Synthesis and antifungal activity of 3-(1,3,4-oxadiazol-5-yl)-indoles and 3-(1,3,4-oxadiazol-5-yl)methyl-indoles

Article abstract of DOI:10.1016/j.ejmech.2013.01.038

On the basis of the principle of combination of active structural moieties, a modified and efficient synthetic method for three series of novel indole-based 1,3,4-oxadiazoles is described. Bioassays conducted at Syngenta showed that several of the synthesized compounds exhibit higher antifungal activity than pimprinine, the natural product which inspired this synthesis. Two main structural alterations were found to broaden the spectrum of biological activity in most cases. Compounds 3g, 6c, 6e, 6h, 9d, 9e, 9h and 9m (Fig. 1) were identified as the most active on the biological assays, and will be studied further.

Full text of DOI:10.1016/j.ejmech.2013.01.038

European Journal of Medicinal Chemistry 63 (2013) 22e32
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antifungal activity of 3-(1,3,4-oxadiazol-5-yl)-indoles and
3-(1,3,4-oxadiazol-5-yl)methyl-indoles
,
Ming-Zhi Zhang a, Nick Mulholland b, David Beattie b, Dianne Irwin b, Yu-Cheng Gu b, Qiong Chen a
,
*
Guang-Fu Yang a, John Clough b
a Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China
b Syngenta Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
On the basis of the principle of combination of active structural moieties, a modified and efficient
synthetic method for three series of novel indole-based 1,3,4-oxadiazoles is described. Bioassays con-
ducted at Syngenta showed that several of the synthesized compounds exhibit higher antifungal activity
than pimprinine, the natural product which inspired this synthesis. Two main structural alterations were
found to broaden the spectrum of biological activity in most cases. Compounds 3g, 6c, 6e, 6h, 9d, 9e, 9h
and 9m (Fig. 1) were identified as the most active on the biological assays, and will be studied further.
Ó 2013 Elsevier Masson SAS. All rights reserved.
Received 7 December 2012
Received in revised form
25 January 2013
Accepted 30 January 2013
Available online 9 February 2013
Keywords:
Indole
1,3,4-Oxadiazole
Synthesis
Antifungal activity
Structureeactivity relationships
1. Introduction
on bioassays at Syngenta, where it demonstrated weak antifungal
activity. In addition, a 4-chloro-analogue of pimprinine called
Indole derivatives are an important class of heterocyclic com-
pounds with a wide range of biological activities [1]. Indole is
a substructural element of many natural products, and is widely
used as a scaffold in agricultural and medicinal chemistry. For
example, indole-3-acetic acid, also known as IAA, is a key plant
growth hormone [2], and tryptophan, an essential amino acid,
participates in many essential biological processes [3]. Indome-
thacin is a non-steroidal anti-inflammatory drug [4]. Sumatriptan,
Frovatriptan and Zolmitriptan are used to treat acute migraine at-
tacks and headaches [5]. Reserpine, an indole alkaloid, is an anti-
psychotic and antihypertensive drug that has been used for the
control of high blood pressure and for the relief of psychotic
symptoms [6]. And vinblastine is an antimicrotubule drug used to
treat certain kinds of cancer, including Hodgkin’s lymphoma and
non-small cell lung cancer [7] (Fig. 2).
streptochlorin, also a natural product, has a good spectrum of
antifungal activity, but low potency (Table 4).
Compounds containing a 1,3,4-oxadiazole ring display a broad
spectrum of biological activities, including anticancer [9], anti-
microbial [10], antineoplastic [11], antifungal [12,13], antibacterial
[14] and anti-HIV [15] activities. For example, Oxadiazon is the first
oxadiazole herbicide developed by Rhone-Poulenc and launched
in 1969, Metoxadiazone is a widely used household insecticide
developed by Sumitomo Chemical and launched in 1978, (S)-9b is
reported to exhibit highly selective and potent inhibitory activity
against glycogen synthase kinase 3
b (GSK-3b) [16], MK-0633
p-toluenesulfonate was identified as a potent and selective inhibi-
tor of 5-lipoxygenase (5-LO) [17], 3(H) is reported to be a human
neutrophil elastase inhibitor and is in clinical evaluation [18],
Zibotentan is an endothelin receptor antagonist as an anticancer
candidate [19], and Raltegravir, also called MK-0518, was the first
HIV-integrase inhibitor approved by the FDA in October 2007 for
the treatment of HIV/AIDS-infected patients [15,20] (Fig. 3).
1,3,4-Oxadiazole is a very good bioisostere of amide and ester
functional groups and is reported to contribute substantially to
pharmacological activity by participating in hydrogen bonding in-
teractions with various receptors [21]. On the basis of the principle
Pimprinine, an indole alkaloid originally isolated in 1963 from
the filtrates of cultures of Streptomyces pimprina [8], belongs to the
class of naturally occurring 5-(3-indolyl)oxazoles. It was screened
* Corresponding author.
E-mail address: qchen@mail.ccnu.edu.cn (Q. Chen).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.01.038

M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 63 (2013) 22e32
23
CF3
N
N
N
Cl
N
N
N
N
N
O
O
O
O
N
N
N
N
Et
H
Et
Et
3g
6e
6h
6c
N
N
N
N
N
N
N
N
O
O
O
O
Cl
O
N
H
N
N
H
N
H
H
9m
9e
9h
9d
Fig. 1. Structures of the most active synthetic pimprinine derivatives.
of combination of active structural moieties, it has been reported
that the substitution by oxadiazoles at the 3-position of the indole
nucleus enhances these activities [22,23].
2. Materials and methods
2.1. Chemistry
As a continuation of our extensive research program aimed at
the discovery of novel bioactive compounds, we have described our
use of pimprinine as a lead structure on which to carry out opti-
mization with the aim of discovering synthetic analogues with
simple structures and improved antifungal activity [24]. In the
work described in this paper, our focus has been on the replace-
ment of the oxazole ring of pimprinine with an oxadiazole ring. In
addition, the structureeactivity relationships of 3-(1,3,4-oxadiazol-
5-yl)-indoles and analogues are also described.
The reagents were all analytically pure. All solvents and liquid
reagents were dried by standard methods in advance and distilled
before use. Methyl indole-3-carboxylate and ethyl indole-3-acetate
were bought from the Alfa Aesar Company (Tianjin, China). Yields
were not optimized. 1H NMR spectra were recorded on a VARIAN
Mercury-Plus 400/600 spectrometer in CDCl3 or DMSO-d6 with
TMS as the internal reference. 13C NMR and 13C DEPT spectra were
recorded in CDCl3 or DMSO-d6 on a Varian Mercury-Plus 400/600
Although many synthetic approaches to 1,3,4-oxadiazoles have
been described [25], few of these are suitable for the preparative
synthesis of indole-based 1,3,4-oxadiazole derivatives for a number
of reasons. Modifying a method described by Hai-Liang Zhu [26],
we have efficiently synthesized three series of indole-based 1,3,4-
oxadiazole derivatives, some of which showed antifungal activity,
and the structureeactivity relationships within a series of such
compounds is summarized.
(100/150 MHz) spectrometer and chemical shifts (d) are given in
ppm relative to the centre line of a triplet at 77.0 ppm of CDCl3 or
39.5 ppm of DMSO-d6. High resolution mass spectra (HRMS) were
acquired in positive mode on a WATERS MALDI SYNAPT G2 HDMS
(MA, USA) or Agilent 6224 TOF LC/MS (ESI). MS spectra were
determined using a Trace MS 2000 organic mass spectrometry, and
the signals were given in m/z. Melting points were taken on a Büchi
B-545 melting point apparatus and are uncorrected.
Fig. 2. Structures of indole-containing drugs and natural products.

24
M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 63 (2013) 22e32
O
N
N
S
O
O
O
O
N
H
SO
HO
CF
O
N
3
Cl
2
O
3
N
N
N
N
O
N
Cl
O
O
O
O
O
F
Oxadiazon
Metoxadiazone
.
(S)-9b
MK-0633 p-toluenesulfonate
O
N
N
O
N
N
O
H
N
O
OK
F
N
O
N
N
O
S
N
H
N
H
N
N
N
H N
2
N
O
N
O
O
O
O
N
H
N
Zibotentan
O
Raltegravir
3(H)
Fig. 3. Structures of 1,3,4-oxadiazole-containing agrochemicals, enzyme inhibitors and drugs.
2.1.1. Preparation of 1H-indole-3-carbohydrazide 2 (Scheme 1)
Hydrazine hydrate (99%, 2 mL, 40 mmol) was added in one
portion to methyl indole-3-carboxylate 1 (10 mmol, 1.75 g) dis-
solved in dry ethanol (50 mL) at room temperature, and the
resulting solution was heated under reflux for 8 h. The reaction
mixture was allowed to cool and the solid obtained was filtered off
and washed with a small quantity of ethanol to give the 1H-indole-
3-carbohydrazide 2. Yield: 1.66 g, 95%, white solid, mp 234e236 ꢀC;
J ¼ 6.0 Hz, 1H), 9.00 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
d 10.6,
18.3, 99.7, 112.4, 120.3, 121.1, 122.8, 124.1, 127.7, 136.4, 161.7, 165.3.
HRMS (MALDI): m/z 214.0980. Calcd. for C12H11N3O: 214.0980
[M þ H]þ.
2.1.2.3. Data for 3c. White solid, mp 144e146 ꢀC. 1H NMR
(600 MHz, CDCl3):
d
1.09 (t, J ¼ 7.8 Hz, 3H), 1.87e1.93 (m, 2H), 2.93
(t, J ¼ 7.8 Hz, 3H), 7.31 (t, J ¼ 3.6 Hz, 1H), 7.48 (t, J ¼ 5.4 Hz, 1H), 7.92
1H NMR (600 MHz, DMSO-d6):
d 4.34 (s, 2H), 7.10e7.11 (m, 2H), 7.43
(s, 1H), 8.26 (d, J ¼ 7.8 Hz, 1H), 9.10 (s, 1H). 13C NMR (100 MHz,
(t, J ¼ 3.6 Hz, 2H), 7.98 (s, 1H), 8.15 (d, J ¼ 7.2 Hz, 3H), 9.18 (s, 1H),
DMSO-d6): d 13.4 19.6, 26.4, 99.7, 112.4, 120.2, 121.1, 122.7, 124.1,
11.55 (s,1H); EI-MS: m/z (%) 175 (Mþ, 22),144 (100),116 (17), 89 (11).
127.7, 136.4, 161.7, 164.2. HRMS (MALDI): m/z 250.0944. Calcd. for
C
13H13N3O: 250.0956 [M þ Na]þ.
2.1.2. General procedure for the synthesis of target compounds 3
(Scheme 1)
2.1.2.4. Data for 3d. White solid, mp 167e169 ꢀC. 1H NMR
(600 MHz, DMSO-d6): 1.05 (s, 9H), 2.72 (s, 2H), 7.25e7.30 (m, 2H),
7.58 (d, J ¼ 7.8 Hz, 1H), 8.13 (d, J ¼ 7.8 Hz, 1H), 8.16 (s, 1H), 12.04 (s,
1H). 13C NMR (150 MHz, DMSO-d6):
29.0, 31.2, 38.1, 99.7, 112.4,
Equimolar quantities of compound 2 (1 mmol) and a substituted
carboxylic acid were dissolved in phosphoryl chloride (5 mL) and
heated at 80 ꢀC for 3e6 h, the progress of reaction being monitored
by TLC. The reaction mixture was then heated under reduced
pressure to allow excess phosphoryl chloride to distill off, and the
residue was subjected to flash chromatography on silica gel using
15e25% acetone in petroleum ether as eluent to give the target
compounds 3aem (Table 1).
d
d
120.1, 122.8, 124.1, 127.8, 136.5, 161.8, 163.0. HRMS (MALDI): m/z
294.0982. Calcd. for C15H17N3O: 294.1009 [M þ K]þ.
2.1.2.5. Data for 3e. White solid, mp 148e150 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
d
0.83 (t, J ¼ 7.2 Hz, 3H), 1.42 (s, 6H), 1.77 (q,
J ¼ 7.2 Hz, 2H), 7.26e7.39 (m, 2H), 7.56 (d, J ¼ 7.2 Hz, 1H), 8.11 (d,
2.1.2.1. Data for 3a. White solid, mp 236e238 ꢀC. 1H NMR
J ¼ 7.2 Hz, 1H), 8.19 (s, 1H), 12.05 (s, 1H). 13C NMR (150 MHz, DMSO-
(400 MHz, CDCl3):
d
2.63 (m, 3H), 7.32e7.35 (m, 1H), 7.48 (t,
d6): d 9.0, 25.3, 33.6, 35.6, 99.7, 112.4, 120.1, 121.1, 122.8, 124.1, 127.9,
J ¼ 7.8 Hz, 1H), 7.90 (s, 1H), 8.27 (d, J ¼ 7.8 Hz, 1H), 8.63 (s, 1H). 13
C
136.5, 161.8, 169.5. HRMS (MALDI): m/z 256.1449. Calcd. for
NMR (100 MHz, DMSO-d6):
d
10.5, 99.7, 112.4, 120.3, 121.1, 122.8,
C
15H17N3O: 256.1450 [M þ H]þ.
124.1, 127.7, 136.5, 161.4, 161.8. HRMS (MALDI): m/z 222.0648. Calcd.
for C11H9N3O: 222.0643 [M þ Na]þ.
2.1.2.6. Data for 3f. White solid, mp 151e152 ꢀC. 1H NMR (600 MHz,
CDCl3):
d
0.86 (s, 9H), 1.04 (d, J ¼ 4.8 Hz, 3H), 1.14e1.17 (m, 3H), 1.35
2.1.2.2. Data for 3b. White solid, mp 205e207 ꢀC. 1H NMR
(d, J ¼ 13.8 Hz,1H), 2.06e2.07 (m,1H), 2.80e2.83 (m, 2H), 7.24e7.28
(m, 2H), 7.54 (t, J ¼ 7.8 Hz, 1H), 8.10 (d, J ¼ 7.2 Hz, 1H), 8.15 (s, 1H),
(600 MHz, CDCl3):
7.32 (t, J ¼ 3.6 Hz, 1H), 7.49 (t, J ¼ 6.6 Hz, 1H), 7.91 (s, 1H), 8.27 (d,
d
1.47 (t, J ¼ 7.8 Hz, 3H), 2.98 (q, J ¼ 7.8 Hz, 2H),
12.00 (s, 1H). 13C NMR (150 MHz, DMSO-d6):
d 22.6, 27.9, 29.6, 30.7,
1
R
N
N
CONHNH
COOMe
2
O
EtOH, Reflux
POCl , Reflux
3
.
1
8eq. NH NH H O
R COOH
2
2
2
N
H
N
H
N
H
95%
3
1
2
Scheme 1. Synthesis of 2-indolyl-5-substituted-1,3,4-oxadiazoles 3.

M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 63 (2013) 22e32
25
J ¼ 7.2 Hz, 1H), 8.39 (s, 1H), 12.14 (s, 1H). 13C NMR (100 MHz, DMSO-
Table 1
Reaction times and yields in the synthesis of compounds 3.
d6): d 99.3, 112.5, 120.3, 121.3, 122.9, 124.1, 124.9, 125.6, 125.8, 128.9,
Entry
R1
Time
Yield
131.3,134.0,136.5,152.0,160.7,162.3. HRMS (MALDI): m/z 296.0597.
Calcd. for C16H10ClN3O: 296.0591 [M þ H]þ.
3a
3b
3c
3d
3e
3f
3g
3h
3i
CH3
CH3CH2
6 h
6 h
3 h
3 h
3 h
3 h
6 h
6 h
5 h
5 h
6 h
6 h
5 h
81%
83%
81%
71%
74%
71%
63%
70%
45%
37%
47%
49%
67%
2.1.2.13. Data for 3m. White solid, mp 226e228 ꢀC. 1H NMR
CH3CH2CH2
(CH3)3CCH2
CH3CH2(CH3)2C
(CH3)3CCH2(CH3)CHCH2
CF3
CH2Cl
2-F-C6H4
2-I-C6H4
(600 MHz, DMSO-d6):
d
2.42 (s, 3H), 7.29 (t, J ¼ 3.6 Hz, 1H), 7.46 (d,
J ¼ 3.6 Hz, 2H), 7.56 (d, J ¼ 7.2 Hz,1H), 8.02 (d, J ¼ 7.2 Hz,1H), 8.18 (d,
J ¼ 6.6 Hz,1H), 8.32 (s, 1H),12.09 (s, 1H). 13C NMR (100 MHz, DMSO-
d6):
d 21.1, 99.5, 112.5, 120.3, 121.0, 121.2, 122.8, 124.2, 126.3, 128.4,
129.9, 136.5, 141.5, 161.7, 161.9. HRMS (MALDI): m/z 298.0961. Calcd.
3j
3k
3l
for C17H13N3O: 298.0956 [M þ Na]þ.
2-Cl-C6H4
3-Cl-C6H4
4-Me-C6H4
3m
2.1.3. Preparation of 1-ethyl-1H-indole-3-carboxylic acid methyl
ester 4 (Scheme 2) [27]
NaH (60% dispersion in mineral oil, 0.96 g, 40.00 mmol) was
added in portions to a stirred solution of methyl indole-3-
carboxylate 1 (3.50 g, 20.00 mmol) in anhydrous THF (50 mL)
cooled in an ice bath. The resulting mixture was then allowed
slowly to warm to r.t. After stirring for 30 min, ethyl bromide
(2.62 g, 24.0 mmol) in anhydrous THF (5 mL) was added dropwise.
When TLC monitoring showed complete consumption of the
starting material, the reaction mixture was evaporated under
reduced pressure to leave a residue that was treated with ice water
(300 mL). The resulting solid was filtrated off and recrystallized
from acetone/petroleum ether (60e90 ꢀC) to give the desired in-
termediate 4. Yield: 4.02 g, 99%.
33.7, 49.4, 98.6, 112.4, 120.2, 121.1, 122.8, 124.1, 127.8, 136.4, 161.7,
163.5. 13C DEPT (100 MHz, DMSO-d6): CH3 (methyl): 22.6, 29.6; CH2
(methylene): 33.8, 49.4; CH (methine): 27.9, 112.4, 120.2, 121.1,
122.8, 127.7. HRMS (MALDI): m/z 298.1941. Calcd. for C18H23N3O:
298.1919 [M þ H]þ.
2.1.2.7. Data for 3g. White crystal, mp 219e221 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
d
7.31e7.36 (m, 2H), 7.61 (d, J ¼ 7.2 Hz, 1H),
8.13 (d, J ¼ 6.6 Hz, 1H), 8.43 (s, 1H), 12.35 (s, 1H). 13C NMR (150 MHz,
DMSO-d6):
d
97.8e97.0 (d, JCeF ¼ 5.7 Hz, 1C), 112.7e112.8 (d, JCe
¼ 23.0 Hz, 1C), 115.7, 117.5, 120.0, 120.1, 124.1, 130.4, 136.6,
F
151.7e152.0 (d, JCeF ¼ 42.6 Hz, 1C), 164.1. HRMS (MALDI): m/z
254.0503. Calcd. for C11H6F3N3O: 254.0541 [M þ H]þ.
2.1.4. Preparation of 1-ethyl-1H-indole-3-carbohydrazide 5
(Scheme 2)
2.1.2.8. Data for 3h. White solid, mp 204e206 ꢀC. 1H NMR
Hydrazine hydrate (99%, 2 mL, 40 mmol) was added in one
portion to a solution of compound 4 (2.03 g, 10 mmol) in dry
ethanol (50 mL) and the mixture was then heated at reflux for 10 h.
The reaction mixture was cooled and the solid obtained was filtered
off and washed with a small quantity of ethanol to give the desired
intermediate 2. Yield: 1.99 g, 98%, white solid, mp 144e146 ꢀC. 1H
(600 MHz, DMSO-d6):
d 5.16 (s, 2H), 7.27e7.32 (m, 1H), 7.58 (d,
J ¼ 7.8 Hz, 1H), 8.13 (d, J ¼ 7.2 Hz, 1H), 8.26 (s, 1H), 12.14 (s, 1H). 13
C
NMR (100 MHz, DMSO-d6):
d 33.5, 98.9, 112.6, 120.2, 121.4, 123.0,
124.1, 128.7, 136.5, 160.5, 163.0. HRMS (MALDI): m/z 234.0415.
Calcd. for C11H8ClN3O: 234.0434 [M þ H]þ.
NMR (600 MHz, DMSO-d6):
d
1.39 (t, J ¼ 7.2 Hz, 3H), 4.22 (q,
2.1.2.9. Data for 3i. Pale pink solid, mp 226e228 ꢀC. 1H NMR
J ¼ 7.2 Hz, 2H), 4.35 (s, 2H), 7.13 (t, J ¼ 7.2 Hz, 1H), 7.19 (t, J ¼ 7.2 Hz,
1H), 7.52 (d, J ¼ 8.4, Hz, 1H), 8.01 (s, 1H), 8.13 (d, J ¼ 7.2 Hz, 1H), 9.13
(400 MHz, DMSO-d6):
(t, J ¼ 7.2 Hz, 1H), 8.10 (d, J ¼ 7.2 Hz, 1H), 8.17e8.19 (m, 1H), 8.30 (s,
1H), 12.11 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
99.2, 105.8,
d 7.26e7.29 (m, 2H), 7.32e7.52 (m, 3H), 7.73
(s, 1H). 13C NMR (150 MHz, DMSO-d6):
d 15.1, 40.7, 108.2, 110.1,
d
120.5, 121.2, 121.8, 126.6, 129.4, 135.6, 164.9. HRMS (ESI): m/z
111.7e112.5 (t, JCeF ¼ 41.8 Hz,1C),111.9e112.5 (d, JCeF ¼ 20.6 Hz,1C),
120.2, 121.4, 122.9, 124.9, 125.2, 128.6, 129.4, 133.6, 136.5, 157.9,
162.9, 169.2. HRMS (MALDI): m/z 280.0878. Calcd. for C16H10FN3O:
280.0886 [M þ H]þ.
226.0959. Calcd. for C11H13N3O: 226.0956 [M þ Na]þ.
2.1.5. General procedure for the synthesis of target compounds 6
(Scheme 2)
Equimolar quantities of compound 5 (1 mmol) and a substituted
carboxylic acid were dissolved in phosphoryl chloride (5 mL) and
heated under reflux for 3e6 h, the progress of reaction being
monitored by TLC. The reaction mixture was then heated under
reduced pressure to allow excess phosphoryl chloride to distill off,
and the residue was purified by flash chromatography on silica gel
using 15e25% acetone in petroleum ether as eluent to give the
target compounds 6aez (Table 2).
2.1.2.10. Data for 3j. White solid, mp 197e199 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
d
7.27e7.31 (m, 2H), 7.37 (d, J ¼ 7.8 Hz, 1H),
7.56 (d, J ¼ 7.2 Hz,1H), 7.65 (d, J ¼ 7.8 Hz, 1H), 7.94 (d, J ¼ 7.8 Hz,1H),
8.17 (t, J ¼ 8.4 Hz, 1H), 8.27 (s, 1H), 12.12 (s, 1H). 13C NMR (100 MHz,
DMSO-d6):
d 95.7, 99.2, 112.5, 120.2, 121.4, 122.9, 124.1, 128.6, 129.1,
131.3, 132.7, 136.5, 140.7, 145.7, 161.8, 162.3. HRMS (MALDI): m/z
387.9927. Calcd. for C16H10IN3O: 387.9947 [M þ H]þ.
2.1.2.11. Data for 3k. Light yellow solid, mp 209e211 ꢀC. 1H NMR
2.1.5.1. Data for 6a. White solid, mp 129e131 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
d
7.27e7.28 (m, 2H), 7.57 (d, J ¼ 7.8 Hz, 1H),
(600 MHz, CDCl3):
d
1.54 (t, J ¼ 7.2 Hz, 3H), 2.61 (s, 3H), 4.24 (q,
7.62 (t, J ¼ 7.8 Hz, 1H), 7.65 (t, J ¼ 7.8 Hz, 1H), 7.76 (d, J ¼ 7.8 Hz, 1H),
J ¼ 7.2 Hz, 2H), 7.30e7.33 (m, 2H), 7.41 (d, J ¼ 7.8 Hz, 1H), 7.81 (s,
8.13e8.17 (m, 2H), 8.29 (s, 1H), 12.11 (s, 1H). 13C NMR (100 MHz,
1H), 8.25 (d, J ¼ 7.2 Hz, 1H). 13C NMR (150 MHz, DMSO-d6):
d 10.5,
DMSO-d6):
d
99.2, 112.6, 120.1, 121.4, 122.9, 124.1, 128.8, 129.4, 131.1,
15.3, 41.0, 98.9, 110.8, 120.6, 121.3, 122.8, 124.6, 130.0, 136.0, 161.4,
131.7, 132.2, 132.8, 136.5, 140.7, 161.0, 162.3. HRMS (MALDI): m/z
161.5. HRMS (MALDI): m/z 250.0930. Calcd. for
C13H13N3O:
296.0562. Calcd. for C16H10ClN3O: 296.0591 [M þ H]þ.
250.0956 [M þ Na]þ.
2.1.2.12. Data for 3l. White solid, mp 244e246 ꢀC. 1H NMR
2.1.5.2. Data for 6b. White solid, mp 62e64 ꢀC. 1H NMR (600 MHz,
CDCl3):
1.45 (t, J ¼ 7.8 Hz, 3H), 1.55 (t, J ¼ 7.2 Hz, 3H), 2.96 (q,
J ¼ 7.8 Hz, 2H), 4.25 (q, J ¼ 7.2 Hz, 2H), 7.30e7.34 (m, 2H), 7.41 (d,
(600 MHz, DMSO-d6):
d
7.29e7.30 (m, 2H), 7.58 (d, J ¼ 9.0 Hz, 1H),
d
7.66e7.72 (m, 2H), 8.10 (d, J ¼ 7.2 Hz, 1H), 8.14 (s, 1H), 8.18 (d,

26
M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 63 (2013) 22e32
COOMe
CONHNH
2
COOMe
EtOH, Reflux
THF, NaH, r.t.
CH CH Br
.
8eq. NH NH H O
3
2
N
N
Et
N
2
2
2
H
Et
99%
98%
1
4
5
2
R
N
N
O
POCl , Reflux
3
2
R COOH
N
Et
6
Scheme 2. Synthesis of 2-(1-ethyl-indolyl)-5-substituted-1,3,4-oxadiazoles 6.
J ¼ 7.8 Hz, 1H), 7.83 (s, 1H), 8.25 (d, J ¼ 7.2 Hz, 1H). 13C NMR
2.1.5.5. Data for 6e. White solid, mp 78e80 ꢀC. 1H NMR (600 MHz,
DMSO-d6):
(150 MHz, DMSO-d6):
d
10.6, 15.3, 18.3, 41.0, 98.9, 110.8, 120.6, 121.3,
d
0.84 (t, J ¼ 7.2 Hz, 3H), 1.42 (s, 6H), 1.45 (t, J ¼ 7.2 Hz,
122.8, 124.6, 130.0, 136.0, 161.4, 165.2. HRMS (MALDI): m/z
3H),1.78 (t, J ¼ 7.2 Hz, 3H), 4.35 (t, J ¼ 7.2 Hz, 2H), 7.31e7.34 (m, 2H),
264.1100. Calcd. for C14H15N3O: 264.1113 [M þ Na]þ.
7.64 (d, J ¼ 7.2 Hz, 1H), 8.15 (t, J ¼ 7.8 Hz, 2H), 8.27 (s, 1H). 13C NMR
(150 MHz, DMSO-d6):
d 8.1, 15.2, 25.2, 33.5, 35.5, 40.9, 98.9, 110.7,
2.1.5.3. Data for 6c. Light yellow oil. 1H NMR (600 MHz, CDCl3):
120.4, 121.2, 122.7, 124.6, 130.0, 135.9, 161.4, 169.4. HRMS (MALDI):
d
1.08 (t, J ¼ 7.2 Hz, 3H), 1.54 (t, J ¼ 7.2 Hz, 3H), 1.89e1.92 (m, 2H),
m/z 322.1313. Calcd. for C17H21N3O: 322.1322 [M þ K]þ.
2.91 (t, J ¼ 7.2 Hz, 3H), 4.25 (q, J ¼ 7.2 Hz, 2H), 7.32 (m, 2H), 7.42 (d,
J ¼ 7.8 Hz, 1H), 7.83 (s, 1H), 8.24 (d, J ¼ 7.8 Hz, 1H). 13C NMR
2.1.5.6. Data for 6f. Red oil. 1H NMR (600 MHz, DMSO-d6):
d 0.88 (s,
(150 MHz, DMSO-d6):
d
13.4, 15.2, 19.6, 26.4, 41.0, 98.9, 110.7, 120.6,
9H), 1.05 (d, J ¼ 3.0 Hz, 3H), 1.14e1.19 (m, 1H), 1.38 (d, J ¼ 14.4 Hz,
1H), 1.45 (t, J ¼ 6.6 Hz, 3H), 2.08e2.09 (m, 1H), 2.78e2.82 (m, 1H),
2.84e2.88 (m, 1H), 4.36 (q, J ¼ 6.6 Hz, 2H), 7.30 (t, J ¼ 7.2 Hz, 1H),
7.33e7.34 (m, 1H), 7.66 (d, J ¼ 8.4 Hz, 2H), 8.16 (d, J ¼ 7.8 Hz, 1H),
121.3, 122.7, 124.6, 129.9, 136.0, 161.4, 164.2. HRMS (MALDI): m/z
294.1003. Calcd. for C15H17N3O: 294.1009 [M þ K]þ.
2.1.5.4. Data for 6d. Light yellow oil. 1H NMR (600 MHz, DMSO-d6):
8.25 (s, 1H). 13C NMR (150 MHz, DMSO-d6):
d 15.2, 22.4, 27.9, 29.5,
d
1.11 (s, 9H), 1.54 (t, J ¼ 7.2 Hz, 3H), 2.84 (s, 2H), 4.25 (q, J ¼ 7.2 Hz,
30.6, 33.7, 40.9, 49.4, 98.8, 110.8, 120.5, 121.2, 122.7, 124.5, 126.3,
2H), 7.30e7.34 (m, 2H), 7.42 (d, J ¼ 7.8 Hz, 1H), 7.84 (s, 1H), 8.24 (d,
129.9, 135.9, 161.4, 163.4. HRMS (MALDI): m/z 364.1778. Calcd. for
J ¼ 7.8 Hz, 2H). 13C NMR (150 MHz, DMSO-d6):
d
15.2, 29.0, 31.0,
C
20H27N3O: 364.1791 [M þ K]þ.
38.0, 40.9, 98.9, 111.7, 120.4, 121.2, 122.7, 124.6, 126.3, 127.9, 129.9,
135.9, 161.4, 162.9. HRMS (MALDI): m/z 284.1744. Calcd. for
C
2.1.5.7. Data for 6g. White crystal, mp 140e142 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
1.45 (t, J ¼ 6.6 Hz, 3H), 4.36 (q, J ¼ 6.6 Hz,
2H), 7.35 (t, J ¼ 7.2 Hz, 1H), 7.71 (d, J ¼ 7.8 Hz, 1H), 8.10 (d, J ¼ 7.2 Hz,
1H), 8.48 (s, 1H). 13C NMR (150 MHz, DMSO-d6):
15.2, 41.3, 97.0,
17H21N3O: 284.1763 [M þ H]þ.
d
Table 2
d
Reaction times and yields in the synthesis of compounds 6.
111.2, 115.7, 120.3, 122.0, 123.2, 124.5, 132.4, 136.1, 151.7, 151.9, 163.8.
HRMS (MALDI): m/z 282.0820. Calcd. for C13H10F3N3O: 282.0854
[M þ H]þ.
Entry
R2
Time
Yield
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
CH3
CH3CH2
6 h
6 h
6 h
4 h
5 h
6 h
5 h
6 h
6 h
6 h
6 h
6 h
3 h
6 h
6 h
6 h
6 h
6 h
3 h
6 h
6 h
6 h
6 h
5 h
5 h
6 h
72%
61%
71%
73%
45%
78%
71%
43%
70%
54%
49%
59%
22%
60%
28%
51%
55%
62%
43%
68%
60%
55%
63%
48%
42%
53%
CH3CH2CH2
(CH3)3CCH2
CH3CH2(CH3)2C
(CH3)3CCH2(CH3)CHCH2
CF3
CH2Cl
CCl3
C6H5
2-F-C6H4
2-Cl-C6H4
2-I-C6H4
3-Cl-C6H4
3-NO2-C6H4
3-Pyridyl
2.1.5.8. Data for 6h. White solid, mp 116e118 ꢀC. 1H NMR
(600 MHz, CDCl3):
d
1.56 (t, J ¼ 7.2 Hz, 3H), 4.27 (q, J ¼ 7.2 Hz, 2H),
4.49 (s, 2H), 7.32e7.37 (m, 2H), 7.43 (d, J ¼ 7.8 Hz, 1H), 7.92 (s, 1H),
8.26 (d, J ¼ 7.2 Hz, 1H). 13C NMR (150 MHz, DMSO-d6):
d 15.3, 33.5,
41.1, 98.1, 111.0, 120.5, 121.6, 123.0, 124.6, 130.9, 136.0, 160.5, 162.7.
HRMS (MALDI): m/z 284.0539. Calcd. for C13H12ClN3O: 284.0567
[M þ Na]þ.
2.1.5.9. Data for 6i. White solid, mp 131e133 ꢀC. 1H NMR (600 MHz,
DMSO-d6):
7.36 (m, 2H), 7.68 (d, J ¼ 7.2 Hz, 1H), 8.12 (d, J ¼ 7.8 Hz, 1H), 8.51
(s, 1H). 13C NMR (150 MHz, DMSO-d6):
15.3, 41.3, 96.9, 111.2, 120.3,
d
1.48 (t, J ¼ 7.2 Hz, 3H), 4.37 (q, J ¼ 7.2 Hz, 2H), 7.31e
4-Cl-C6H4
d
4-Br-C6H4
4-NO2-C6H4
4-Me-C6H4
4-MeO-C6H4
3,5-Di-Me-C6H3
3,4,5-Tri-MeO-C6H2
C6H5CH2
122.0, 124.5, 132.3, 136.1, 160.9, 164.3. HRMS (MALDI): m/z
6s
6t
329.9986. Calcd. for C13H10Cl3N3O: 329.9968 [M þ H]þ.
6u
6v
6w
6x
6y
6z
2.1.5.10. Data for 6j. White solid, mp 170e171 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
d
1.47 (t, J ¼ 7.2 Hz, 3H), 4.37 (q, J ¼ 7.2 Hz,
1H), 7.32e7.35 (m, 2H), 7.65e7.66 (m, 3H), 7.69 (d, J ¼ 7.8 Hz, 1H),
2-Me-C6H5CH2
(E)-C6H5CH:CH
8.13e8.14 (m, 2H), 8.21 (d, J ¼ 7.8 Hz, 1H), 8.41 (s, 1H). 13C NMR
(150 MHz, CDCl3):
d 15.2, 41.1, 98.6, 110.9, 120.5, 120.6, 121.5, 123.7,

M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 63 (2013) 22e32
27
124.6, 126.2, 126.4, 129.4, 130.8, 131.5, 136.1, 161.8. HRMS (MALDI):
2H), 7.30e7.36 (m, 2H), 7.69 (d, J ¼ 7.8 Hz, 1H), 7.86 (t, J ¼ 7.2 Hz,
2H), 8.04e8.06 (m, 2H), 8.19 (d, J ¼ 7.8 Hz, 1H), 8.42 (s, 1H). 13C NMR
m/z 290.1268. Calcd. for C18H15N3O: 290.1293 [M þ H]þ.
(150 MHz, DMSO-d6):
d 15.3, 41.1, 98.5, 111.0, 120.6, 121.6, 122.9,
2.1.5.11. Data for 6k. White solid, mp 160e162 ꢀC. 1H NMR
124.6, 125.1, 128.2, 131.0, 131.3, 132.5, 136.1, 161.2, 161.9. HRMS
(600 MHz, CDCl3):
d
1.58 (t, J ¼ 7.2 Hz, 3H), 4.29 (q, J ¼ 7.2 Hz, 2H),
(MALDI): m/z 390.0191. Calcd. for
C18H14BrN3O: 390.0218
7.29e7.36 (m, 4H), 7.45 (t, J ¼ 7.2 Hz, 1H), 7.53e7.54 (m, 1H), 8.00 (s,
[M þ Na]þ.
1H), 8.20 (t, J ¼ 7.2 Hz, 1H), 8.35e8.36 (m, 1H). 13C NMR (150 MHz,
DMSO-d6):
d
15.3, 41.1, 98.4, 110.8e111.1 (t, JCeF ¼ 247 Hz, 1C), 109.9,
2.1.5.19. Data for 6s. Yellow solid, mp 191e193 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
111.7e111.9 (d, JCeF ¼ 213 Hz, 1C), 111.1, 116.0, 120.7, 123.6, 124.6,
129.3, 136.1, 148.8, 159.2, 160.6, 162.7, 163.0. HRMS (MALDI): m/z
346.0753. Calcd. for C18H141FN3O: 346.0758 [M þ K]þ.
d
1.48 (t, J ¼ 7.2 Hz, 3H), 4.37 (q, J ¼ 6.6 Hz,
2H), 7.31e7.36 (m, 2H), 7.70 (t, J ¼ 7.8 Hz,1H), 7.98 (s, 1H), 8.31e8.32
(m, 3H), 8.39 (d, J ¼ 8.4 Hz, 2H). 13C NMR (150 MHz, DMSO-d6):
d
15.3, 41.2, 99.0, 111.1, 116.0, 120.7, 123.6, 124.6, 129.3, 136.1, 148.8,
2.1.5.12. Data for 6l. White solid, mp 140e142 ꢀC. 1H NMR
(600 MHz, CDCl3):
159.2, 160.6, 162.7, 163.0. HRMS (MALDI): m/z 357.0997. Calcd. for
d
1.57 (t, J ¼ 7.2 Hz, 3H), 4.28 (q, J ¼ 7.2 Hz, 2H),
C
18H14N4O3: 357.0964 [M þ Na]þ.
7.34e7.35 (m, 2H), 7.44e7.48 (m, 3H), 7.58 (d, J ¼ 7.8 Hz, 1H), 7.97 (s,
1H), 8.13 (d, J ¼ 7.2 Hz, 1H), 8.35 (d, J ¼ 6.6 Hz, 1H). 13C NMR
2.1.5.20. Data for 6t. White solid, mp 163e165 ꢀC. 1H NMR
(600 MHz, CDCl3):
(150 MHz, DMSO-d6):
d
15.3, 41.1, 98.3, 110.0, 120.5, 121.6, 122.8,
d
1.46 (t, J ¼ 7.2 Hz, 3H), 2.42 (s, 3H), 4.39 (q,
122.9, 124.6, 127.9, 131.0, 131.1, 131.2, 131.6, 132.8, 136.0, 160.0, 162.1.
HRMS (MALDI): m/z 324.0925. Calcd. for C18H14ClN3O: 324.0904
[M þ H]þ.
J ¼ 6.6 Hz, 2H), 7.31e7.35 (m, 2H), 7.45 (d, J ¼ 7.8 Hz, 2H), 7.69 (d,
J ¼ 7.8 Hz,1H), 8.03 (d, J ¼ 7.8 Hz, 2H), 8.21 (d, J ¼ 7.8 Hz,1H), 8.41 (s,
1H). 13C NMR (150 MHz, CDCl3):
d 15.3, 21.1, 41.1, 98.7, 120.5, 120.7,
121.0,124.6,126.2,126.3,129.3,130.0,130.5,136.1,141.6,161.5,161.9.
HRMS (MALDI): m/z 326.1249. Calcd. for C19H17N3O: 326.1269
[M þ Na]þ.
2.1.5.13. Data for 6m. White solid, mp 155e157 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
d
1.57 (t, J ¼ 7.2 Hz, 3H), 4.29 (q, J ¼ 7.8 Hz,
2H), 7.22 (t, J ¼ 7.2 Hz, 1H), 7.33e7.36 (m, 2H), 7.45 (d, J ¼ 7.3 Hz,
1H), 7.52 (t, J ¼ 7.2 Hz, 1H), 7.97 (d, J ¼ 7.8 Hz, 1H), 7.99 (s, 1H), 8.09
(d, J ¼ 7.8 Hz,1H), 8.38 (d, J ¼ 7.2 Hz,1H). 13C NMR (150 MHz, DMSO-
2.1.5.21. Data for 6u. White solid, mp 85e87 ꢀC. 1H NMR (600 MHz,
CDCl3):
d
1.56 (t, J ¼ 7.2 Hz, 3H), 3.87 (s, 3H), 4.26 (q, J ¼ 7.2 Hz, 2H),
d6):
d
15.3, 41.1, 98.4, 111.0, 120.5, 121.6, 124.6, 128.6, 127.7, 129.1,
6.92 (d, J ¼ 8.4 Hz, 2H), 7.32e7.34 (m, 2H), 7.40e7.41 (m,1H), 7.89 (s,
130.8, 131.3, 131.4, 132.8, 136.1, 140.7, 161.8, 162.0. HRMS (MALDI):
1H), 8.04 (d, J ¼ 9.0 Hz, 2H), 8.32 (t, J ¼ 6.6 Hz, 1H). 13C NMR
m/z 438.0074. Calcd. for C18H14IN3O: 438.0079 [M þ Na]þ.
(150 MHz, DMSO-d6): d 15.6, 41.5, 55.8, 99.2, 111.2, 115.2, 116.5,
121.0, 121.8, 123.2, 125.1, 128.5, 130.8, 136.5, 150.1, 154.6, 161.6, 162.1.
HRMS (MALDI): m/z 320.1369. Calcd. for C19H17N3O2: 320.1399
[M þ H]þ.
2.1.5.14. Data for 6n. White solid, mp 162e164 ꢀC. 1H NMR
(600 MHz, CDCl3):
d
1.47 (t, J ¼ 7.2 Hz, 3H), 4.38 (q, J ¼ 7.2 Hz, 2H),
7.31e7.36 (m, 2H), 7.65e7.71 (m, 3H), 8.09 (d, J ¼ 7.2 Hz, 1H), 8.11 (s,
1H), 8.19 (d, J ¼ 8.4 Hz, 1H), 8.45 (s, 1H). 13C NMR (150 MHz, DMSO-
2.1.5.22. Data for 6v. White solid, mp 110e112 ꢀC. 1H NMR
d6):
d
15.3, 41.1, 98.4, 111.0, 120.6, 121.6, 122.9, 124.6, 125.0, 125.6,
(600 MHz, DMSO-d6):
d
1.59 (t, J ¼ 7.2 Hz, 3H), 2.43 (s, 6H), 4.29 (q,
125.8,131.1, 131.3, 131.4, 134.1,136.1,160.7, 162.0. HRMS (MALDI): m/
J ¼ 7.2 Hz, 2H), 7.17 (s, 1H), 7.24e7.25 (m, 1H), 7.37 (t, J ¼ 3.6 Hz, 2H),
z 346.0706. Calcd. for C18H14ClN3O: 346.0723 [M þ Na]þ.
7.45 (t, J ¼ 5.4 Hz, 1H), 8.00e8.01 (m, 2H),8.33e8.34 (m, 1H). 13C
NMR (150 MHz, DMSO-d6):
d 15.2, 20.7, 41.0, 98.7, 110.9, 120.6,
2.1.5.15. Data for 6o. Light yellow solid, mp 163e164 ꢀC. 1H NMR
(600 MHz, CDCl3):
123.5, 124.6, 127.0, 130.7, 134.1, 136.0, 137.7, 161.5. HRMS (MALDI):
d
1.62 (t, J ¼ 7.2 Hz, 3H), 4.33 (q, J ¼ 7.2 Hz, 2H),
m/z 356.1151. Calcd. for C20H19N3O: 356.1165 [M þ K]þ.
7.38e7.46 (m, 3H), 7.77 (t, J ¼ 7.8 Hz, 1H), 8.02 (s, 1H), 8.34 (d,
J ¼ 7.2 Hz,1H), 8.40 (d, J ¼ 7.8 Hz,1H), 8.54 (d, J ¼ 6.6 Hz,1H), 8.95 (s,
2.1.5.23. Data for 6w. White solid, mp 115e117 ꢀC. 1H NMR
1H). 13C NMR (150 MHz, DMSO-d6):
d
15.3, 41.1, 98.3, 111.0, 120.5,
(600 MHz, CDCl3):
d
1.59 (t, J ¼ 7.2 Hz, 3H), 3.92 (s, 3H), 3.99 (s, 6H),
122.9, 124.5, 125.1, 125.8, 127.3, 130.5, 131.2, 132.2, 135.4, 147.8,
160.3, 165.5. HRMS (MALDI): m/z 335.1149. Calcd. for C18H14N4O3:
335.1144 [M þ H]þ.
4.29 (q, J ¼ 6.6 Hz, 2H), 7.35e7.38 (m, 4H), 7.45 (d, J ¼ 7.2 Hz, 1H),
7.95 (s, 1H), 8.33 (d, J ¼ 7.2 Hz, 1H). 13C NMR (150 MHz, DMSO-d6):
d
15.3, 41.1, 56.1, 56.2, 60.3, 98.7, 103.7, 104.2, 110.9, 118.5, 119.0,
120.7, 121.6, 122.9, 124.6, 130.8, 136.1, 140.2, 153.5, 161.6, 161.8.
HRMS (MALDI): m/z 402.1447. Calcd. for C21H21N3O4: 402.1430
[M þ Na]þ.
2.1.5.16. Data for 6p. Light yellow solid, mp 138e140 ꢀC. 1H NMR
(600 MHz, CDCl3):
d
1.60 (t, J ¼ 7.2 Hz, 3H), 4.32 (q, J ¼ 7.2 Hz, 2H),
7.37e7.38 (m, 2H), 7.46 (d, J ¼ 7.2 Hz,1H), 7.97 (s, 1H), 8.32e8.33 (m,
1H), 8.50 (d, J ¼ 7.8 Hz,1H), 8.78e8.80 (m, 1H), 9.38 (s, 1H). 13C NMR
2.1.5.24. Data for 6x. Light yellow solid, mp 112e114 ꢀC. 1H NMR
(150 MHz, CDCl3):
d
15.2, 41.1, 98.4, 111.1, 120.4, 120.6, 121.4, 121.8,
(600 MHz, DMSO-d6):
d
1.41 (t, J ¼ 6.0 Hz, 3H), 4.32 (q, J ¼ 6.6 Hz,
122.7, 124.4, 130.9, 131.0, 133.6, 136.1, 147.0, 160.0, 162.1. HRMS
2H), 4.36 (s, 2H), 7.29 (t, J ¼ 7.2 Hz, 1H), 7.31e7.33 (m, 2H), 7.41 (t,
(MALDI): m/z 291.1218. Calcd. for C17H14N4O: 291.1246 [M þ H]þ.
J ¼ 7.2 Hz, 4H), 7.64 (d, J ¼ 7.8 Hz, 1H), 8.12 (d, J ¼ 7.8 Hz, 1H), 8.21 (s,
1H). 13C NMR (150 MHz, DMSO-d6):
d 15.3, 30.7, 41.0, 98.6, 110.9,
2.1.5.17. Data for 6q. White solid, mp 139e141 ꢀC. 1H NMR
(600 MHz, CDCl3):
120.5, 121.4, 122.8, 124.6, 127.2, 128.7, 128.8, 130.2, 134.9, 135.9,
161.8, 163.1. 13C DEPT (100 MHz, DMSO-d6): CH3 (methyl): 15.3; CH2
(methylene): 30.8, 41.0; CH (methine):110.9, 120.5, 121.4, 122.8,
127.2, 128.7, 128.8, 130.2. HRMS (MALDI): m/z 342.0990. Calcd. for
d
1.59 (t, J ¼ 7.8 Hz, 3H), 4.31 (q, J ¼ 7.2 Hz, 2H),
7.34e7.36 (m, 2H), 7.46 (d, J ¼ 8.4 Hz, 2H), 7.53 (d, J ¼ 9.0 Hz, 1H),
7.98 (s, 1H), 8.11 (d, J ¼ 8.4 Hz, 1H), 8.32 (d, J ¼ 6.6 Hz, 1H). 13C NMR
(150 MHz, CDCl3):
d
15.7, 41.5, 99.0, 111.4, 121.0, 122.0, 123.0, 123.4,
C
19H17N3O: 342.1009 [M þ K]þ.
125.0, 128.5, 130.0, 131.3, 136.5, 136.7, 161.5, 162.3. HRMS (MALDI):
m/z 324.0869. Calcd. for C18H14ClN3O: 324.0904 [M þ H]þ.
2.1.5.25. Data for 6y. White solid, mp 127e129 ꢀC. 1H NMR
(600 MHz, CDCl3):
d
1.53 (t, J ¼ 7.2 Hz, 3H), 2.45 (s, 3H), 4.24 (q,
2.1.5.18. Data for 6r. White solid, mp 158e160 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
J ¼ 7.2 Hz, 2H), 4.27 (s, 2H), 7.20e7.21 (m, 3H), 7.27e7.31 (m, 3H),
d
1.47 (t, J ¼ 7.2 Hz, 3H), 4.35 (q, J ¼ 7.2 Hz,
7.40 (d, J ¼ 8.4 Hz, 1H), 7.79 (s, 1H), 8.18 (d, J ¼ 7.8 Hz, 1H). 13C NMR

28
M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 63 (2013) 22e32
Table 3
(150 MHz, DMSO-d6): d 15.3, 19.1, 28.8, 41.0, 98.6, 110.8, 120.5, 121.3,
Reaction times and yields in the synthesis of compounds 9.
122.8, 124.6, 126.2, 127.4, 129.6, 130.2, 130.3, 133.3, 135.9, 136.6,
161.7, 162.8. HRMS (MALDI): m/z 340.1406. Calcd. for C20H19N3O:
340.1426 [M þ Na]þ.
Entry
R3
Time
Yield
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
CH3
CH3CH2
5 h
5 h
6 h
5 h
5 h
5 h
5 h
5 h
5 h
3 h
3 h
6 h
6 h
6 h
3 h
5 h
73%
66%
71%
60%
76%
66%
45%
53%
44%
53%
48%
51%
66%
71%
57%
62%
2.1.5.26. Data for 6z. White solid, mp 105e107 ꢀC. 1H NMR
CH3CH2CH2
(CH3)3CCH2
CH3CH2(CH3)2C
(CH3)3CCH2(CH3)CHCH2
CF3
CH2Cl
CCl3
2-F-C6H4
3-Cl-C6H4
(600 MHz, DMSO-d6):
d
1.48 (t, J ¼ 6.6 Hz, 3H), 4.38 (q, J ¼ 6.6 Hz,
2H), 7.32e7.34 (m, 2H), 7.39 (m, 2H), 7.49 (t, J ¼ 6.6 Hz, 2H), 7.68e
7.70 (m, 2H), 7.81 (d, J ¼ 7.2 Hz, 1H), 8.25 (d, J ¼ 7.2 Hz, 1H), 8.36 (s,
1H). 13C NMR (150 MHz, DMSO-d6):
d 15.2, 41.0, 98.7, 110.4, 110.8,
120.6, 121.5, 122.9, 124.6, 127.6, 127.7, 128.8, 129.0, 129.7, 130.6,
134.9, 136.0, 137.5, 161.0, 161.9. HRMS (MALDI): m/z 354.0992.
Calcd. for C20H17N3O: 354.1009 [M þ K]þ.
4-Br-C6H4
4-MeO-C6H4
4-Me-C6H4
3,5-Di-MeO-C6H3
3,4,5-Tri-MeO-C6H2
2.1.6. Preparation of (1H-indol-3-yl)-acetic acid hydrazide 8
(Scheme 3)
Hydrazine hydrate (99%, 2 mL, 40 mmol) was added to a solution
of compound 7 (2.03 g, 10 mmol) in dry ethanol (50 mL) and the
resulting mixture was heated under reflux for 8 h. The reaction
mixture was cooled to room temperature and the solid obtained
was filtered off and washed with a small quantity of ethanol to give
the desired intermediate 8. Yield: 1.80 g, 95%, white solid, mp 125e
2.1.7.3. Data for 9c. White solid, mp 82e84 ꢀC. 1H NMR (600 MHz,
CDCl3):
d
0.98 (t, J ¼ 7.8 Hz, 3H),1.74e1.78 (m, 2H), 2.75 (t, J ¼ 7.8 Hz,
127 ꢀC. 1H NMR (600 MHz, DMSO-d6):
d
3.46 (s, 2H), 4.20 (s, 2H),
2H), 4.32 (s, 2H), 7.12e7.13 (m, 2H), 7.22 (t, J ¼ 7.8 Hz, 1H), 7.37 (d,
6.98 (t, J ¼ 7.8 Hz, 1H), 7.07 (t, J ¼ 7.8 Hz, 1H), 7.18 (s, 1H), 7.34 (d,
J ¼ 7.2 Hz, 1H), 7.64 (d, J ¼ 7.8 Hz, 1H), 8.40 (s, 1H). 13C NMR
J ¼ 7.8 Hz, 1H), 7.58 (d, J ¼ 7.8 Hz, 1H), 9.16 (s, 1H), 10.87 (s, 1H). 13
C
(150 MHz, CDCl3): d 10.8, 19.9, 22.1, 27.2, 108.3, 111.2, 118.6, 119.7,
NMR (150 MHz, DMSO-d6):
d
30.8, 108.7, 111.3, 118.3, 118.7, 120.8,
122.9, 123.3, 126.7, 136.1, 165.8, 167.1. HRMS (ESI): m/z 242.1285.
123.6, 127.2, 136.1, 170.3. EI-MS: m/z (%) 189 (Mþ, 26), 144 (14), 130
Calcd. for C14H15N3O: 242.1293 [M þ H]þ.
(100), 77 (7).
2.1.7.4. Data for 9d. White solid, mp 109e111 ꢀC. 1H NMR
2.1.7. General procedure for the synthesis of target compounds 9
(Scheme 3)
(600 MHz, CDCl3): d 0.90 (s, 9H), 2.50 (s, 2H), 4.32 (s, 2H), 7.00 (t,
J ¼ 7.2 Hz, 1H), 7.10 (t, J ¼ 7.8 Hz, 1H), 7.31 (s, 1H), 7.38 (d, J ¼ 7.8 Hz,
Equimolar quantities of compound 5 (1 mmol) and a substituted
carboxylic acid were dissolved in phosphoryl chloride (5 mL) and
heated under reflux at 80 ꢀC for 3e6 h, the progress of reaction
being monitored by TLC. The reaction mixture was then heated
under reduced pressure to allow excess phosphoryl chloride to
distill off, and the residue was purified by flash chromatography on
silica gel using 15e25% acetone in petroleum ether as eluent to give
the target compounds 9aep (Table 3).
1H), 7.49 (d, J ¼ 7.8 Hz, 1H), 11.04 (s, 1H). 13C NMR (150 MHz, DMSO-
d6): d 21.5, 29.0, 31.1, 38.0,107.1,111.6,118.2,118.7,121.3,123.9,126.6,
136.2, 165.2, 165.8. HRMS (MALDI): m/z 270.1581. Calcd. for
C
16H19ClN3O: 270.1606 [M þ H]þ.
2.1.7.5. Data for 9e. White solid, mp 103e105 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
d
0.69 (t, J ¼ 7.8 Hz, 3H), 1.26 (s, 6H), 1.63 (t,
J ¼ 7.2 Hz, 2H), 4.31 (s, 2H), 7.01 (t, J ¼ 7.2 Hz, 1H), 7.11 (t, J ¼ 7.2 Hz,
1H), 7.30 (s, 1H), 7.38 (d, J ¼ 7.8 Hz, 1H), 7.51 (d, J ¼ 7.8 Hz, 1H), 11.03
2.1.7.1. Data for 9a. White solid, mp 84e86 ꢀC. 1H NMR (600 MHz,
(s, 1H). 13C NMR (150 MHz, DMSO-d6):
d 8.7, 21.5, 25.2, 33.5, 35.5,
CDCl3):
7.23 (t, J ¼ 7.2 Hz, 1H), 7.38 (d, J ¼ 7.8 Hz, 1H), 7.64 (d, J ¼ 7.8 Hz, 1H),
8.36 (s, 1H). 13C NMR (150 MHz, CDCl3):
10.9, 22.0, 108.2, 111.2,
d
2.44 (s, 3H), 4.31 (s, 3H), 7.15 (t, J ¼ 7.2 Hz, 1H), 7.18 (s, 1H),
107.1, 111.6, 118.3, 118.6, 121.3, 123.9, 126.6, 136.2, 165.7, 171.7. 13C
DEPT (100 MHz, DMSO-d6): CH3 (methyl): 8.8, 25.2; CH2 (methyl-
ene): 21.5, 33.5; CH (methine):111.6, 118.3, 118.7, 121.3, 123.9. HRMS
(MALDI): m/z 270.1571. Calcd. for C16H19ClN3O: 270.1606 [M þ H]þ.
d
118.6, 122.3, 123.0, 123.1, 126.7, 136.1, 163.9, 165.9. HRMS (ESI): m/z
214.0970. Calcd. for C12H11N3O: 214.0980 [M þ H]þ.
2.1.7.6. Data for 9f. Red oil. 1H NMR (600 MHz, CDCl3):
d 0.84 (s,
2.1.7.2. Data for 9b. White solid, mp 65e67 ꢀC. 1H NMR (600 MHz,
9H), 1.01 (d, J ¼ 6.6 Hz, 3H), 1.14e1.16 (m, 1H), 1.28e1.30 (m, 1H),
2.02e2.03 (m,1H), 2.64e2.79 (m, 2H), 4.36 (s, 2H), 7.19 (t, J ¼ 7.2 Hz,
1H), 7.22e7.26 (m, 2H), 7.30 (s, 1H), 7.42 (d, J ¼ 7.8 Hz, 1H), 7.68 (d,
CDCl3):
d
1.33 (t, J ¼ 7.8 Hz, 3H), 2.81 (d, J ¼ 7.8 Hz, 2H), 4.32 (s, 2H),
7.15 (t, J ¼ 7.8 Hz, 1H), 7.18 (s, 1H), 7.23 (t, J ¼ 7.8 Hz, 1H), 7.38 (d,
J ¼ 7.8 Hz, 1H), 7.65 (d, J ¼ 7.8 Hz, 1H), 8.31 (s, 1H). 13C NMR
J ¼ 7.8 Hz, 1H), 8.28 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
d 21.4,
(100 MHz, CDCl3):
d
10.4, 18.9, 21.9, 107.6, 111.4, 118.3, 119.5, 122.0,
22.3, 27.8, 29.5, 30.5, 33.6, 49.2, 107.0, 111.5, 118.2,118.6,121.2, 123.9,
123.2, 126.6, 136.1, 165.9, 168.0. HRMS (ESI): m/z 228.1127. Calcd. for
C
126.6, 136.2, 165.7, 169.9. HRMS (MALDI): m/z 312.2060. Calcd. for
C
13H13N3O: 228.1137 [M þ H]þ.
19H25N3O: 312.2076 [M þ H]þ.
N N
O
CH COOEt
CH CONHNH
2
2
2
3
R
EtOH, Reflux
POCl , Reflux
3
.
3
N
8eq. NH NH H O
N
H
R COOH
2
2
2
H
N
H
98%
9
8
7
Scheme 3. Synthesis of 2-(3-indolyl)-methyl-5-substituted-1,3,4-oxadiazoles 9.

M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 63 (2013) 22e32
29
2.1.7.7. Data for 9g. White solid, mp 103e105 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
4.46 (s, 2H), 7.19 (t, J ¼ 7.2 Hz, 1H), 7.24e
7.25 (m, 2H), 7.42 (d, J ¼ 7.8 Hz, 1H), 7.65 (d, J ¼ 7.8 Hz, 1H), 8.18
(s, 1H). 13C NMR (100 MHz, DMSO-d6):
21.4, 105.6, 110.7, 111.6,
114.8, 118.1e118.8 (d, JCeF ¼ 108 Hz, 1C), 121.4, 124.5, 126.5, 136.5,
161.2, 168.7. HRMS (MALDI): m/z 290.0529. Calcd. for C12H8F3N3O:
290.0517 [M þ Na]þ.
1H), 7.09 (d, J ¼ 8.4 Hz, 2H), 7.14 (t, J ¼ 7.8 Hz,1H), 7.41e7.42 (m, 2H),
7.63 (d, J ¼ 7.8 Hz, 1H), 7.87 (d, J ¼ 9.0 Hz, 1H), 11.11 (s, 1H). 13C NMR
d
(150 MHz, DMSO-d6):
d 21.6, 55.4, 107.0, 111.6, 114.8, 115.8, 118.3,
d
118.8, 121.4, 124.2, 126.7, 128.1, 136.2, 161.8, 163.9, 165.5. HRMS
(MALDI): m/z 306.1218. Calcd. for C18H15N3O2: 306.1243 [M þ H]þ.
2.1.7.14. Data for 9n. White solid, mp 147e149 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
d
2.35 (s, 3H), 4.44 (s, 2H), 7.05 (t, J ¼ 7.2 Hz,
2.1.7.8. Data for 9h. White solid, mp 110e112 ꢀC. 1H NMR
1H), 7.14 (t, J ¼ 7.2 Hz,1H), 7.36 (d, J ¼ 8.4 Hz, 2H), 7.41e7.43 (m, 2H),
(600 MHz, DMSO-d6):
1H), 7.10 (d, J ¼ 7.8 Hz, 1H), 7.35e7.39 (m, 2H), 7.52 (d, J ¼ 7.8 Hz,
1H), 11.08 (s, 1H). 13C NMR (150 MHz, DMSO-d6):
21.4, 33.2, 106.5,
d
4.39 (s, 2H), 5.00 (s, 2H), 7.01 (d, J ¼ 7.8 Hz,
7.63 (d, J ¼ 7.8 Hz, 1H), 7.83 (d, J ¼ 7.8 Hz, 1H), 11.11 (s, 1H). 13C NMR
(150 MHz, DMSO-d6):
d 21.1, 21.6, 55.4, 106.9, 111.7, 118.3, 118.8,
d
120.7, 121.4, 124.2, 126.3, 126.7, 129.9, 136.3, 141.9, 164.1, 165.8.
HRMS (MALDI): m/z 290.1273. Calcd. for C18H15N3O: 290.1293
[M þ H]þ.
111.6, 118.2, 118.8, 121.4, 124.2, 126.6, 136.2, 163.8, 167.2. HRMS
(MALDI): m/z 286.0131. Calcd. for C12H10ClN3O: 286.0149 [M þ K]þ.
2.1.7.9. Data for 9i. White solid, mp 142e143 ꢀC. 1H NMR
2.1.7.15. Data for 9o. White solid, mp 124e126 ꢀC. 1H NMR
(400 MHz, CDCl3):
(m, 2H), 7.41 (d, J ¼ 6.8 Hz, 1H), 7.69 (d, J ¼ 8.0 Hz, 1H), 8.22 (s,
1H). 13C NMR (100 MHz, DMSO-d6):
10.6, 18.3, 99.7, 111.4, 120.3,
d
4.45 (s, 2H), 7.19 (t, J ¼ 7.2 Hz, 1H), 7.23e7.25
(600 MHz, CDCl3): d 3.82 (s, 6H), 4.44 (s, 2H), 6.57 (s, 1H), 7.13 (s,
2H), 7.18 (d, J ¼ 7.8 Hz, 1H), 7.57 (d, J ¼ 7.2 Hz, 2H), 7.40 (d,
d
J ¼ 7.82 Hz, 1H), 7.74 (d, J ¼ 8.4 Hz, 1H), 8.20 (s, 1H). 13C NMR
121.1, 122.8, 124.1, 127.7, 136.4, 161.7, 165.3. HRMS (MALDI): m/z
(100 MHz, DMSO-d6): d 21.6, 55.5, 103.7, 104.1, 106.8, 111.6, 118.3,
315.9833. Calcd. for C12H8Cl3N3O: 315.9811 [M þ H]þ.
118.8, 121.4, 124.2, 126.7, 136.3, 161.0, 163.8, 166.2. HRMS (MALDI):
m/z 336.1352. Calcd. for C19H17N3O3: 336.1348 [M þ H]þ.
2.1.7.10. Data for 9j. Pale pink solid, mp 116e118 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
d
4.47 (s, 2H), 7.05 (t, J ¼ 7.2 Hz, 1H), 7.13 (t,
2.1.7.16. Data for 9p. White solid, mp 182e184 ꢀC. 1H NMR
(600 MHz, DMSO-d6): d 3.73 (s, 3H), 3.85 (s, 3H), 4.44 (s, 2H), 7.05 (t,
J ¼ 7.2 Hz, 1H), 7.36e7.38 (m, 1H), 7.39e7.47 (m, 5H), 7.62 (d,
J ¼ 7.8 Hz, 1H), 7.98 (t, J ¼ 7.2 Hz, 1H), 11.10 (s, 1H). 13C NMR
J ¼ 7.2 Hz, 1H), 7.13 (t, J ¼ 7.2 Hz, 1H), 7.19 (s, 1H), 7.41 (m, 2H), 7.65
(100 MHz, DMSO-d6):
d
21.5, 106.8, 111.6, 111.7, 111.8, 116.3, 118.3e
(d, J ¼ 7.8 Hz,1H),11.10 (s,1H). 13C NMR (150 MHz, DMSO-d6):
d 21.7,
118.8 (d, JCeF ¼ 71.3 Hz, 1C), 124.6, 125.3, 126.7, 129.4, 130.2, 134.1,
56.0, 60.2, 103.6, 106.9, 111.6, 118.4, 118.6, 118.7, 121.4, 124.2, 126.7,
136.3, 140.3, 153.4, 163.9, 166.0. HRMS (MALDI): m/z 388.1272.
Calcd. for C20H19N3O4: 388.1273 [M þ Na]þ.
136.2, 158.2, 160.6, 163.2. HRMS (MALDI): m/z 294.1023. Calcd. for
C
17H12FN3O: 294.1043 [M þ H]þ.
2.1.7.11. Data for 9k. White solid, mp 141e143 ꢀC. 1H NMR
(600 MHz, DMSO-d6):
2.2. X-ray diffraction analysis
d
4.46 (s, 2H), 7.05 (t, J ¼ 7.8 Hz, 1H), 7.13 (t,
J ¼ 7.8 Hz, 1H), 7.41e7.44 (m, 2H), 7.57e7.66 (m, 3H), 7.71 (d,
Crystal structures of compound 3h, 6g and 9k are shown in
Fig. 4.
J ¼ 7.2 Hz, 1H), 7.89 (d, J ¼ 7.8 Hz, 1H), 7.99 (s, 1H). 13C NMR
(100 MHz, DMSO-d6):
d
20.5, 106.7, 111.6, 118.3, 118.8, 121.4, 124.3,
Colourless crystals of compound 3h (0.23 mm ꢁ 0.20 mm ꢁ
0.20 mm) were mounted on a quartz fibre with protection oil. Cell
dimensions and intensities were measured at 299 K on a Bruker
CCD DUO area detector diffractometer with graphite mono-
ꢀ
125.0, 125.3, 125.8, 126.7, 131.6, 134.0, 136.2, 162.9, 166.5, 168.0.
HRMS (MALDI): m/z 332.0549. Calcd. for C17H12ClN3O: 332.0567
[M þ Na]þ.
chromated Mo Ka radiation (
l
¼ 0.71073 A); qmax ¼ 32.00; 9126
2.1.7.12. Data for 9l. White solid, mp 158e160 ꢀC. 1H NMR
measured reflections; 2955 independent reflections (Rint ¼ 0.0169)
of which 6320 had [I > 2s(I)]. The structure was solved by direct
methods using SHELXS-97. Collected data were corrected for
absorbance by using SADABS based upon the Laue symmetry using
equivalent reflections with the multi-scan method. Structure so-
lution and refinement were carried out with the SHELXTL software
package and the structure was solved by the direct method. Full-
matrix least-squares refinement based on F2 using the weight of
(600 MHz, DMSO-d6):
d
4.45 (s, 2H), 7.04 (t, J ¼ 7.2 Hz, 1H), 7.13 (t,
J ¼ 7.2 Hz, 1H), 7.39e7.42 (m, 2H), 7.61 (d, J ¼ 7.8 Hz, 1H), 7.77 (d,
J ¼ 9.0 Hz, 2H), 7.86 (d, 2H), 11.10 (s, 1H). 13C NMR (150 MHz, DMSO-
d6):
d 21.6, 106.7, 111.6, 118.3, 118.8, 121.4, 122.6, 124.3, 125.4, 126.7,
128.2, 132.5, 136.2, 163.4, 166.3. HRMS (MALDI): m/z 354.0229.
Calcd. for C17H12BrN3O: 354.0242 [M þ H]þ.
2.1.7.13. Data for 9m. Light yellow solid, mp 116e118 ꢀC. 1H NMR
u
¼ 1/[
s
2(Fo2) þ (0.0485P)2 þ 0.3358P] gave final values of
(600 MHz, DMSO-d6):
d
3.82 (s, 3H), 4.43 (s, 2H), 7.06 (t, J ¼ 7.8 Hz,
R1 ¼ 0.0300,
u
R2 ¼ 0.0869 [I > 2s(I)], and GOF(F) ¼ 1.084 for 149
Fig. 4. Crystal structures of compound 3h, 6g and 9k.

30
M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 63 (2013) 22e32
restraints and 2955 parameters reflections. Maximum shift/
error ¼ 0.001(3), max/min residual electron density ¼ 0.420/
ꢂ0.227 e Åꢂ3. Hydrogen atoms were observed and placed at their
ideal positions, then they were refined with a fixed value of their
isotropic displacement parameter being equal to 1.2e1.5 times of
Ueq of their parent atoms. In compound 3h, C11H8ClN3O, the ben-
zene and pyrrole rings are almost coplanar [dihedral angle ¼ 2.8
(2)ꢀ]. The dihedral angle between the pyrrole and oxadiazole rings
is 4.7 (5)ꢀ. The crystal structure is stabilized by NeH/N hydrogen
bonds and there are also weak NeH/C interactions.
859393 (compound 9k). Copies of the data can be obtained free
of charge via http://www.ccdc.cam.ac.uk/.
2.3. Biological assays
The materials and methods used in the biological assays con-
ducted at Syngenta are the same as those described in our earlier
work [24]. The results of the biological testing against seven phy-
topathogenic fungi are shown in Table 4.
Colourless crystals of compound 6g (0.16 mm ꢁ 0.12 mm ꢁ
0.10 mm) were mounted on a quartz fibre with protection oil. Cell
dimensions and intensities were measured at 299 K on a Bruker
3. Results and discussion
3.1. Chemistry
CCD DUO area detector diffractometer with graphite mono-
ꢀ
chromated Mo Ka radiation (
l
¼ 0.71073 A); qmax ¼ 28.97; 16,840
Three series of indole derivatives containing the 1,3,4-
oxadiazole ring were efficiently synthesized in moderate to good
yields, and were screened for antifungal activity. The first series of
compounds 3 were prepared in a two-step process involving con-
version of a carboxylic acid into the corresponding hydrazide and
then condensation with a different carboxylic acid and ring closure
with dehydration. We observed that many of this first series of
indole derivatives (3aem) have high melting points, a feature often
associated with low solubility and hence limited bioavailability.
Two strategies were therefore used in attempts to make analogues
with lower melting points and improved bioavailability. First, we
synthesized the compounds 6aez in which the indole ring nitrogen
had been substituted with an ethyl group, and second, we prepared
the compounds 9aep in which a methylene bridge had been
introduced between the indole and oxadiazole rings.
Treatment of the indole esters (1, 4, 7) with hydrazine hydrate in
ethanol overnight afforded the corresponding hydrazides (2, 5, 8) in
almost quantitative yields. Subsequent condensation between the
hydrazide and a variety of substituted benzoic or aliphatic car-
boxylic acids followed by dehydrative ring closure in the same pot
was achieved by treatment with phosphoryl chloride at 80 ꢀC under
reflux and led to the target 1,3,4-oxadiazoles (3, 5, 9). It is worth
noting that the excess phosphoryl chloride could easily be distilled
out of the reaction mixture and recycled.
measured reflections; 4878 independent reflections (Rint ¼ 0.0297)
of which 5281 had [I > 2s(I)]. The structure was solved by direct
methods using SHELXS-97. Collected data were corrected for
absorbance by using SADABS based upon the Laue symmetry using
equivalent reflections with the multi-scan method. Structure so-
lution and refinement were carried out with the SHELXTL software
package and the structure was solved by the direct method. Full-
matrix least-squares refinement based on F2 using the weight of
u
¼ 1/[
s
2(Fo2) þ (0.1040P)2 þ 0.3447P] gave final values of
R1 ¼ 0.0524,
u
R2 ¼ 0.1604 [I > 2s(I)], and GOF(F) ¼ 1.083 for 384
restraints and 4878 parameters reflections. Maximum shift/
error ¼ 0.001(3), max/min residual electron density ¼ 0.388/
ꢂ0.266 e Åꢂ3. Hydrogen atoms were observed and placed at their
ideal positions, then they were refined with a fixed value of their
isotropic displacement parameter being equal to 1.2e1.5 times of
Ueq of their parent atoms. In compound 6g, C13H10F3N3O, the
benzene and pyrrole rings are almost coplanar [dihedral
angle ¼ 9.2 (0)ꢀ]. The dihedral angle between the indole and oxa-
diazole rings is 3.7 (8)ꢀ. The crystal structure is stabilized by F/F
interactions.
Colourless crystals of compound 9k (0.20 mm ꢁ 0.15 mm ꢁ
0.10 mm) were mounted on a quartz fibre with protection oil. Cell
dimensions and intensities were measured at 297 K on a Bruker
CCD DUO area detector diffractometer with graphite mono-
We observed that in the key 1,3,4-oxadiazole-forming reaction,
the unsubstituted indole compounds (3aem and 9aep) were more
readily prepared (80 ꢀC, 3e6 h) than their N-substituted counter-
parts (6aez) (reflux, 3e6 h).
We also noted that, although the yields were not optimized, the
oxadiazole-forming reaction was sensitive to the nature of the
substituents. It was found that electron-donating substituents such
as MeO-groups increase the rate of reaction and lead to moderate
or good yields of products. Similarly, reactions with aliphatic
acids proceed smoothly. By contrast, examples with electron-
withdrawing substituents gave lower isolated yields, e.g. just 28%
for compound 6o (3-NO2-C6H4) and 22% for 6m (2-I-C6H4).
ꢀ
chromated Mo K
a
radiation (
l
¼ 0.71073 A); qmax ¼ 31.09; 12,814
measured reflections; 4289 independent reflections (Rint ¼ 0.0256)
of which 4054 had [I > 2s(I)]. The structure was solved by direct
methods using SHELXS-97. Collected data were corrected for
absorbance by using SADABS based upon the Laue symmetry using
equivalent reflections with the multi-scan method. Structure so-
lution and refinement were carried out with the SHELXTL software
package and the structure was solved by the direct method. Full-
matrix least-squares refinement based on F2 using the weight of
u
¼ 1/[
s
2(Fo2) þ (0.0872P)2 þ 0.0890P] gave final values of
R1 ¼ 0.0467,
u
R2 ¼ 0.1368 [I > 2s(I)], and GOF(F) ¼ 1.050 for 204
restraints and 4289 parameters reflections. Maximum shift/
error ¼ 0.001(3), max/min residual electron density ¼ 0.262/
ꢂ0.171 e Åꢂ3. Hydrogen atoms were observed and placed at their
ideal positions, then they were refined with a fixed value of their
isotropic displacement parameter being equal to 1.2e1.5 times of
Ueq of their parent atoms. In compound 9k, C17H13N3O, the benzene
and pyrrole rings of the indole are almost coplanar [dihedral
angle ¼ 0.1 (9)ꢀ], and the same is true for the toluene and oxadia-
zole rings [dihedral angle ¼ 0.4 (0)ꢀ]. The dihedral angle between
the pyrrole and oxadiazole rings is 5.7 (0)ꢀ. The crystal structure is
stabilized by NeH/N hydrogen bonds and there are also weak Ce
3.2. Antifungal activity and the structureeactivity relationships
The oxadiazoles that have been synthesized are bioisosteres of
pimprinine. We speculated that the additional nitrogen atom of the
oxadiazole ring in comparison to the oxazole ring would participate
in hydrogen bonding interactions and contribute substantially to
the antifungal activity. Indeed, several of the synthesized com-
pounds displayed patterns of activity with improved spectrum and/
or potency compared to that of pimprinine. For the purposes of
structureeactivity relationship analysis, the antifungal activity of
derivatives of compound 3 can be compared to their equivalents of
compounds 6 and 9. It was noticeable that where compounds were
active it was most commonly against Pythium dissimile, and that the
antifungal activity lacked potency, rarely extending to the lower
H/p interactions.
The crystallographic data have been deposited with the Cam-
bridge Crystallographic Data Centre with the deposition No. CCDC-
859394 (compound 3h), CCDC-859392 (compound 6g) and CCDC-

M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 63 (2013) 22e32
31
Table 4
oxadiazole rings. For example, while compound 3e was only active
against P. dissimile at 20 ppm, the equivalent 6e also displayed ac-
tivity against Septoria tritici and Uromyces viciae-fabae at 100 ppm,
and 9e was less active against P. dissimile but was active against
U. viciae-fabae, and gave weak activity against other species. Sim-
ilarly, while 3h was entirely inactive, compound 6h produced
strong activity against P. dissimile, and 9h was also active against
the species at high rates. Both 6h and 9h also showed weak activity
against other species.
This improvement in activity is not seen with all derivatives,
however. 3g was active against P. dissimile and U. viciae-fabae, while
6g was inactive and 9g lost the activity against U. viciae-fabae. 3d
was only active against P. dissimile, while 6d was inactive on all
assays and 9d showed a broader spectrum, although with weak
activity.
Antifungal activities of pimprinine derivatives.
Species
PHYa
Rate
SEPb URO PYT
ALT
BOT
GIB
20
Compound
200 60 100
100
20
2
20
0
2
20
0
2
2
Pimprinine
0
0
0
0
49
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
27
0
0
0
0
49
0
0
49
0
49
0
0
49
0
0
51
49 36
27
55
0
0
99
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
99
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Streptochlorin
3a
3b
3c
3d
3e
99 99 99
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
55
0
0
0
0
e
e
e
e
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
27
49
49
0
49
0
0
0
0
0
0
0
0
0
0
0
0
0
0
55
99
99
3f
0
0
0
55
0
0
99
0
0
0
99 49
99 27
0
0
3g
3h
3i
3j
3k
3l
3m
6a
6b
6c
6d
6e
0
0
0
0
0
0
0
0
0
0
0
0
0
0
More generally, it is noticeable that almost all the derivatives of
compound 3 with substitution on the benzene ring were inactive,
while equivalent derivatives of compounds 6 and 9 were usually
active against P. dissimile, and sometimes display a broader spec-
trum of activity (e.g. 9j).
18
0
0
0
0
0
0
0
0
18
36
18
0
0
0
27
0
0
0
55
0
0
e
66
0
99
0
99
0
0
0
0
4. Conclusions
6f
0
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
e
e
e
e
e
e
e
0
0
0
0
In conclusion, we have efficiently synthesized three series of
indole-based 1,3,4-oxadiazole derivatives, designed as analogues of
the antifungal natural product pimprinine, and evaluated their
antifungal activities.
Biological testing showed that the synthesized derivatives dis-
played an altered pattern of biological activity compared to the
natural product pimprinine and that in most cases biological ac-
tivity is improved by N-ethylation of the indole nitrogen to give
compounds 6, or by introducing a methylene bridge between the
indole and oxadiazole rings to give compounds 9. The compounds
3g, 6c, 6e, 6h, 9d, 9e, 9h and 9m (Fig. 1) were identified as the most
promising candidates for further study.
0
0
0
0
0
0
0
49
0
0
0
0
99 99 27
99
27
77
27
99
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
27
0
0
0
0
0
0
0
e
e
e
e
e
e
e
e
e
e
e
0
0
0
0
0
55
0
27
0
99
99 49
99
27 27
0
6s
6t
0
0
0
0
55
0
27
0
99
0
0
0
6u
6v
6w
6x
6y
6z
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
Further structural optimization of indole-based 1,3,4-oxadiazole
derivatives is well under way, alongside more detailed biological
testing of the most active compounds, with the aim of improving
their levels of antifungal activity.
0
0
0
0
0
0
49 55
99 77
99 49
0
0
0
0
99
0
0
0
0
0
0
0
NC
0
0
0
0
0
Acknowledgements
e
e
e
e
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
27
99
0
99 49
55 27 27
0
99
99
0
27
0
0
We thank the Biology Team at Syngenta for their kind help in
screening the compounds for biological activity. We are grateful
to the financial support for this work from the National Key Tech-
nologies R&D Program (2011BAE06B05) and the NSFC (No.
21172091, No. 21272091).
0
0
0
0
0
0
0
0
0
0
0
55
0
0
0
0
0
0
0
49
55
0
49
0
0
18
0
0
0
55
55 55
55
0
0
References
0
0
0
0
0
0
0
0
0
0
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