, Bidalur, Devanahalli, Near Woodrich Resort,
Bangalore 562110, Karnataka, India
e-mail: Chandra_jan25@yahoo.co.in
123

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Med Chem Res (2013) 22:4239–4252
Our previous studies on clubbed triazolyl-thiazoles
Chemistry
(Shiradkar et al., 2007a, b) proved that isopropyl thiazole
moiety, on coupling with other heterocyclic rings, provides
biologically active novel compounds that could be
explored as potent antimicrobial and antitubercular agents
(Mallikarjuna et al., 2009); (Suresh Kumar et al., 2010a, b,
2012, doi 10.1007/s00044-012-0092-0). The present study
illustrates the design and synthesis of some novel 4- iso-
propyl thiazoles and link them with 1,3,4-oxadiazole and
1,2,4-triazoles by sulfone and study the use of an oxygen
atom as a bioisosteric linker, which has a marginally
smaller bond angle and much greater electronegativity,
which results in an analog with increased potency as
antimicrobial (bacterial and fungal) and antitubercular
activity against M. tuberculosis H37Rv strain.
The reaction sequences employed for synthesis of target
isopropyl thiazole derivatives are illustrated in Scheme 1
and their Physical properties are depicted in Table 1. The
key isopropyl thiazole intermediates (1, 2, and 5) were
synthesized as reported in the literature. (Mallikarjuna
et al., 2009); (Suresh Kumar et al., 2010a, b, 2012, doi
10.1007/s00044-012-0092-0).
The important intermediate 3-(substituted benzylthio)-
5-(4-isopropylthiazol-2-yl)-4-phenyl-4H-1,2,4-triazoles
3a–3e was prepared by condensation of compound 1 with
phenylisothiocyanate in the presence of ethanol. Schiff bases
6a–6e were obtained on reacting triazole 5 with various
substituted benzaldehydes in the presence of catalytic amount
O
N
S
NH2
HN
1
i
N
N
S
N
N
N
N
N
SH
SH
N
N
O
N
S
N
H2N
S
5
ii
SH
iii
9
iii
2
N
N
SH
N
N
N
S
N
N
N
N
N
S
N
R 1
N
S
6a-c
R 2
O
S
S
3a-e
iii
10a-h
R 1
iv
iv
N
N
S
R 1
N
N
N
S
N
N
N
N
N
N
O
O
S
N
S
O
S
7a-q
iv
S
R 2
R 1
O
R 1
O
11a-e
4a-e
N
N
O
S
N
R 1
N
O
S
N
R 2
8a-l
Scheme 1 Synthesis of 4-Isopropyl thiazole derived sulfonyl derivatives 4a–4e, 8a–8l, and 11a–11e
123

Med Chem Res (2013) 22:4239–4252
4241
Table 1 Analytical and physico-chemical data of synthesized sulfonyl derivatives 4a–4e, 8a–8l, and 11a–11e
Compound R1
R2
Solvent system M.p (oC)a/crystallization Yield % Analysis of C, H, N found (Calc.)b
solvent
(%)
84
C
H
N
4a
–
CHCl3:CH3OH 175–177 (ethanol)
(9:2)
C-48.37 (48.38) H-3.48(3.47) N-10.74(10.75)
F
Br
4b
–
CHCl3:CH2OH 164–166 (ethanol)
(8:1)
86
C-55.0(55.01) H-4.24(4.28) N-13.87(13.85)
F
F
F
4c
–
CHCl3:CH2OH 161–163 (ethanol)
(9:1)
74
C-50.10(50.08) H-3.80(3.83) N-11.13(11.18)
Br
4d
CHCl3:CH2OH 189–191 (ethanol)
(9:1)
71
C-52.88(52.87) H-3.80(3.84) N-11.75(11.78)
F
Cl
4e
CHCl3:CH2OH 203–205 (ethanol)
(9:1)
63
C-51.96(51.95) H- 3.77(3.75) N-11.02(11.06)
O
F
F
F
8a
CHCl3:CH3OH 225–227 (ethanol)
(9:1)
84
C-45.21(45.24) H-2.93(2.95) N-11.98(11.95)
F
F
F
Br
123

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Med Chem Res (2013) 22:4239–4252
Table 1 continued
Compound R1
R2
Solvent system M.p (oC)a/crystallization Yield % Analysis of C, H, N found (Calc.)b
solvent
(%)
C
H
N
8b
CHCl3:CH3OH 212–214 (ethanol)
(8:2)
76
C-49.73(49.75) H-3.25(3.26) N-12.61(12.62)
F
F
F
F
F
8c
CHCl3:CH2OH 271–273 (ethanol)
(9:1)
86
91
71
75
C-50.62(50.65) H- 3.48(3.45) N-13.42(13.44)
C-46.65(46.68) H-3.20(3.24) N-12.36(12.34)
C-46.65(46.62) H-3.20(3.24) N-12.36(12.35)
C-51.39(51.38) H-3.56(3.58) N-13.04(13.06)
F
F
Cl
8d
CHCl3:CH2OH 208–211 (ethanol)
(8:2)
F
F
Br
8e
CHCl3:CH2OH 224–226 (ethanol)
(9:2)
F
Br
F
8f
CHCl3:CH3OH 202–204 (ethanol)
(9:1)
F
F
F
F
8g
CHCl3:CH3OH 195–197 (ethanol)
(9:1)
70
C-54.92(54.94) H-4.01(4.05) N-12.14(12.12)
Cl
F
123

Med Chem Res (2013) 22:4239–4252
4243
Table 1 continued
Compound R1
R2
Solvent system M.p (oC)a/crystallization Yield % Analysis of C, H, N found (Calc.)b
solvent
(%)
C
H
N
8h
CHCl3:CH2OH 191–194 (ethanol)
(9:2)
65
C-48.18(49.68) H-3.49(3.48) N-12.77(12.80)
C-45.33(45.35) H-3.11(3.12) N-12.01(12.05)
C-49.86(49.85) H-3.45 (3.42) N-12.63(12.62)
Br
F
8i
CHCl3:CH2OH 186–189 (ethanol)
(9:2)
69
F
Br
Cl
8j
CHCl3:CH3OH 193–195 (ethanol)
(9:1)
91
Cl
F
F
F
8k
CHCl3:CH2OH 187–189 (ethanol)
(8:1)
69
C-50.77(50.76) H-3.68(3.65) N-13.46(13.48)
Cl
Cl
8l
CHCl3:CH2OH 194–196 (ethanol)
(9:1)
59
C-54.20(54.24) H-3.93(3.95) N-14.36(14.39)
F
F
11a
–
CHCl3:CH3OH 180–182 (ethanol)
(8:1)
84
C-46.9(46.95) H-3.68(3.66) N-10.95(10.94)
Cl
123

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Med Chem Res (2013) 22:4239–4252
Table 1 continued
Compound R1
R2
Solvent system M.p (oC)a/crystallization Yield % Analysis of C, H, N found (Calc.)b
solvent
(%)
C
H
N
11b
–
CHCl3:CH3OH 169–172 (ethanol)
(8:2)
78
C-42.00(42.02) H-3.29(3.27)
N-9.81(9.82)
Br
11c
–
CHCl3:CH3OH 182–184 (ethanol)
(9:1)
92
C-46.04(46.02) H-3.38(3.36) N-10.07(10.04)
F
F
F
11d
–
CHCl3:CH3OH 191–195 (ethanol)
(9:1)
82
C-51.50(51.50) H-4.33(4.31) N-12.04(12.02)
11e
–
CHCl3:CH3OH 199–201 (ethanol)
(9:1)
73
C-44.83(44.85) H-3.26(3.25) N-10.46 (10.45)
F
Cl
a
Melting point range of the compounds
b
Elemental analysis of C, H, and N were within 0.4 % of theoretic value
of concentrated sulfuric acid in ethanol (Mallikarjuna et al.,
2009); (Suresh Kumar et al., 2010a, b, 2012, doi 10.1007/s
00044-012-0092-0).
derivatives 4a–4e, 8a–8l, and 2-(substituted benzylsulfonyl)-
5-(4-isopropylthiazol-2-yl)-1,3,4-oxadiazoles 11a–11e (John
et al., 1994).
The key intermediate 5-(4-isopropylthiazol-2-yl)-1,3,
4-oxadiazole-2-thiol 9 was prepared by one pot procedure
which involves reacting compound 1 with carbon disulfide
under strong basic conditions followed by acidification
with dilute hydrochloric acid. Condensation of isopropyl
intermediates 2, 6a–6c, and 9 with substituted benzyl
bromides in the presence of potassium hydroxide and
methanol produced a series of thio benzyl derivatives
3a–3e, 7a–7q, and 2-(substituted benzylthio)-5-(4-isopro-
pylthiazol-2-yl)-1,3,4-oxadiazoles 10a–10h (Patil et al.,
2010).
Biologic activity
The standard strains were procured from the American
Type Culture Collection (ATCC) and Gene Bank, Institute
of Microbial Technology, Chandigarh, India. The anti-
bacterial activity of the synthesized target compounds
(4a–4e, 8a–8l, and 11a–11e) was performed by broth
dilution method (Eweiss et al., 1986) against the following
standard bacterial strains: Staphylococcus aureus (ATCC
11632), Streptococcus faecalis (ATCC 14506), Bacillus
subtilis (ATCC 60511), Klebsiella pneumoniae (ATCC
10031), Escherichia, and Pseudomonas aeruginosa (ATCC
Further on, oxidation of isopropyl thiazole derivatives 3a–3e,
7a–7q, and 10a–10h in the presence of 3-chloro per
benzoic acid (m-CPBA) and MDC afforded target sulfonyl
123

Med Chem Res (2013) 22:4239–4252
4245
10145), and antifungal activity against Yeasts: Saccharo-
myces cerevisiae (ATCC 9763, Sc) and Candida tropicalis
(ATCC 1369, CT), mold: Aspergillus niger (ATCC 6275).
MIC of compounds was determined against M. tuberculosis
H37Rv strain by broth dilution assay method. The cyto-
toxicity of the synthesized compounds was evaluated for
their cytotoxic potential using A549 (lung adenocarcinoma)
cell lines in the presence of fetal bovine serum.
group. 1H NMR spectrum of sulfones depicts the downfield
shift of –SO2CH2– protons compared with –SCH2 deriva-
tives 3a–3e indicating the formation of oxidized deriva-
1
tives. H NMR of compound 4a shows sharp singlet at d
4.91 accountable for CH2 group, doublet at d 1.05 represent
6 protons of terminal isopropyl group. Further molecular
ion peaks at 521 and 523 (1:1 isotopic peak for bromine)
confirm the molecular weight of compound 4a.
The 1H NMR spectra of Schiff bases 8a–8l display singlet
between d 9.53–9.71 ppm corresponding to one proton char-
acteristic of N=CH group and stretching band around 1,324
(assym) and 1,142 (sym) cm-1 due to SO2 group. Further,
(M?2) peak at 586.00 in mass spectra is in agreement with
molecular formula C22H17BrF3N5O2S2 of compound 8a.
The 1H NMR spectrum of compounds 11a–11e illustrate
singlet peak between d 4.91 and 4.98 accounting for SCH2
Results and discussion
Chemistry
The IR spectrum of series 4a–4e illustrates stretching band
at around 1,322 (assym), and 1,141 (sym) cm-1 due to SO2
Table 2 Antibacterial and antifungal activity of compounds 4a–4e, 8a–8l, and 11a–11e expressed as MIC (lg/mL)
Compounds
Gram-positive organismsa
Gram-negative organismsb
Fungic
Sa
Sf
Bs
Kp
Ec
Pa
Sc
Ct
An
4a
31.25
4
31.25
8
16
16
8
16
16
8
16
16
16
16
16
16
16
62.5
62.5
31.25
4
31.25
31.25
16
16
4b
8
16
16
16
4
16
4c
8
16
16
16
16
4d
16
31.25
8
31.25
8
8
8
16
31.25
31.25
16
4e
31.25
31.25
8
4
2
8
16
8a
31.25
16
16
31.25
16
4
8
16
8b
8
16
8
4
8
8c
31.25
31.25
16
31.25
16
8
31.25
8
62.5
8
16
31.25
8
8d
16
8
8
8
8e
31.25
8
31.25
8
8
8
62.5
8
31.25
16
31.25
4
8f
4
4
8
8g
8
4
4
31.25
16
8
16
62.5
16
4
31.25
31.25
16
4
31.25
31.25
8
31.25
125
8
8h
62.5
31.25
4
62.5
31.25
8
8
8
8i
8
31.25
16
62.5
8
8j
4
8
4
8k
8
8
31.25
62.5
8
31.25
31.25
8
62.5
31.25
4
8
16
8
8
8
8l
4
8
4
16
8
11a
16
31.25
31.25
16
8
8
8
16
11b
8
31.25
31.25
31.25
8
8
4
8
62.5
8
31.25
31.25
8
31.25
125
16
11c
8
2
8
4
11d
62.5
8
16
8
8
8
4
11e
31.25
B5
B5
–
4
8
4
16
–
8
8
Ciprofloxacin
Norfloxacin
Flucanozole
a
B5
B5
–
B1
B1
–
B1
B1
–
B1
B1
–
B5
B5
–
–
–
–
–
–
B1
B1
B1
The screening organisms. Gram-positive bacteria: Staphylococcus aureus (ATCC 11632, Sa), Streptococus faecalis (ATCC 14506, Sf), and
Bacillus subtilis (ATCC 60511, Bs)
b
The screening organisms. Gram-negative bacteria: Klebsiella penumoniae (ATCC 10031, Kp), Escherichia coli (ATCC 10536, Ec), and
Pseudomonas aeruginosa (ATCC 10145, Pa)
c
The screening organisms. Yeasts: Saccharomyces cerevisiae (ATCC 9763, Sc) and Candida tropicalis (ATCC 1369, Ct), mold: Aspergillus
niger (ATCC 6275, An)
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Med Chem Res (2013) 22:4239–4252
group. Further, peaks at 164.25 (oxadiazole-C2), 153.26
(oxadiazole-C5) in 13C NMR spectra and m/z at 417.05 in
mass spectrum of compound 11c were found to be in con-
formity with its molecular formula of the assigned structure.
growth cycle of pathogen as well as a means of augmenting
fundamental drug activity (Mallikarjuna et al., 2009).
Structurally, modifications engendering desirable drug
properties (enhanced penetration and decreased resistance)
are optimally made at –SH group. Modifying the linkage
between triazole/oxadiazole and isopropyl thiazole by SO2
instead of –SH (i.e., by increasing the oxidation state of
sulfur atom) would significantly augment the antimicrobial
potency of the heterocycles (John et al., 1994) The
enhanced antimicrobial ability of the sulphonyl derivatives
instead of unsubstituted, or simple SCH3 substitution is
because of the inductive properties of the SO2 group, which
exhibit amphoteric behavior. This amphoteric behavior has
been found to play an extremely important role in anti-
bacterial activity by influencing dissociation constant.
In line with the above discussion, our rationale has been
to prepare various sulphonyl derivatives (4a–4e, 8a–8l, and
11a–11e) with enhanced lipophilicity and to examine their
efficacy against selected strains of Gram-positive, Gram-
negative bacteria, yeasts, molds, and MTB H37Rv.
Biologic activity
The results of the antimicrobial testing of the synthesized
target compounds (4a–4e, 8a–8l, and 11a–11e) against
selected Gram-positive, Gram-negative bacteria, yeasts,
molds, and M. tuberculosis strain H37Rv are illustrated in
Tables 2 and 3. The results exhibit interesting trends in
structure activity relationship (SAR) studies based on
various substitutions at the acidic –SH group.
The –SH proton of compound 2, 5, and 9 is acidic
enough and substitution reaction could be achieved on this
group in the presence of a base (Klimesova et al., 2004);
(Pomarnacka and Kornicka, 2001). Several recent experi-
ments indicate that incorporation of hydrophobic moieties
into the framework of isopropyl thiazole enhance pene-
tration of drug into tissues of mammalian host and into the
waxy cell wall of bacterium. This strategy of drug design
has been proposed as a vehicle for controlled study of
Evaluating the antimicrobial activity of the synthesized
3-(substituted benzylsulfonyl)-5-(4-isopropylthiazol-2-yl)-
4-phenyl-4H-1,2,4-triazoles 4a–4e revealed that compounds
were more effective against the Gram-negative bacteria
at MIC 2–16 lg/mL. Particularly, 4- triflouromethoxy-
substituted compound 4e exhibited excellent inhibition at
MIC 2–8 lg/mL against tested Gram-negative bacteria and
1 lg/mL against M. tuberculosis H37Rv. In contradiction to
compound 4b comprising trifluoro methyl substitution
which displays moderate to good inhibition against tested
Gram-positive organisms. This excellent inhibition of
compound 4e is attributed to the participation of the free
electron pairs on the oxygen of SO2 group by resonance and
increased electron density in the aromatic system.
Table 3 Comparison of in vitro
Compound
MIC values
(lg/mL) of
M. tuberculosis
H37Rv
antimycobacterial activity of
compounds 4a–4e, 8a–8l, and
11a–11e against drug-sensitive
Mycobacterium tuberculosis
H37Rv strain
4a
8
4b
4
4c
8
4d
4
4e
1
8a
8
Schiff bases 8a–8l derived from 1, 2, 4-triazoles are
reported to possess significant antimicrobial activity, partic-
ularly against M. tuberculosis H37Rv because of its increased
ability to penetrate bacterial cell (Walczak et al., 2004). The
SAR studies and antimicrobial activity of Schiff bases 8a–8l
illustrate compound 8b comprising trifluoro methyl substitu-
tion exhibited excellent inhibition against M. tuberculosis
H37Rv at MIC 0.5 lg/mL compared to its antifungal inhibi-
tion at MIC 4–16 lg/mL; this increased activity is attributed
to the presence of fluorine atoms (highly electro negative) in
the molecule which increases lipophilicity and affects the
partitioning of a molecule into membranes and facilitates
hydrophobic interactions of the molecule with specific bind-
ing sites on either receptor or enzymes (Bazile et al., 1992);
(Bermejo et al., 1999). Compounds 8f and 8j also depict good
antimicrobial activity and excellent antitubercular inhibition
at MIC 2 and 4 lg/mL, respectively.
8b
0.5
8
8c
8d
8
8e
16
2
8f
8g
8
8h
8
8i
8
8j
4
8k
8
8l
4
11a
11b
11c
11d
11e
Isoniazid
4
4
2
4
4
The antimicrobial activity of 2-(substituted benzylsulfo-
0.25
nyl)-5-(4-isopropylthiazol-2-yl)-1,3,4-oxadiazoles 11a–11e
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Med Chem Res (2013) 22:4239–4252
4247
Fig. 1 Cytotoxic activity of
compounds 8b, 8f, 8j, 4e, and
11c tested in A549 cells by
MTT assay. The bars reflect the
viable cells in each treatment.
Cells represent cells alone
without any treatment, DMSO
denotes the vehicle control. The
experiment was done in
Cytotoxicity Results
4
3
2
1
0
Cells
DMSO
8b
8f
8j
duplicate with triplicate
readings of each experiment
4e
11c
Treatment
exhibit interesting SAR trends. In drug design, halogen atoms
are used to improve penetration through lipid membranes and
tissues. They may also present a significant reactivity
depending on the structure of the molecule. Compound 11c
comprising 2-CF3 on phenyl ring demonstrates improved
antimicrobial activity against tested bacterial and fungal
species and excellent inhibition against M. tuberculosis
H37Rv at MIC 2 lg/mL. However, compounds 11a and 11b
possessing4-Cland 4-Brsubstitution onphenylringexhibited
moderate antimicrobial activity against Gram-positive spe-
ciesand goodactivity against tested Gram-negative speciesK.
pneumonia and E. coli than P. aeruginosa at MIC 2-8 lg/mL.
The SAR analysis indicates the volume of the halogen as a
feasiblerestrictivefactorsince bromine, thelargest halogen,is
more deleterious to the antitubercular activity than chlorine or
fluorine. Based onthese data, wemayinferthatsubstituent(R)
is a steric and/or restricted position which should be carefully
considered in the future design of antitubercular targets.
The most active antitubercular compounds 8b, 8f, 8j, 4e,
and 11c were tested for their cytotoxic potential using
A549 (lung adenocarcinoma) cell lines in the presence of
fetal bovine serum. As shown in Fig. 1, compound 8f
showed maximum cytotoxicity at the concentration of
250 mM. The other compounds 8b, 8j, 4e, and 11c showed
appreciable cytotoxicity of about 50 % of the vehicle
control at a concentration of 250 mM.
antituberculosis screening of these series showed that all
the compounds were active; in particular, compounds 4e
and 8b exhibited excellent antitubercular activity at MIC 1
and 0.5 lg/mL, respectively, when compared with first line
drug such as Isoniazid. The promising in vitro antimicro-
bial activity and low-toxicity profile of the clubbed Iso-
propylthiazole class of compounds make them certain
promising molecules for further lead optimization in the
development of novel antimycobacterial agents.
Experimental
Chemical protocols
Melting points were determined in open capillary tubes in a
Thomas Hoover melting point apparatus and are uncor-
rected. Infrared spectra were recorded on Shimadzu FT-IR
1
157, H 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).
General procedure to synthesize sulfonyl derivatives
4a–4e, 8a–8l, and 2-(substituted benzylsulfonyl)-5-
(4- isopropylthiazol-2-yl)-1,3,4-oxadiazoles 11a–11e
Conclusion
To a solution of thio derivatives 3a–3e, 7a–7q, and
10a–10h (2 mmol) in CH2Cl2 (5 mL) m-CPBA (m-chlo-
roperbenzoic acid) (75 % purity, 6.8 mmol) was added at
0–5 °C. The mixture was stirred for 30 min, and the
completion of the reaction was monitored through TLC.
After the completion of the reaction, reaction mixture was
quenched with 20 % aqueous Na2S2O3 solution. The
organic phase was separated and the aqueous phase was
washed with 1 M NaOH solution and brine, dried over
In conclusion, this work demonstrates the synthesis of
series of novel clubbed Isopropylthiazole-derived sulpho-
nyl derivatives and their in vitro evaluation of antimicro-
bial (bacterial and fungal) and antitubercular activity
against M. Tuberculosis H37Rv strain. Antimicrobial study
revealed that compounds 8b, 8f, and 11c demonstrate
significant activity against tested Gram-positive and Gram-
negative bacteria and fungal species. The in vitro
123

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Med Chem Res (2013) 22:4239–4252
anhydrous Na2S2O4, filtered, and concentrated to afford
target compounds in excellent yields.
isopropyl), 51.63(CH2), 120–168 (Ar), 141.44 (triazole-
C5), 162.73 (thiazole C4), 164.62 (thiazole C2).
m/e: 475.7 (100.0 %).
Synthesis of 3-(4-bromo-2-fluorobenzylsulfonyl)-5-(4-isopro-
pylthiazol-2-yl)-4-phenyl-4H-1,2,4-triazole 4a IR (KBr) mmax
,
Synthesis of 3-(4-(trifluoromethoxy)benzylsulfonyl)-5-(4-iso-
cm-1: 1611 (C=N), 3057 (Ar C–H), 1322 (assym), 1141
propylthiazol-2-yl)-4-phenyl-4H-1,2,4-triazole 4e IR (KBr)
max, cm-1: 1622 (C=N), 3053 (Ar C–H), 1325 (assym),
(sym) SO2.
m
1H NMR (DMSO-d6, 300 MHz) d: 1.05(d, J = 8.5 Hz,
6H, 2CH3), 2.89(m, 1H, isopropyl), 4.91(s, 2H, CH2),
7.3–7.7 (m, 8H, phenyl and 1H of thiazole-C5).
13C NMR (DMSO-d6, 300 MHz) d: 21.34 (terminal
2CH3-isopropyl), 24.44 (tertiary-1C- isopropyl), 53.43
(CH2), 112.10 (thiazole-C5), 121–155 (Ar), 143.23 (tria-
zole-C5), 160.61 (thiazole C2), 165.32 (thiazole C4).
m/e: 523.01 (M?2), 521.01 (100.0 %).
1147 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.05(d, J = 8.5 Hz,
6H, 2CH3), 3.32 (m, 1H, isopropyl), 5.04(s, 2H, CH2),
7.1–7.6 (m, 9H, phenyl and 1H of thiazole-C5).
13C NMR (DMSO-d6, 300 MHz) d: 11.65 (thiazole-C5),
21.14 (terminal 2CH3-isopropyl), 25.36 (tertiary-1C- iso-
propyl), 51.01(CH2), 120–168 (Ar), 142.66 (triazole-C5),
161.58 (thiazole C4), 163.65 (thiazole C2).
m/e: 510.09 (M?2), 509.09 (M?1), 508.09 (100.0 %).
Synthesis of 3-(4-(trifluoromethyl)benzylsulfonyl)-5-(4-iso-
propylthiazol-2-yl)-4-phenyl-4H-1,2,4-triazole 4b IR (KBr)
max, cm-1: 1611 (C=N),3054 (Ar C–H), 1325 (assym),
Synthesis of N-(2,6-difluorobenzylidene)-3-(4-bromo-2-
fluorobenzylsulfonyl)-5-(4-isopropylthiazol-2-yl)-4H-1,2,
4-triazole-4-amine 8a IR (KBr) mmax, cm-1: 3357 (NH),
1654 (C=N), 1326 (assym), 1144 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.32(d, J = 8.5 Hz,
6H, 2CH3), 2.98 (m, 1H, isopropyl), 5.09(s, 2H, CH2),
7.3–7.9 (m, 6H, phenyl and 1H of thiazole-C5), 9.53 (s, 1H,
N=CH).
13C NMR (DMSO-d6, 300 MHz) d: 23.12 (terminal
2CH3-isopropyl), 30.123 (tertiary-1C- isopropyl), 52.14
(CH2), 116.19 (thiazole-C5), 125–132 (Ar), 142.51 (tria-
zole-C5), 153.14 (thiazole C2), 161.21 (thiazole C4),
164.44 (HC=N).
m
1146 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.05(d, J = 8.5 Hz,
6H, 2CH3), 3.02 (m, 1H, isopropyl), 4.98(s, 2H, CH2),
7.2–7.6 (m, 9H, phenyl and 1H of thiazole-C5).
13C NMR (DMSO-d6, 300 MHz) d: 11.16 (thiazole-C5),
22.11 (terminal 2CH3-isopropyl), 24.32 (tertiary-1C- iso-
propyl), 51.62(CH2), 122–155 (Ar), 141.44 (triazole-C5),
160.24 (thiazole C2), 164.58 (thiazole C4).
m/e: 492.09 (100.0 %).
Synthesis of 3-(4-bromobenzylsulfonyl)-5-(4-isopropylthiazol-
2-yl)-4-phenyl-4H-1,2,4-triazole 4c IR (KBr) mmax, cm-1
1611 (C=N), 3052 (Ar C–H), 1327 (assym), 1145 (sym)
m/e: 586.00 (M?2, 84.3 %), 463.1 (3.8 %), 102.1
(11.8 %).
:
SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.06 (d, J = 8.5 Hz,
6H, 2CH3), 2.82 (m, 1H, isopropyl), 5.05(s, 2H, CH2),
6.9–7.9 (m, 9H, phenyl and 1H of thiazole-C5).
13C NMR (DMSO-d6, 300 MHz) d: 11.22 (thiazole-C5),
21.51 (terminal 2CH3-isopropyl), 23.11 (tertiary-1C- iso-
propyl), 51.62(CH2), 122–165 (Ar), 164.51 (thiazole C4),
161.15 (thiazole C2), 142.59 (triazole-C5).
Synthesis of N-(2,6-difluorobenzylidene)-3-(4-(trifluoro-
methyl)benzylsulfonyl)-5-(4-isopropylthiazol-2-yl)-4H-1,2,
4-triazol-4-amine 8b IR (KBr) mmax, cm-1: 3342 (NH),
1621 (C=N), 1323 (assym), 1145 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.08(d, J = 8.5 Hz,
6H, 2CH3), 2.94 (m, 1H, isopropyl), 5.22(s, 2H, CH2), 7.3–
7.8 (m, 7H, phenyl and 1H of thiazole-C5), 9.65 (s, 1H,
N=CH).
m/e: 505.01 (M?2), 503.02 (100.0 %).
13C NMR (DMSO-d6, 300 MHz) d: 24.55 (terminal
2CH3-isopropyl), 29.12 (tertiary-1C- isopropyl), 52.60
(CH2), 116.24 (thiazole-C5), 124–138 (Ar), 141.54 (tria-
zole-C5), 152.31 (thiazole C2), 161.12 (thiazole C4),
164.44 (HC=N).
Synthesis of 3-(5-chloro-2-fluorobenzylsulfonyl)-5-(4-isopro-
pylthiazol-2-yl)-4-phenyl-4H-1,2,4-triazole 4d IR (KBr) mmax
,
cm-1: 1615 (C=N), 3057 (Ar C–H), 1329 (assym), 1152
(sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.05(d, J = 8.5 Hz,
6H, 2CH3), 2.82 (m, 1H, isopropyl), 4.96(s, 2H, CH2),
7.3–7.6 (m, 8H, phenyl and 1H of thiazole-C5).
13C NMR (DMSO-d6, 300 MHz) d: 11.27 (thiazole-
C5), 21.53 (terminal 2CH3-isopropyl), 23.16 (tertiary-1C-
m/e: 557.3 (M?2, 92 %), 556.3 (M?1), 417.3 (7.0 %),
432.3
Synthesis of N-(2,6-difluorobenzylidene)-3-(4-chlorobenz-
ylsulfonyl)-5-(4-isopropylthiazol-2-yl)-4H-1,2,4-triazol-4-
123

Med Chem Res (2013) 22:4239–4252
4249
amine 8c IR (KBr) mmax, cm-1: 3351 (NH), 1644 (C=N),
1329 (assym), 1146 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.05(d, J = 8.5 Hz,
6H, 2CH3), 2.95 (m, 1H, isopropyl), 5.05(s, 2H, CH2),
7.1–7.7 (m, 7H, phenyl and 1H of thiazole-C5), 9.62 (s, 1H,
N=CH).
13C NMR (DMSO-d6, 300 MHz) d: 24.61 (terminal
2CH3-isopropyl), 29.16 (tertiary-1C- isopropyl), 53.42
(CH2), 116.32 (thiazole-C5), 124–141 (Ar), 141.62 (tria-
zole-C5), 152.51 (thiazole C2), 161.22 (thiazole C4),
164.31 (HC=N).
(CH2), 115.14 (thiazole-C5), 122–148 (Ar), 140.21 (tria-
zole-C5), 154.22 (thiazole C2), 160.55 (thiazole C4),
165.67 (HC=N).
m/e: 537.10 (100.0 %), 538.10 (M?1).
Synthesis of 3-(4-chlorobenzylsulfonyl)-N-(4-fluoroben-
zylidene)-5-(4-isopropylthiazol-2-yl)-4H-1,2,4-triazol-
4-amine 8g IR (KBr) mmax, cm-1: 3325 (NH), 1636
(C=N), 1325 (assym), 1143 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.05 (d, J = 8.5 Hz,
6H, 2CH3), 3.05 (m, 1H, isopropyl), 5.04(s, 2H, CH2), 7.3–7.8
(m, 8H, phenyl and 1H of thiazole-C5), 9.65 (s, 1H, N=CH).
13C NMR (DMSO-d6, 300 MHz) d: 22.68 (terminal
2CH3-isopropyl), 27.41 (tertiary-1C- isopropyl), 52.68
(CH2), 115.24 (thiazole-C5), 124–156 (Ar), 140.21 (tria-
zole-C5), 154.11 (thiazole C2), 160.32 (thiazole C4),
165.54 (HC=N).
m/e: 523.87 (M?2), 522.06 (M?1), 521.96.
Synthesis of N-(2,6-difluorobenzylidene)-3-(4-bromobenz-
ylsulfonyl)-5-(4-isopropylthiazol-2-yl)-4H-1,2,4-triazol-4-
amine 8d IR (KBr) mmax, cm-1: 3353 (NH), 1648
(C=N),1322 (assym), 1143 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.05(d, J = 8.5 Hz,
6H, 2CH3), 2.91 (m, 1H, isopropyl), 5.12(s, 2H, CH2),
7.3–7.8 (m, 7H, phenyl and 1H of thiazole-C5), 9.63 (s, 1H,
N=CH).
13C NMR (DMSO-d6, 300 MHz) d: 24.51 (terminal
2CH3-isopropyl), 29.44 (tertiary-1C- isopropyl), 54.46
(CH2), 116.55 (thiazole-C5), 124–139 (Ar), 141.32 (tria-
zole-C5), 152.69 (thiazole C2), 161.62 (thiazole C4),
164.58 (HC=N).
m/e: 506.07 (M?2), 504.07 (100.0 %).
Synthesis of 3-(4-bromobenzylsulfonyl)-N-(4-fluorobenzy-
lidene)-5-(4-isopropylthiazol-2-yl)-4H-1,2,4-triazol-4-amine
8h IR (KBr) mmax, cm-1: 3354 (NH), 1625 (C=N), 1328
(assym), 1144 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.28(d, J = 8.5 Hz,
6H, 2CH3), 3.02 (m, 1H, isopropyl), 5.02(s, 2H, CH2), 7.3–7.8
(m, 8H, phenyl and 1H of thiazole-C5), 9.62 (s, 1H, N=CH).
13C NMR (DMSO-d6, 300 MHz) d: 22.66 (terminal
2CH3-isopropyl), 27.51 (tertiary-1C-isopropyl), 52.21 (CH2),
115.91 (thiazole-C5), 124–155 (Ar), 140.21 (triazole-C5),
154.65 (thiazole C2), 160.11 (thiazole C4), 165.22 (HC=N).
m/e: 550.23 (M?2), 549.13 (M?2), 548.49 (100.0 %).
m/e: 566.01 (100.0 %).
Synthesis of 3-(4-bromo-2-fluorobenzylsulfonyl)-N-(4-fluo-
robenzylidene)-5-(4-isopropylthiazol-2-yl)-4H-1,2,4-tria-
zol-4-amine 8e IR (KBr) mmax, cm-1: 3332 (NH), 1654
(C=N), 1329 (assym), 1145 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.06(d, J = 8.5 Hz,
6H, 2CH3), 2.95 (m, 1H, isopropyl), 5.01(s, 2H, CH2), 7.3–
7.8 (m, 7H, phenyl and 1H of thiazole-C5), 9.62 (s, 1H,
N=CH).
13C NMR (DMSO-d6, 300 MHz) d: 24.61 (terminal
2CH3-isopropyl), 27.25 (tertiary-1C- isopropyl), 53.82
(CH2), 112.54 (thiazole-C5), 124–141 (Ar), 141.21 (tria-
zole-C5), 154.31 (thiazole C2), 161.32 (thiazole C4),
164.62 (HC=N).
Synthesis of 3-(4-bromo-2-fluorobenzylsulfonyl)-N-(4-chlo-
robenzylidene)-5-(4-isopropylthiazol-2-yl)-4H-1,2,4-tria-
zol-4-amine 8i IR (KBr) mmax, cm-1: 3323(NH), 1651
(C=N), 1327 (assym), 1150 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.05(d, J = 8.5 Hz,
6H, 2CH3), 3.09 (m, 1H, isopropyl), 5.05(s, 2H, CH2), 7.3–7.8
(m, 7H, phenyl and 1H of thiazole-C5), 9.63 (s, 1H, N=CH).
13C NMR (DMSO-d6, 300 MHz) d: 22.41 (terminal
2CH3-isopropyl), 27.68 (tertiary-1C- isopropyl), 52.47
(CH2), 115.61 (thiazole-C5), 124–158 (Ar), 140.61 (tria-
zole-C5), 153.26 (thiazole C2), 161.62 (thiazole C4),
165.44 (HC=N).
m/e: 568.61 (M?2, 100.0 %). 566.01 (100.0 %).
Synthesis of 3-(4-(trifluoromethyl)benzylsulfonyl)-N-(4-flu-
orobenzylidene)-5-(4-isopropylthiazol-2-yl)-4H-1,2,4-tria-
zole-4-amine 8f IR (KBr) mmax, cm-1: 3351 (NH), 1622
(C=N), 1325 (assym), 1143 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.05(d, J = 8.5 Hz,
6H, 2CH3), 3.03 (m, 1H, isopropyl), 4.98(s, 2H, CH2),
7.3–7.8 (m, 8H, phenyl and 1H of thiazole-C5), 9.71 (s, 1H,
N=CH).
13C NMR (DMSO-d6, 300 MHz) d: 24.35 (terminal
2CH3-isopropyl), 27.21 (tertiary-1C- isopropyl), 53.14
m/e: 584.9 (M?2), 582.36 (100.0 %).
Synthesis of 3-(4-(trifluoromethyl)benzylsulfonyl)-N-(4-chlo-
robenzylidene)-5-(4-isopropylthiazol-2-yl)-4H-1,2,4-triazol-
4-amine 8j IR (KBr) mmax, cm-1: 3352 (NH), 1623 (C=N),
1324 (assym), 1147 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.04(d, J = 8.5 Hz,
6H, 2CH3), 3.08 (m, 1H, isopropyl), 4.97(s, 2H, CH2), 7.3–7.8
(m, 8H, phenyl and 1H of thiazole-C5), 9.62 (s, 1H, N=CH).
123

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Med Chem Res (2013) 22:4239–4252
13C NMR(DMSO-d6, 300 MHz)d: 23.19(terminal 2CH3-
13C NMR(DMSO-d6, 300 MHz)d: 21.36(terminal 2CH3-
isopropyl), 31.36 (tertiary-1C-isopropyl), 51.44(CH2), 114.12
(thiazole-C5), 122–175 (Ar), 154.25 (oxadiazole-C5), 159.05
(thiazole-C2), 161.55 (thiazole C4), 164.25 (oxadiazole-C2).
m/e: 428.97 (M?2), 427.97 (M?1), 425.97 (93.1 %).
isopropyl), 26.61 (tertiary-1C- isopropyl), 51.49 (CH2),
114.61 (thiazole-C5), 122–158 (Ar), 144.33 (triazole-C5),
154.22 (thiazole C2), 160.55 (thiazole C4), 163.36 (HC=N).
m/e: 556.06 (M?2), 554.07 (100.0 %).
Synthesis of N-(4-chlorobenzylidene)-3-(4-chlorobenzy-
lsulfonyl)-5-(4-isopropylthiazol-2-yl)-4H-1,2,4-triazol-4-
amine 8k IR (KBr) mmax, cm-1: 3361 (NH), 1611 (C=N),
1324 (assym), 1142 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.04(d, J = 8.5 Hz,
6H, 2CH3), 3.01 (m, 1H, isopropyl), 4.99(s, 2H, CH2), 7.3–7.8
(m, 8H, phenyl and 1H of thiazole-C5), 9.64 (s, 1H, N=CH).
13C NMR (DMSO-d6, 300 MHz) d: 23.44 (terminal
2CH3-isopropyl), 26.31 (tertiary-1C- isopropyl), 52.32
(CH2), 115.60 (thiazole-C5), 121–155 (Ar), 143.53 (tria-
zole-C5), 155.61 (thiazole C2), 161.32 (thiazole C4),
164.44 (HC=N).
Synthesis of 2-(2-(trifluoromethyl)benzylsulfonyl)-5-(4-iso-
propylthiazol-2-yl)-1,3,4-oxadiazole 11c IR (KBr) mmax
,
cm-1: 1632 (C=N), 3059 (Ar C–H), 1325 (assym), 1148
(sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.35(d, J = 8.5 Hz,
6H, 2CH3), 3.14 (m, 1H, isopropyl), 4.91(s, 2H, CH2),
7.4–7.9 (m, 4H, phenyl and 1H of thiazole-C5).
13C NMR (DMSO-d6, 300 MHz) d: 22.25 (terminal
2CH3-isopropyl), 32.55 (tertiary-1C-isopropyl), 52.15(CH2),
113.25 (thiazole-C5), 122–175 (Ar), 153.26 (oxadiazole-C5),
158.36(thiazole-C2), 160.55 (thiazole C4), 164.25 (oxadiaz-
ole-C2).
m/e: 521.04 (M ? 2), 519.04 (100.0 %).
m/e: 418.05 (M?1), 417.05 (100.0 %).
Synthesis of 2-(benzylsulfonyl)-5-(4-isopropylthiazol-2-yl)-
1,3,4-oxadiazole 11d IR (KBr) mmax, cm-1: 1628 (C=N),
3052 (Ar C–H), 1327 (assym), 1151 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.22(d, J = 8.5 Hz,
6H, 2CH3), 3.04 (m, 1H, isopropyl), 4.92(s, 2H, CH2), 7.2–
7.8 (m, 5H, phenyl and 1H of thiazole-C5).
13C NMR (DMSO-d6, 300 MHz) d: 22.25 (terminal 2CH3-
isopropyl), 32.55 (tertiary-1C-isopropyl), 52.15(CH2), 113.25
(thiazole-C5), 122–175 (Ar), 157.54(thiazole-C2), 152.25
(oxadiazole-C5), 161.25 (thiazole C4), 165.22 (oxadiazole-C2).
m/e: 351.06 (M?2),350.06 (M?1), 349.06 (100.0 %).
Synthesis of N-(2,6-difluorobenzylidene)-3-(benzylsulfo-
nyl)-5-(4-isopropylthiazol-2-yl)-4H-1,2,4-triazol-4-amine
8l IR (KBr) mmax, cm-1: 3351 (NH), 1644 (C=N), 1329
(assym), 1146 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.02(d, J = 8.5 Hz,
6H, 2CH3) 2.99 (m, 1H, isopropyl), 4.98(s, 2H, CH2), 7.3–7.7
(m, 8H, phenyl and 1H of thiazole-C5), 9.62 (s, 1H, N=CH).
13C NMR (DMSO-d6, 300 MHz) d: 24.61 (terminal
2CH3-isopropyl), 29.16 (tertiary-1C-isopropyl), 53.42
(CH2), 116.32 (thiazole-C5), 124–141 (Ar), 141.62 (tria-
zole-C5), 152.51 (thiazole C2), 161.22 (thiazole C4),
164.31 (HC=N).
Synthesis of 2-(5-chloro-2-fluorobenzylsulfonyl)-5-(4-iso-
m/e: 488.10 (M?1), 349.1, 250.2.
propylthiazol-2-yl)-1,3,4-oxadiazole 11e IR (KBr) mmax
,
Synthesis of 2-(4-chlorobenzylsulfonyl)-5-(4-isopropylthi-
azol-2-yl)-1,3,4-oxadiazole 11a IR (KBr) mmax, cm-1
1671 (C=N), 3057 (Ar C–H), 1326 (assym), 1144 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.02(d, J = 8.5 Hz,
6H, 2CH3), 3.03 (m, 1H, isopropyl), 4.94(s, 2H, CH2), 7.2–
7.7 (m, 4H, phenyl and 1H of thiazole-C5).
13C NMR (DMSO-d6, 300 MHz) d: 22.41 (terminal
2CH3-isopropyl), 32.07 (tertiary-1C-isopropyl), 50.25(CH2),
115.32 (thiazole-C5), 122–165 (Ar), 151.21 (thiazole-C2),
154.54 (oxadiazole-C5), 161.95 (thiazole C4), 165.71
(oxadiazole-C2).
cm-1: 1622 (C=N), 3056 (Ar C–H), 1324 (assym), 1157
:
(sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.32(d, J = 8.5 Hz,
6H, 2CH3), 3.11 (m, 1H, isopropyl), 4.94(s, 2H, CH2),
7.2–7.8 (m, 3H, phenyl and 1H of thiazole-C5).
13C NMR(DMSO-d6, 300 MHz)d: 21.36(terminal 2CH3-
isopropyl), 32.44 (tertiary-1C-isopropyl), 51.74(CH2), 112.65
(thiazole-C5), 122–168 (Ar), 152.11(thiazole-C2), 154.38
(oxadiazole-C5), 164.32 (thiazole C4), 165.15 (oxadiazole-
C2).
m/e: 400.91 (100.0 %).
m/e: 385.82 (M?2), 383.91 (100.0 %).
Synthesis of 2-(4-bromobenzylsulfonyl)-5-(4-isopropylthi-
azol-2-yl)-1,3,4-oxadiazole 11b IR (KBr) mmax, cm-1
Biologic protocol
:
1671 (C=N), 3057 (Ar C–H), 1325 (assym), 1142 (sym) SO2.
1H NMR (DMSO-d6, 300 MHz) d: 1.31(d, J = 8.5 Hz,
6H, 2CH3), 3.05 (m, 1H, isopropyl), 4.98(s, 2H, CH2),
7.2–7.7 (m, 4H, phenyl and 1H of thiazole-C5).
Antimicrobial activity
The antimicrobial susceptibility testing was performed
in vitro by broth microdilution method (Hassan et al., 1983);
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Med Chem Res (2013) 22:4239–4252
4251
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.
(Khalil et al., 1993). The MIC determination of the synthe-
sized compounds was carried out in side-by-side comparison
with ciprofloxacin and norfloxacin against Gram-positive
bacteria (S. aureus, S. faecalis, B. subtilis) and Gram-
negative bacteria (K. penumoniae, E. coli, P. aeruginosa).
The antifungal activity was assayed against yeasts
(C. tropicalis, S. cerevisiae) and molds (A. niger). The
minimal inhibitory concentrations (MIC, lg/mL) were
defined as the lowest concentrations of a compound that
completely inhibited the growth of each strain. Test com-
pounds (10 mg) were dissolved in dimethylsulfoxide
(DMSO, 1 mL) and then diluted in culture medium (Muel-
ler–Hinton Broth for bacteria and Sabouraud Liquid Medium
for fungi) to obtain final concentrations of 0.5, 1, 2, 4, 8, 16,
31.25, 62.5, 125, 250, and 500 lg/mL. DMSO never
exceeded 1 % v/v. The tubes were inoculated with
105 cfu mL-1 (colony-forming unit/mL) and incubated at
37 °C for 24 h. The growth control consisting of media
(positive control) and media with DMSO (negative control)
at same dilutions as used in the experiments were employed.
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