A regio- and stereoselective 1,3-dipolar cycloaddition for the synthesis of new-fangled dispiropyrrolothiazoles as antimycobacterial agents

Article abstract of DOI:10.1016/j.bmcl.2012.10.059

A series of dispiropyrrolothiazoles compounds were synthesized using 1,3-dipolar cycloaddition and were screened for antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv and INH resistant M. tuberculosis strains. Two of them were showing good activity with MIC of less than 1 μM. Compound (5f) was found to be the most active with MIC of 0.210 and 8.312 μM respectively.

Full text of DOI:10.1016/j.bmcl.2012.10.059

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7418–7421
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Bioorganic & Medicinal Chemistry Letters
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A regio- and stereoselective 1,3-dipolar cycloaddition for the synthesis
of new-fangled dispiropyrrolothiazoles as antimycobacterial agents
Abdulrahman I. Almansour a, Sadath Ali d, Mohamed Ashraf Ali b,c,d, , Rusli Ismail b, Tan Soo Choon b,
⇑
Velmurugan Sellappan d, Karthi keyan Elumalai d, Suresh Pandian d
a Department of Chemistry, College of Sciences, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia
b Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia
c New Drug Discovery Research, Department of Medicinal Chemistry, Alwar Pharmacy College, Alwar, Rajasthan 301030, India
d New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar, Rajasthan 301030, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2012
Revised 23 September 2012
Accepted 12 October 2012
Available online 22 October 2012
A series of dispiropyrrolothiazoles compounds were synthesized using 1,3-dipolar cycloaddition and
were screened for antimycobacterial activity against Mycobacterium tuberculosis H37Rv and INH resistant
M. tuberculosis strains. Two of them were showing good activity with MIC of less than 1
(5f) was found to be the most active with MIC of 0.210 and 8.312 M respectively.
lM. Compound
l
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Antimycobacterial
1,3-Dipolar cycloaddition
Azomethine ylide
Intermolecular
Indanone
Dispiro
Over the last century, tuberculosis (TB) has killed more than
100 million people and this has continued relatively unchanged
over the last 50 years, despite the development of effective antitu-
berculous drugs. TB disproportionally affecting the world’s poorest
populations, and remains one of the major public health problems
in the 21st century.1 TB drug development has made substantial
progress in the past decade.2 TB continues to affect the young
and the middle-aged adults faster than any other disease apart
from AIDS. In 2007, about 13.7 million prevalent cases of with
1.3 million deaths were reported and 0.5 million cases of multi-
drug-resistant (MDR-TB) among HIV negative incident cases of
TB were reported. Today, TB remains one of the leading infectious
disease around the world. the emerging drug-resistant strains of
the disease are presenting a new challenge in the ever changing
battle to control and prevent TB.2 The spread of Multidrug-resis-
tant tuberculosis (MDR-TB) and the appearance of extensively
drug-resistant tuberculosis (XDR-TB) pose new challenges for the
control of fatal tuberculosis. So it is vital that new, reasonable
and nontoxic drugs to be developed, which act by different mech-
anism from those of existing drugs. Such drugs would greatly
tackle resistance emergency.3
The next threat for tuberculosis is the emergence of drug resis-
tant strains of Mycobacterium tuberculosis. The antituberculosis
drugs that are currently utilized in the treatment are associated
with severe toxicity and adverse effects. In spite of toxicity on
repeated dosing of isoniazid (INH) is still considered to be a first
line drug in the chemotherapy of tuberculosis.4
Spiro compounds especially are known for their antimycobacte-
rial properties and many of them have shown comparable or even
better activities than some of the first-line TB drugs.5,6 Hence, our
group has synthesized and evaluated a series of novel five and
six-membered heterocyles using various technique in the purpose
to obtain novel and more potent antimycobacterial agents.7–13 As
part of the ongoing our research program to synthesis the novel
five-membered heterocyclic derivatives and were screened for
antimycobacterial activity against Mycobacterium tuberculosis
H37Rv (MTB) and INH resistant Mycobacterium tuberculosis
(INHR-MTB) (Schemes 1 and 2).
Herein we report the synthesis of indanone substituted dispiro-
pyrrolothiazoles through [3+2]-cycloaddition reaction of azome-
thine ylide generated in situ from 1-morpholinoindoline-2,
3-dione and thiazoline-4-carboxylic acid to arylmethylideneinda-
nones. The synthesized compounds were screened for their
antimycobacterial activity and the results are presented in this
Letter.
⇑
Corresponding author.
E-mail address: asraf80med@yahoo.com (M.A. Ali).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.059

A. I. Almansour et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7418–7421
7419
O
O
O
O
O
Ar
O
S
Ar-CHO
EtOH
NaOH
3-4hrs
N
N
N
O
3
O
N
O
N
O
O
O
S
5a-e
O
O
+
COOH
N
O
H
F3CO
Ar
O
NH
2
1
4
Ar
O
S
N
O
O
NH
O
F3CO
5f-j
Scheme 1. Protocol for synthesis of titled compounds.
S
O
r
N
R1
S
-CO2
O
O
+
CO2H
N
H
R1
N
N
R
R
2
3/4
O
O
O
Ar
1
O
O
N
Ar
N
O
R1
S
O
R
5a-j
Scheme 2. Plausible mechanism for the regioselective formation of compounds 5a–j.
The reactions were initially performed by heating an equimolar
mixture of the starting materials under reflux in methanol and
were subsequently investigated under microwave irradiation in a
focused microwave synthesizer, as this technique has evolved as
a valuable alternative to conventional heating for the introduction
of energy into reactions and has clear benefits in many chemical
transformations, including cycloadditions, in terms of rate acceler-
ations and yield enhancements. As in the case of the thermal
reactions, an equimolar mixture of the starting materials 1–3/4 in
methanol was subjected to microwave irradiation14–26 for 4–8 min
until completion of the reaction (TLC) and the pyrrolothiazole
derivatives purified by crystallization. The results obtained for
both methods are summarized in (Table 1), and they clearly show
that microwave irradiation lead to an enhancement in the yield of
the product (88–92%) over the conventional thermal method
(66–72%). This cycloaddition proceeds regioselectively with the
electron rich carbon of the dipole adding to the b-carbon of the
,b-unsaturated moiety of 1 and stereoselectively affording only
one diastereomer exclusively, despite the presence of four stereo-
a
centres in the product.
The structure of the newly synthesized dispiropyrrolothiazoles
were elucidated using NMR, CHN and mass spectrometry. All the
analytical and spectral data showed that the synthesized
compounds were in full agreement with the proposed structures.
In the 1H NMR spectrum, the signals of the respective protons of
the synthesized compounds were verified on the basis of their
chemical shifts, multiplicities and coupling constants. 1H NMR
spectrum of 5e showed
a multiplet in the region d 0.85–
0.91 ppm corresponding to morpholino CH2 groups; a doublets at
2.98, 3.03 ppm with (J = 11.4 Hz, 3.6 Hz) is due to H-3 protons.
The doublets 3.20, 3.28 ppm (J = 6.6, 6.9 Hz) is due to each H-1
protons and the doublet at 3.75, 3.93 ppm (J = 21.3 Hz, 1.2) is due

7420
A. I. Almansour et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7418–7421
Table 1
Comparison of the reaction time, yields for thermal and microwave-assisted [3+2]-cycloaddition reactions and antimycobacterial activity of pyrrolidine derivatives 5a–j
O
O
Ar
N
O
R1
S
O
N
R
Compd
Ar
R
R1
Conventional method (MeOH,
reflux)
Microwave irradiation
(MIC)
MTBa
lM
(MIC)
l
Cytotoxicity
(lg/mL)
(100 °C,100 W)
M MTBb
Time (h)
Yield (%)
Yield (%)
Time (min)
Yield (%)
5a
5b
5c
5d
5e
5f
5g
5h
Pyridyl–
4-Fluorophenyl–
3,4-Dimethoxyphenyl– Morpholino
Phenyl–
2-Chlorophenyl–
Pyridyl–
4-Fluorophenyl–
3,4-Dimethoxyphenyl–
Phenyl–
Morpholino
Morpholino
H
H
H
H
H
6
72
66
70
72
68
67
68
72
70
66
—
5
7
6
5
8
4
5
5
91
92
90
87
88
92
88
86
92
90
—
2.419
8.121
26.219
35.121
24.195
>6.25
18.295
8.312
16.638
22.214
>6.25
36.415
11.23
>62.5
>62.5
>62.5
>62.5
>62.5
>62.5
>62.5
>62.5
>62.5
>62.5
>62.5
4.5
4.5
3.5
2.5
21.195
>6.25
6.295
0.210
0.720
12.21
>6.25
11.415
0.730
Morpholino
Morpholino
H
H
H
H
H
—
OCF3 4.0
OCF3 3.0
OCF3 3.5
OCF3 2.5
OCF3 4.0
5i
5j
4
4.5
—
2-Chlorophenyl–
—
Isoniazid
—
—
a
Mycobacterium tuberculosis H37Rv.
INH resistant Mycobacterium tuberculosis.
b
one proton each of H-300CH2 proton, singlet at 3.84, 3.86 ppm due
to OCH3 proton, while the other protons of multiplet at 4.81 ppm
H-7a proton, doublets at 4.01 ppm due to H-7 proton respectively.
The aromatic protons appear doublets at around 6.6, 6.8 and 7.9
(J = 5.7 Hz, J = 3.3 Hz and 7.5 Hz) and muliplets at 7.11–7.35 ppm.
The synthesized compounds 5a–j was tested for their antimyco-
bacterial activity in vitro against Mycobacterium tuberculosis (MTB-
with reduced reaction time compared to conventional heating.
Among the newer derivatives, compounds 5f exhibited good activ-
ity against MTB and INHR-MTB. It is conceivable that derivatives
showing antimycobacterial activity can be further modified to
exhibit better potency than standard drugs. Further studies to
acquire more information about quantitative structure–activity
relationships (QSAR) are in progress in our laboratory.
H
37Rv) and INHR-MTB using agar dilution method27 for the deter-
mination of minimum inhibitory concentration (MIC). The MIC was
defined as the minimum concentration of compound required to
inhibit 90% of bacterial growth and MIC’s of the compounds were
reported in (Table 1) with standard drug INH for comparison.
Among the ten newly synthesized compounds, compound 5f pro-
duced highest worth and exhibited >90% inhibition against MTB
Acknowledgment
This project was supported by Research Center, College of
Science, King Saud University and thanks to Universiti Sains
Malaysia for biological studies.
at a concentration of 0.210
followed by 5g, 5a, and 5e showing moderate inhibitory activity
at 0.720, 2.419, 6.295 M, against INHR-MTB 13.638, 15.121 and
18.295 M and respectively. The pyridine group substitution (5f)
lM and against INHR-MTB 8.312 lM,
Supplementary data
l
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
10.059.
l
derivatives displayed relatively higher inhibitory activity in gen-
eral. However the electron rich group such as chloro, flouro substi-
tuted analogues produced potent inhibitory against both tested
strains. On the other hand the analogue dimethoxy substituted
phenyl (5c), (5h) and phenyl substituted groups (5d) and (5i)
showed relatively moderate to low antitubercular activity. These
reports clearly showed 4-trifluorometoxy substituted analogue
with pyridyl substitution causes remarkable improvement in anti-
mycobacterial activity higher inhibitory activity against both
tested organisms instead of N-substituted morpholino analogues.
All the compounds were tested for cytotoxicity (IC50) in VERO
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