A highly atom economic, chemo-, regio- and stereoselective synthesis and evaluation of spiro-pyrrolothiazoles as antitubercular agents

Article abstract of DOI:10.1016/j.bmcl.2009.10.107

The 1,3-dipolar cycloaddition of azomethine ylides derived from substituted isatins and 1,3-thiazolane-4-carboxylic acid to a series of 1-methyl-3,5-bis[(E)-arylmethylidene]-tetrahydro-4(1H)-pyridinones afforded novel spiro-pyrrolothiazoles chemo-, regio- and stereoselectively in quantitative yields. These compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB) using agar dilution method. Among the synthesized compounds, spiro[5.3′′]-5′′-nitrooxindole-spiro-[6.3′]-1′-methyl-5′-(2,4-di-chlorophenylmethylidene)tetrahydro-4′(1H)-pyridinone-7-(2,4-dichlorophenyl)tetra-hydro-1H-pyrrolo[1,2-c][1,3]thiazole (9k) was found to be the most active with a minimum inhibitory concentration (MIC) of 0.6 μM against MTB and MDR-TB.

Full text of DOI:10.1016/j.bmcl.2009.10.107

Bioorganic & Medicinal Chemistry Letters 20 (2010) 350–353
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Bioorganic & Medicinal Chemistry Letters
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A highly atom economic, chemo-, regio- and stereoselective synthesis
and evaluation of spiro-pyrrolothiazoles as antitubercular agents
Subramanian Vedhanarayanan Karthikeyan a, Balasubramanian Devi Bala a, Velanganni Paul Alex Raja a,
b
b
Subbu Perumal a, , Perumal Yogeeswari , Dharmarajan Sriram
*
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
b Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science, Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad 500 078, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The 1,3-dipolar cycloaddition of azomethine ylides derived from substituted isatins and 1,3-thiazolane-4-
Received 26 August 2009
Revised 22 October 2009
Accepted 24 October 2009
Available online 29 October 2009
carboxylic acid to
a series of 1-methyl-3,5-bis[(E)-arylmethylidene]-tetrahydro-4(1H)-pyridinones
afforded novel spiro-pyrrolothiazoles chemo-, regio- and stereoselectively in quantitative yields. These
compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB)
and multi-drug resistant M. tuberculosis (MDR-TB) using agar dilution method. Among the synthesized
compounds, spiro[5.300]-500-nitrooxindole-spiro-[6.30]-10-methyl-50-(2,4-di-chlorophenylmethylidene)-
tetrahydro-40(1H)-pyridinone-7-(2,4-dichlorophenyl)tetra-hydro-1H-pyrrolo[1,2-c][1,3]thiazole (9k) was
Keywords:
Antitubercular activity
Mycobacterium tuberculosis
Multi-drug resistant tuberculosis
Azomethine ylide
found to be the most active with a minimum inhibitory concentration (MIC) of 0.6
and MDR-TB.
lM against MTB
Ó 2009 Elsevier Ltd. All rights reserved.
1,3-Dipolar cycloaddition
Spiro-pyrrolothiazoles
Tuberculosis (TB) is mainly an illness of the respiratory system
caused by Mycobacterium tuberculosis (MTB). About one-third of
the world’s population is infected with TB, among which annually
about 8 million new cases and 3.1 million deaths are reported.1–7
Since 1985 and particularly in the 1990s, a search for new antitu-
berculosis substances has ranked among the priority areas of che-
motherapeutic research8 as (i) the current frontline therapy
consists of administering three drugs (isoniazid, rifampin, and pyr-
azinamide) during an extended period of time9 and (ii) the multi-
drug resistant tuberculosis (MDR-TB) aggravates the problems.
Further, HIV-infected patients have an elevated risk of primary or
reactivated tuberculosis, and such active infectious process may
enhance HIV replication and increase the risk of death. The World
Health Organization (WHO) has estimated that, if the present trend
continues, TB could claim more than 30 million lives between 2000
and 2020.10 Thus, there is an urgent need for the development of
potent new antituberculosis agents, having a unique mechanism
of action different from that of the currently used antitubercular
drugs, effective against both drug-susceptible and drug resistant
strains of M. tuberculosis with low toxicity profiles and shortened
therapy duration.11
Spiro compounds represent an important class of naturally
occurring substances with highly pronounced biological proper-
ties.12 1,3-Dipolar cycloaddition, both inter- or intramolecular, of
nonstabilised azomethine ylides to the olefinic dipolarophiles hav-
ing an exocyclic bond provides a facile route for the synthesis of
many spiroheterocycles comprising five membered nitrogen het-
erocycles.13 Pyrrolo[2,1-b]thiazole is an unusual ring system with
biological activity, viz. antineoplastic,14 hypoglycemic,15 modula-
tors of dopaminergic neurotransmission in CNS in vivo16 and as
c
-lactam analogues of the penems.17 Further, polyhydropyrrol-
o[2,1-b]thiazoles have interesting pharmacological properties and
have been successfully employed as intermediates in the synthesis
of pyrrolidines, such as racemic R-allokainic18 and kainic acids19 or
2S,4R-4-methylpyrrolidine-2,4-dicarboxylate.20 Retrosynthetic anal-
ysis of polyhydropyrrolo[2,1-b]thiazoles shows the 1,3-dipolar
addition of thiazolium ylides to alkenes as the most direct route
for their preparation.
In our ongoing effort to discover novel antitubercular lead can-
didates,21 we have recently reported the synthesis and antimico-
bacterial activity of spiro-pyrrolidines and pyrrolizines 3–522
through 1,3-dipolar cycloaddition of azomethine ylides generated
in situ from isatin 2 and a-amino acids viz. proline, phenylglycine,
and sarcosine to a series of 1-methyl-3,5-bis[(E)-arylmethyli-
dene]tetrahydro-4(1H)-pyridinones 1 (Fig. 1). These compounds
3–5 displayed excellent in vitro antimycobacterial activity against
* Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.107

S. V. Karthikeyan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 350–353
351
Figure 1.
Table 1
M. tuberculosis (MTB) and multi-drug resistant M. tuberculosis
(MDR-TB), wherein 4e with p-F phenyl rings was found to be the
most active in vitro with a MIC of 0.07 M against MTB and were
Yield and mp of spiro-pyrrolothiazoles 7–9
Entry Compd 7–9 Ar
Yield (%)
mp (°C)
l
5.1 and 67.2 times more potent than isoniazid and ciprofloxacin,
respectively. The excellent antimycobacterial activity of spiro-pyr-
rolidines/pyrrolizines in conjunction with the biological potential
of spiro-pyrrolothiazoles prompted us to undertake the synthesis
of the spiro-pyrrolothiazoles with different substituents on the
isatin nucleus and screen them for antimycobacterial activity with
a view to discerning the structural dependence of antimycobacte-
rial activity and report the results in this Letter.
Consequently, in the present work, azomethine ylides were
generated in situ from the reaction of differently substituted isa-
tins 2 with 1,3-thiazolane-4-carboxylic acid 6, which underwent
1,3-dipolar cycloaddition with 1-methyl-3,5-bis[(E)-arylmethyli-
dene]-tetrahydro-4(1H)-pyridinones 1 to afford spiro-[5.300]-oxin-
dole-spiro-[6.30]-10-methyl-50-arylmethylidene-tetrahydro-40(1H)-
pyridinone-7-aryltetrahydro-1H-pyrrolo[1,2-c][1,3]thiazoles 7–9
(Scheme 1).
7
8
9
7
8
9
1
2
3
4
5
6
7
8
9
10
11
12
13
a
b
c
d
e
f
g
h
i
C6H5
95 96 98
97 98 97
98 97 96
96 96 95
97 97 97
96 95 96
96 98
95 98 97
96 97 98
97 96 98
98 96 96
216 222 236
161 235 229
219 231 225
202 203 219
129 228 234
207 238 222
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-BrC6H4
4-PriC6H4
2-ClC6H4
2-MeC6H4
2-MeOC6H4
2,4-Cl2C6H3
a
—
223 214
—
219 223 207
227 221 215
205 199 231
223 225 218
197 209 221
210 231 219
j
k
l
2,4-(MeO)2C6H3 95 95 96
2-Thienyl 95 96 96
m
a
Reaction failed to occur.
The structure of spiro-pyrrolothiazoles 7–9 was elucidated with
the help of 1H, 13C and 2D NMR spectroscopic data as illustrated for
7b. In the 1H NMR spectrum of 7b (Fig. 2) the H-7 appears as a dou-
blet at 4.40 ppm (J = 10.2 Hz) which has a H,H-COSY correlation
with a multiplet (H-7a) at 4.60–4.68 ppm. Further, H-7 shows
HMBCs (Fig. 3) with the carbonyl carbon, C-40 at 197.2 ppm, spiro
carbon, C-6 at 71.5 ppm and C-1 at 33.5 ppm. The 1-CH2 hydrogens
appear as doublets of doublets at 2.78 ppm (J = 10.0, 6.9 Hz) and
3.00 ppm (J = 10.0, 5.6 Hz), respectively. The 3-CH2 hydrogens ap-
pear as a 1H multiplet at 3.45–3.55 ppm and 1H doublet at
3.70 ppm (J = 6.9 Hz) and they show HMBCs with C-7a and oxin-
dole spiro carbon, C-5 at 68.8 and 72.3 ppm, respectively. The dou-
blet at 1.76 ppm (J = 12.3 Hz) and the multiplet at 3.45–3.55 ppm
are assigned to 20-CH2 hydrogens, while the doublet at 3.37 ppm
(J = 14.1 Hz) and the doublet of doublets at 2.86 ppm (J = 14.1,
2.7 Hz) are assigned to the 60-CH2 hydrogens on the basis of
HMBCs. The singlets at 8.31 and 2.07 ppm are due to the NH of
oxindole ring and the N–CH3 hydrogens. The structure determined
from an X-ray crystallographic study of the single crystal of 7b is in
accord with the structure deduced from NMR spectroscopic data
(Figs. 4 and 5).23
These reactions were performed by heating an equimolar mix-
ture of 1-methyl-3,5-bis[(E)-arylmethylidene]-tetrahydro-4(1H)-
pyridinones 1, substituted isatins 2 and 1,3-thiazolane-4-carbox-
ylic acid 6 to reflux in methanol for one hour. After completion
of the reaction (tlc), the reaction mixture was poured into ice-
water, the resulting solid filtered and washed with water to afford
pure spiro-pyrrolothiazoles 7–9. These reactions afford solely the
spiro-pyrrolothiazoles in near quantitative yields (Table 1) and
hence neither crystallization nor column chromatographic purifi-
cation is necessary. A total of thirty eight spiro-pyrrolothiazoles
have been synthesized from this cycloaddition.
All the reactions proceed chemoselectively as the cycloaddi-
tion involves only one C@C bond of 1 furnishing exclusively the
mono spiro-cycloadducts 7–9. This reaction is regioselective with
the addition of the electron rich carbon of the dipole to the b car-
bon of 1 and stereoselective affording only one diastereomer in
excellent yields, albeit four stereocentres are present in these
cycloadducts. The atom economy of the reaction is also very high,
viz. 89–90% as water and carbon dioxide alone are generated as
waste.
Scheme 1. Synthesis of spiro-pyrrolothiazoles.

352
S. V. Karthikeyan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 350–353
Figure 2. Selected 1H and 13C NMR chemical shifts of 7b.
Figure 5. X-ray structure of 7c.
was resistant to rifampicin (RIF), isoniazid (INH) ethambutol and
pyrazinamide (PZA). The minimum inhibitory concentrations
(MIC) of 7–9 and the first line standard drugs are reported in
Table 2.
Figure 3. Selected HMBCs in 7b.
In the first phase of screening, all the compounds, except 7a,
showed excellent in vitro activity against MTB with a MIC of
Table 2
Minimum inhibitory concentrations
(lM) of spiro-pyrrolothiazoles 7–9 against
mycobacterial speciesa
Compd 7–9
MIC (lM)
MTB
MDR-TBb
7
8
9
8
9
a
b
c
d
e
f
g
h
i
j
k
l
49.2
5.4
23.3
22.0
5.7
23.1
5.1
11.0
20.8
2.8
4.4
10.1
5.1
11.0
20.8
1.2
18.9
11.4
5.6
1.3
5.3
10.3
1.4
—
—
—
—
—
—
—
1.4
2.3
—
2.6
—
—
0.6
—
—
2.8
4.7
1.1
—
—
—
—
—
2.4
—
—
c
c
10.6
10.9
23.3
22.0
4.7
19.9
12.1
0.1
—
2.6
5.3
5.1
0.6
9.4
5.5
m
Rifampicin
Isoniazid
Ethambutol
Pyrazinamide
3.8
11.4
61.2
0.4
7.6
50.8
Figure 4. X-ray structure of 7b.
406.1
a
MTB: Mycobacterium tuberculosis; MDR-TB: multi-drug resistant Mycobacterium
tuberculosis.
The compounds were screened for their in vitro antimycobacte-
rial activity against MTB and MDR-TB by agar dilution method for
the determination of MIC in duplicates. The MDR-TB clinical isolate
b
Compounds 4 not screened against MDR-TB, as they showed lower activity
against MTB.
c
Reaction failed and the compound could not be synthesised.

S. V. Karthikeyan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 350–353
353
623.3
(MIC: 50.8
7k–9k, 8h, 9a, 9c, 9h–j and 9m) inhibited MTB with a MIC of less
than 5.7 M and were more active than the ethambutol (MIC:
7.6
l
M and were more potent than the standard pyrazinamide
Acknowledgments
l
M). Nineteen compounds (7b–9b, 7e–9e, 7f–9f,
S.P. thanks the Department of Science and Technology, New
Delhi, for funding a major research project (No. SR/S1/OC-70/
2006) and for funds under (i) IRHPA program for funds for the pur-
chase of a high resolution NMR spectrometer and (ii) FIST program
and the University Grants Commission, New Delhi, for (i) funds un-
der the DRS and ASIST programs and (ii) for funding for a major re-
search project [F. No. 36-155/ 2008 (SR)]. S.V.K. and V.P.A.R. thank
the Council of Scientific and Industrial Research, New Delhi for the
award of a Senior Research Fellowship.
l
l
M). Among thirty eight compounds screened against MTB,
spiro[5.300]-500-nitrooxindole-spiro-[6.30]-10-methyl-50-(2,4-dichlor-
ophenylmethyli-dene)-tetrahydro-40(1H)-pyridinone-7-(2,4-dichl-
orophenyl)tetrahydro-1H-pyrrolo-[1,2-c][1,3]thiazole (9k) was
found to be the most active in vitro with MIC of 0.6 lM against
MTB, being 13 and 85 times more potent than ethambutol and
pyrazinamide, respectively. All the compounds, however, showed
lower activity than rifampicin and isoniazid (MIC: 0.1
0.4 M, respectively).
Subsequently, six compounds (8e, 8k, 9e, 9f, 9h and 9k) that
lM and
l
Supplementary data
displayed maximum activity against MTB were evaluated against
MDR-TB. All these inhibited MDR-TB with MIC ranging from 0.6
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.10.107.
to 2.8
available first line anti-TB drugs, viz. rifampicin (MIC: 3.8
isoniazid (MIC: 11.4 M), ethambutol (MIC: 61.2 M) and pyrazin-
amide (MIC: 406.1
M). The compound, spiro[5.300]-500-nitrooxin-
lM and were found to be more active than all the currently
l
M),
References and notes
l
l
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dole-spiro-[6.30]-10-methyl-50-(2,4-dichlorophenyl-methylidene)-
tetrahydro-40(1H)-pyridinone-7-(2,4-dichlorophenyl)tetrahydro-
1H-pyrrolo-[1,2-c][1,3]-thiazole (9k) again emerged to be the most
active one in vitro with a MIC of 0.6 lM against MDR-TB, as in the
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case of MTB, being more potent than the first line anti-TB drugs,
rifampicin (6 times), isoniazid (19 times), ethambutol (102 times)
and pyrazinamide (677 times).
With respect to structure-MTB activity relationship, the
results demonstrated that the antimycobacterial activity of the
spiro-pyrrolothiazoles diminish in the order: 9 > 8 > 7 as evident
from the fact that ten compounds in series 9 (9a–c, 9e, 9f, 9h–k
and 9m), five in series 8 (8b, 8e, 8f, 8h and 8k), and four in ser-
ies 7 (7b, 7e, 7f and 7k) were more active against MTB than eth-
ambutol (Table 2). Among the compounds from the series 7–9,
8. (a) Terrini, M.; Villani, P. Exp. Opin. Ther. Pat. 2001, 11, 261; (b) Crick, D. C.;
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Kobayashi, J.; Tsuda, M.; Agemi, K.; Shigemori, H.; Ishibashi, M.; Sasaki, T.;
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Chemistry; Wiley-Interscience: New York, 1984; Vol. 2. p 277.
compounds 7f and 7k (MIC: 4.7
lM), 8k (MIC: 1.2 lM), and 9k
(MIC: 0.6 M) were found to be the most active ones. These re-
l
sults demonstrate that the spiro-pyrrolothiazoles with chlorine
at 500-position of the isatin sub-structure is more active than
the unsubstituted isatin nucleus, while the presence of a nitro
group at 500-position conferred maximum activity. Similarly, the
presence of two chlorines in the phenyl rings also enhances
the activity.
14. Lalezari, I.; Schwartz, E. L. J. Med. Chem. 1988, 31, 1427.
15. Aicher, T. D.; Balkan, B.; Bell, P. A.; Brand, L. J.; Cheon, S. H.; Deems, R. O.; Fell, J.
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Nadelson, J.; Simpson, R.; Smith, H. C. J. Med. Chem. 1998, 41, 4556.
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17. (a) Maki, Y.; Sako, M.; Kurahashi, N.; Hirota, K. J. Chem. Soc., Chem. Commun. 1988,
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Tetrahedron Lett. 1986, 27, 3453; (c) Jephcote, V. J.; John, D. I.; Williams, D. J. J. Chem.
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18. Kraus, G. A.; Nagy, J. O. Tetrahedron 1985, 41, 3537.
It is pertinent to note that spiro-pyrrolothiazoles of the present
study having unsubstituted isatin sub-structure and aryl rings with
chlorine at the para position (7b, 5.4
ortho and para positions (7k, 4.7 M) showed better activity than
the previously reported structurally analogous spiro-pyrrolizines22
with p-Cl (3b, 22.73 M) and o,p-Cl2 (3j, 19.94 M) substituents,
lM) and two chlorines at
l
l
l
19. Monn, J. A.; Valli, M. J. J. Org. Chem. 1994, 59, 2773.
20. Esslinger, C. S.; Titus, J. L.; Koch, H. P.; Bridges, R. J.; Chamberlin, A. R. Bioorg.
Med. Chem. 2002, 10, 3509.
which differ from the spiro-pyrrolothiazoles only by the absence
of a sulfur atom. This clearly shows that the sulfur atom of the
spiro-pyrrolothiazoles enhances the activity by about ꢀ4 times.
21. (a) Indumathi, S.; Perumal, S.; Banerjee, D.; Yogeeswari, P.; Sriram, D. Eur. J. Med.
Chem. 2009. doi.org/10.1016/j.ejmech.2009.09.001; (b) Kumar, R.S.; Perumal, S.;
Shetty, K.A.; Yogeeswari, P.; Sriram, D. Eur. J. Med. Chem. 2009. doi.org/10.1016/
j.ejmech.2009.09.034; (c) Kumar, R.S.; Rajesh, S.M.; Perumal, S.; Banerjee, D.;
Yogeeswari, P.; Sriram, D. Eur. J. Med. Chem. 2009. doi.org/10.1016/j.ejmech.
2009.09.044; (d) Balamurugan, K.; Perumal, S.; Reddy, A. S. K.; Yogeeswari, P.;
Sriram, D. Tetrahedron Lett. 2009, 50, 6191; (e) Karthikeyan, S. V.; Perumal, S.;
Shetty, K. A.; Yogeeswari, P.; Sriram, D. Bioorg. Med. Chem. Lett. 2009, 19, 3006; (f)
Kumar, R. R.; Perumal, S.; Senthilkumar, P.; Yogeeswari, P.; Sriram, D. Eur. J. Med.
Chem. 2009, 44, 3821; (g) Kumar, R. R.; Perumal, S.; Manju, S. C.; Bhatt, P.;
Yogeeswari, P.; Sriram, D. Bioorg. Med. Chem. Lett. 2009, 19, 3461.
22. Kumar, R. R.; Perumal, S.; Senthilkumar, P.; Yogeeswari, P.; Sriram, D. J. Med.
Chem. 2008, 51, 5731.
23. Crystallographic data (excluding structure factors) for spiro-pyrrolothiazoles
7b and 7c in this letter have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication numbers CCDC
697774 and 745157. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
Similarly, spiro-pyrrolothiazoles,
8 and 9, respectively, with
chloro- and nitro-substitutions in the isatin ring led to further
enhancement of the activity relative to the compounds with
unsubstituted isatin ring of spiro-pyrrolizines 3, bearing similar
substituents in the aryl rings.
In conclusion, the 1,3-dipolar cycloaddition of azomethine ylide
generated in situ from substituted isatin and 1,3-thiazolane-4-car-
boxylic acid to 1-methyl-3,5-bis[(E)-arylmethyli-dene]tetrahydro-
4(1H)-pyridinones afforded thirty eight spiro-pyrrolothiazoles
7–9 in near quantitative yields. These spiroheterocycles displayed
good in vitro antimycobacterial activity against MTB and MDR-
TB. The antimycobacterial potency of these spiro heterocycles
renders them valid leads for synthesizing new heterocycles
endowed with enhanced activity.