Synthesis and biological evaluation of 2-arylamino-5- (3′-Indolyl)-1,3,4-oxadiazoles as potent cytotoxic agents

Full text of DOI:10.1002/cmdc.201300221

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Rationally simple: Coupling of two key
scaffolds in medicinal chemistry, the
indole and 1,3,4-oxadiazole ring sys-
tems, gave rise to 2-arylamino-5-(3’-in-
dolyl)-1,3,4-oxadiazoles with IC50 values
in the nanomolar range against a panel
of tumor cell lines. Preliminary struc-
ture–activity relationship studies indi-
cate potential for improved selectivity
through further manipulation of the
oxadiazole C-2 and C-5 positions.
M. P. Tantak, A. Kumar, B. Noel, K. Shah,*
D. Kumar*
&& – &&
Synthesis and Biological Evaluation of
2-Arylamino-5-(3’-Indolyl)-1,3,4-
Oxadiazoles as Potent Cytotoxic
Agents
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DOI: 10.1002/cmdc.201300221
Synthesis and Biological Evaluation of 2-Arylamino-5-(3’-
Indolyl)-1,3,4-Oxadiazoles as Potent Cytotoxic Agents
Mukund P Tantak,[a] Anil Kumar,[a] Brett Noel,[b] Kavita Shah,*[b] and Dalip Kumar*[a]
The indole nucleus is a privileged scaffold that is highly preva-
lent in natural and synthetic compounds of medicinal inter-
est.[1] It is found in many clinical therapeutic agents (e.g., indo-
methacin, indorenate and indoramin) and endogenous biologi-
cally active substances (e.g., serotonin, melatonin, tryptophan
and brassinin). Molecules containing an indole nucleus display
a diverse range of biological activities, such as anticancer, anti-
diabetic, antirheumatoidal, antioxidant and antiviral propertie-
s,[2a] and are known to play a crucial role in the immune sys-
tem.[2b,3] In recent years, several indole-containing heterocyclic
compounds with interesting activities have been isolated or
synthesized. For example, Labradorins (1), indolyloxazole-de-
rived natural products, have been reported to exhibit potent
in vitro growth inhibition of human cancer cells with GI50
values of 40.8 mm (non-small-cell lung carcinoma) and 25.8 mm
(pancreatic adenocarcinoma).[4] Camalexin (2) is a characterstic
phytoalexin of Arabidopsis thaliana that is induced by a variety
of plant pathogens.[5] Topsentins (3),
a class of bis-
(indole)alkaloid natural products isolated from the marine
sponge Topsentina genitrix, inhibit the growth of leukemia cells
in vitro.[6] Nortopsentins A–C (4) exhibit in vitro cytotoxicity
against murine leukemia (P388) cells with IC50 values of 16660,
20670 and 4500 mm, respectively.[7] Meridianins (5) and their
analogues have shown good anticancer activities against
human breast adenocarcinoma (MCF-7) cells (IC50 =1.10 mm).[8]
In 2011, Gavagnin et al. reported the isolation of Phidianidine-
s A and B (6) from the marine
opisthobranch mollusk Phidiana
militaris; these natural products
were found to display high cyto-
toxicity against both tumor and
nontumor cell lines.[9] A recent
report from Li et al. described
a series of 2-aryl-4-benzoyl-imi-
dazoles (ABI-III) where replace-
ment of the aryl ring with an
indole nucleus enhanced the an-
tiproliferative activity; the 3-
indole derivative (7) showed re-
markable activity aganist mela-
noma and prostate cancers
through inhibition of tubulin
polymerization, with typical IC50
values around 3.8 nm.[10] Given
the observed improvement in
activity imparted by the intro-
duction of an indole scaffold on
to an imidazole, a similar design
strategy might be used for other
nitrogen-containing heterocycles
that are reported to possess de-
[a] M. P. Tantak, A. Kumar, Prof. D. Kumar+
Department of Chemistry
sirabale physiochemical properties and pharmacokinetic pro-
file, such as oxadiazoles (e.g., IMC-094332 (8) in Scheme 1),[11]
to yield potent cytotoxic agents.
Birla Institute of Technology and Science, Pilani
Pilani 333031, Rajasthan (India)
The five-membered oxadiazole ring system is an important
structural motif, found in a wide range of biologically potent
compounds and known to have applications in medicinal
chemistry as bioisosteres for ester and amide functionali-
ties.[12–14] In particular, 2-arylamino-1,3,4-oxadiazoles are impor-
tant chemical entities due to their interesting biological prop-
erties[15,16] and various applications in materials science as pho-
tosensitizers and organic light-emitting diodes.[17] Indolyl-1,3,4-
E-mail: dalipk@pilani.bits-pilani.ac.in
[b] B. Noel, Prof. K. Shah+
Department of Chemistry
Purdue Cancer Center, Purdue University
560 Oval Drive, West Lafayette, IN 47907 (USA)
E-mail: shah23@purdue.edu
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201300221.
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oxadiazoles (i.e., 9 in Scheme 1), reported as analogues of nat-
urally occurring Labradorins (1), show in vitro cytotoxicity in
the micromolar range.[18] Furthermore, 2-arylamino-5-(2,4-dihy-
droxy-phenyl)-1,3,4-thiadiazoles (e.g., FABT (10) in Scheme 1)
have also emerged as potent cytotoxic agents.[19]
diazoles typically involves the use of mercury and lead salts,
iodine in the presence of base, tosyl chloride in combination
with pyridine, 2-chloro-1-methylpyridinium iodide (Mukaiya-
ma’s reagent), 2-iodoxybenzoic acid (IBX), hydantoin-potassium
iodide, and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroni-
um tetrafluoroborate (TBTU) in the presence of N,N-diisopropy-
lethylamine (DIEA).[14,25–27] In the literature, the required inter-
mediate acylthiosemicarbazides, prepared from reaction of
a carboxylic acid and a thiosemicarbazide, were cyclized to the
corresponding 1,3,4-oxadiazoles by employing coupling re-
agents, such as carbodiimides 1-ethyl-3-(3-dimethylaminopro-
pyl)carbodiimide hydrochloride (EDCI·HCl), N,N’-dicyclohexyl-
carbodiimide (DCC), and PS-carbodiimide.[27] Alternatively, 2-ar-
ylamino-1,3,4-oxadiazoles were synthesized by amination of
oxadiazol-2-ones using phosphorous oxychloride and an ap-
propriate amine.[28] Recently, Telvekar et al. reported the prepa-
ration of 2-arylamino-1,3,4-oxadiazoles by using activated
iodine(III) species, generated in situ from iodobenzene and
oxone in the presence of triethylamine.[26b] Given the versatility
of this last method, synthesis of the designed 2-arylamino-
1,3,4-oxadiazoles (11 a–m) was carried out from readily avail-
able indolylhydrazides (12) via iodobenzene diacetate (IBD)-
mediated desulfurization of the intermediate acylthiosemicar-
bazides (13) (Scheme 2).
Readily available indolylhydrazides 12 were prepared from
the correspoding indole-3-carboxylates and hydrazine hydrate.
Reaction of indolylhydrazides 12 with aryl isothiocyanates in
ethanol gave acylthiosemicarbazides 13 in almost quantitative
yields. Subsequent cyclodesulfurization of acylthiosemicarba-
zides 13 with IBD in acetonitrile afforded final compounds
11 a–m with yields ranging from 72–85%. Attempts using
other hypervalent iodine reagents such as Dess–Martin periodi-
nane (DMP), o-iodoxybenzoic acid (IBX) and [bis(trifluoroace-
toxy)-iodo]benzene required ex-
Cancers are among the most harmful diseases and are a lead-
ing cause of death worldwide.[20a] Over the past decade, several
chemotherapeutic agents have been identified including pacli-
taxel, docetaxel, ixabepilone and doxorubicin. However, due to
drug resistance, toxicity, low bioavailability, and solubility prob-
lems associated with the drugs currently in clinical use, there is
a need to develop more effective drugs with decreased side ef-
fects.[20b] Several bis(indolyl)-thiophenes,[21a] pyrazoles,[21b] fur-
ans,[21c] isoxazoles,[21d] pyrroles,[21e] indolyl-phenyl and azaindo-
lylphenyl thiazoles[21f] have been reported as antiproliferative
agents. Moreover, several indolyloxadiazoles and indolylthiadi-
azoles have been identified as anticancer agents.[22]
On the basis of the above-mentioned observations regard-
ing the potential of oxadiazoles and indoles and our own pre-
vious observations regarding the importance of the indole
motif in conferring anticancer activity together with interesting
cytotoxicity, a series of 2-arylamino-1,3,4-oxadiazoles (11 a–m)
were designed, incorporating both the indolyloxadiazole and
arylamino-oxadiazole key scaffolds, with an aim to obtain
potent and selective cytotoxic agents (Scheme 1).
2-Arylamino-1,3,4-oxadiazoles can be prepared either by cy-
clodehydration of semicarbazides or cyclodesulfurization of thi-
osemicarbazides. Cyclodehydration to form 1,3,4-oxadiazoles
has previously been achieved by using concentrated sulfuric
acid, para-toluenesulfonyl chloride (tosyl chloride), phospho-
rous oxychloride, thionylchloride, bromine, and methyl N-(trie-
thylammoniumsulfonyl)carbamate (Burgess reagent).[23,24] Cy-
clodesulfurization of acylthiosemicarbazides to form 1,3,4-oxa-
tended reaction times (8–10 h)
and gave compounds 11 in com-
paratively poor yields (40–50%).
It was also observed that the re-
action in other solvents includ-
ing dichloromethane and chloro-
form
remained
incomplete,
probably due to poor solubility
of acylthiosemicarbazides 13.
The optimized protocol was
used to prepare 2-arylamino-
1,3,4-oxadiazoles 11 a–m.
2-Arylamino-5-(3’-indolyl)-
1,3,4-oxadiazoles 11 a–m were
assessed for their in vitro cyto-
toxicity against human embryon-
ic kidney cells (HEK293), and
a panel of cancer cell lines: cervi-
cal (HeLa), prostate (LNCaP and
PC3) and breast (MCF-7 and
MDA-MB-231. Doxorubicin was
evaluated in parallel as a positive
control, and the IC50 values were
Scheme 1. Design strategy of 2-arylamino-5-(3’-indolyl)-1,3,4-oxadiazoles. The dashed boxes indicate the key core
structure present in previously reported compounds.
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active in HeLa cells with an IC50 value in the nanomolar range.
Introduction of para-methoxy (11 c) or trimethoxy (11 d) group
in the anilino ring led to compounds with significantly im-
provement cytotoxic activity, particularly against prostate
cancer cell line (PC-3 and LNCaP). The trimethoxy derivative
(11 d) was also found to exhibit potent cytotoxicity in HEK293
cells, with an IC50 value of 0.1 mm.
Compounds 11 e and 11 g with an electronegative substitu-
ent (F and Cl, respectively) on the phenyl group of the C-2
N-arylamino motif (R2) exhibited good cytotoxicity across all
cell lines tested, however, the cytotoxicity observed against
MCF-7 (11 e, IC50 =0.4 mm; 11 g, IC50 =0.1 mm) and HeLa (11 e,
IC50 =1.0 mm; 11 g, IC50 =0.3 mm) cancer cell lines was particu-
larly potent. Furthermore, para-chloro analogue 11 g showed
improved activity against a pancreatic cancer cell line (PC-3,
IC50 =0.2 mm), whereas para-fluoro analogue 11 e was found to
be selectively cytotoxic against HeLa and MCF-7 cells. Replace-
ment of the methyl moiety in compound 11 b by a trifluoro-
methyl group (11 f) imparted improved activity against LNCaP
cells, however, activity was decreased to varying degrees
against the other cell lines tested.
Scheme 2. Optimized protocol for the preparation of 2-arylamino-1,3,4-oxa-
diazoles 11 a–m via cyclodesulfurization of acylthiosemicarbazides 13. Re-
agents and conditions: a) R2NCS, EtOH, 608C 2–3 h, 85–95%; b) PhI(OAc)2,
CH3CN, RT, 3–4 h, 72–85%. For R groups, see Table 1.
determined from the results of the MTT assay (Table 1). The re-
sults indicate that substituents at the C-2 and C-5 positions of
the 1,3,4-oxadiazole ring have significant impact on the poten-
cy of derivatives 11 a–m. Most of the compounds exhibited
significant anticancer activities in the cell lines tested, with IC50
values in the nanomolar to micromolar range.
Introduction of a methoxy group at the indole 5 position of
compound 11 c to give analogue 11 h led to a tenfold im-
provement in activity against HEK293 and MCF-7 cells, and
fourfold improvement against MDA-MB-231 cells. The same
modification to trimethoxy analogue 11 d to give compound
11 i resulted in significantly improved cytotoxicity against HeLa
cells (IC50 <0.001 mm). The presence of a bromo substituent at
the indole 5 position was found to be beneficial for activity. 5-
Bromoindoles 11 j and 11 k displayed improved activity against
The structure–activity relationships (SAR) were probed
through altering substituents in the indole (R1) and N-arylami-
no (R2) moieties. Unsubstituted derivative 11 a (R1 =H; R2 =Ph)
was found to be active against the cancer cell lines tested. In
general, electron-donating groups on the phenyl ring of the
N-arylamino moiety (R2) were found to be beneficial for the ac-
tivity. Analogue 11 b with methyl substituent displayed en-
hanced activity against all cell lines tested, but was particularly
Table 1. In vitro cytotoxicity data for 2-arylamino-5-(3’-indolyl)-1,3,4-oxadiazoles 11 a–m against a panel of cell lines.[a]
Compd
R1
R2
IC50 [mm][b]
HEK293
HeLa
LNCaP
MCF-7
PC3
MDA-MB-231
11 a
11 b
11 c
11 d
11 e
11 f
11 g
11 h
11 i
11 j
11 k
11 l
11 m
Doxorubicin
Labradorin 1
H
H
H
H
H
H
H
C6H5
4-CH3C6H4
4-OCH3C6H4
3,4,5-(OCH3)3C6H2
4-FC6H4
1.5Æ0.01
2.4Æ0.04
1.0Æ0.01
0.1Æ0.01
7.2Æ0.14
10.6Æ0.1
4.7Æ0.14
0.1Æ0.01
0.3Æ0.01
0.6Æ0.006
1.1Æ0.01
1.1Æ0.02
0.2Æ0.01
0.4Æ0.02
–
2.2Æ0.04
<0.001[c]
3.1Æ0.1
3.0Æ0.01
2.8Æ0.01
0.5Æ0.01
0.9Æ0.01
11.2Æ0.13
0.6Æ0.01
1.0Æ0.06
4.6Æ0.03
0.7Æ0.03
0.2Æ0.01
0.6Æ0.01
5.7Æ0.47
3.7Æ0.07
0.3Æ0.01
–
1.6Æ0.01
0.2Æ0.01
1.0Æ0.01
0.5Æ0.03
0.4Æ0.03
0.2Æ0.01
0.1Æ0.01
0.1Æ0.004
6.4Æ0.4
4.7Æ0.40
0.8Æ0.07
0.1Æ0.01
0.2Æ0.01
9.7Æ0.38
2.7Æ0.01
0.2Æ0.02
0.7Æ0.01
2.0Æ0.1
0.8Æ0.01
0.2Æ0.01
7.6Æ0.19
0.9Æ0.06
4.3Æ0.31
5.8Æ0.1
0.5Æ0.01
1.0Æ0.04
0.2Æ0.01
0.3Æ0.03
10.3Æ0.30
<0.001[c]
0.1Æ0.002
1.7Æ0.03
0.8Æ0.03
1.5Æ0.12
0.9Æ0.04
–
4-CF3C6H4
4-ClC6H4
1.5Æ0.06
1.9Æ0.04
55.0Æ3.5
0.9Æ0.03
0.3Æ0.03
64.4Æ0.51
0.8Æ0.01
1.5Æ0.11
–
5-OCH3
5-OCH3
5-Br
5-Br
H
4-OCH3C6H4
3,4,5-(OCH3)3C6H2
4-OCH3C6H4
3,4,5-(OCH3)3C6H2
CH2C6H5
1.1Æ0.01
1.4Æ0.01
<0.001[c]
0.1Æ0.003
1.4Æ0.06
16.23[d]
0.2Æ0.01
0.2Æ0.01
0.1Æ0.01
0.1Æ0.01
0.7Æ0.02
–
6-F
4-OCH3C6H4
[a] Human embryonic kidney cells (HEK293), and cervical (HeLa), prostate (LNCaP and PC3) and breast (MCF-7 and MDA-MB-231) cancer cells. [b] IC50
values were obtained from dose–response curves by nonlinear regression using a curve fitting program (GraphPad Prism 5.0). Data are the mean Æstan-
dard error of the mean (SEM) of at three independent experiments performed in triplicate. SEM was <10% for all values. IC50 values <0.1 mm are given in
bold. [c] Due to the potent nature of the compound and the limitations of the assay used, the IC50 value could not be accurately determined. [d] Data con-
verted from the half maximal growth inhibition (GI50) value of 3.9 mgmLÀ1 given in Ref. [4].
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the MDA-MB-231 cell line over the unsubstituted indole ana-
logues 11 c and 11 d, however derivative 11 j with a single me-
thoxy group in the para position of the N-arylamino moiety
(R2) also exhibited a 30-fold improvement in cytotoxicity
against the HeLa cell line. Compound 11 l with an unsubstitut-
ed indole (R1 =H) and an N-benzyl moiety in the R2 position
exhibited cytotoxicity in the nanomolar range against MCF-7
cells and good cytotoxicity against all other cell lines test with
the except of MDA-MB-231. Incorporation of a fluoro substitu-
ent at the 6 position of the indole ring was found to be benefi-
cial for activity. 6-Fluoroindole 11 m showed improved cytotox-
icity over analogue 11 c against HEK293 cells (IC50 =0.2 mm)
and breast cancer cell lines (MCF-7, IC50 =0.1 mm; MDA-MB-231,
IC50 =0.8 mm).
lines tested. Interestingly, compounds 11 i and 11 l although
exceedingly potent against most cell lines tested, were not as
cytotoxic in MDA-MB-231 cells. Compounds with electron-with-
drawing substituents in the C-2 N-aryl ring (11 e–g) exhibited
a greater range of IC50 values across the tested cell lines, indi-
cating potential selective cytotoxicity. Also, the introduction of
electron-donating (MeO) and electron-withdrawing (Br and F)
substituents in the indolyl ring resulted in derivatives with en-
hanced cytotoxicity, and again, the spread of IC50 values sug-
gests some potential selectivity. Finally, preliminary mechanism
of action studies indicated that these compounds induce
apoptosis in MDA-MB-231 cancer cells, though further studies
are required to confirm the molecular mechanism of these
agents.
Finally, we investigated the mechanism of cell death in
MDA-MB-231 cells using two compounds: 11 a and 11 e, select-
ed for their potency against this cell line (IC50 =0.8 and 4.3 mm,
respectively). After incubation for 48 h, MDA-MB-231 cells were
fixed and stained with propidium iodide, and their nuclear
morphology was analyzed using fluorescence microscopy.
While DMSO-treated control cells revealed normal healthy
nuclei, inhibitor-treated cells showed apoptotic nuclei
(Figure 1), suggesting that apoptosis is the major mechanism
Experimental Section
Chemistry
All laboratory grade reagents were obtained commercially from Al-
drich or Spectrochem. The reactions were monitored by thin layer
chromatography (TLC) performed on commercially available Merck
precoated plates (silica gel 60 F254, 0.25 mm). Melting points (mp)
were determined on an Ez Melt melting point apparatus and are
uncorrected.1H NMR spectra were recorded on a Bruker advance II
(400 MHz) spectrophotometer using [D6]DMSO as a solvent. Mass
spectra (MS) were obtained on a Bruker ProFLEX III MALDI-TOF
(matrix: 2,5-dihydroxybenzoic acid (2,5-DHB)) or a ABI Sciex 5800
ESI-TOF mass spectrometer. Analyses were performed on
a Waters 515 HPLC system equipped with a reverse-phase Sunfire
C18 column (5 mm, 4.6 mmꢁ250 mm) and photodiode array detec-
tors, at a flow rate of 1 mLminÀ1 and a gradient of solvent A
(MeOH) and solvent B (CH3CN). HPLC traces for all final products
(11 a–m) are provided in the Supporting Information.
Figure 1. Propidium iodide staining of MDA-MB-231 cells treated with com-
pounds 11 a and 11 e for 48 h. DMSO was used as a control. Scale: 10 mm.
Synthesis of indole-3-carbohydrazides (12): A solution of indole-
3-carboxylic acid (1 mmol) in EtOH (20 mL) was treated with a cata-
lytic amount of concentrated sulfuric acid (0.2 mL), and the reac-
tion was heated at reflux for 20 h. After completion, the solvent
was removed in vacuo, and the residue was extracted with EtOAc
(2ꢁ15 mL). The combined organic extracts were washed with satu-
rated aq NaHCO3 (25 mL), dried over anhydrous Na2SO4, filtered
and concentrated in vacuo to give the corresponding ester in
good yield (85–95%). The ester was used in the subsequent step
without further purification A solution of the ester (1 mmol) and
NH2NH2·H2O (2 mmol) in EtOH (15 mL) was heated at reflux for 4 h.
The reaction mixture was cooled to RT, and the resultant solid was
isolated by filtration and recrystallized from EtOH to obtain pure
hydrazides 12.
by which these 2-arylamino-1,3,4-oxadiazoles promote cell
death in MDA-MB-231 cancer cells. Some recent studies on aryl-
amino-1,3,4-oxadiazoles and analogues have shown that the
antiproliferative activities of these oxadiazoles could be due to
the inhibition of tubulin polymerization or inhibition of kinases,
such as GSK3b, VEGFR-2 and CK2.[11b,29a] Another study by
Ziedan et al. has shown that indole-based 3,5-disubstituted ox-
adiazole promote apoptosis, which is consistent with our fin-
dings.[29b] However, the exact molecular target of 2-arylamino-
5-(3’-indolyl)-1,3,4-oxadiazoles remains unknown at this stage,
and further mechanism of action studies are currently under-
way.
Indole-3-carbohydrazide (12a): White solid (850 mg, 85%): Rf =
0.30 (hexane/EtOAc, 1:9); mp: 232–2348C; 1H NMR (400 MHz,
[D6]DMSO): d=11.31 (s, 1H), 9.14 (s, 1H), 8.17 (d, J=7.1 Hz, 1H),
7.95 (d, J=2.8 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.20–6.99 (m, 2H),
3.95 ppm (s, 2H); IR (KBr): n˜ =3256, 3109, 1660, 1607, 1583, 1523,
1433, 1240, 736 cmÀ1; MS (ESI): m/z (%): 175.2 [M]+ (100).
In summary, a convenient and general protocol for the syn-
thesis of a range of 2-arylamino-5-(3’-indolyl)-1,3,4-oxadiazoles
in high yields by employing IBD-mediated oxidative desulfuri-
zation of readily available acylthiosemicarbazides 13 has been
developed. Results from anticancer screening showed that
compounds 11 a–m possess significant antiproliferative activity
against a panel of cell lines. The most potent compounds
(11 b, 11 i and 11 l), with N-(tolyl), N-(trimethoxyphenyl) and N-
(benzyl) motifs at the C-2 position of the 1,3,4-oxadiazole core,
exhibited IC50 values in the nanomolar range against most cell
5-Methoxyindole-3-carbohydrazide (12b): White solid (900 mg,
90%): Rf =0.28 (hexane/EtOAc, 1:9); mp: 178–1798C; 1H NMR
(400 MHz, [D6]DMSO): d=11.68 (s, 1H), 9.64 (s, 1H), 7.61 (s, 1H),
7.49 (s, 1H), 7.40 (d, J=8.0 Hz, 2H), 4.18 (s, 2H), 3.86 ppm (s, 3H);
IR (KBr): n˜ =3340, 3290, 3050, 2920, 1646, 1605, 1545, 778,
724 cmÀ1; MS (ESI): m/z (%): 206.2 [M+H]+ (100).
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5-Bromoindole-3-carbohydrazide (12c): White solid (900 mg,
90%): Rf =0.32 (hexane/EtOAc, 1:9); mp: 255–2578C; 1H NMR
(400 MHz, [D6]DMSO): d=11.68 (s, 1H), 9.78 (s, 1H), 7.62 (s, 1H),
7.52 (s, 1H), 7.46 (d, J=8.00 Hz, 2H), 4.23 ppm (s, 2H); IR (KBr): n˜ =
3340, 3290, 3050, 2920, 1646, 1605, 1545, 778, 724 cmÀ1; MS (ESI):
m/z (%): 253.0 [M]+ (100).
3.70 ppm (s, 3H); 13C NMR (100.6 MHz, [D6]DMSO): d=158.2, 155.5,
152.9, 136.3, 135.1, 131.9, 125.7, 123.9, 122.4, 120.6, 120.3, 112.0,
99.9, 94.6, 60.1, 55.5 ppm; IR (KBr): n˜ =3494, 3209, 1650, 1560,
1504, 1450, 1234, 1126, 955, 817, 748 cmÀ1; HRMS (MALDI): m/z
[M+H]+ calcd for C19H19N4O4: 367.1406, found: 367.0526; HPLC:
tR =2.85 min (98.2% purity).
6-Fluoroindole-3-carbohydrazide (12d):[22a] Off-white solid
(850 mg, 85%): Rf =0.33 (hexane/EtOAc, 1:9); mp: 204–2058C; IR
(KBr): n˜ =3310, 3163, 3070, 2931, 1620, 1542, 1442, 1218, 1141,
N-(4-Fluorophenyl)-5-(1H-indol-3-yl)-1,3,4-oxadiazol-2-amine
(11e): Light brown powder (72 mg, 81%): Rf =0.45 (hexane/EtOAc,
5:5); mp: 215–2178C; 1H NMR (400 MHz, [D6]DMSO): d=11.58 (s,
1H), 10.24 (s, 1H), 8.15 (d, J=7.0 Hz, 1H), 7.81 (d, J=3.4 Hz, 1H),
7.68–7.64 (m, 2H), 7.51–7.49 (m, 1H), 7.26–7.18 (m, 2H), 7.09–
7.02 ppm (m, 2H); IR (KBr): n˜ =3409, 3294, 1643, 1581, 1535, 1488,
1350, 1126, 940, 740 cmÀ1; HRMS (MALDI): m/z [M+H]+ calcd for
C16H12FN4O: 295.0995, found: 295.1038; HPLC: tR =2.97 min (99.0%
purity).
778, 724 cmÀ1
.
Synthesis of 1-(indole-3-carbonyl)-4-arylthiosemicarbazides (13):
Indole-3-carbohydrazide 12 (2.8 mmol) and aryl isothiocyanate
(2.8 mmol) were added to a round-bottom flask containing EtOH
(10 mL), and the reaction was stirred at 608C for 2–3 h. The resul-
tant solid was isolated by filtration and dried in vacuo to obtain
thiosemicarbazides 13 in good yield (85–95%). The products were
obtained in sufficient purity to be used without further purification
in the next step. Characterization data for thiosemicarbazides 13a–
m are given in the Supporting Information.
5-(1H-Indol-3-yl)-N-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-
amine (11 f): Off-white powder (77 mg, 85%): Rf =0.55 (hexane/
EtOAc, 4:6); mp: 206–2088C; 1H NMR (400 MHz, [D6]DMSO): d=
11.57 (s, 1H), 10.65 (s, 1H), 8.17 (d, J=7.6 Hz, 1H), 7.89 (d, J=
11.2 Hz, 2H), 7.83 (d, J=7.7 Hz, 2H), 7.59 (d, J=7.7 Hz, 1H), 7.51 (d,
J=7.4 Hz, 1H), 7.28–7.19 ppm (m, 2H); IR (KBr): n˜ =3425, 3271,
1643, 1572, 1427, 1326, 1249, 1118, 804, 725 cmÀ1; HRMS (MALDI):
m/z [M+H]+ calcd for C17H12F3N4O: 345.0963, found: 345.0812;
HPLC: tR =3.13 min (98.9% purity).
Synthesis of 2-arylamino-5-(indolyl)-1,3,4-oxadiazoles (11a–m):
A solution of thiosemicarbazide 12 (0.85 mmol) in dry CH3CN
(5 mL) was cooled to 108C and treated portionwise with iodoben-
zene diacetate (1 mmol). The reaction was stirred for 3–4 h at RT.
Upon completion, the solvent was removed in vacuo, and the resi-
due was triturated with hexane to afford crude product. Recrystali-
zation from EtOH gave pure compound 11 in good yield (72–85%).
N-(4-Chlorophenyl)-5-(1H-indol-3-yl)-1,3,4-oxadiazol-2-amine
(11g): Off-white powder (69 mg, 77%): Rf =0.50 (hexane/EtOAc,
4:6); mp: 237–2398C; 1H NMR (400 MHz, [D6]DMSO): d=11.85 (s,
1H), 10.67 (s, 1H), 8.09 (d, J=7.6 Hz, 1H), 7.96 (s, 1H), 7.67 (d, J=
7.6 Hz, 2H), 7.54 (d, J=7.7 Hz, 1H), 7.43 (d, J=7.4 Hz, 2H), 7.27–
7.24 ppm (m, 2H); IR (KBr): n˜ =3409, 3294, 1643, 1581, 1535, 1488,
1215, 1126, 740, 680 cmÀ1; MS (ESI): m/z (%): 311.2 [M+H]+ (100);
HPLC: tR =3.20 min (99.2% purity).
5-(1H-Indol-3-yl)-N-phenyl-1,3,4-oxadiazol-2-amine (11a): Light
brown powder (133 mg, 75%): Rf =0.45 (hexane/EtOAc, 4:6); mp:
1
212–2148C; H NMR (400 MHz, [D6]DMSO): d=11.73 (s, 1H), 9.87 (s,
1H), 8.07 (d, J=7.3 Hz, 1H), 7.86 (s, 1H), 7.98 (d, J=2.8 Hz, 1H),
7.52 (t, J=8.2 Hz, 3H), 7.22 (td, J=13.8, 6.5 Hz, 2H), 7.13 ppm (d,
J=8.3 Hz, 2H); 13C NMR (100.6 MHz, [D6]DMSO): d=158.6, 156.0,
139.5, 136.9, 129.5, 126.9, 124.4, 123.0, 121.8, 121.2, 120.7, 117.3,
112.8, 100.3 ppm; IR (KBr): n˜ =3193, 1620, 1550, 1450, 1178, 750,
694 cmÀ1; MS (ESI): m/z (%): 277.1 [M+H]+ (100); HPLC: tR =
2.67 min (97.7% purity).
5-(5-Methoxy-1H-indol-3-yl)-N-(4-methoxyphenyl)-1,3,4-oxadia-
zol-2-amine (11h): Off-white powder (69 mg, 77%): Rf =0.35
(hexane/EtOAc, 3:7); mp: 210–2128C; 1H NMR (400 MHz,
[D6]DMSO): d=11.51 (s, 1H), 10.05 (s, 1H), 8.10 (s, 1H), 7.77 (d, J=
2.6 Hz, 1H), 7.61 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.39 (d, J=8.8 Hz,
1H), 6.90–6.78 (m, 3H), 3.86 (s, 3H), 3.77 ppm (s, 3H); IR (KBr): n˜ =
5-(1H-Indol-3-yl)-N-(4-methylphenyl)-1,3,4-oxadiazol-2-amine
(11b): Redish brown powder (191 mg, 78%): Rf =0.50 (hexane/
EtOAc, 4:6); mp: 240–2428C; 1H NMR (400 MHz, [D6]DMSO): d=
11.71 (s, 1H), 10.22 (s, 1H), 8.12 (d, J=7.3 Hz, 1H), 7.87 (d, J=
2.8 Hz, 1H), 7.52–7.54 (m, 3H), 7.18–7.25 (m, 2H), 7.14 (d, J=
8.3 Hz, 2H), 2.29 ppm (s, 3H); 13C NMR (100.6 MHz, [D6]DMSO): d=
158.2, 155.5, 136.3, 136.2, 130.2, 129.1, 125.5, 123.9, 122.4, 120.5,
120.3, 116.8, 111.9, 100.2, 20.3 ppm; IR (KBr): n˜ =3178, 1612, 1581,
1504, 1420, 1160, 954, 748 cmÀ1; HRMS (MALDI): m/z [M+H]+
calcd for C17H15N4O: 291.1246, found: 291.1237; HPLC: tR =3.15 min
(98.0% purity).
3317, 3178, 1650, 1581, 1512, 1419, 1234, 1180, 970, 720 cmÀ1
;
HRMS (MALDI): m/z [M+H]+ calcd for C18H17N4O3: 337.1301, found:
337.1664; HPLC: tR =3.10 min (98.7% purity).
5-(5-Methoxy-1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)-1,3,4-ox-
adiazol-2-amine (11i): Light brown powder (66 mg, 72%): Rf =0.30
(hexane/EtOAc, 3:7); mp: 250–2528C; 1H NMR (400 MHz,
[D6]DMSO): d=11.31 (s, 1H), 10.06 (s, 1H), 8.03 (d, J=8.8 Hz, 1H),
7.59 (s, 1H), 6.99 (s, 2H), 6.90 (d, J=8.6 Hz, 1H), 6.77 (d, J=8.6 Hz,
1H), 3.81 (s, 6H), 3.78 (s, 3H), 3.67 ppm (s, 3H); 13C NMR
(100.6 MHz, [D6]DMSO): d=161.3, 156.3, 153.3, 152.9, 137.2, 137.1,
132.0, 125.1, 121.3, 118.4, 110.5, 106.9, 95.0, 94.6, 60.1, 55.6,
55.0 ppm; IR (KBr): n˜ =3217, 3186, 1658, 1604, 1350, 995, 833,
702 cmÀ1; HRMS (MALDI): m/z [M+H]+ calcd for C20H21N4O5:
397.1512, found: 397.141; HPLC: tR =2.88 min (97.2% purity).
5-(1H-Indol-3-yl)-N-(4-methoxyphenyl)-1,3,4-oxadiazol-2-amine
(11c): Light brown powder (67 mg, 75%): Rf =0.45 (hexane/EtOAc,
4:6); mp: 215–2178C; 1H NMR (400 MHz, [D6]DMSO): d=11.83 (s,
1H), 10.27 (s, 1H), 8.09 (d, J=7.0 Hz, 1H), 7.93 (s, 1H), 7.56–7.51
(m, 3H), 7.27–7.21 (m, 2H), 6.96 (d, J=8.8 Hz, 2H), 3.73 ppm (s,
3H); IR (KBr): n˜ =3340, 3139, 1635, 1570, 1512, 1458, 1226, 1141,
1030, 833, 794 cmÀ1; MS (ESI): m/z (%): 307.1 [M+H]+ (100); HPLC:
tR =3.48 min (98.3% purity).
5-(5-Bromo-1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)-1,3,4-oxa-
diazol-2-amine (11j): Brown powder (69 mg, 75%): Rf =0.32
(hexane/EtOAc, 3:7); mp: 263–2658C; 1H NMR (400 MHz,
[D6]DMSO): d=12.65 (s, 1H), 10.32 (s, 1H), 8.36–8.32 (m, 2H), 8.18
(s, 1H), 7.61 (s, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.45 (dd, J=8.6, 1.9 Hz,
1H), 4.08 (s, 3H), 3.99 (s, 3H), 3.94 ppm (s, 3H); IR (KBr): n˜ =3260,
3240, 1643, 1550, 1512, 1427, 1242, 1141, 686 cmÀ1; HRMS (MALDI):
5-(1H-Indol-3-yl)-N-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-2-
amine (11d): Light brown powder (73 mg, 80%): Rf =0.45 (hexane/
EtOAc, 3:7); mp: 263–2658C; 1H NMR (400 MHz, [D6]DMSO): d=
11.67 (s, 1H), 10.23 (s, 1H), 8.14 (d, J=7.5 Hz, 1H), 7.85 (s, 1H), 7.51
(d, J=7.6 Hz, 1H), 7.26–7.18 (m, 2H), 7.03 (s, 2H), 3.85 (s, 6H),
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 2 – 7
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m/z [M+H]+ calcd for C19H18BrN4O4: 447.0491, found: 446.9796;
HPLC: tR =3.21 min (98.7% purity).
A in PBS for 1 h, rinsed, and stained with 2.5 mgmLÀ1 propidium
iodide in PBS for 1 h. Before mounting with Mowiol, coverslips
were washed twice with PBS and once with H2O. Each experiment
was repeated three independent times. Images were taken using
a Nikon Eclipse E600 microscope (Nikon Instruments, Melville, NY,
USA).
5-(5-Bromo-1H-indol-3-yl)-N-(4-methoxyphenyl)-1,3,4-oxadiazol-
2-amine (11k): Light brown powder (73 mg, 78%): Rf =0.35
(hexane/EtOAc, 3:7); mp: 199–2018C; 1H NMR (400 MHz,
[D6]DMSO): d=11.67 (s, 1H), 9.98 (s, 1H), 9.47 (d, J=7.7 Hz, 1H),
8.36–8.28 (m, 1H), 8.17 (d, J=9.0 Hz, 1H), 7.45–7.25 (m, 3H), 6.86
(dd, J=8.7, 8.6 Hz, 2H), 3.77 ppm (s, 3H); IR (KBr): n˜ =3240, 3109,
1674, 1473, 1419, 1311, 1226, 1134, 933, 765 cmÀ1; HRMS (MALDI):
m/z [M+H]+ calcd for C17H14BrN4O2: 387.0280, found: 387.0356;
HPLC: tR =2.96 min (97.3% purity).
Acknowledgements
The authors gratefully acknowledge the University Grants Com-
mission (UCG), New Delhi (India) for financial support and the
Sophisticated Analytical Instrumentation Facility (SAIF), Panjab
University (India) for providing analytical support.
N-Benzyl-5-(1H-indol-3-yl)-1,3,4-oxadiazol-2-amine (11l): Off-
white powder (68 mg, 76%): Rf =0.45 (hexane/EtOAc, 3:7); mp:
1
268–2708C; H NMR (400 MHz, [D6]DMSO): d=11.73 (s, 1H), 9.87 (s,
1H), 8.07 (d, J=7.3 Hz, 1H), 8.00 (d, J=7.6 Hz, 1H), 7.86 (s, 1H),
7.48–7.47 (m, 1H), 7.41–7.33 (m, 3H), 7.30–7.23 (m, 3H), 4.44 ppm
(s, 2H); 13C NMR (100.6 MHz, [D6]DMSO): d=162.5, 155.8, 139.2,
136.6, 128.8, 127.8, 127.5, 126.4, 124.5, 122.9, 121.0, 120.7, 112.8,
100.8, 46.7 ppm; IR (KBr): n˜ =3217, 3186, 1658, 1604, 1350, 995,
833, 702 cmÀ1; MS (ESI): m/z (%): 291.3 [M+H]+ (100); HPLC: tR =
2.99 min (98.3% purity).
Keywords: anticancer activity · apoptosis · cytotoxic agents ·
indoles · 1,3,4-oxadiazoles
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EtOAc, 3:7); mp: 259–2618C; 1H NMR (400 MHz, [D6]DMSO): d=
11.74 (s, 1H), 10.13 (s, 1H), 8.06 (dd, J=8.7, 5.5 Hz, 1H), 7.84 (s,
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Revised: June 7, 2013
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