Synthesis and biological evaluation of indolyl glyoxylamides as a new class of antileishmanial agents

Article abstract of DOI:10.1016/j.bmcl.2010.08.119

A series of indolylglyoxylamide derivatives have been synthesized and evaluated in vitro against amastigote form of Leishmania donovani. Compound 8c has been identified as the most active analog of the series with IC₅₀ value of 5.17 μM and SI value of 31.48, and is several folds more potent than the standard drugs sodium stilbogluconate and pentamidine.

Full text of DOI:10.1016/j.bmcl.2010.08.119

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6191–6194
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of indolyl glyoxylamides as a new class
of antileishmanial agents
Shikha S. Chauhan a, Leena Gupta a, Monika Mittal b, Preeti Vishwakarma b, Suman Gupta b,
Prem M. S. Chauhan a,
⇑
a Division of Medicinal and Process Chemistry, Central Drug Research Institute, CSIR, Lucknow 226001, India
b Parasitology Division, Central Drug Research Institute, CSIR, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 July 2010
Revised 23 August 2010
Accepted 24 August 2010
Available online 16 September 2010
A series of indolylglyoxylamide derivatives have been synthesized and evaluated in vitro against amas-
tigote form of Leishmania donovani. Compound 8c has been identified as the most active analog of the
series with IC50 value of 5.17
lM and SI value of 31.48, and is several folds more potent than the standard
drugs sodium stilbogluconate and pentamidine.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Antileishmanial
Indolylglyoxylamides
Tetrahydro-b-carboline
Leishmaniasis is one of the most neglected tropical diseases
caused by an obligate intracellular protozoan parasite belonging
to the genus Leishmania.1 It is transmitted to mammals by the bite
of an insect vector, namely, the phlebotomine sand fly. The parasite
exists in two different forms, the motile flagellated form (prom-
astigotes) found in the gut of the sand fly vector and the non-flag-
ellated form (amastigotes) found in the mammalian host, that is,
the cause of the acute disease.2 It manifests mainly in three clinical
forms: visceral leishmaniasis (VL), cutaneous leishmaniasis (CL),
and mucocutaneous leishmaniasis (MCL). Visceral leishmaniasis
(VL) commonly known as kala azar is caused by Leishmania dono-
vani and is most lethal, if left untreated.3 According to WHO esti-
and cutaneous leishmaniasis. Despite its great efficacy, miltefosine
is limited by its extremely long half-life (6–8 days), low therapeu-
tic index, and teratogenicity in animals.7 In view of the foregoing
facts, there is an urgent need for the development of antileishma-
nial agents based on new molecular scaffolds.
It has been reported earlier that indolylglyoxylamide derivatives
have anticancer activity.8 More recently, we have demonstrated
indolylglyoxylamide derivatives as potent antileishmanial agents.
Here, it was observed that indolylglyoxylamide derivatives,
obtained from tryptamine were more active as compared to those
obtained from cyclic/acyclic amines.9 Based on the above observa-
tion and our continuation of studies on chemotherapy of leishmania,
weplannedto synthesizea seriesof indolylglyoxylamidederivatives
mations, 12 million people are infected worldwide, with
2
million new cases per year, out of which 5,00,000 cases correspond
using L- and D-tryptophan methyl ester, followed by the conversion
of these esters into their corresponding acids (Table. 1).
to the visceral form.4
Unfortunately, treatment options for leishmaniasis are very
limited. Antimonials which have been the first line of treatment
options for VL for more than 50 years suffer from major side effects
including cardiac arrhythmia and pancreatitis.5 The second line
treatment option for VL includes pentamidine, miltefosine, and
amphotericin B. However, all of these drugs suffer from moderate
to severe side effects. Pentamidine, which is an aromatic diami-
dine, can lead to renal, pancreatic, and hepatic toxicity along with
hypotension and dysglycemia.6 Miltefosine, a phosphocholine ana-
log, is the first oral antileishmanial agent used to cure both visceral
Moreover, natural and synthetic b-carbolines and tetrahydro-
b-carbolines alkaloids are well-known compounds that possess a
variety of biological properties.10 Recent studies have pointed
b-carboline alkaloids as potential antileishmanial agents.11
Further, our group has also synthesized some novel b-carboline
derivatives showing good antileishmanial activity.12 Prompted by
this and in continuation of our efforts towards synthesis of novel
indolylglyoxylamide derivatives as antileishmanial agents we fur-
ther planned to synthesize another series of indolylglyoxylamide
derivatives with various tetrahydro-b-carbolines (Table.1).
All of these compounds were investigated for their in vitro
antileishmanial activity. Many of these derivatives were found to
possess strong inhibitory activity against L. donovani when
compared to the standard drugs. In this communication, we have
⇑
Corresponding author. Tel.: +91 522 2262411x4470; fax: +91 522 2623405.
E-mail addresses: prem_chauhan_2000@yahoo.com, premsc58@hotmail.com
(P.M.S. Chauhan).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.119

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S. S. Chauhan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6191–6194
Table 1
Various indolylglyoxylamide derivatives (6a–h) were synthe-
sized in high yield by reaction of -tryptophan methyl ester (2)
with different indole oxalyl chlorides (5) in presence of Et3N in
THF at room temperature for 4 h and were then converted to their
acid derivatives (7a–h) by refluxing them with 2 N HCl and acetic
All the synthesized compounds (6a–h), (7a–h), and (8a–h)
D/L
Compd no.
Isomer
R1
R2
R3
R4
6a
6b
6c
6d
6e
6f
6g
6h
7a
7b
7c
7d
7e
7f
L
H
H
H
H
Br
Br
OCH3
OCH3
H
H
H
H
Br
H
H
Cl
Cl
H
H
H
H
H
H
Cl
Cl
H
H
H
H
H
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
CH3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
H
D
L
acid (Scheme 1). The ester (2) was prepared by reaction of D/L-tryp-
D
L
tophan (1) with thionyl chloride in methanol. Similarly, another
series of indolylglyoxylamide derivatives (8a–p) were also synthe-
sized in high yield by reaction of indole oxalyl chloride (5) with dif-
ferent tetrahydro-b-carboline derivatives by refluxing in THF in
presence of K2CO3 (Scheme 2). These cis/trans isomers of b-carbo-
D
L
D
L
D
L
line derivatives were prepared by the reaction of D/L tryptophan (1)
with thionyl chloride in methanol and then the methyl ester (2)
was cyclized by Pictet–Spengler cyclization in the presence of dif-
ferent aromatic aldehydes.13 All the synthesized compounds are
well characterized by spectroscopic method such as IR, mass,
NMR, and elemental analysis.14
D
L
D
L
Br
7g
7h
8a
OCH3
OCH3
H
D
L
L
/cis
For assessing the activity of compounds against the amastigote
stage of the parasite, mouse macrophage cell line (J-774A.1) in-
fected with promastigotes expressing luciferase firefly reporter
gene was used. Cells were seeded in a 96-well plate (4 Â 104
8b
8c
8d
8e
8f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
Br
/trans
H
C2H5
C2H5
CH(CH3)2
CH(CH3)2
Cl
D
D
D
D
/cis
H
/trans
/cis
H
cells/100 lL/well) in RPMI-1640 containing 10% fetal calf serum
H
/trans
and the plates were incubated at 37 °C in a CO2 incubator. After
8g
8h
8i
H
L
L
L
L
/trans
/trans
/cis
24 h, the medium was replaced with fresh medium containing sta-
H
H
tionary phase promastigotes (4 Â 105/100
lL/well). Promastigotes
invade the macrophage and are transformed into amastigotes.
Br
Br
Br
Br
Br
Br
Br
Br
CH3
8j
CH3
/trans
The test material in appropriate concentrations (0.62–40 lM) in
8k
8l
C2H5
C2H5
CH(CH3)2
CH(CH3)2
Cl
D
D
D
D
/cis
complete medium was added after replacing the previous medium
and the plates were incubated at 37 °C in a CO2 incubator for 72 h.
After incubation, the drug containing medium was decanted and
/trans
/cis
8m
8n
8o
8p
/trans
50 lL PBS was added in each well and mixed with an equal volume
L
L
/trans
/trans
of Steady GloÒ reagent. After gentle shaking for 1–2 min, the read-
ing was taken in a luminometer.15 The inhibition of parasitic
growth is determined by comparison of the luciferase activity of
drug treated parasites with that of untreated controls as described
above. IC50 of antileishmanial activity were evaluated by logit
regression analysis.
H
reported the synthesis of novel indolylglyoxylamide derivatives
and their in vitro antileishmanial activity.
H2N
H2N
a
H3CO
N
H
O
HO
N
H
O
1
2
+
O
R1
R2
R1
R2
Cl
b
O
N
H
N
H
4a R1=R2=H
5
4b R1=H, R2=Cl
4c R1=Br,R2=H
4d R1=OMe, R2=H
c
O
O
H
H
N
R1
R2
N
R1
R2
d
O
O
N
H
H3CO
O
N
H
N
H
HO
O
N
H
6a-h
7a-h
Scheme 1. Reagents and conditions: (a) SOCl2, MeOH, reflux; (b) (COCl)2, THF, 0 °C; (c) THF, Et3N, rt, 4 h; (d) 2 N HCl, acetic acid, reflux, 2 h.

S. S. Chauhan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6191–6194
6193
O
H3CO
HN
N
H
H2N
a
R4
H3CO
N
H
O
R3
2
3
O
H3CO
+
O
O
R1
R2
N
R1
R2
Cl
N
H
b
O
N
H
R4
O
N
H
R3
5
8a-p
Scheme 2. Reagents and conditions: (a) different aromatic aldehyde, MeOH, reflux; (b) THF, K2CO3, reflux, 5h.
Indolylglyoxylamides derivatives (6a–h) prepared by combin-
ing - and -tryptophan methyl ester with substituted indole oxalyl
chlorides, were evaluated in vitro against transgenic L. donovani
Among all the indolylglyoxylamide derivatives (8a–h), synthe-
sized by combining indole oxalyl chlorides with tetrahydro-b-carb-
olines, most of them showed better inhibitory activity with the IC50
L
D
amastigotes. Though, a few of these compounds showed up to
values in the range of 3.79–8.04 lM and SI values in the range of
99–100% inhibition at 40
l
M concentrations but on further screen-
2.60–31.48 when compared to the standard drugs like Pentami-
dine (IC50 = 20.43, SI = 2.58) and SSG (IC50 = 71.90, SI = 5.53).
Among these indolylglyoxylamides, compound 8c having ethyl
group at the para position of the phenyl ring of tetrahydro-b-carb-
oline has emerged as the most promising candidate of this series
ing, they were not selective against amastigote model and were
overall found to be inactive and toxic. In order to increase the
activity and decrease the toxicity we converted these indo-
lylglyoxylamide derivatives (6a–h) into their corresponding acids
(7a–h) but unfortunately this resulted into the complete loss in
activity. Interestingly, the in vitro biological activities of indo-
lylglyoxylamide derivatives (8a–p) prepared by combining tetra-
hydro-b-carbolines (3) with indole/5-bromo indole oxalyl
chlorides, have shown encouraging results with IC50 values in the
which possess strong inhibitory activity with IC50 of 5.17 lM and
high selectivity index of 31.48. This lead molecule is 12- and 5-fold
more selective than the standard drugs Pentamidine and Sodium
stibogluconate (SSG), respectively. With the aim to study the influ-
ence of structural parameters on the antileishmanial activity, we
made several structural modifications in the molecules. In order
to find the influence of stereochemical modulations on the antile-
ishmanial activity of these indolylglyoxylamide derivatives, we
used different isomers of tetrahydro-b-carbolines but no signifi-
cant change was observed in its activity. Variation at the phenyl
ring of tetrahydro-b-carbolines showed remarkable influence on
the antileishmanial activity of these indolylglyoxylamide deriva-
tives. It was observed that an electron withdrawing group at phe-
nyl ring resulted in the decrease in IC50 values of these compounds.
Compound 8g, with chloro group at para position of the phenyl
range of 3.79–8.04 lM (Table 2.).
Table 2
Antileishmanial in vitro activity against intracellular amastigotes
Compd no.
Antiamastigote activity Cytotoxicity
IC50 M) CC50 M)
Selectivity
indexa (SI)
(l
(l
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
7.37
6.79
5.17
8.04
6.74
6.02
4.36
3.79
5.18
4.79
5.36
5.86
3.91
4.44
4.02
4.09
27.43
34.40
162.76
30.90
32.65
15.09
11.35
30.09
10.08
8.83
11.62
9.48
7.77
9.04
7.64
3.72
5.07
31.48
3.84
4.84
2.51
2.60
7.94
1.95
1.84
2.17
1.62
1.99
2.04
1.90
1.77
2.58
5.53
ring showed IC50 of 4.36
at the ortho position of the phenyl ring showed IC50 of 3.79
l
M and compound 8h with bromo group
M.
l
These values are much lower than their corresponding analog 8b
having methyl group at para position of phenyl ring with IC50 of
6.79 lM.
Further, to investigate the SAR effect of electron withdrawing
substituent on indole, we synthesized another set of indo-
lylglyoxylamides (8i–p) by combining 5-bromoindole oxalyl
chloride with same tetrahydro-b-carbolines as above. These com-
pounds also showed good inhibitory activity with IC50 values in
the range of 3.91–5.86 lM and these values were lower than their
analogous derivatives (8a–h). Moreover, compound 8j, with
methyl-substituted phenyl ring of tetrahydro-b-carboline showed
7.25
52.82
398.26
PentamidineÒ 20.43
SSGÒ
71.90
SSGÒ = sodium stibogluconate.
Selectivity index (SI) defined by the ratio CC50 (J-774 A-1 cells)/IC50 (Leish-
mania amastigotes).
IC50 of 4.79
chloro and bromo-substituted phenyl ring showed slightly low
IC50 of 4.02 M and 4.09 M, respectively. It reflects that an
lM and their corresponding analogs 8o and 8p with
a
l
l

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S. S. Chauhan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6191–6194
Commun. 2007, 355, 1091; (e) Gupta, L.; Srivastava, K.; Singh, S.; Puri, S. K.;
Chauhan, P. M. S. Bioorg. Med. Chem. Lett. 2008, 18, 3306; (f) Rook, Y.;
Schmidtke, K.-U.; Gaube, F.; Schepmann, D.; Wunsch, B.; Heilmann, J.;
Lehmann, J.; Winckler, T. J. Med. Chem. 2010, 53, 3611.
electron withdrawing group at the phenyl ring of tetrahydro-
b-carboline showed similar effect on the IC50 value as in above
case. But, by analyzing their in vitro activity data, it was found that
though their IC50 was lower than that of their corresponding ana-
logs (8a–h), they were more toxic and less selective. All these re-
sults clearly indicate that inclusion of 5-bromo indole in place of
indole in indolylglyoxylamide significantly increases the toxicity
of the final compounds (8i–p).
In conclusion, this study has identified indolylglyoxylamides of
tetrahydro-b-carbolines as an entirely new structural class of indo-
lylglyoxylamides with antileishmanial activity. The potent activity
and simple synthesis of these indolylglyoxylamides suggest that
they are potential candidates for the development of new antile-
ishmanial drugs and have opened a new avenue for further
exploration.
11. (a) Kam, T. S.; Sim, K. M.; Koyano, T.; Komiyama, K. Phytochemistry 1999, 50,
75; (b) Lala, S.; Pramanick, S.; Mukhopadhyay, S.; Bandyopadhyay, S.; Basu, M.
K. J. Drug Target. 2004, 12, 165; (c) Costa, E. V.; Pinheiro, M. L. B.; Xavier, C. M.;
Silva, J. R. A.; Amaral, A. C. F.; Souza, A. D. L.; Barison, A.; Campos, F. R.; Ferreira,
A. G.; Machado, G. M. C.; Leon, L. L. P. J. Nat. Prod. 2006, 69, 292.
12. (a) Kumar, R.; Khan, S.; Verma, A.; Srivastava, S.; Viswakarma, P.; Gupta, P.;
Meena, S.; Singh, N.; Sarkar, J.; Chauhan, P. M. S. Eur. J. Med. Chem. 2010, 45,
3274; (b) Kumar, A.; Katiyar, S. B.; Gupta, S.; Chauhan, P. M. S. Eur. J. Med. Chem.
2006, 41, 106.
13. (a) Tseng, M. C.; Liang, Y. M.; Chu, Y. H. Tetrahedron Lett. 2005, 46, 6131; (b)
Wang, L. T.; Huang, H.; Ye, Z. L.; Wu, Y.; Wang, X. C. Synth. Commun. 2006, 36,
2627; (c) Muthukrishnan, M.; More, S. V.; Garud, D. R.; Ramana, C. V. J.
Heterocycl. Chem. 2006, 43, 767; (d) Saha, B.; Sharma, S.; Sawant, D.; Kundu, B.
Tetrahedron Lett. 2007, 48, 1379.
14. Spectroscopic data for 8b: Yield: 72.0%; ESMS: 492 (M+1); mp: 160–162 °C;
IR(KBr) 3366, 3055, 2950, 1738, 1625, 1516, 1239, 822, 747 cmÀ1 1H NMR
;
(CDCl3, 200 MHz): 9.00 (br s, 1NH), 8.38–7.09 (m, 14H), 6.36 (s, 1H), 4.90–4.83
(m, 1H), 3.67 (s, 3H), 3.63–3.47 (m, 2H), 2.15 (s, 3H); 13C (CDCl3, 50 MHz):
186.53, 170.86, 149.87, 138.33, 137.34, 136.91, 136.69, 135.20, 128.73, 127.89,
127.52, 122.34, 120.98, 119.07, 118.75, 112.12, 109.56, 55.61, 52.40, 51.73,
24.55, 21.89; Anal. Calcd for C30H25N3O4: Calculated: C, 73.30; H, 5.13; N, 8.55.
Found: C, 73.42; H, 5.26; N, 8.28. Spectroscopic data for 8c: Yield: 74.0%; ESMS:
506 (M+1); mp: 172–174 °C; IR (KBr) 3358, 3018, 2924, 1740, 1624, 1517,
Acknowledgements
S.S.C. and L.G. thank ICMR and UGC, New Delhi, for financial
assistance and to the Sophisticated Analytical Instrument Facility,
CDRI, Lucknow for providing spectroscopic data. CDRI communica-
tion No. 7952.
1216, 831, 761 cmÀ1 1H NMR (CDCl3, 200 MHz): 9.05 (br s, 1NH), 7.89–7.30
;
(m, 14H), 6.87 (s, 1H), 5.05–5.02 (m, 1H), 3.67–3.25 (m, 5H), 2.67–2.63 (m, 2H),
1.29 (t, 3H, J = 5.80 Hz); 13C (CDCl3, 50 MHz): 185.35, 171.14, 144.57, 136.21,
135.94, 134.82, 130.14, 129.12, 127.86, 126.51, 124.38, 122.58, 119.83, 118.68,
119.98, 11.12, 107.92, 53.98, 52.13, 51.63, 28.54, 21.78, 15.67; Anal. Calcd for
References and notes
C
31H27N3O4: Calculated: C, 73.65; H, 5.38; N, 8.31. Found: C, 73.99; H, 5.15; N,
8.09. Spectroscopic data for 8e: Yield: 70.0%; ESMS: 520 (M+1); mp: 162–
164 °C; IR (KBr) 3378, 3057, 2958, 1742, 1623, 1515, 1239, 831, 746 cmÀ1 1H
1. Akopyants, N. S.; Kimblin, N.; Secundino, N.; Patrick, R.; Peters, N.; Lawyer, P.;
Dobson, D. E.; Beverley, S. M.; Sacks, D. L. Science 2009, 324, 265.
2. Rogers, M.; Kropf, P.; Choi, B. S.; Dillon, R.; Podinovskaia, M.; Bates, P.; Muller, I.
PLoS Pathog. 2009, 5, e1000555.
;
NMR (CDCl3, 300 MHz): 9.01 (br s, 1NH), 8.36–7.02 (m, 14H), 6.82 (s, 1H),
5.02–5.00 (m, 1H), 3.23–2.87 (m, 8H), 1.26 (d, 6H, J = 6.88 Hz); 13C (CDCl3,
75 MHz): 185.31, 169.86, 168.55, 149.13, 136.30, 136.09, 135.89, 134.91,
130.17, 129.07, 126.50, 126.22, 124.37, 122.57, 122.08, 121.97, 119.81, 118.66,
114.60, 111.99, 111.10, 107.85, 56.18, 51.90, 51.55, 33.82, 23.93, 23.61; Anal.
Calcd for C32H29N3O4: Calculated: C, 73.97; H, 5.63; N, 8.09. Found: C, 73.47; H,
5.97; N, 8.32. Spectroscopic data for 8f: Yield: 73.0%; ESMS: 520 (M+1); mp:
3. http://www.who.int/tdr/diseases/leish/diseaseinfo.htm.; (b) Sharma, U.; Singh,
S. Indian J. Exp. Biol. 2009, 47, 412.
4. WHO, Available at: http://www.who.int/leishmaniasis/burden/en.
5. Murray, H. W.; Berman, J. D.; Davies, C. R.; Saravia, N. G. Lancet 2005, 366, 1561.
6. Poola, N. R.; Kalis, M.; Plakogiannis, F. M.; Taft, D. R. J. Antimicrob. Chemother.
2003, 52, 397.
158–160 °C; IR (KBr) 3362, 3056, 2957, 1737, 1625, 1516, 1238, 829, 746 cmÀ1
;
7. Herwaldt, B. L. N. Engl. J. Med. 1999, 341, 1840.
1H NMR (CDCl3, 200 MHz): 8.93 (br s, 1NH), 8.33–6.95 (m, 14H), 6.39 (s, 1H),
5.10–5.09 (m, 1H), 3.66–2.67 (m, 8H), 1.21 (d, 6H, J = 6.90 Hz); 13C (CDCl3,
50 MHz): 184.36, 170.99, 148.99, 148.20, 136.58, 136.28, 136.23, 135.51,
132.50, 128.71, 126.92, 126.43, 124.09, 123.10, 122.48, 122.02, 119.89, 118.44,
111.89, 111.22, 107.52, 57.62, 52.96, 52.62, 33.67, 23.89, 23.60; Anal. Calcd for
8. (a) Li, W. T.; Hwang, D. R.; Chen, C. P.; Shen, C. W.; Huang, C. L.; Chen, T. W.; Lin,
C. H.; Chang, Y. L.; Chang, Y. Y.; Lo, Y. K.; Tseng, H. Y.; Lin, C. C.; Song, J. S.; Chen,
H. C.; Chen, S.; Wu, S. H.; Chen, C. T. J. Med. Chem. 2003, 46, 1706; (b) James, D.
A.; Koya, K.; Li, H.; Liang, G.; Xia, Z.; Ying, W.; Wu, Y.; Sun, L. Bioorg. Med. Chem.
Lett. 2008, 18, 1784; (c) Li, W. T.; Hwang, D. R.; Song, J. S.; Chen, C. P.; Chuu, J. J.;
Hu, C. B.; Lin, H. L.; Huang, C. H.; Huang, C. Y.; Tseng, H. Y.; Lin, C. C.; Chen, T.
W.; Lin, C. H.; Wang, H. S.; Shen, C. C.; Chang, C. M.; Chao, Y. S.; Chen, C. T. J.
Med. Chem. 2010, 53, 2409.
C
32H29N3O4: Calculated: C, 73.97; H, 5.63; N, 8.09. Found: C, 73.48; H, 5.08; N,
8.17. Spectroscopic data for 8g: Yield: 72.0%; ESMS: 512 (M+1); mp: 162–
164 °C; IR (KBr) 3390, 3022, 2936, 1732, 1625, 1518, 1218, 769 cmÀ1 1H NMR
;
(CDCl3 + CD3OD, 200 MHz): 9.12 (br s, 1NH), 9.05 (br s, 1NH), 7.10–8.31 (m,
13H), 6.41 (s, 1H), 4.81 (m, 1H), 3.73 (s, 3H), 3.59–3.34 (m, 2H); 13C
(CDCl3 + CD3OD, 50 MHz): 188.33, 176.06, 144.67, 137.90, 136.86, 135.76,
132.53, 130.12, 129.96, 127.97, 127.06, 125.86, 123.36, 123.23, 122.11, 117.83,
116.10, 115.28, 108.23, 61.39, 56.39, 52.67, 51.81, 26.51; Anal. Calcd for
9. Gupta, L.; Talwar, A.; Nishi; Palne, S.; Gupta, S.; Chauhan, P. M. S. Bioorg. Med.
Chem. Lett. 2007, 17, 4075.
10. (a) Srivastava, S. K.; Agarwal, A.; Chauhan, P. M. S.; Agarwal, S. K.; Bhaduri, A.
P.; Singh, S. N.; Fatima, N.; Chatterjee, R. K. J. Med. Chem. 1999, 42, 1667; (b)
Kuo, P. C.; Shi, L. S.; Damu, A. G.; Su, C. R.; Huang, C. H.; Ke, C. H.; Wu, J. B.; Lin,
A. J.; Bastow, K. F.; Lee, K. H.; Wu, T. S. J. Nat. Prod. 2003, 66, 1324; (c) Sun, B.;
Morikawa, T.; Matsuda, H.; Tewtrakul, S.; Wu, L. J.; Harima, S.; Yoshikawa, M. J.
Nat. Prod. 2004, 67, 1464; (d) Wang, Y.-H.; Tang, J.-G.; Wang, R.-R.; Yang, L.-M.;
Dong, Z.-J.; Du, L.; Shen, X.; Liu, J.-K.; Zheng, Y.-T. Biochem. Biophys. Res.
C
29H22ClN3O4: Calculated: C, 68.04; H, 4.33; N, 8.21. Found: C, 68.24; H, 4.06;
N, 8.39.
15. Porwal, S.; Chauhan, S. S.; Chauhan, P. M. S.; Shakya, N.; Verma, A.; Gupta, S. J.
Med. Chem. 2009, 52, 5793.