Synthesis, molecular docking study and antitumor activity of novel 2-phenylindole derivatives

Article abstract of DOI:10.1016/j.ejmech.2011.11.007

The starting material, 4-(1-indol-2-yl)phenol 1 was obtained via Fischer synthesis. Vilsmeir Haack^'s formylation of 1 gave the carboxaldehyde derivative 2 which was subjected to different reactions affording the 3-substituted compounds 3-10. Co

Full text of DOI:10.1016/j.ejmech.2011.11.007

European Journal of Medicinal Chemistry 47 (2012) 387e398
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, molecular docking study and antitumor activity of novel
2-phenylindole derivatives
,
a
a
Sally S. El-Nakkadya, Mona M. Hanna b , Hanaa M. Roaiah , Iman A.Y. Ghannam
*
a Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, El-Bohouth Street,
12622 Dokki, Cairo, Egypt
b Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, El-Kasr El-Eini Street, 11562 Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
The starting material, 4-(1-indol-2-yl)phenol 1 was obtained via Fischer synthesis. Vilsmeir Haack’s
formylation of 1 gave the carboxaldehyde derivative 2 which was subjected to different reactions
affording the 3-substituted compounds 3e10. Compound 1 reacted with halo esters to give 11 and 12a,b.
The reaction of 12a with various amino derivatives gave compounds 13e16. The hydrazide derivative 15a
reacted with 1,3-diketones, ethyl acetoacetate and aromatic carboxylic acid derivatives to give 17a,b, 18
and 19aee, respectively. Antitumor activity of target compounds were tested against breast cancer cell
lines (MCF-7) and (MDA-MB-231). The most potent compound was 3e with IC50 ¼ 1.60 nM against (MCF-
7). Docking was performed on colchicine binding site of tubulin to study the binding mode of the
designed compounds.
Article history:
Received 8 June 2011
Received in revised form
29 October 2011
Accepted 2 November 2011
Available online 11 November 2011
Keywords:
2-Phenylindoles
Indole carboxaldehyde
Antitumor activity
Breast cancer cell lines MCF-7 and MDA-
MB-231
Ó 2011 Elsevier Masson SAS. All rights reserved.
Docking study
1. Introduction
The indole nucleus emerged as a versatile skeleton for the
development of compounds with promising antiproliferative
Today, more than ever, scientists are doing a great deal of
research to help prevent or beat cancer. Although there are a large
number of anticancer drugs currently used, many new chemical
classes of anticancer agents affecting a variety of biological targets
have emerged and are under clinical trials for the production of
novel effective and less toxic drugs.
activity [7e9]. A variety of 2-phenylindoles I was found to inhibit
the growth of human breast cancer cells by different mechanisms
depending on the type and position of the substituents [10e13].
Recently, 2-phenylindole-3-carboxaldehydes II proved to exert an
antimitotic activity in human breast cancer cells by inhibition of
tubulin polymerization (Fig. 1) [14,15]. Furthermore, several
modifications on the 3-formyl group were carried out in order to
overcome the in-vivo instability of the aldehyde functional group.
These modifications included the formation of oximes, methyl-
amine, propanedinitriles, hydrazones and other derivatives that
proved to possess high stability and good antimitotic activity
[15e17]. Some of these indole derivatives were structurally opti-
mized through 3D-QSAR and docking studies on tubulin [18]. These
findings encouraged us for further exploration of novel anticancer
drugs possessing the 2-phenylindole scaffold and bearing different
substituents on the 2-phenyl moiety. Furthermore, it was of our
interest to focus on the synthesis of the 3-carboxaldehyde phe-
nylindole and perform several modifications on the formyl group
aiming to give rise to new potent and stable anticancer agents.
Docking studies were performed to assess the binding mode of the
active compounds into the colchicine binding site of tubulin.
Microtubules, cylindrical protein polymers composed of
a- and
b
-tubulin heterodimers, are the basic components of cell structure,
which take part in a wide number of pivotal cellular functions [1,2].
Inhibition of microtubule formation leads to mitotic arrest
promotes vascular disruption and eventually leads to cell death by
apoptosis [3,4]. Hence, tubulin is a common target of attack for
many anticancer drugs [5]. Vinca alkaloid, taxanes and other anti-
mitotic agents are used for the treatment of cancer, however,
difficulty in synthesis and high cost limited their uses [6]. There-
fore, searching for new antimitotic agents with better activity is still
in progress.
* Corresponding author. Tel.: þ20 122 2174170.
E-mail address: mmauricebta@gmail.com (M.M. Hanna).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.11.007

388
S.S. El-Nakkady et al. / European Journal of Medicinal Chemistry 47 (2012) 387e398
CHO
R2
The hydrazinecarbothioamide derivative 5 was prepared by the
reaction of the formyl derivative 2 with thiosemicarbazide. The 1H
NMR displayed 2 signals at 8.04 and 9.91 ppm corresponding to
NH2 and NeNH protons respectively. The carboxaldehyde oxime
derivative 6 was obtained by condensation of the starting formyl
derivative 2 with hydroxylamine hydrochloride. 1H NMR of 6
showed a new exchangeable signal at 11.30 ppm corresponding to
OH proton of the oxime group.
Bu
R
R1
N
N
H
H
II
I
R1= OH, CH3
R2= H, alkyl
R= OH, OCH3
Reaction of the formyl derivative 2 with the active methylene of
barbituric and thiobarbituric acids gave the heterocyclic derivatives
7a,b respectively. IR spectrum of 7b revealed the presence of 3
stretching bands at 3417, 3371 cmꢀ1 and 3123 cmꢀ1 assigned for
OH, indole NH and pyrimidine NH, respectively, in addition to
a broad band at 1652 cmꢀ1 attributed to the 2C]O groups. 1H NMR
of 7b showed a new exchangeable signal at 12.51 ppm corre-
sponding to the 2 NH protons of the pyrimidine ring.
Fig. 1. Examples of 2-phenylindole derivatives with anticancer activity.
2. Results and discussion
2.1. Chemistry
The synthetic pathways adopted for the preparation of the
desired new compounds are illustrated in Schemes 1e3. The known
starting material 1 was reported to be obtained via Fischer
synthesis [19,20]. Scheme 1 illustrates the synthesis of the 3-formyl
derivative 2 from the starting material 1 via Vilsmeir Haack’s for-
mylation using POCl3 and dimethylformamide (DMF) [15,21]. The
IR spectrum of 2 revealed C]O stretching band of formyl group at
1696 cmꢀ1 1H NMR spectrum showed an exchangeable signal at
8.35 assigned to the OH proton and a non exchangeable signal at
9.94 ppm corresponding to the formyl proton, in addition to the
indole and phenyl protons.
The propanedinitrile derivative 8 was obtained by the reaction
of the starting formyl derivative 2 with malononitrile. IR spectrum
of 8 revealed a new stretching band of the nitrile groups at
2214 cmꢀ1. 1H NMR showed a signal at 7.93 ppm corresponding to
the vinyl proton CH]C.
The 3-substituted indole derivatives 9a,b and 10 were prepared
via the reaction of the formyl derivative 2 with the appropriate
amine namely, o-phenylenediamine, o-aminophenol and ethyl-
enediamine, respectively. 1H NMR of 9a showed 2 multiplets at
7.12e7.19 ppm and 7.55e7.61 ppm and an exchangeable singlet at
12.21 ppm corresponding to the aromatic protons and NH proton of
benzimidazole respectively. 1H NMR of 10 showed a multiplet at
7.07 ppm attributed to imidazole protons and a new exchangeable
singlet at 8.40 ppm corresponding to imidazole NH.
The hydrazides 3aef and the hydrazones 4aec were obtained by
the reaction of the formyl derivative 2 with different substituted
acid hydrazides and hydrazines, respectively.
NNHCOR
OH
N
OH
NH
N
H
N
1
OH
H
N
H
a
3a R= CH3
3b R= C6H5
10
b
i
3c R= o-NH2-C6H4
3d R= p-NH2-C6H4
3e R= p-NO2-C6H4
3f R= p-Cl-C6H4
CHO
h
N
OH
X
c
N
H
OH
2
NNHR
N
H
g
OH
9a X= NH
9b X=O
N
H
e
f
d
4a R= CH3
4b R= C6H5
4c R= o-Cl-C6H4
CN
NOH
CN
X
OH
HN
NH
OH
N
H
N
H
O
O
6
NNHCSNH2
OH
8
OH
N
H
N
H
5
7a X=O
7b X=S
Scheme 1. Reagents and solvents: a: POCl3, DMF; b: ReCOeNHNH2, absolute ethanol; c: R-NHNH2, absolute ethanol; d: NH2CSNHNH2, absolute ethanol; e: NH2OH. HCl, absolute
ethanol, pyridine; f: thio/barbituric acid(s), absolute ethanol; g: malononitrile, absolute ethanol; h: o-phenylenediamine or o-aminophenol, absolute ethanol; i: ethylenediamine,
absolute ethanol.

S.S. El-Nakkady et al. / European Journal of Medicinal Chemistry 47 (2012) 387e398
389
OH
N
H
a
1
b
OCOOCH3
N
H
OCH2COO
R
SO2NHR
11
N
H
f
12a R= CH3
12b R= CH2CH5
c
OCH2CO NH
OCH2CONHR
N
H
N
H
16a R=H
16b R=
e
CH3
13a R=H
d
13b R= CH2CH2OH
13c R= pyridin-4-yl
13d R= pyrazin-2-yl
O
N
S
16c R=
N
OCH2CONHNHR
OCH2COR
N
H
N
H
15a R= H
14a R= N(CH2CH2OH)2
14b R= N(CH3)2
14c R= pyrrolidin-1-yl
15b R= C6H5
15c R= COCH3
15d R= CSNH2
Scheme 2. Reagents and solvents: a: CleCOOeCH3, dry acetone, K2CO3 anhydrous; b: BreCH2COOeR, dry acetone, K2CO3 anhydrous; c: RNH2, absolute ethanol; d: secondary
amines, absolute ethanol; e: ReNHeNH2, absolute ethanol; f: sulfonamides, dry acetone, K2CO3 anhydrous.
Other targeted 2-phenylindole derivatives were prepared as
shown in Scheme 2. Methyl chloroformate reacted with 1 to give
the methyl carbonate derivative 11. The 1H NMR of 11 revealed
a signal at 4.02 ppm corresponding to the methyl protons. The ester
derivative 12a was obtained by the reaction of the starting material
1 with methyl bromoacetate adopting the same procedure used for
preparation of 12b [22,23]. The 1H NMR of 12a displayed 2 new
signals at 3.51 ppm and 4.37 ppm corresponding to the methyl and
methylene protons respectively.
Aminolysis of the ester derivative 12a was carried out using
different primary and secondary amines affording 13aed and
14aec, respectively. 1H NMR of 14b revealed 2 singlets at 3.35 and
3.36 ppm corresponding to the 2 methyl protons.
Reaction of 12a with hydrazines, acetohydrazide and thio-
semicarbazide afforded derivatives 15aed, respectively. 1H NMR of
15a showed the presence of new exchangeable signals at 4.40 ppm
and 9.41 ppm corresponding to the NH2 and NH hydrazide,
respectively.
The ester derivative 12a reacted also with different sulfon-
amides to give the corresponding sulfonamido derivatives 16aec.
IR spectrum of 16c revealed a stretching band of the amidic C]O
group at 1630 cmꢀ1 and absorption bands at 1324 cmꢀ1 and
1137 cmꢀ1 attributed to the SO2 group. 1H NMR of 16c revealed the
presence of 2 multiplets at 6.67e6.69 ppm and 7.12e7.14 ppm
corresponding to the thiazole protons and an exchangeable signal
at 10.50 ppm corresponding to the NHeSO2 proton. 13C NMR
OCH2CONHNH2
N
H
a
c
15a
N
b
OCH2COR
OCH2
N
N
H
N
H
O
R
19a R= C6H5
CH3
N
19b R= p-NH2-C6H4
19c R= o-NH2-C6H4
19d R= o-OH-C6H4
17a R=
N
CH3
N
CH3
Ph
19e R=6-methoxyquinolin-2-yl
OCH2CO
N
N
N
H
17b
N
R=
O
18
CH3
Scheme 3. Reagents and solvents: a: acetylacetone or benzoylacetone, absolute ethanol; b: ethyl acetoacetate, absolute ethanol; c: RCOOH, POCl3.

390
S.S. El-Nakkady et al. / European Journal of Medicinal Chemistry 47 (2012) 387e398
spectrum of 16c showed 2 signals at 124.50 ppm and 152.24 ppm
corresponding to the thiazole carbon atoms and a signal at
168.50 ppm corresponding to the C]O carbon atom.
were found to be the most potent in this series. Some modifications
performed on the 3-formyl derivative 2 led to decrease in activity as
shown in hydrazinecarbothioamide, carboxaldehyde oxime,
methylene hybrids and propanedinitrile derivatives 5, 6, 7a,b and 8,
respectively. Introduction of a heterocyclic moiety at position 3
displayed good activity, the 3-benzoxazole derivative 9b revealed
better activity than the benzimidazole isostere 9a, while the
imidazole derivative 10 showed a slight decrease in activity.
The methyl acetate derivative 12a was found to be more potent
than the methyl carbonate analog 11 which may be attributed to
the presence of the methylene spacer in 12a. Furthermore,
compound 12a exhibited better activity than its ethyl ester analog
12b that showed a marked decrease in activity suggesting an
optimum chain length in the ester moiety. The amide derivatives
13aed and 14aec showed good to moderate activity except the
hydroxyethyl acetamide derivative 13b that exhibited a marked
drop in activity. However, the pyrido derivative 13c and the pyr-
rolidino derivative 14c were the most active of these series. The
hydrazide derivative 15a revealed higher activity than the other
substituted hydrazide 15b,c and thiosemicarbazide 15d. Sulfon-
amide derivatives 16aec, in general showed good activity. The N-
thiazolesulfonamido derivative 16c was the most potent, while; the
unsubstituted sulfanilamido derivative 16a was the least.
Cyclization of the hydrazide derivative 15a with different dike-
tones; acetylacetone and benzoylacetone was achieved resulting in
the pyrazolo-indole derivatives 17a,b (Scheme 3). 1H NMR of 17b
revealed a new signal at 2.05 ppm corresponding to the methyl
protons in addition to the aromatic protons of the phenyl groups.
Furthermore, the pyrazolone derivative 18 was obtained by
cyclization of the hydrazide derivative 15a with ethyl acetoacetate.
1H NMR of 18 revealed a singlet at 1.21 ppm corresponding to the
methyl protons and singlet at 2.25 attributed to the pyrazole
protons.
The hydrazide derivative 15a reacted with different aromatic
carboxylic acid derivatives in POCl3 to give the corresponding
oxadiazole derivatives 19aee. 1H NMR of 19e showed a character-
istic singlet at 3.93 ppm corresponding to the methoxy protons in
addition to the signals assigned for the quinoline protons and the
other usual protons of the basic structure.
2.2. Antitumor activity
All the newly synthesized compounds and the starting material
1 were tested for their cytotoxic activity against MCF-7 (human
breast cancer cell line) using the method of Skehan et al [24e26]
and were compared to vincristine as reference drug. The most
active compounds 2, 3b, 3c, 3d, 3e, 3f, 4a, 4b, 4c, 9b, 14c, 16b, 16c
and 19a, revealing IC50 < 20 nM against MCF-7 were further tested
against MDA-MB-231 cell line.
Cytotoxic activities of the tested compounds were expressed as
IC50 in nM and were recorded in Table 1. Most of the tested
compounds showed good anticancer activity against the 2 breast
cell lines.
Regarding the activity against MCF-7, the 3-formyl derivative 2
was found to be more potent than the starting phenylindole
derivative 1. Most of the prepared hydrazide-based indole deriva-
tives 3aef revealed good activity when compared with the refer-
ence drug. Compound 3e exhibited the best activity showing
IC50 ¼ 1.60 nM being more active than vincristine (IC50 ¼ 2.00 nM).
The 4-amino and 4-chloro benzohydrazides 3d and 3f, respectively,
revealed similar IC50 values, indicating that the activity is not
related to the electronic nature of the substituent. On the other
hand, aliphatic substitution 3a decreased the activity. Among the
hydrazone-based indole derivatives 4aec compounds 4b and 4c
The pyrazolone derivative 18 exhibited better activity than the
pyrazolo derivatives 17a,b. Furthermore, most of the indolyl oxa-
diazole derivatives 19aee were found to be good anticancer agents.
However, changing the position of amino group in the aniline
moiety from the ortho position 19c to the para position 19b
decreased the activity.
Regarding the activity against MDA-MB-231, all the tested
compounds revealed good cytotoxic profile, however, it was lower
than that recorded against MCF-7 except for compounds 9b and
16b especially the latter that was as twice as potent against MDA-
MB-231. It is noteworthy that the reference drug vincristine also
showed lower activity against MDA-MB-231 (IC 50 ¼ 6.00 nM) than
MCF-7 (IC 50 ¼ 2.00 nM).
2.3. Molecular docking
Molecular Operating Environment (MOE) based molecular
docking was done for the starting compound 1, the target
compounds having IC50 < 25 nM (MCF-7): 2, 3b, 3c, 3d, 3e, 3f, 4a,
4b, 4c, 9a, 9b, 13c, 14c, 15a, 16a, 16b, 16c, 19a, 19e and vincristine on
tubulin co-crystallized with colchicine obtained from the protein
Table 1
IC50 values of the tested compounds on MCF-7 and MDA-MB-231 cell lines.
Cpd.
IC50 nM ꢁ SE
Cpd.
IC50 nM ꢁ SE
Cpd.
IC50 nM ꢁ SE
MCF-7
MDA-MB-231
MCF-7
MDA-MB-231
MCF-7
MDA-MB-231
1
2
71.80 ꢁ 0.19
9.00 ꢁ 0.13
32.30 ꢁ 0.18
18.70 ꢁ 0.13
17.90 ꢁ 0.23
3.70 ꢁ 0.11
1.60 ꢁ 0.20
3.80 ꢁ 0.14
17.70 ꢁ 0.19
6.70 ꢁ 0.17
5.70 ꢁ 0.15
32.00 ꢁ 0.24
27.60 ꢁ 0.19
41.80 ꢁ 0.25
55.10 ꢁ 0.23
n.d.
8
9a
9b
10
87.70 ꢁ 0.15
23.50 ꢁ 0.17
17.50 ꢁ 0.23
28.40 ꢁ 0.17
93.60 ꢁ 0.17
35.00 ꢁ 0.18
101.70 ꢁ 0.13
37.60 ꢁ 0.24
96.80 ꢁ 0.25
21.10 ꢁ 0.21
36.30 ꢁ 0.25
27.50 ꢁ 0.22
34.30 ꢁ 0.25
14.80 ꢁ 0.24
20.00 ꢁ 0.21
n.d.
n.d.
15b
15c
15d
16a
16b
16c
17a
17b
18
19a
19b
19c
19d
19e
28.00 ꢁ 0.23
92.90 ꢁ 0.25
44.70 ꢁ 0.23
24.20 ꢁ 0.17
17.50 ꢁ 0.22
7.40 ꢁ 0.20
43.20 ꢁ 0.12
48.90 ꢁ 0.20
31.80 ꢁ 0.25
13.70 ꢁ 0.23
48.00 ꢁ 0.10
26.00 ꢁ 0.21
39.00 ꢁ 0.25
22.10 ꢁ 0.18
2.00 ꢁ 0.22
n.d.
n.d.
n.d.
n.d.
9.56 ꢁ 0.11
28.97 ꢁ 0.25
n.d.
n.d.
n.d.
42.19 ꢁ 0.23
3a
3b
3c
3d
3e
3f
4a
4b
4c
5
n.d.
15.34 ꢁ 0.19
28.17 ꢁ 0.14
29.73 ꢁ 0.12
37.84 ꢁ 0.23
32.50 ꢁ 0.18
37.20 ꢁ 0.26
47.55 ꢁ 0.11
25.08 ꢁ 0.13
31.58 ꢁ 0.18
n.d.
n.d.
11
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
12a
12b
13a
13b
13c
13d
14a
14b
14c
15a
18.33 ꢁ 0.23
n.d.
n.d.
n.d.
n.d.
6.00 ꢁ 0.14
6
7a
7b
n.d.
n.d.
n.d.
n.d.
42.19 ꢁ 0.21
n.d.
Vincristine
n.d.: Not determined.

S.S. El-Nakkady et al. / European Journal of Medicinal Chemistry 47 (2012) 387e398
391
data bank (code, 1SA0.pdb). Docked structures for 4 selected
3. Experimental
compounds (3e, 3f, 4c and 16b) are shown in Fig. 2. From previous
report about the binding mode of antitubulin agents into the
cochicine-binding site and from the experimental docking of
vincristine, it was noted that the amino acids involved in the
3.1. Chemistry
Melting points are uncorrected and were recorded by Open
Capillary tube method using on Electro-thermal Melting Point
apparatus. Infra red spectra (KBr discs) were recorded on Jasco FT/
IR 6100 Fourier Transformer spectrophotometer in the Central
Services Unit at the National Research Centre (NRC). 1H NMR
spectra were recorded on JEOL EX-270 spectrometer at 500 MHz
and 13C NMR at 125 MHz in the Central Services Unit at the (NRC).
interaction were Cys-b241, Lys-b254, Asn-a101, Thr-A179, Tyr-A224,
Gn-A176. Furthermore, the main interaction of certain arylth-
ioindoles bearing an ester moiety at position 2 of the indole
included a hydrogen bond between the carbonyl group of the ester
function and lysine in the binding site [27e29]. Our target
compounds were successfully docked in the colchicine binding
pocket of tubulin as referred from the surrounding amino acids. H-
bonding interaction with amino acids in the binding pocket was
observed for most compounds in addition to hydrophobic inter-
actions. The most common interaction encountered in all docked
structures is that between the phenolic OH, which acted as H-bond
Chemical shifts values (d) are given in parts per million. Mass
spectra were recorded on GC/MS FINNIGAN MAT SSQ 7000 digital
DEC 3000 and JEOL JMS-AX 500 mass spectrometers at in the
Central Services Unit at the (NRC) as well as GC/MS Shimadzu QP-
2010 plus mass spectrometer at the Microanalytical Centre-Cairo
University. Elemental analyses were performed on Vario El Ele-
mentar in the MicroAnalytical Unit of the Central Services Unit at
the (NRC).
acceptor, and lys
b254. For instance, compound 3b, 3c, 3d, 3f, 4b, 4c
and 9a formed an H bond with lys
b254 through the phenolic OH.
Additional hydrophobic interaction through the 2-phenyl ring of 3b
and 3f was also observed. Compounds substituted at the phenolic
OH 13c, 14c and 16b were also capable of forming this type of
interaction since the OH group is not H bond donor but H bond
acceptor group. Moreover, other heteroatoms in the side chain
could participate in the same interaction as acceptor groups as
displayed by the docked compound 16b and 16c. On the other hand,
the most active compound 3e showed a hydrogen bond between
3.1.1. 2-(4-Hydroxyphenyl)-1H-indole-3-carboxaldehyde 2
Phosphorous oxychloride (11 ml, 72.40 mmol) was added
dropwise to dimethylformamide (DMF) (10 ml) while cooling in an
ice bath and the reaction mixture was stirred for 1 h. A solution of
compound 1 (5 g, 2.40 mmol) in (DMF) (5.25 ml, 72 mmol) was
added dropwise to the formylating mixture with continuous stir-
ring and kept at room temperature for 2 h. The mixture was then
poured onto ice cold water and neutralized with dilute ammonia
solution whereby; the formed precipitate was collected by vacuum
filtration and crystallized from absolute ethanol to give greenish
brown crystals, 90% yield, m.p. 160 ꢂC. IR: nmax/cmꢀ1 3400e3155
(OH, NH stretching); 3063 (CH aromatic); 1696 (C]O); 1580 (C]C).
the indole NH and Asn-a101. According to this docking study, the
importance of the presence of a free or substituted phenolic OH
group on the 2-phenyl ring of the indole core was established. At
the same time, it could be concluded that the binding mode of our
target compounds in the colchicine binding site of tubulin sug-
gested that they might act through inhibition of tubulin.
Fig. 2. Simplified structures of compounds 3e, 3f, 4c and 16b docked in the colchicine binding site of tubulin.

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S.S. El-Nakkady et al. / European Journal of Medicinal Chemistry 47 (2012) 387e398
1H NMR (DMSO-d6,):
d
6.96e6.99 (d, J ¼ 8.10 Hz, 2H, aromatic
exchanged by D2O). Anal. calcd. for C22H18N4O2 (370.40): C, 71.34;
H, 4.90; N, 15.13. Found: C, 71.05; H, 5.03; N, 15.36.
protons); 7.18e7.28 (m, 2H, indole proton); 7.45e7.48 (d,
J ¼ 8.10 Hz, 2H, aromatic protons); 7.59e7.62 (d, J ¼ 8.10 Hz, 1H,
indole proton); 8.16e8.19 (d, J ¼ 8.10 Hz,1H, indole proton); 8.35 (br
s, 1H, OH exchanged by D2O); 9.94 (s, 1H, CHO); 12.21 (s, 1H, NH
exchanged by D2O). MS: m/z (%): 237 (Mþ, 100%). Anal. calcd. for
C15H11NO2 (237.25): C, 75.94; H, 4.67; N, 5.90. Found: C, 75.90; H,
4.61; N, 5.71.
3.1.2.5. N0-{[2-(4-Hydroxyphenyl)-1H-indol-3-yl]methylene}-4-nitro-
benzohydrazide 3e. Compound 3e was prepared from 2 and p-nitro-
benzoic acid hydrazide and crystallized from petroleum ether
(60e80 ꢂC). Orange solid, 83% yield, m.p. 220 ꢂC. IR: nmax/cmꢀ1
3385e3172 (OH, NH stretching); 3055 (CH aromatic); 1645(C]O);
1602 (C]N); 1582 (C]C); 1491, 1339 (NO2). 1H NMR (DMSO-d6):
3.1.2. General procedure for the preparation of 3aef
Compound 2 (1 g, 4.22 mmol) and the carboxylic acid hydra-
zide derivative (5.10 mmol) were refluxed for 2 h in absolute
ethanol (20 ml) in the presence of 2e3 drops of glacial acetic acid.
Cold water was then added to the hot mixture and the formed
precipitate, was filtered and crystallized from the appropriate
solvent.
d
7.01 (m, 2H, aromatic protons); 7.16e7.19 (d, J ¼ 8.10 Hz, 2H, indole
protons); 7.42 (m, 2H, aromatic protons); 7.50e7.53 (m, 1H, indole
proton); 8.17 (m, 2H, aromatic protons); 8.34e8.37 (m, 2H, aromatic
protons); 8.60 (br s, 1H, OH exchanged by D2O); 8.86e8.89 (m, 2H,
indole proton and CH]N); 9.05 (s, 1H, NH]N exchanged by D2O);
11.80 (s, 1H, NH exchanged by D2O). MS: m/z (%): 400 (Mþ, 20.91%),
209 (100%). Anal. calcd. for C22H16N4O4 (400.39): C, 66.00; H, 4.03; N,
13.99. Found: C, 66.36; H, 4.43; N, 14.25.
3.1.2.1. N0-{[2-(4-Hydroxyphenyl)-1H-indol-3-yl]methylene} aceto-
hydrazide 3a. Brown solid, 70% yield, m.p. 240 ꢂC (absolute
ethanol). IR: nmax/cmꢀ1 3393 (OH stretching); 3200 (NH stretch-
ing); 3064 (CH aromatic); 2922 (CH aliphatic); 1641(C]O); 1608
3.1.2.6. 4-Chloro-N0-{[2-(4-hydroxyphenyl)-1H-indol-3-yl]methylene}
benzohydrazide 3f. Compound 3f was prepared from 2 and p-chlor-
obenzoic acid hydrazide. Yellow solid, 76% yield, m.p. 275 ꢂC (abso-
lute ethanol). IR: nmax/cmꢀ1 3392e3151 (OH, NH stretching); 3056
(CH aromatic); 1642 (C]O); 1604 (C]N); 1570 (C]C); 670 (CeCl).
(C]N); 1554 (C]C).1H NMR (DMSO-d6,):
d 2.24 (s, 3H, ]NeCH3);
6.95e7.10 (m, 2H, aromatic protons); 7.15e7.18 (d, J ¼ 8.10 Hz, 2H,
indole protons); 7.42e7.45 (d, J ¼ 8.10 Hz, 2H, aromatic protons);
8.16e8.18 (d, J ¼ 5.40 Hz, 1H, indole proton); 8.28 (s, 1H, CH]N);
8.37 (m, 1H, indole proton); 10.82 (s, 1H, OH exchanged by D2O);
11.00 (s, 1H, NH exchanged by D2O); 11.64 (s, 1H, NH exchanged by
D2O). Anal. calcd. for C17H15N3O2 (293.32): C, 69.61; H, 5.15; N,
14.33. Found: C, 69.58; H, 4.85; N, 14.01.
1H NMR (DMSO-d6):
d
6.92e6.94 (d, J ¼ 10 Hz, 2H, aromatic protons);
7.17e7.33 (m, 2H, indole protons); 7.41e7.43 (d, J ¼ 10 Hz, 2H,
aromatic protons); 7.55e7.57 (d, J ¼ 10 Hz, 2H, aromatic protons);
7.76 (m, 1H, indole proton); 8.10e8.20 (m, 3H, aromatic protons and
CH]N); 8.12e8.14 (d, J ¼ 10 Hz, 1H, indole proton); 10.01 (s, 1H, OH
exchanged by D2O); 10.15 (s, 1H, NH]N exchanged by D2O); 12.16 (s,
1H, NH exchanged by D2O). 13C NMR (DMSO-d6):
d 107.22 (indole
3.1.2.2. N0-{[2-(4-Hydroxyphenyl)-1H-indol-3-yl] methylene} benzo-
hydrazide 3b. White solid, 65% yield, m.p. 135e137 ꢂC (pet.ether
60e80 ꢂC). IR: nmax/cmꢀ1 3431e3110 (OH, NH stretching); 3051 (CH
aromatic); 1644 (C]O); 1610 (C]N); 1576 (C]C). 1H NMR (DMSO-
carbon); 111.22 (indole carbon); 115.78 (aromatic carbons); 120.68
(aromatic carbon); 121.62 (indole carbon); 122.29 (indole carbons);
122.49 (indole carbon); 125.93 (aromatic carbons); 130.62 (aromatic
carbons); 136.21 (aromatic carbon); 143.78 (CH]N); 155.00
(CeNH2); 158.34 (CeOH); 168.0 5 (C]O).MS: m/z (%): 389 (Mþ,12%),
57(100%). Anal. calcd. for C22H16N3O2Cl (389.83): C, 67.78; H, 4.14; Cl,
9.09; N, 10.7. Found: C, 67.53; H, 4.35; Cl, 9.25; N, 10.56.
d6):
d 4.31 (s, 1H, OH exchanged by D2O); 6.76 (m, 2H, aromatic
protons); 7.02 (m, 2H, indole protons); 7.36 (m, 2H, aromatic
protons); 7.48 (m, 3H, aromatics and indole proton); 7.78e7.90 (m,
3H, aromatic and indole proton); 8.55 (s, 1H, OH exchanged by
D2O); 8.88 (s, 1H, CH]N); 10.82 (s, 1H, NH exchanged by D2O);
11.82 (s, 1H, NH exchanged by D2O). Anal. calcd. for C22H17N3O2
(355.39): C, 74.35; H, 4.82; N, 11.82. Found: C, 74.62; H, 4.89; N,
11.51.
3.1.3. General procedure for the preparation of 4aed
Compound 2 (1 g, 4.22 mmol) and the hydrazine derivative
(5.10 mmol) were refluxed in absolute ethanol (20 ml) in the
presence of 2e3 drops of glacial acetic acid for the appropriate
time. Cold water was then added to the hot mixture and the formed
precipitate, was filtered and crystallized from petroleum ether
(60e80 ꢂC).
3.1.2.3. 2-Amino-N0-{[2-(4-hydroxyphenyl)-1H-indol-3-yl]methylene}
benzohydrazide 3c. White solid, 75% yield, m.p. >300 ꢂC (absolute
ethanol). IR: nmax/cmꢀ1 3396e3231 (NH2, OH, NH stretching); 3057
(CH aromatic); 1643 (C]O); 1603 (C]N); 1585 (C]C). 1H NMR
3.1.3.1. 4-{3-[(2-Methylhydrazono)methyl]-1H-indol-2-yl}
phenol
(DMSO-d6):
d
4.1 (s, 2H, NH2 exchanged by D2O); 6.8e7.02 (m, 6H,
4a. Compound 4a was prepared from 2 and methylhydrazine for
2 h. Brown solid, 68% yield, m.p. 135 ꢂC. IR: nmax/cmꢀ1 3395 (OH
stretching); 3250 (NH stretching); 3057 (CH aromatic); 2920 (CH
aromatic and indole protons); 7.16 (m, 1H, aromatic proton); 7.41
(m, 2H, aromatic protons); 7.50e7.53 (m, 2H, aromatic and indole
protons); 8.37 (m, 1H, indole proton); 8.55 (s, 1H, OH exchanged by
D2O); 8.88 (s, 1H, CH]N); 10.82 (s, 1H, NH exchanged by D2O);
11.82 (s, 1H, NH exchanged by D2O). Anal. calcd. for C22H18N4O2
(370.40): C, 71.34; H, 4.90; N, 15.13. Found: C, 71.20; H, 4.98; N,
14.89.
aliphatic); 1606 (C]N); 1590 (C]C). 1H NMR (DMSO-d6):
d 3.29 (s,
3H, CH3); 6.71(m, 2H, aromatic protons); 6.93 (m, 1H, indole
proton); 7.19 (m, 1H, indole proton); 7.40e7.41 (m, 2H, aromatic
protons); 7.56 (m, 1H, indole proton); 8.12 (s, 1H, CH]N); 8.35 (m,
1H, indole proton); 9.80 (s, 1H, OH exchanged by D2O); 10.20 (s, 1H,
NHeCH3 exchanged by D2O); 12.15 (s, 1H, NH exchanged by D2O).
Anal. calcd. for C16H15N3O (265.31): C, 72.43; H, 5.70; N, 15.84.
Found: C, 72.21; H, 5.88; N, 15.74.
3.1.2.4. 4-Amino-N0-{[2-(4-hydroxyphenyl)-1H-indol-3-yl]methylene}
benzohydrazide 3d. Brown solid, 80% yield, m.p. >300 ꢂC (pet.ether
60e80 ꢂC). IR: nmax/cmꢀ1 3386e3149 (NH2, OH, NH stretching);
3050 (CH aromatic); 1642 (C]O); 1600 (C]N); 1596 (C]C). 1H
3.1.3.2. 4-{3-[(2-Phenylhydrazono)methyl]-1H-indol-2-yl}phenol 4b.
Compound 4b was prepared from 2 and phenyl hydrazine for 4 h.
Dark brown solid, 80% yield, m.p. 110 ꢂC. IR: nmax/cmꢀ1 3393 (OH
stretching); 3256 (NH stretching); 3053 (CH aromatic); 1599 (C]N);
NMR (DMSO-d6):
d 4.10 (s, 2H, NH2 exchanged by D2O); 6.96e6.98
(m, 4H, aromatic protons); 7.16 (m, 2H, indole protons); 7.47 (m, 2H,
aromatic protons); 7.49e7.60 (m, 3H, aromatic and indole protons);
8.15 (s, 1H, OH); 8.31e8.33 (m, 1H, indole proton); 8.84 (s, 1H, CH]
N); 10.20 (s, 1H, NH]N exchanged by D2O); 11.77 (s, 1H, NH
1588e1589. (C]C). 1H NMR (DMSO-d6):
d
6.64e6.66 (m, 1H,
aromatic proton); 6.68e6.87 (m, 2H, aromatic protons); 6.93e6.96

S.S. El-Nakkady et al. / European Journal of Medicinal Chemistry 47 (2012) 387e398
393
(m, 2H, indole protons); 6.99e7.35 (m, 2H, aromatic protons);
7.17e7.35 (m, 4H, aromatic protons); 7.44e7.47 (m, 1H, indole
proton); 8.20 (s, 1H, CH]N); 8.31 (m, 1H, indole proton); 9.86 (s, 1H,
OH exchanged by D2O); 11.44 (s, 2H, NH]N, NH exchanged by D2O).
Anal. calcd. for C21H17N3O (327.38): C, 77.04; H, 5.23; N, 13.84. Found:
C, 77.19; H, 5.01; N, 13.56.
poured onto cold water and the precipitate was filtered and crys-
tallized from petroleum ether (60e80 ꢂC).
3.1.6.1. 5-{[2-(4-Hydroxyphenyl)-1H-indol-3-yl] methylene} pyrimi-
dine-2,4,6 (1H,3H,5H)-trione 7a. Compound 7a was prepared from
2 and barbituric acid. Brown solid, 85% yield, m.p. 175 ꢂC. IR: nmax
/
cmꢀ1 3419 (OH stretching); 3370e3157 (NH stretching); 3050 (CH
aromatic); 2950 (CH aliphatic); 1684 (C]O); 1612 (C]N); 1582
3.1.3.3. 4-{3-[(2-(2-Chlorophenyl) hydrazono) methyl]-1H-indol-2-
yl} phenol 4c. Compound 4c was prepared from 2 and o-chlor-
ophenyl hydrazine for 5 h. Light brown solid, 77% yield, m.p.
120e122 ꢂC. IR: nmax/cmꢀ1 3355 (OH, NH stretching); 3055 (CH
aromatic); 1597 (C]N); 1565 (C]C); 593 (CeCl). 1H NMR (DMSO-
(C]C). 1H NMR (DMSO-d6):
d 6.97 (m, 2H, aromatic protons); 7.13
(m, 2H, indole protons); 7.22 (m, 1H, indole proton); 7.40 (m, 2H,
aromatic protons); 7.95 (m, 1H, indole proton); 8.13 (s, 1H, CH]C);
8.72 (s, 2H, NH pyrimidine exchanged by D2O); 9.43 (s, 1H, OH
exchanged by D2O); 10.92 (s, 1H, NH exchanged by D2O). Anal.
calcd. for C19H13N3O4 (347.32): C, 65.70; H, 3.77; N, 12.10. Found: C,
65.79; H, 3.64; N, 12.31.
d6):
d 4.42 (s, 1H, NH]N exchanged by D2O); 6.74e6.77 (m, 2H,
aromatic protons); 6.80 (m, 2H, aromatic protons); 7.00e7.03 (m,
2H, indole protons); 7.22e7.25 (d, J ¼ 8.10 Hz, 1H, aromatic proton);
7.44e7.46 (m, 1H, aromatic proton); 7.54e7.57 (d, J ¼ 8.10 Hz, 2H,
aromatic protons); 7.59e7.62 (d, J ¼ 8.10 Hz, 1H, indole proton);
8.38e8.39 (m, 1H, indole proton); 8.67 (s, 1H, CH]N); 9.58 (s, 1H,
OH exchanged by D2O); 11.57 (s, 1H, NH exchanged by D2O). MS: m/
z (%): 361 (Mþ, 100%); 362 (Mþ þ 1, 27.65%). Anal. calcd. for
C21H16ClN3O (361.82): C, 69.71; H, 4.46; Cl, 9.80; N, 11.61. Found: C,
69.32; H, 4.22; Cl, 9.78; N, 11.25.
3.1.6.2. 5-{[2-(4-Hydroxyphenyl)-1H-indol-3-yl]methylene}-2-thio-
xodihydropyrimidine-4,6 (1H,5H)-dione 7b. Compound 7b was
prepared from 2 and thiobarbituric acid. Green solid, 73% yield, m.p.
210 ꢂC. IR: nmax/cmꢀ1 3417 (OH stretching); 3371e3123 (NH
stretching); 3049 (CH aromatic); 2950 (CH aliphatic); 1652 (C]O);
1611 (C]N); 1572 (C]C); 1253 (C]S). 1H NMR (DMSO-d6):
d 6.98
(m, 2H, aromatic protons); 7.13e7.16 (d, J ¼ 8.1 Hz, 2H, indole
protons); 7.23e7.25 (m, 1H, indole proton); 7.53e7.56 (d,
J ¼ 8.10 Hz, 2H, aromatic protons); 7.63e7.66 (d, J ¼ 8.10 Hz, 1H,
indole proton); 7.78 (s, 1H, CH]C); 9.92 (s, 1H, OH exchanged by
D2O); 11.62 (s, 1H, NH exchanged by D2O); 12.51 (br s, 2H, NH
exchanged by D2O). MS: m/z (%): 364 (Mþ þ 1, 1.50%); 365 (Mþ þ 2,
1.65%); 209 (100%). Anal. calcd. For C19H13N3O3S (363.39): C, 62.80;
H, 3.61; N, 11.50; S, 8.82. Found: C, 62.65; H, 3.95; N, 11.78; S, 8.59.
3.1.4. 2-{[2-(4-Hydroxyphenyl)-1H-indol-3-yl]methylene}
hydrazinecarbothioamide 5
Compound 2 (1 g, 4.22 mmol) and thiosemicarbazide (0.5 g,
5.50 mmol) were refluxed in absolute ethanol (20 ml) in the
presence of 2e3 drops of glacial acetic acid for 2 h. Cold water was
then added to the hot mixture and the precipitate was filtered and
crystallized from absolute ethanol. Off white solid, 73% yield, m.p.
233e235 ꢂC. IR: nmax/cmꢀ1 3393e3251 ( NH2, OH, NH stretching);
3131 (NH]N stretching); 3037 (CH aromatic); 1591 (C]N); 1588
3.1.7. 2-{[2-(4-Hydroxyphenyl)-1H-indol-3-yl] methylene}
propanedinitrile 8
(C]C); 1268 (C]S). 1H NMR (DMSO-d6):
d 6.94e6.97 (d,
Compound 2 (1 g, 4.22 mmol) and malononitrile (0.4 g,
5.10 mmol) were refluxed in absolute ethanol (30 ml) in the pres-
ence of 2e3 drops piperidine for 2 h. The mixture was then poured
onto cold water and the precipitate was collected and crystallized
from petroleum ether (60e80 ꢂC). Dark brown, 46% yield, m.p.
150e152 ꢂC. IR: nmax/cmꢀ1 3453 (OH stretching); 3266 (NH
stretching); 3055 (CH aromatic); 2214 (C^N); 1553 (C]C). 1H NMR
J ¼ 8.10 Hz, 2H, aromatic protons); 7.13e7.20 (m, 2H, indole
protons); 7.35e7.38 (m, 1H, indole proton); 7.45e7.48 (d,
J ¼ 8.10 Hz, 2H, aromatic protons); 8.04 (s, 2H, NH2 exchanged by
D2O); 8.27e8.30 (d, J ¼ 8.10 Hz, 1H, indole proton); 8.46 (s, 1H,
CH]N); 9.91 (s, 1H, OH exchanged by D2O); 11.14 (s, 1H, NH]N
exchanged by D2O); 11.73 (s, 1H, NH exchanged by D2O). MS: m/z
(%): 310 (Mþ, 0.44%); 312 (Mþ þ 2, 1.85%); 209 (100%). Anal. calcd.
for C16H14N4OS (310.37): C, 61.92; H, 4.55; N, 18.05; S, 10.33. Found:
C, 61.87; H, 4.78; N, 18.17; S, 10.25.
(DMSO-d6):
d
6.97e7.05 (d, J ¼ 8.10 Hz, 2H, aromatic protons);
7.24e7.33 (m, 2H, indole protons); 7.50e7.70 (m, 3H, indole and
aromatic protons); 7.93 (s, 1H, CH]C vinyl); 8.05e8.08 (d,
J ¼ 8.10 Hz, 1H, indole proton); 12.22 (s, 1H, OH exchanged by D2O);
12.89 (s, 1H, NH exchanged by D2O). Anal. calcd. for C18H11N3O
(285.30): C, 75.78; H, 3.89; N, 14.73. Found: C, 75.54; H, 3.75; N,
14.96.
3.1.5. 2-(4-Hydroxyphenyl)-1H-indole-3-carboxaldehyde oxime 6
Compound 2 (1 g, 4.22 mmol) and the hydroxylamine hydro-
chloride (1 g, 14.50 mmol) were refluxed in absolute ethanol
(20 ml) in the presence of 3 ml pyridine for 10 h. The mixture was
then poured onto cold water. The obtained light brown precipitate
was collected by filtration and crystallized from petroleum ether
(60e80 ꢂC). 90% yield, m.p. 228e230 ꢂC. IR: nmax/cmꢀ1 3410 (OH
stretching); 3289 (NH stretching); 3059 (CH aromatic); 1611 (C]
3.1.8. General procedure for the preparation of 9a,b
Compound 2 (1 g, 4.22 mmol) and the appropriate aniline
derivative (6.33 mmol) were refluxed in absolute ethanol (30 ml) at
70 ꢂC for 7 h. The reaction mixture was then poured onto water and
the precipitate was filtered, collected and crystallized from petro-
leum ether (60e80 ꢂC).
N); 1597 (C]C). 1H NMR (DMSO-d6):
d
6.94e6.97 (d, J ¼ 8.10 Hz,
2H, aromatic protons); 7.03e7.13 (m, 2H, indole protons);
7.14e7.43 (m, 3H, aromatic and indole protons); 8.03e8.06 (d,
J ¼ 8.10 Hz, 1H, indole proton); 8.23 (s, 1H, CH]N); 10.59 (s, 1H,
OH exchanged by D2O); 11.30 ( br s, 1H, OH exchanged by D2O);
11.59 (s, 1H, NH exchanged by D2O). Anal. calcd. for C15H12N2O2
(252.27): C, 71.42; H, 4.79; N, 11.10. Found: C, 71.22; H, 4.57; N,
11.26.
3.1.8.1. 2-{[2-(4-Hydroxyphenyl)-1H-indol-3-yl]}-1H-benzo[d] imid-
azole 9a. Compound 9a was prepared from 2 and o-phenylenedi-
amine. Orange solid, 80% yield, m.p. 200 ꢂC (dec.). IR: nmax/cmꢀ1
3374e3155 (OH, NH stretching); 3057 (CH aromatic); 1611 (C]N);
1561 (C]C). 1H NMR (DMSO-d6):
d
6.81e6.84 (d, J ¼ 8.10 Hz, 2H,
aromatic protons); 6.90e6.93 (d, J ¼ 8.10 Hz, 2H, indole protons);
7.12e7.19 (m, 2H, aromatic protons); 7.44e7.47 (d, J ¼ 8.10 Hz, 2H,
aromatic protons); 7.55e7.61 (m, 2H, aromatic protons); 7.82e7.84
(d, J ¼ 5.40 Hz, 1H, indole proton); 8.14e8.17 (d, J ¼ 8.10 Hz, 1H,
indole proton); 9.81 (s, 1H, OH exchanged by D2O); 11.81 (s, 1H, NH
3.1.6. General procedure for the preparation of 7aeb
Compound 2 (1 g, 4.22 mmol) and barbituric or thiobarbituric
acid (4.22 mmol) were refluxed in absolute ethanol (30 ml) in the
presence of 2e3 drops piperidine for 2 h. The mixture was then

394
S.S. El-Nakkady et al. / European Journal of Medicinal Chemistry 47 (2012) 387e398
exchanged by D2O); 12.21 (s, 1H, NH exchanged by D2O). MS: m/z
(%):325 (Mþ, 19.20%); 209 (100%). Anal. calcd. for C21H15N3O
(325.36): C, 77.52; H, 4.65; N, 12.91. Found: C, 77.31; H, 4.42; N,
12.88.
MS: m/z (%):281 (Mþ, 100%). Anal. calcd. for C17H15NO3 (281.31): C,
72.58; H, 5.37; N, 4.98. Found: C, 72.76; H, 5.19; N, 4.76.
3.1.11.2. Ethyl 2-[4-(1H-indol-2-yl)phenoxy]acetate 12b [22,23].
Compound 12b was prepared from 1 and ethyl bromoacetate. Buff
solid, 75% yield, m.p. 150 ꢂC. IR: nmax/cmꢀ1 3392 (NH stretching);
3048 (CH aromatic); 2922e2853 (CH aliphatic); 1732 (C]O) ester;
3.1.8.2. 2-{[2-(4-Hydroxyphenyl)-1H-indol-3-yl]}-1H-benzo[d] oxa-
zole 9b. Compound 9b was prepared from 2 and o-aminophenol.
Brown solid, 75% yield, m.p. 210 ꢂC. IR: nmax/cmꢀ1 3363e3184 (OH,
NH stretching); 3055 (CH aromatic); 1608 (C]N); 1572 (C]C). 1H
1576 (C]N). 1H NMR (DMSO-d6):
d 1.34 (t, 3H, CH2eCH3); 4.36 (q,
2H, CH2eCH3); 4.75 (s, 2H, OeCH2); 6.80 (s, 1H, indole proton);
7.05e7.07 (d, J ¼ 5.40 Hz, 2H, indole protons); 7.18e7.21 (m, 2H,
aromatic protons); 7.21e7.35 (m, 1H, indole proton); 7.46e7.48 (d,
J ¼ 5.40 Hz, 2H, aromatic protons); 7.67e7.70 (d, J ¼ 8.10 Hz, 1H,
indole proton); 8.65 (s, 1H, NH exchanged by D2O). MS: m/z (%) 295
(Mþ, 100). Anal. calcd. for C18H17NO3 (295.33): C, 73.20; H, 5.80; N,
4.74. Found: C, 73.34; H, 5.99; N, 4.88.
NMR (DMSO-d6,): d 6.90e7.00 (m, 2H, phenyl protons); 6.19 (m, 2H,
indole protons); 7.23 (m, 2H, phenyl protons); 7.38 (m, 2H, ben-
zoxazole protons); 7.46 (m, 1H, indole proton); 7.60 (m, 2H, ben-
zoxazole protons); 8.16 (m, 1H, indole proton); 10.08 (s, 1H, OH
exchanged by D2O); 12.23 (s, 1H, NH exchanged by D2O). Anal.
calcd. for C21H14N2O2 (326.35): C, 77.29; H, 4.32; N, 11.58. Found: C,
77.44; H, 4.15; N, 11.36.
3.1.12. General procedure for the preparation of 13aed
Compound 12a (1 g, 3.56 mmol) and the appropriate primary
amine (3.56 mmol) were refluxed in absolute ethanol (50 ml) for
8 h. The reaction mixture was then cooled, the formed precipitate
was filtered and crystallized from absolute ethanol.
3.1.9. 2-{[2-(4-Hydroxyphenyl)-1H-indol-3-yl]}-1H-imidazole 10
Compound 10 was prepared from 2 (1 g, 4.22 mmol) and eth-
ylenediamine (0.40 g, 6.67 mmol) according to the procedure used
for the preparation of 9a,b. The precipitate was filtered and crys-
tallized from petroleum ether (60e80 ꢂC). Green solid, 82% yield,
m.p. 195e196 ꢂC. IR: nmax/cmꢀ1 3390e3183 (OH, NH stretching);
3061 (CH aromatic); 1611 (C]N); 1596 (C]C). 1H NMR (DMSO-d6):
3.1.12.1. 2-[4-(1H-Indol-2-yl) phenoxy] acetamide 13a. Compound
13a was prepared from 12a and ammonia solution. White solid, 80%
yield, m.p. 210 ꢂC. IR: nmax/cmꢀ1 3422e3165(NH2, NH stretching);
3049 (CH aromatic); 2921 (CH aliphatic); 1670 (C]O amidic); 1540
d
6.90 (m, 2H, phenyl protons); 6.95e6.98 (d, J ¼ 8.10 Hz, 2H, indole
protons); 7.07 (m, 2H, imidazole protons); 7.44 (m, 2H, phenyl
protons); 7.58e7.61 (m, 1H, indole proton); 8.17 (m, 1H, indole
proton); 8.31 (s, 1H, OH exchanged by D2O); 8.40 (br s, 1H, NH
exchanged by D2O); 11.43 (s,1H, NH exchanged by D2O). Anal. calcd.
for C17H13N3O (275.30): C, 74.17; H, 4.76; N, 15.26. Found: C, 74.41;
H, 4.55; N, 15.41.
(C]C). 1H NMR (DMSO-d6):
d 4.46 (s, 2H, OeCH2); 6.76 (s, 1H,
indole proton); 6.92e6.95 (m, 2H, indole protons); 6.97e7.03 (m,
2H, aromatic protons); 7.20 (s, 2H, NH2 exchanged by D2O);
7.35e7.45 (m, 1H, indole proton); 7.48e7.56 (m, 2H, aromatic
protons); 7.78 (m, 1H, indole proton); 11.41 (s, 1H, NH exchanged by
D2O). Anal. calcd. for C16H14N2O2 (266.29): C, 72.16; H, 5.30; N,
10.52. Found: C, 72.34; H, 5.44; N, 10.34.
3.1.10. 4-(1H-Indol-2-yl) phenyl methyl carbonate 11
Compound 1 (2 g, 9.60 mmol) and methyl chloroformate
(0.90 ml, 9.60 mmol) were refluxed in the presence of anhydrous
potassium carbonate (3 g, 14.50 mmol) in dry acetone (100 ml) for
10 h. The mixture was then cooled, filtered and the filtrate was
poured onto crushed ice. The buff precipitate formed was collected
by filtration and crystallized from absolute ethanol. 68% yield, m.p.
180 ꢂC. IR: nmax/cmꢀ1 3388e3362 (NH2, NH stretching); 3051 (CH
aromatic); 2915 (CH aliphatic); 1741 (C]O) ester; 1552 (C]C). 1H
3.1.12.2. 2-[4-(1H-Indol-2-yl) phenoxy]-N-(2-hydroxyethyl) acet-
amide 13b. Compound 13b was prepared from 12a and ethanol-
amine for 8 h. Green solid, 90% yield, m.p. 163 ꢂC. IR: nmax/cmꢀ1
3430 (OH stretching); 3340e3231 (NH stretching); 3056 (CH
aromatic); 2923 (CH aliphatic); 1651(C]O amidic); 1589 (C]C). 1H
NMR (DMSO-d6):
d 3.23 (m, 2H, NeCH2); 3.43 (m, 2H, CH2eOH);
4.52 (s, 2H, OeCH2); 4.75 (s, 1H, OH exchanged by D2O); 6.76 (s, 1H,
indole proton); 6.93e6.96 (d, J ¼ 8.10 Hz, 2H, indole protons);
7.03e7.06 (m, 2H, aromatic protons); 7.34e7.37 (d, J ¼ 8.10 Hz, 1H,
indole proton); 7.46e7.49 (d, J ¼ 8.10 Hz, 2H, aromatic protons);
7.78e7.80 (d, J ¼ 5.40 Hz, 1H, indole proton); 8.06 (s, 1H, NHeCO
exchanged by D2O); 11.43 (s,1H, NH exchanged by D2O). Anal. calcd.
for C18H18N2O3 (310.35): C, 69.66; H, 5.85; N, 9.03. Found: C, 69.79;
H, 5.68; N, 8.78.
NMR (DMSO-d6):
d 4.02 (s, 3H, CH3); 6.87 (s, 1H, indole proton);
7.20e7.35 (m, 4H, indole and aromatic protons); 7.47e7.50 (d,
J ¼ 8.10 Hz, 1H, indole proton); 7.75e7.78 (d, J ¼ 8.10 Hz, 2H,
aromatic protons); 7.69e7.72 (d, J ¼ 8.10 Hz, 1H, indole proton);
8.78 (s, 1H, NH exchanged by D2O). MS: m/z (%): 267 (Mþ, 100%).
Anal. calcd. for C16H13NO3 (267.28): C, 71.90; H, 4.90; N, 5.24.
Found: C, 71.74; H, 4.62; N, 5.33.
3.1.12.3. 2-[4-(1H-Indol-2-yl) phenoxy]-N-(pyridin-4-yl) acetamide
13c. Compound 13c was prepared from 12a and p-aminopyridine.
Green solid 85% yield, m.p. 198e200 ꢂC. IR: nmax/cmꢀ1
3422e3251(NH stretching); 2948 (CH aromatic); 2919 (CH
aliphatic); 1647(C]O amidic).; 1609 (C]N); 1530 (C]C). 1H NMR
3.1.11. General procedure for the preparation of 12a,b
Compound
1 (2 g, 9.60 mmol) and alkyl bromoacetate
(9.60 mmol) were treated similarly as in the experimental proce-
dure adopted for the synthesis of 11. The obtained solid was crys-
tallized from absolute ethanol.
(DMSO-d6):
d 4.60 (s, 2H, OeCH2); 6.80 (s, 1H, indole proton);
6.97e7.00 (d, J ¼ 8.10 Hz, 2H, indole protons); 7.03 (m, 2H, aromatic
protons); 7.25 (s, 1H, NHeCO exchanged by D2O); 7.50 (m, 3H,
aromatic and indole protons); 7.80 (m, 1H, indole proton);
8.45e8.56 (m, 4H, aromatic protons); 11.45 (s, 1H, NH exchanged by
D2O). Anal. calcd. for C21H17N3O2 (343.38): C, 73.45; H, 4.99; N,
12.24. Found: C, 73.28; H, 5.23; N, 12.53.
3.1.11.1. Methyl 2-[4-(1H-indol-2-yl)phenoxy]acetate 12a. Compound
12a was prepared from 1 and methyl bromoacetate. Buff solid, 80%
yield, m.p. 170 ꢂC. IR: nmax/cmꢀ1 3433 (NH stretching); 3056 (CH
aromatic); 2922e2854 (CH aliphatic); 1758 (C]O) ester; 1520 (C]
C). 1H NMR (DMSO-d6):
d 3.51 (s, 3H, CH3); 4.37 (s, 2H, OeCH2); 6.40
(s, 1H, indole proton); 6.64e6.68 (d, J ¼ 8.10 Hz, 2H, indole protons);
6.76e6.88 (m, 2H, aromatic protons); 6.87e6.95 (m, 1H, indole
proton); 7.05e7.08 (d, J ¼ 8.10 Hz, 2H, aromatic protons); 7.28e7.31
(d, J ¼ 8.10 Hz,1H, indole proton); 8.26 (s,1H, NH exchanged by D2O).
3.1.12.4. 2-[4-(1H-Indol-2-yl) phenoxy]-N-(pyrazin-2-yl) acetamide
13d. Compound 13d was prepared from 12a and 2-aminopyrazine.
Green solid, 84 %yield, m.p.100e101 ꢂC. IR: nmax/cmꢀ1 3428e3250

S.S. El-Nakkady et al. / European Journal of Medicinal Chemistry 47 (2012) 387e398
395
(NH stretching); 2949 (CH aromatic); 2920 (CH aliphatic); 1649
(C]O amidic); 1612 (C]N); 1551 (C]C).1H NMR (DMSO-d6):
4.68 (s, 2H, OeCH2); 6.36 (s, 1H, NHeCO exchanged by D2O); 6.74
3.1.14.1. 2-[4-(1H-Indol-2-yl)
phenoxy]
acetohydrazide
15a.
Compound 15a was prepared from 12a and methylhydrazine. Buff
solid, 93% yield, m.p. 230 ꢂC (absolute ethanol). IR: nmax/cmꢀ1 3435
(NH stretching); 3317 and 3263 (eNH2 stretching); 3049 (CH
aromatic); 2921 (CH aliphatic); 1668 (C]O amidic); 1523 (C]C).1H
d
(s, 1H, indole proton); 6.97e7.00 (d, J ¼ 8.10 Hz, 2H, indole
protons); 7.05 (m, 2H, aromatic protons); 7.34e7.37 (d, J ¼ 8.10 Hz,
1H, indole proton); 7.46e7.49 (d, J ¼ 8.10 Hz, 2H, aromatic
protons); 7.65 (m, 1H, indole proton); 7.75e7.78 (d, J ¼ 8.10 Hz, 2H,
aromatic protons); 7.85 (s, 1H, aromatic proton); 11.40 (s, 1H, NH
exchanged by D2O). MS, m/z (%): 344 (Mþ, 1.50%). Anal. calcd. for
C20H16N4O2 (344.37): C, 69.76; H, 4.68; N, 16.27. Found: C, 69.59; H,
4.62; N, 16.45.
NMR (DMSO-d6): d 4.40 (s, 2H, NH2); 4.55 (s, 2H, OeCH2); 6.79 (s, 1H,
indole proton); 6.98e7.01 (d, J ¼ 8.10 Hz, 2H, indole protons);
7.04e7.07 (d, J ¼ 8.10 Hz, 2H, aromatic protons); 7.37e7.39 (d,
J ¼ 5.40 Hz, 1H, indole proton); 7.49e7.51 (d, J ¼ 5.40 Hz, 2H, aromatic
protons); 7.78e7.82 (d, J ¼ 8.10 Hz, 1H, indole proton); 9.41 (s, 1H, NH
exchanged by D2O); 11.44 (s, 1H, NH exchanged by D2O). Anal. calcd.
for C16H15N3O2 (281.31): C, 68.31; H, 5.37; N, 14.94. Found: C, 68.08;
H, 5.59; N, 14.72.
3.1.13. General procedure for the preparation of 14aec
Compound 12a (1 g, 3.56 mmol) and the appropriate secondary
amine (3.56 mmol) were refluxed in absolute ethanol (40 ml) for
5 h. The reaction mixture was cooled and the formed precipitate
was filtered and crystallized from the absolute ethanol.
3.1.14.2. 2-[4-(1H-Indol-2-yl) phenoxy]-N0-phenylacetohydrazide 15b.
Compound 15b was prepared from 12a and phenyl hydrazine. Brown
solid 60% yield, m.p. 200 ꢂC (pet. ether 60e80 ꢂC). IR: nmax/cmꢀ1 3430
(OH stretching); 3340e3231 (NH stretching); 3056 (CH aromatic);
2923 (CH aliphatic); 1651 (C]O amidic); 1510 (C]C). 1H NMR
3.1.13.1. 2-[4-(1H-Indol-2-yl) phenoxy]-N, N-bis (2-hydroxyethyl)
acetamide 14a. Compound 14a was prepared from 12a and dieth-
anolamine. Greenish white, 96% yield, m.p. 188 ꢂC. IR: nmax/cmꢀ1
3436 (OH stretching); 3358 (NH stretching); 3050 (CH aromatic);
2936 (CH aliphatic); 1644 (C]O amidic); 1497 (C]C).1H NMR
(DMSO-d6): d 3.71 (s,1H, NeNH exchanged by D2O); 4.85 (s, 2H, CH2);
6.76 (s, 1H, indole proton); 6.94e7.01 (m, 3H, aromatic and indole
protons); 7.03e7.08 (m, 4H, aromatic protons); 7.35e7.38 (d,
J ¼ 8.10 Hz, 2H, aromatic protons); 7.47e7.50 (d, J ¼ 8.10 Hz, 3H,
indole and aromatic protons); 7.76e7.79 (d, J ¼ 8.10 Hz, 1H, indole
proton); 11.41 (s, 2H, CH2eNH, NH exchanged by D2O). Anal. calcd. for
C22H19N3O2 (357.41): C, 73.93; H, 5.36; N, 11.76. Found: C, 73.74; H,
5.56; N, 11.56.
(DMSO-d6):
d 3.37 (m, 4H, 2NeCH2eCH2); 3.65 (m, 4H,
2CH2eCH2eOH); 4.81 (s, 1H, OH exchanged by D2O); 4.93 (s, 2H,
OeCH2); 5.10 (s, 1H, OH exchanged by D2O); 6.73 (s, 1H, indole
proton); 6.95e6.98 (d, J ¼ 8.10 Hz, 2H, indole protons); 7.01e7.04
(m, 2H, aromatic protons); 7.34e7.37 (d, J ¼ 8.10 Hz, 1H, indole
proton); 7.46e7.49 (d, J ¼ 8.10 Hz, 2H, aromatic protons); 7.71e7.74
(d, J ¼ 8.10 Hz, 1H, indole proton); 11.40 (s, 1H, NH exchanged by
D2O). Anal. calcd. for C20H22N2O4 (354.40): C, 67.66; H, 6.26; N, 7.90.
Found: C, 67.58; H, 6.49; N, 7.63.
3.1.14.3. 2-[4-(1H-Indol-2-yl) phenoxy]-N0-acetylacetohydrazide 15c.
Compound 15c was prepared from 12a and acetohydrazide. Brown
solid, 75% yield, m.p. 140 ꢂC (absolute ethanol). IR: nmax/cmꢀ1 3432
(NH stretching); 3052 (CH aromatic); 2923e2855 (CH aliphatic);
1662 (C]O amidic, acetyl); 1546 (C]C).1H NMR (DMSO-d6):
d 1.30 (s,
3.1.13.2. 2-[4-(1H-Indol-2-yl) phenoxy]-N, N-dimethylacetamide
14b. Compound 14a was prepared from 12a and dimethylamine.
Yellowish green solid, 95% yield, m.p. 265e267 ꢂC. IR: nmax/cmꢀ1
3389 (NH stretching); 3053 (CH aromatic); 2921e2853 (CH
aliphatic); 1633 (C]O amidic); 1586 (C]C). 1H NMR (DMSO-d6):
3H, COeCH3); 4.25 (s, 2H, (NHeNH) exchanged by D2O); 4.88 (s, 2H,
OeCH2); 6.82 (s, 1H, indole proton); 7.02 (m, 2H, indole protons);
7.06e7.09 (m, 2H, aromatic protons); 7.41e7.43 (m, 1H, indole
proton); 7.53e7.56 (d, J ¼ 8.10 Hz, 2H, aromatic protons); 7.82e7.85
(d, J ¼ 8.10 Hz,1H, indole proton); 11.47 (s,1H, NH exchanged by D2O).
Anal. calcd. for C18H17N3O (323.35): C, 66.86; H, 5.30; N,13.00. Found:
C, 66.53; H, 5.07; N, 13.39.
d
3.35 (s, 3H, NeCH3); 3.36 (s, 3H, NeCH3); 4.80 (s, 2H, OeCH2);
6.97 (s, 1H, indole proton); 7.17e7.25 (m, 2H, indole protons);
7.30e7.41 (m, 2H, aromatic protons); 7.42e7.47 (m, 1H, indole
proton); 7.49e7.55 (m, 2H, aromatic protons); 7.91 (m, 1H, indole
proton); 11.50 (s, 1H, NH exchanged by D2O). MS, m/z (%): 394 (Mþ,
1.48%); 105 (100%). Anal. calcd. for C18H18N2O2 (394.35): C, 73.45; H,
6.16; N, 9.52. Found: C, 73.22; H, 6.37; N, 9.26.
3.1.14.4. 2-{2-[4-(1H-Indol-2-yl) phenoxy] acetyl}hydrazinecarbo-
thioamide 15d. Compound 15d was prepared from 12a and thio-
semicarbazide. Brown solid, 80% yield, m.p. 118e120 ꢂC (absolute
ethanol). IR: nmax/cmꢀ1 3431e3367 (NH, NH2 stretching); 3052 (CH
aromatic); 2922 (CH aliphatic); 1669 (C]O amidic); 1558 (C]C);
3.1.13.3. 2-[4-(1H-Indol-2-yl) phenoxy]-1-(pyrrolidin-1-yl) ethanone
14c. Compound 14c was prepared from 12a and pyrrolidine. Green
solid, 86% yield, m.p. 190e192 ꢂC. IR: nmax/cmꢀ1 3417 (NH stretch-
ing); 3051 (CH aromatic); 2923e2857 (CH aliphatic); 1655 (C]O
1212 (C]S).1H NMR (DMSO-d6):
d 1.19 (s, 2H, NHeNH exchanged
by D2O); 4.14 (s, 2H, NH2 exchanged by D2O); 4.80 (s, 2H, OeCH2);
6.73 (s, 1H, indole proton); 6.93e6.98 (m, 2H, indole protons);
7.02e7.05 (m, 2H, aromatic protons); 7.32 (m, 1H, indole proton);
7.45e7.50 (m, 2H, aromatic protons); 7.74 (m, 1H, indole protons);
11.38 (s, 1H, NH exchanged by D2O). Anal. calcd. for C17H16N4O2S
(340.40): C, 59.98; H, 4.74; N, 16.46; S, 9.42. Found: C, 59.62; H,
4.57; N, 16.33; S, 9.16.
amidic); 1534 (C]C). 1H NMR (DMSO-d6):
d 1.81 (m, 4H, pyrrolidine
protons); 3.07 (m, 4H, pyrrolidine protons); 4.57 (s, 2H, OeCH2);
6.75 (s, 1H, indole proton); 6.75e7.01 (d, J ¼ 8.10 Hz, 2H, indole
protons); 7.05 (m, 2H, aromatic protons); 7.35e7.37 (d, J ¼ 5.40 Hz,
1H, indole proton); 7.46e7.49 (d, J ¼ 8.10 Hz, 2H, aromatic protons);
7.75e7.78 (d, J ¼ 8.10 Hz, 1H, indole proton); 11.41 (s, 1H, NH
exchanged by D2O). Anal. calcd. for C20H20N2O2 (320.38): C, 74.98;
H, 6.29; N, 8.74. Found: C, 75.16; H, 6.46; N, 8.67.
3.1.15. General procedure for the preparation of 16aec
Compound 12a (1 g, 3.56 mmol) and the appropriate sulfon-
amide (3.56 mmol) were stirred in dry acetone (50 ml) in the
presence of anhydrous potassium carbonate (1 g, 4.83 mmol) for
10 h. The reaction mixture was then filtered while hot. Upon
cooling, crystals separated out and were filtered and recrystallized
from absolute ethanol.
3.1.14. General procedure for the preparation of 15aed
Compound 12a (1 g, 3.56 mmol) and the hydrazide or hydra-
zine derivative (3.56 mmol) were refluxed in absolute ethanol
(30 ml) for 2 h. The reaction mixture was then cooled and the
precipitate was filtered and crystallized from the appropriate
solvent.
3.1.15.1. 2-[4-(1H-Indol-2-yl) phenoxy]-N-(4-sulfamoylphenyl) acet-
amide 16a. Compound 16a was prepared from 12a and

396
S.S. El-Nakkady et al. / European Journal of Medicinal Chemistry 47 (2012) 387e398
sulfanilamide. Light yellow crystals, 75% yield, m.p. 190 ꢂC. IR: nmax
/
3.1.16.2. 2-[4-(1H-Indol-2-yl) phenoxy]-1-(5-methyl-3-phenyl-1H-
pyrazol-1-yl) ethanone 17b. Compound 17b was prepared from 15a
and benzoylacetone. White solid, 60% yield, m.p. 208e209 ꢂC.
(absolute ethanol). IR: nmax/cmꢀ1 3498 (NH stretching); 3055 (CH
aromatic); 2922e2855 (CH aliphatic); 1667 (C]O); 1610 (C]N);
cmꢀ1 3460e3376 (NH2 stretching); 3246 (eNH stretching); 3052
(CH aromatic); 2923 (CH aliphatic); 1636 (C]O); 1598 (C]N); 1504
(C]C); 1312e1147 (SO2).1H NMR (DMSO-d6):
d 5.88 (s, 2Hs,
OeCH2); 6.61e6.64 (d, J ¼ 8.10 Hz, 2H, aromatic protons); 6.75 (s,
1H, indole proton); 6.95e7.05 (m, 4H, indole protons, aromatic
protons); 7.15 (br 2s, 2H, SO2eNH2 exchanged by D2O); 7.48e7.51
(d, J ¼ 8.10 Hz, 3H, indole and aromatic protons); 7.81e7.87 (m, 3H,
aromatic and indole protons); 11.40 (s, 2H, NH exchanged by D2O).
Anal. calcd. for C22H19N3O4S (421.47): C, 62.69; H, 4.54; N, 9.97; S,
7.61. Found: C, 62.49; H, 4.78; N, 10.23; S, 7.69.
1546 (C]C). 1H NMR (DMSO-d6):
d 2.05 (s, 3H, CH3); 4.52 (s, 2H,
OeCH2); 5.04 (s, 1H, pyrazole proton); 6.73 (s, 1H, indole proton);
6.95 (m, 2H, indole protons); 7.05 (m, 2H, aromatic protons); 7.25
(m, 3H, aromatic protons); 7.36 (m, 2H, aromatic protons); 7.48 (m,
1H, indole proton); 7.53 (m, 2H, aromatic protons); 7.73 (m, 1H,
indole proton); 11.38 (s,1H, NH exchanged by D2O). MS (m/z %): 408
(M þ 1þ, 1.78%). Anal. calcd. for C26H21N3O2 (407.46): C, 76.64; H,
5.19; N, 10.31. Found: C, 76.34; H, 5.54; N, 10.18.
3.1.15.2. 2-[4-(1H-Indol-2-yl) phenoxy]-N-{4-[N-(5-methylisoxazol-
3-yl) sulfamoyl] phenyl} acetamide 16b. Compound 16c was
prepared from 12a and sulfamethoxazole. Gray crystals, 90% yield,
m.p. 250e252 ꢂC. IR: nmax/cmꢀ1 3465e3179 (NH stretching); 3051
(CH aromatic); 2921 (CH aliphatic); 1620 (C]O); 1597(C]N); 1547
3.1.17. 1-{2-[4-(1H-Indol-2-yl) phenoxy] acetyl}-3-methyl-1H-
pyrazol-5(4H)-one 18
Compound 18 was prepared from 15a and ethyl acetoacetate by
the same procedure used for the preparation of 17a,b. Off white
(C]C); 1363e1148 (SO2).1H NMR (DMSO-d6):
d 2.21 (s, 3H, CH3);
5.90 (s, 2H, OeCH2); 6.48e6.51 (d, J ¼ 8.1 Hz, 2H, aromatic protons);
6.65 (s, 2H, thiazole and indole protons); 6.95 (m, 4H, indole and
aromatic protons); 7.37e7.40 (d, J ¼ 8.1 Hz, 3H, indole and aromatic
protons); 7.75 (m, 3H, indole and aromatic protons); 10.25 (s, 1H,
NHeSO2 exchanged by D2O); 11.32 (s, 2H, NH exchanged by D2O).
MS (m/z %): 502 (Mþ, 0.03%); 145 (100%). Anal. calcd. for
C26H22N4O5S (502.54): C, 62.14; H, 4.41; N, 11.15; S, 6.38. Found: C,
62.33; H, 4.79; N, 11.44; S, 6.09.
solid, 80% yield, m.p. 140 ꢂC (dec.). (pet. ether 60e80 ꢂC). IR: nmax
/
cmꢀ1 3429e3285 (NH stretching); 3052 (CH aromatic); 2923e2857
(CH aliphatic); 1696e1665 (2C]O); 1612 (C]N); 1537 (C]C). 1H
NMR (DMSO-d6): d 1.21 (s, 3H, CH3); 2.25 (s, 2H, pyrazole protons);
4.69 (s, 2H, OeCH2); 6.77 (s, 1H, indole proton); 6.96e6.99 (d,
J ¼ 8.10 Hz, 2H, indole protons); 7.03e7.05 (d, J ¼ 5.40 Hz, 2H,
aromatic protons); 7.35e7.38 (d, J ¼ 8.10 Hz, 1H, indole proton);
7.47e7.50 (d, J ¼ 8.10 Hz, 2H, aromatic protons); 7.79 (m, 1H, indole
proton); 11.42 (s, 1H, NH exchanged by D2O). Anal. calcd. for
C20H17N3O3 (347.37): C, 69.15; H, 4.93; N, 12.10. Found: C, 68.66; H,
5.36; N, 12.25.
3.1.15.3. 2-[4-(1H-Indol-2-yl) phenoxy]-N-[4-(N-thiazol-2-ylsulfamoyl)
phenyl] acetamide 16c. Compound 16c was prepared from 12a and
sulfathiazole. Yellow crystals, 93% yield, m.p. 210 ꢂC. IR: nmax/cmꢀ1
3432e3189 (NH stretching); 3092 (CH aromatic); 2919 (CH
aliphatic); 1630 (C]O); 1581 (C]N); 1530 (C]C); 1324e1137
3.1.18. General procedure for the preparation of 19aee
Compound 15a (1 g, 3.56 mmol), the appropriate carboxylic acid
derivative (3.56 mmol) and phosphorous oxychloride (4 ml,
26 mmol) were refluxed on a water bath for 2 h at 80 ꢂC. The
reaction mixture was then poured onto ice/cold water and
neutralized by NaHCO3 solution. The so formed precipitate was
filtered and crystallized from the appropriate solvent.
(SO2).1H NMR (DMSO-d6):
d 5.78 (s, 2H, OeCH2); 6.48e6.50 (m,
2H, aromatic protons); 6.67e6.69 (m, 2H, indole and thiazole
protons); 6.95 (m, 4H, indole and aromatic protons); 7.12e7.14 (m,
1H, thiazole proton); 7.36e7.39 (m, 3H, indole and aromatic
protons); 7.71 (m, 3H, indole and aromatic protons); 10.50 (s, 1H,
NHeSO2 exchanged by D2O); 11.35 (s, 2H, NH indole, NHeCO
exchanged by D2O). 13C NMR (DMSO-d6):
d
62.50 (OeCH2); 107.45
3.1.18.1. 2-{[4-(1H-Indol-2-yl) phenoxy] methyl}-5-phenyl-1,3,4-
oxadiazole 19a. Compound 19a was prepared from 15a and ben-
zoic acid. Green solid, 63% yield, m.p. 160 ꢂC (dec.). (pet. ether
60e80 ꢂC). IR: nmax/cmꢀ1 3421 (NH stretching); 3054 (CH
aromatic); 2921 (CH aliphatic); 1609 (C]N); 1544 (C]C). 1H NMR
(indole carbon); 112.43 (indole and aromatic carbons); 124.50
(indole and thiazole carbons); 127.78 (indole, thiazole and
aromatic carbons); 152.24 (aromatic and thiazole carbons); 168.50
(C]O). MS (m/z %): 504 (Mþ, 1.78%). Anal. calcd. for C25H20N4O4S2
(504.58): C, 59.51; H, 4.00; N, 11.10; S, 12.71. Found: C, 59.89; H,
3.87; N, 11.45; S, 12.52.
(DMSO-d6):
d 4.55 (m, 2H, OeCH2); 6.76 (s, 1H, indole proton);
6.96e6.99 (d, J ¼ 8.1 Hz, 2H, indole protons); 7.03e7.05 (d,
J ¼ 8.10 Hz, 2H, aromatic protons); 7.35e7.37 (m, 5H, aromatic
protons); 7.50e7.52 (d, J ¼ 5.40 Hz, 1H, indole proton); 7.56e7.59
(m, 2H, aromatic protons); 7.78e7.80 (m, 1H, indole proton); 11.43
(s, 1H, NH exchanged by D2O). Anal. calcd. for C23H17N3O2
(367.40): C, 75.19; H, 4.66; N, 11.44. Found: C, 74.82; H, 4.85; N,
11.49.
3.1.16. General procedure for the preparation of 17a,b
Compound 15a (1 g, 3.56 mmol) and corresponding diketones
(3.56 mmol) were refluxed in absolute ethanol (30 ml) for 5 h. The
reaction mixture was cooled and the precipitate was filtered and
crystallized from the appropriate solvent.
3.1.16.1. 2-[4-(1H-Indol-2-yl) phenoxy]-1-(3,5-dimethyl-1H-pyrazol-
1-yl) ethanone 17a. Compound 17a was prepared from 15a and
acetylacetone. White solid, 85% yield, m.p. 260 ꢂC. (pet. ether
60e80 ꢂC). IR: nmax/cmꢀ1 3234 (NH stretching); 3056 (CH
aromatic); 2921e2855 (CH aliphatic); 1699 (C]O); 1612 (C]N);
3.1.18.2. 4-{5-[(4-(1H-Indol-2-yl) phenoxy) methyl]-1,3, 4-oxadiazol-
2-yl}aniline 19b. Compound 19b was prepared from 15a and p-
aminobenzoic acid. Dark violet solid, 86% yield, m.p. 140e142 ꢂC.
(pet. ether 60e80 ꢂC). IR: nmax/cmꢀ1 3328e3215 (NH2, NH
stretching); 3055 (CH aromatic); 2924 (CH aliphatic); 1604 (C]N);
1556 (C]C). 1H NMR (DMSO-d6):
d
1.21 (s, 3H, eN]CeCH3); 1.69
1498 (C]C). 1H NMR (DMSO-d6):
d 4.52 (m, 2H, OeCH2); 6.78 (s,
(s, 3H, NeCeCH3); 4.16 (s, 2H, OeCH2); 4.82 (s, 1H, pyrazole
proton); 6.76 (s, 1H, indole proton); 6.86 (m, 2H, indole protons);
6.99e7.02 (d, J ¼ 8.10 Hz, 2H, aromatic protons); 7.35e7.47 (m, 2H,
aromatic protons); 7.69e7.72 (d, J ¼ 8.10 Hz, 1H, indole proton);
7.77e7.79 (d, J ¼ 8.10 Hz, 1H, indole proton); 11.46 (s, 1H, NH
exchanged by D2O). Anal. calcd. for C21H19N3O2 (345.39): C, 73.03;
H, 5.54; N, 12.17. Found: C, 72.62; H, 5.89; N, 12.23.
1H, indole proton); 6.97 (m, 2H, indole protons); 7.03e7.06 (m, 2H,
aromatic protons); 7.20e7.36 (m, 4H, aromatic protons); 7.48 (m,
1H, indole proton); 7.76 (m, 2H, aromatic protons); 7.79 (m, 1H,
indole proton); 8.00 (s, 2H, NH2 exchanged by D2O); 11.42 (s,1H, NH
exchanged by D2O). MS (m/z %): 382 (Mþ, 0.71%); 209 (100%). Anal.
calcd. for C23H18N4O2 (382.41): C, 72.24; H, 4.74; N, 14.65. Found: C,
72.34; H, 4.88; N, 14.45.

S.S. El-Nakkady et al. / European Journal of Medicinal Chemistry 47 (2012) 387e398
397
3.1.18.3. 2-{5-[(4-(1H-Indol-2-yl) phenoxy) methyl]-1,3, 4-oxadiazol-
3.3. Molecular docking
2-yl}aniline 19c. Compound 19c was prepared from 15a and
anthranilic acid. Brown solid, 89% yield, m.p. 100e102 ꢂC. (absolute
ethanol). IR: nmax/cmꢀ1 3422e3250 (NH2, NH stretching); 3057(CH
aromatic); 2922 (CH aliphatic); 1612 (C]N); 1542 (C]C). 1H NMR
All molecular modeling calculations and docking studies were
performed using ‘Molecular Operating Environment (MOE) version
2008.10 release of Chemical Computing Group’s’. The program
operated under ‘Windows XP’ operating system installed on an
Intel Pentium IV PC with a 2.8 MHz processor and 512 RAM.
The target compounds were built using the MOE builder inter-
face and subjected to energy minimization using the included
MOPAC. The produced model was subjected to Systematic Confor-
mational Search where all items were set as default with RMS
gradient of 0.01 kcal/mol and RMS distance of 0.1 Å.
(DMSO-d6):
d 4.50 (s, 2H, OeCH2); 6.85 (s, 1H, indole proton);
6.97e7.00 (m, 2H, indole protons); 7.03e7.07 (m, 2H, aromatic
protons); 7.23e7.36 (m, 4H, aromatic protons); 7.42 (m, 1H, indole
proton); 7.48 (m, 2H, aromatic protons); 7.80 (m, 1H, indole
proton); 8.18 (s, 2H, NH2 exchanged by D2O); 11.46 (s, 1H, NH
exchanged by D2O). Anal. calcd. for C23H18N4O2 (382.41): C, 72.24;
H, 4.74; N, 14.65. Found: C, 72.59; H, 4.63; N, 14.57.
The X-ray crystallographic structure of tubulin co-crystallized
with colchicine was obtained from the Protein Data Bank; code
“1SAO.pdb”. The enzyme was prepared for docking studies as
follows:
3.1.18.4. 2-{5-[(4-(1H-Indol-2-yl) phenoxy) methyl]-1,3,4-oxadiazol-
2-yl} phenol 19d. Compound 19d was prepared from 15a and sal-
icylic acid. Dark green solid, 75% yield, m.p. 250 ꢂC. (pet. ether
60e80 ꢂC). IR: nmax/cmꢀ1 3393 (OH stretching); 3265 (NH stretch-
ing); 3054 (CH aromatic); 2923(CH aliphatic); 1607 (C]N); 1541
a. The ligand molecule was removed form the enzyme active site.
b. Hydrogen atoms were added to the isolated target with their
standard geometry.
c. A connect and type procedure was run for automatic comple-
tion of missed bonds during isolation and crystallization.
d. The target was fixed to be dealt as a rigid structure.
e. The active site was isolated by the Alpha site finder tool using
the binding amino acids as key elements in isolation.
f. Dummies were created around the active site.
(C]C). 1H NMR (DMSO-d6):
d 4.54 (s, 2H, OeCH2); 6.77 (s, 1H,
indole proton); 6.97 (m, 2H, indole protons); 7.04 (m, 2H, aromatic
protons); 7.38 (m, 4H, aromatic protons); 7.40 (m, 1H, indole
proton); 7.50 (m, 2H, aromatic protons); 7.72 (m, 1H, indole
proton); 9.65 (s, 1H, eOH exchanged by D2O); 11.41 (s, 1H, NH
exchanged by D2O). Anal. calcd. for C23H17N3O3 (383.40): C, 72.05;
H, 4.47; N, 10.96. Found: C, 71.99; H, 4.26; N, 10.80.
3.1.18.5. 2-{[4-(1H-Indol-2-yl) phenoxy] methyl}-5-(6-methoxyquinolin-
2-yl)-1,3,4-oxadiazole 19e. Compound 19e was prepared from 15a
and 6-methoxyquinolinic acid. Dark violet solid, 80% yield, m.p.
>300 ꢂC. (absolute ethanol). IR: nmax/cmꢀ1 3396 (NH stretching);
3059 (CH aromatic); 2923e2853 (CH aliphatic); 1614 (C]N);
Acknowledgments
The authors would like to thank Dr. Yassin M. Nissan, molecular
modeling laboratory, Faculty of Pharmacy, Cairo University for his
kind help in performing the molecular docking study.
1548 (C]C). 1H NMR (DMSO-d6):
d 3.93 (s, 3H, OeCH3); 4.60 (m,
2H, OeCH2); 6.72 (s, 1H, indole proton); 6.92 (m, 2H, indole
protons); 7.10 (m, 3H, aromatic protons); 7.23 (m, 1H, aromatic
proton); 7.37 (m, 1H, aromatic proton); 7.51 (m, 3H, indole and
aromatic protons); 7.64 (m, 2H, indole and aromatic protons);
8.22e8.24 (m, 1H, aromatic proton); 11.45 (s, 1H, NH exchanged
by D2O). MS (m/z %): 448 (Mþ, 1.23%); 150 (100%). Anal. calcd. for
C27H20N4O3 (448.47): C, 72.31; H, 4.49; N, 12.49. Found: C, 72.55;
H, 4.39; N, 12.54.
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