Synthesis of some heterocyclic compounds derived from indole as antimicrobial agents

Article abstract of DOI:10.1080/00397911.2017.1403627

Recently, indoles are considered interesting heterocyclic compounds due to their wide range of biological activities such as antimicrobial activity. Herein, some new indole derivatives containing heterocyclic moieties were synthesized using 3-chloro-1H-Indole-2-carbaldehyde (1) as a starting material, then allowed to react with compounds containing active methylene under Knoevenagel condensation and afforded the corresponding compounds (2, 3, 9). Also, the compound (1) when allowed to react with hydrazine derivatives gave the corresponding thiosemiccarbazone, semicarbazone, and hydrazone derivatives (4, 5, 6). Reaction of thiosemicarbazone derivatives with α-halognated carbonyl compounds gave the thiazolyl indole derivatives (10, 12a–b). Cyclic chalcones (11a–c) were obtained when compound (10) reacted with different aromatic aldehydes. The structures of all new synthesized compounds were confirmed on the basis of spectral analysis, IR, 1H NMR, 13C NMR, and MS spectroscopy. All synthesized compounds were evaluated for their antimicrobial activity. Compounds (2, 5, 7, 8, 11a, 12a) showed high antibacterial activity and compounds (3, 6, 9, 10, 11a, 12a) showed high antifungal activity.

Full text of DOI:10.1080/00397911.2017.1403627

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of some heterocyclic compounds
derived from indole as antimicrobial agents
Mostafa Sayed, Adel M. Kamal El-Dean, Mostafa Ahmed & Reda Hassanien
To cite this article: Mostafa Sayed, Adel M. Kamal El-Dean, Mostafa Ahmed & Reda Hassanien
(2018): Synthesis of some heterocyclic compounds derived from indole as antimicrobial agents,
Synthetic Communications, DOI: 10.1080/00397911.2017.1403627
To link to this article: https://doi.org/10.1080/00397911.2017.1403627
View supplementary material
Published online: 22 Jan 2018.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1403627
Synthesis of some heterocyclic compounds derived from
indole as antimicrobial agents
a
b
a
a
Mostafa Sayed , Adel M. Kamal El-Dean , Mostafa Ahmed , and Reda Hassanien
a
b
Department of Chemistry, New Valley Faculty of Science, Assiut University, Assiut, Egypt; Department of
Chemistry, Faculty of Science, Assiut University, Assiut, Egypt
ABSTRACT
ARTICLE HISTORY
Recently, indoles are considered interesting heterocyclic compounds
due to their wide range of biological activities such as antimicrobial
activity. Herein, some new indole derivatives containing heterocyclic
moieties were synthesized using 3-chloro-1H-Indole-2-carbaldehyde
Received 14 September
2017
KEYWORDS
Indole; Knoevenagel;
synthesis; thiazolidinone
(
1) as a starting material, then allowed to react with compounds
containing active methylene under Knoevenagel condensation and
afforded the corresponding compounds (2, 3, 9). Also, the compound
(
1) when allowed to react with hydrazine derivatives gave the
corresponding thiosemiccarbazone, semicarbazone, and hydrazone
derivatives (4, 5, 6). Reaction of thiosemicarbazone derivatives with
α-halognated carbonyl compounds gave the thiazolyl indole
derivatives (10, 12a–b). Cyclic chalcones (11a–c) were obtained when
compound (10) reacted with different aromatic aldehydes. The
structures of all new synthesized compounds were confirmed on
the basis of spectral analysis, IR, 1H NMR, 13C NMR, and MS
spectroscopy. All synthesized compounds were evaluated for their
antimicrobial activity. Compounds (2, 5, 7, 8, 11a, 12a) showed high
antibacterial activity and compounds (3, 6, 9, 10, 11a, 12a) showed
high antifungal activity.
GRAPHICAL ABSTRACT
CONTACT Mostafa Ahmed
Assiut University, Assiut 72511, Egypt.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
drmostafa@scinv.au.edu.eg
Department of Chemistry, New Valley Faculty of Science,
1
13
Supplemental data (full experimental detail, H and C NMR spectra) can be accessed on the publisher’s website.
©
2017 Taylor & Francis

2
M. SAYED ET AL.
Introduction
In recent years, indole and other heterocyclic compounds containing indole derivatives
have attracted great important due to their wide use as alkaloids.[1] Among the myriad
[
2]
of biologically active heterocycles, nitrogen-containing heterocycles play a key role.
In fact, recent surveys have reported that a large number of molecules currently under
investigation by researchers contain nitrogen heterocycles, and of these, indoles, pyrimidyl,
pyrazolyl, thiazolyl, and pyridyl indoles constitute the most important family of com-
pounds. These heterocycles have the common indole framework which is commonly found
[
3–7]
in pharmaceutical drugs and natural products.
Indoles are interesting heterocyclic
compounds and a lot of derivatives of these compounds are considered compounds of
great interest for their wide range of biological activities, such as antitumor,
[
8,9]
[10]
antiviral,
anti-inflammatory,[11] and anxiolytic
[12,13]
and are also useful for the treatment of cancer
These novel biological activities are due to their ability
[
14]
and immune-related diseases.
to interact with DNA. Indole is first prepared by Fischer who proposed that aromatic
heterocycle indole derivatives could be obtained by the reaction of a substituted phenylhy-
[
15]
drazine and an aldehyde or ketone under acidic conditions. The reaction was discovered
in 1883 by Hermann Emil Fischer. Today antimigraine drugs of the triptan class are often
[
16]
synthesized by this method.
Also, heterocyclic compounds containing indole have long
been the subject of chemical and biological research where some pyrazolo, pyrimidyl
[
17–22]
indoles used as analgesic.
The antibacterial activity of this class of compounds has
been underexplored. Moreover, indole derivatives have fascinated importance in
medicinal chemistry, exhibiting pharmacological and therapeutic properties such as
[
23–25]
[26–29]
[30]
[31]
antidepressant,
growth regulatory properties.
pyrazole and thiazole moieties have great importance as antioxidant,
antiplatelet,
antihypertensive,
herbicidal,
and plant
[
32,33]
Indoles containing other heterocyclic moieties specially
[
34,35]
antiproliferative,[
36,37]
and anticancer agents
[38]
in the present work, we report on the
efficient synthesis of indole derivatives containing heterocyclic moieties such as pyrazole,
thiazole, and thiophen. This study focused on the synthesis and biochemical evaluation
of the newly synthesized heterocyclic compounds which was then subjected through
antimicrobial evaluations.
Results and discussion
Chemistry
As shown in Scheme 1 when 3-chloro-1H-Indole-2-carbaldehyde (1), which synthesized
according to the reported procedures by Vilsimeier Haack reaction, when allowed to
react with malonic acid in ethanol and piperidine as catalyst, decarboxylation was
occurred and gave compound 2. Also, when compound 1 subjected to react with
cyanoacetamide in ethanol in the presence of catalytic amount of piperidine afforded the
corresponding compound 2. The structures of the previous obtained compounds were elu-
cidated by elemental and spectral analyses where IR spectrum of compound 2 showed
−
1
1
appearance of new band at 1661 cm characteristic of C=O and its H NMR spectrum
showed appearance of singlet signal at δ ¼ 11.5 ppm characteristic of OH, also IR spectrum
−1
of compound 3 showed appearance of new bands at 2211, 3197, 3419, and 3519 cm
1
characteristic of CN and NH, NH groups and its H NMR spectrum showed appearance
2

SYNTHETIC COMMUNICATIONS®
3
Scheme 1. Reaction of starting material with malonic acid and semicarbazide derivatives.
of signal at δ ¼ 5.91 ppm characteristic of NH group. Compound 1 was reacted with
2
thiosemicarbazide and semicarbazide in acetic acid affording thiosemicarbazone and
semicarbazone derivatives 4, 5. The structures of thiosemicarbazone and semicarbazone
derivatives were confirmed on the basis of spectral data where IR spectrum of
−1
compound 5 showed appearance of bands at 1724, 3164, 3425, and 3456 cm characteristic
of C=O, NH, and NH groups, also IR spectrum of compound 4 showed appearance of
2
−
1
bands at 1232, 3297, and 3469 cm characteristic of C=S and NH groups, while
H NMR spectrum showed appearance of singlet signal at δ ¼ 11.68 ppm characteristic
2
1
of NH group.
2
The condensation of 3-chloro-1H-indole-2-carbaldehyde with ethyl cyanoacetate in
ethanol give compound 7 which allowed to react with hydrazine hydrate to give com-
pound 9. The IR spectrum of compound 9 showed appearance of new bands at 3245,
−
1
−1
3
314, and 3350 cm characteristics of NH, NH , band at 1685 cm characteristic of
2
C=O and disappearance of band characteristic of CN group in the starting compound
1
7
, also H NMR spectrum of compound 9 showed disappearance of signal characteristic
of ester group and appearance of new singlet signals for NH, NH at δ ¼ 5.58 and 10.53
2
ppm, respectively. On the other hand, when compound 1 allowed to react with cyanoa-
cetohydrazide in ethanol in the presence of piperidine as a basic catalyst gave the corre-
sponding N′-((3-chloro-1H-indol-2-yl) methylene)-2-cyanoacetohydrazide 6, the latter
compound was reacted with ethyl cyanoacetate and elemental sulfur in triethylamine
to give compound 8. The structures of the new compounds were proved by spectral
analysis, where IR spectrum of compound 6 showed appearance of new absorption bands
−
1
at 1693, 2278 cm characteristic of C=O and CN groups, also its 1H NMR spectrum
showed appearance of new singlet signal at δ ¼ 3.94 ppm characteristic of methylene
group. The IR spectrum of compound 8 showed appearance of new absorption bands
−
1
at 1724, 3378, and 3425 cm characteristics of C=O ester and NH group, also its 1H
2
NMR spectrum showed appearance of new triplet signal at δ ¼ 1.39 ppm characteristic

4
M. SAYED ET AL.
Scheme 2. Synthesis of thienyl and pyrazolylindole derivatives. Note: DMF, dimethylformamide; TEA,
triethylamine.
of CH and quartet signal at δ ¼ 4.43 ppm characteristic of CH group, as shown in
3
2
Scheme 2.
The treatment of 2-((3-chloro-1H-indol-yl)methylene)hydrazinethiocarboxamide 4
with ethyl chloroacetate in the presence of fused sodium acetate and pyridine afforded
compound 10, when the latter compound allowed to react with aromatic aldehydes
afforded corresponding cyclic chalcones 11a–c. Also, when compound 4 reacted with
phenacyl bromide or chloroacetone gave thiazolidine derivatives 12a, b. The structures
of the obtained compounds were elucidated by elemental and spectral analyses, where
−1
IR spectrum of compound 10 showed appearance of new band at 1722 cm characteristic
of C=O group and showed also disappearance of band characteristic of NH group in
2
1
the starting material 4, while H NMR spectrum showed appearance of singlet signal at
δ ¼ 3.90 ppm characteristic of CH . Also, IR spectrum of compound 11b showed appear-
2
−
1
1
ance of bands at 1716, 3435 cm characteristics of C=O and NH groups, while H NMR
spectrum of the same compound showed appearance of singlet signal at δ ¼ 9.46 ppm
characteristic of CH and showed also disappearance of signal characteristic of CH group
2
which existed in the starting material. The structure of compound 12a was elucidated by
spectral analyses, where IR spectrum showed appearance of new band at 3460 cm−1 char-
acteristics of NH group and disappearance of band characteristic of amino group in the
1
starting material 4, H NMR spectrum showed appearance of two singlet signals at δ ¼ 9.52
and 2.44 ppm characteristic of CH=N and CH groups as shown in Scheme 3.
3
Antimicrobial activity
All the new synthesized compounds listed in Table 1 were screened for their in vitro
antimicrobial activity against model Gram-positive (Staphylococcus aureus, Streptococcus
pneumonia, and Bacillus subtilis) and Gram-negative bacteria (Pseudomonas sp,
Haemophilus influenza, and Pseudomonas aeruginosa), including multidrug-resistant
species, yeasts, and mold. The MICs are compared with the results obtained for standard
antibacterial ciprofloxacin and streptomycin, and their antifungal activity against five fun-
gal strains (Candida albicans, Aspergillus fumigatus, Penicillium sp, Geotrichum candidum,
and Syncephalastrum racemosum). The antimicrobial activities of the tested compounds
[
13]
−1
were evaluated by the reported method
using 0.005% (50 µg mL ) concentration of
selected compounds in dimethyl sulfoxide (DMSO) as a solvent. The inhibition zone

SYNTHETIC COMMUNICATIONS®
5
Scheme 3. Reaction of thiosemicarbazone derivatives with α-halocarbonyl compounds.
(
mm) was compared with clotrimazole as a standard for antifungal activity. In the case of
antibacterial activity, the inhibition zone (mm) was compared with a series of antibiotics
according to the sensitivity of each type of bacteria to the most effective antibiotic for it
as a standard. The biological activity as expressed by the growth inhibition zone of the
tested microorganism is listed in Tables 1 and 2.
From the data in Table 1, it could be stated that all the investigated compounds
presented remarkable antibacterial properties against Gram-positive bacteria and
compounds (2, 12a) have the highest antibacterial activity against all strains of bacteria,
with values close to those of the corresponding reference antibiotics (ciprofloxacin and
streptomycin, respectively), while compound (1) showed low antibacterial activity among
all the tested compounds. Furthermore, compounds (5, 8, 11a) displayed also excellent
−
1
Table 1. Antibacterial activity, (inhibition zone, mm) and MIC (µg mL ) of the synthesized
compounds.
Staphylococcus
aureus
(Gram+)
Streptococcus
pneumoniae
(Gram+)
Bacillus
subtilis
(Gram+)
Pseudomonas
aeruginosa
(Gram−)
Pseudomonas
sp
(Gram−)
Haemophilus
influenza
(Gram−)
No.
1
2
3
4
5
6
7
8
9
5 (6.0)
18 (5.0)
15 (5.0)
14 (0.7)
17 (6.0)
12 (7.0)
11 (4.0)
9 (5.0)
8 (7.0)
19 (5.0)
16 (4.0)
14 (6.0)
14 (4.0)
15 (8.0)
17 (4.0)
18 (6.0)
20 (4.0)
16 (6.0)
19 (4.0)
17 (6.0)
22 (5.0)
7 (8.0)
17 (5.0)
11 (0.7)
18 (6.0)
19 (4.0)
17 (5.0)
20 (7.0)
19 (6.0)
18 (4.0)
17 (7.0)
16 (6.0)
20 (4.0)
21 (4.0)
8 (9.0)
22 (5.0)
20 (5.0)
16 (5.0)
16 (5.0)
17 (6.0)
14 (5.0)
16 (5.0)
20 (3.0)
19 (4.0)
13 (4.0)
12 (5.0)
25 (4.0)
Strptomycin
9 (5.0)
21 (6.0)
20 (5.0)
19 (6.0)
19 (5.0)
18 (8.0)
15 (4.0)
18 (0.5)
16 (6.0)
19 (4.0)
15 (5.0)
12 (8.0)
22 (5.0)
11 (8.0)
17 (6.0)
18 (5.0)
17 (0.8)
19 (4.0)
22 (4.0)
19 (5.0)
13 (8.0)
19 (6.0)
20 (5.0)
19 (5.0)
18 (4.0)
21 (4.0)
10 (5.0)
19 (4.0)
17 (6.0)
21 (7.0)
1
1
1
0
1a
2a
25 (5.0)
Ref.
Ciprofloxecin
Note: Numbers out parentheses represent the diameter of inhibition zone in (mm) of compounds 1-12; Numbers in
−
1
parentheses represent the MIC (minimum inhibition concentration) in (mg mL ) of compounds 1-12.

6
M. SAYED ET AL.
−
1
Table 2. Antifungal activity, (inhibition zone, mm) and MIC (µg mL ) of the synthesized compounds.
No. Penicillium sp Candida albicans Geotrichum candidum Aspergillus fumigatus Syncephalastrum racemosum
1
10 (4.0)
15 (5.0)
17 (6.0)
15 (4.0)
19 (5.0)
11 (6.0)
14 (4.0)
15 (5.0)
17 (5.0)
16 (4.0)
14 (6.0)
19 (5.0)
20 (4.0)
11 (5.0)
15 (5.0)
14 (7.0)
19 (5.0)
14 (5.0)
19 (6.0)
17 (5.0)
16 (6.0)
17 (6.0)
19 (7.0)
15 (5.0)
20 (5.0)
22 (5.0)
13 (4.0)
14 (4.0)
20 (5.0)
17 (5.0)
16 (5.0)
18 (5.0)
17 (4.0)
18 (4.0)
21 (5.0)
17 (5.0)
18 (5.0)
22 (4.0)
26 (5.0)
11 (5.0)
18 (7.0)
14 (6.0)
17 (5.0)
15 (4.0)
16 (6.0)
15 (6.0)
17 (6.0)
14 (5.0)
18 (9.0)
17 (4.0)
20 (9.0)
21 (4.0)
9 (5.0)
18 (4.0)
17 (5.0)
14 (6.0)
17 (4.0)
19 (10)
18 (4.0)
21 (4.0)
20 (5.0)
17 (3.0)
15 (5.0)
20 (8.0)
22 (7.0)
2
3
4
5
6
7
8
9
1
1
1
0
1a
2a
Ref.
Ketocanazole
activity against other bacterial strains S. aureus, S. pneumonia, and H. influenza, the
inhibition of B. subtilis and P. aeruginosa was achieved by compounds (7) and (2). In
conclusion, the data in Table 1 showed that compounds 2,3 which have the acrylic acid
and cyan acrylamide moieties in position 2 in indole system has the highest antibacterial
activity, while the starting previously reported compound (1) which has only indole moiety
has low activity against Gram-positive and Gram-negative bacteria also, we could see that
all new synthesized compounds have antibacterial activity against all the strains of bacteria
higher than that of the starting compound (1) making our work is useful for improving the
antibacterial activity. The antifungal results for tested compounds against five fungal
species are summarized in Table 2. From Table 2, it could be stated that all the investigated
compounds presented remarkable antifungal activities against five types of fungi
C. albicans, A. fumigatus, Penicillium sp, G. candidum, and S. racemosum, where the
data showed that the compound (12a) which has the indole nucleus with 2-methylthiazolyl
substituent has the highest antifungal activity against all the strains of fungi, from Tables 1
and 2, it could be stated that compound (12a) has an antibacterial activity against all the
strains of Gram-positive and Gram-negative bacteria, with values close to those of the
corresponding standers and has high antifungal activity against different types of fungal
species. On the other hand, compounds (9) and (10) have antifungal activity close to
stander ketoconazole against fungal species, whereas the starting compound (1) has the
lowest antifungal activity against the same fungal strains which states that the new synthe-
sized compounds improved the activity. On the other hand, compounds (3), (6), and (9)
showed high antifungal activity against G. candidum and S. racemosum, while compound
(
(
11a) showed the highest antifungal activity against C. albicans. However, compounds (2),
5), and (7) showed moderate activity.
Conclusion
In this study, some new indole derivatives containing heterocyclic moieties were
synthesized using 3-chloro-1H-Indole-2-carbaldehyde (1) as a starting material. All new
synthesized compounds were screened against their in vitro antimicrobial activity,
compound (12a) which has the indole nucleus with 2-methylthiazolyl substituent has
the highest antibacterial and antifungal activities.

SYNTHETIC COMMUNICATIONS®
7
Experimental
All melting points are uncorrected and measured on a Fischer-Johns apparatus. Elemental
analyses were determined on an Elementar Analysen system GmbH-VarioEL V.3 micro-
analyzer in the central lab of Assiut University. Their results were found to be in good
agreement (�0.2%) with the calculated values. IR spectra were recorded on a Pye-Unicam
1
Sp-100 spectrophotometer using KBr wafer technique. H NMR experiments were run at
3
00 MHz on a Varian Mercury VX-300 NMR and Bruker (400 MHz) spectrometer using
tetramethylsilane (TMS) as an internal standard in deuterated dimethyl sulfoxide (d6).
Mass spectra were obtained on JEOL JMS-600 apparatus. Preparative and analytical TLC
were performed on silica gel plates (Fluka 70643-50EA. Sigma-Aldrich, Germany) using
UV light. All reactions were performed under air atmosphere. Compound (1) was prepared
[
39]
according to the literature procedure.
General procedure for the synthesis of compound (11a–c)
A mixture of compound (10) (0.5 g, 1.7 mmol), aromatic aldehyde (1.7 mmol), and
catalytic amount of piperidine was added to ethanol, the resultant mixture was heated at
reflux for 4 h, the reaction mixture was allowed to cool, the precipitate obtained was
collected, dried, and recrystallized from the appropriate solvent.
5
-Benzylidene-2-(2-((3-chloro-1H-indol-2-yl) methylene)hydrazinyl)thiazol-4(5H)-
one(11a)
The compound obtained recrystallized from ethanol/dioxane as a yellow crystal in 83.3%
−
1
yield, mp >300 °C IR: υ (cm ): 3051 (CH aromatic), 2923(CH aliphatic), 1702 (C=O),
1
3
9
1
1
435 (NH), H NMR (DMSO-d ) δ (ppm) 7.02–7.77 (m, 9H, Ar–H), 7.77 (s, 1H, CH),
6
13
.66 (s, 1H, CH), 11.85 (s, 1H, NH), 13.5 (s, 1H, NH), C NMR (DMSO-d ) δ (ppm)
12.44, 112.88, 119.52, 121.30, 124.46, 124.60, 127.64, 128.84, 128.84, 129.38, 129.38,
30.07, 132.83, 132.97, 134.39, 136.43, 176.95, 181.53, Anal. Calcd. for C H ClN OS
380.05) C, 59.92; H, 3.44; Cl, 9.31; N, 14.71; S, 8.42%. Found: C, 59.85; H, 3.49; Cl,
.40; N, 14.65; S, 8.0%.
6
19
13
4
(
9
References
[
[
[
1] Mizoguchi, H.; Oikawa, H.; Oguri, H. Biogenetically Inspired Synthesis and Skeletal
Diversification of Indole Alkaloids. Nat. Chem. 2014, 6, 57–64. DOI: 10.1038/nchem.1798.
2] Deiters, A.; Martin, S. F. Synthesis of Oxygen-and Nitrogen-Containing Heterocycles by Ring-
Closing Metathesis. Chem. Rev. 2004, 104(5), 2199–2238. DOI: 10.1002/chin.200431268.
3] Dandia, A.; Arya, K.; Sati, M.; Sharma, R. Facile Microwave-Assisted One-Pot Solid Phase
0
Synthesis of Spiro [3H-indole-3,4 -pyrazolo[3,4-b] pyridines]. Heterocycl. Commun. 2003, 9,
4
15–420. DOI: 10.1515/hc.2003.9.4.415.
[
[
4] Lee, S.; Park, S.-B. An Efficient One-Step Synthesis of Heterobiaryl Pyrazolo[3,4-b]Pyridines via
Indole Ring Opening. Org. Lett. 2009, 11, 5214–5217. DOI: 10.1021/ol902147u.
5] Raghunath, S.-A.; Manjunatha, Y.; Rayappa, K. Synthesis, Antimicrobial, and Antioxidant
Activities of Some New Indole Analogues Containing Pyrimidine and Fused Pyrimidine
Systems. Med. Chem. Res. 2012, 21, 3809–3817. DOI: 10.1007/s00044-011-9915-7.
[6] Saundane, A.-R.; Vijaykumar, K.; Vaijinath, A.; Walmik, P. Synthesis, Antimicrobial and
Antioxidant Activities of Some New Indole Derivatives Containing Pyridopyrimidine and

8
M. SAYED ET AL.
Pyrazolopyridine Moieties. Med. Chem. Res. 2013, 22, 806–817. DOI: 10.1007/s00044-012-
0
066-2.
[
7] Saundane, A.-R.; Walmik, P.; Yarlakatti, M.; Katkar, V.; Verma, V.-A. Synthesis and
Biological Activities of Some New Annulated Pyrazolopyranopyrimidines and Their Deriva-
tives Containing Indole Nucleus. J. Heterocycl. Chem. 2014, 51, 303–314. DOI: 10.1002/
jhet.1582.
[
8] Niemyjska, M.; Maciejewska, D.; Wolska, I.; Truszkowski, P. Synthesis, Structural
Investigations, and Anti-Cancer Activity of New Methyl Indole-3-Carboxylate Derivatives.
J. Mol. Struct. 2012, 1026, 30–35. DOI: 10.1016/j.molstruc.2012.05.031.
9] Farghaly, A.-R. Synthesis of Some New Indole Derivatives Containing Pyrazoles with Potential
Antitumor Activity. Arkivoc. 2010, 11, 177–187.
[
[
10] Giampieri, M.; Balbi, A.; Mazzei, M.; La Colla, P.; Ibba, C.; Loddo, R. Antiviral Activity of
Indole Derivatives. Antiviral Res. 2009, 83, 179–185. DOI: 10.1016/j.antiviral.2009.05.001.
11] Rani, P.; Srivastava, V.; Kumar, A. Synthesis and Antiinflammatory Activity of
Heterocyclic Indole Derivatives. Eur. J. Med. Chem. 2004, 39, 449–452. DOI: 10.1016/j.ejmech.
[
2
003.11.002.
[
[
[
12] Andrés-Gil, J.-I.; Bartolomé-Nebreda, J.-M.; Alcázar-Vaca, M.-J.; de las Mercedes Garcia-
Martin, M.; Megens, A. A. H. P. Isoxazoline-Indole Derivatives with an Improved
Antipsychotic and Anxiolytic Activity. Google Patents, 2009.
13] Sedláčková, N.; Ponechalová, V.; Ujházy, E.; Dubovický, M.; Mach, M. Anxiolytic Activity
of Pyridoindole Derivatives SMe1EC2 and SMe1M2: Behavioral Analysis Using Rat Model.
Interdiscip. Toxicol. 2011, 4, 211–215.
14] Singh Sidhu, J.; Singla, R.; Jaitak, V. Indole Derivatives as Anticancer Agents for Breast Cancer
Therapy: A Review. Anti-Cancer Agents Med. Chem. (Formerly Curr. Medi. Chem.-Anti-Cancer
Agents) 2016, 16, 160–173. DOI: 10.2174/1871520615666150520144217.
[
[
15] Fischer, E.; Jourdan, F. Ueber Die Hydrazine Der Brenztraubensäure. Eur. J. Inorg. Chem. 1883,
16, 2241–2245. DOI: 10.1002/cber.188301602141.
16] Noey, E.-L.; Yang, Z.; Li, Y.; Yu, H.; Richey, R.-N.; Merritt, J.-M.; Kjell, D.-P.; Houk, K.-N.
Origins of Regioselectivity in the Fischer Indole Synthesis of a Selective Androgen Receptor
Modulator. J. Org. Chem. 2017, 15, 212–219. DOI: 10.1021/acs.joc.7b00878.
[
17] Kawashima, Y.; Sato, M.; Hatada, Y.; Okuyama, S.; Amanuma, F.; Nakashima, Y.; Sota, K.;
Moriguchi, I. Furo [3, 2-b] indole Derivatives. III.: Structure-Activity Studies of 4,
6
-Disubstituted N-(3-Piperidinopropyl) furo [3, 2-b] indole-2-carboxamide Derivatives for
Analgesic and Antiinflammatory Activities. Chem. Pharm. Bull. 1986, 34, 3267–3272. DOI:
1
0.1248/cpb.34.3267.
[
[
[
[
[
18] Chavan, R.-S.; More, H.-N.; Bhosale, A.-V. Synthesis, Characterization and Evaluation of
Analgesic and Anti-Inflammatory Activities of Some Novel Indoles. Trop. J. Pharm. Res.
2
011, 10, 463–473. DOI: 10.4314/tjpr.v10i4.12.
19] Mandour, A.; El-Sawy, E.; Shaker, K.; Mustafa, M. Synthesis, Anti-Inflammatory, Analgesic and
Anticonvulsant Activities of 1, 8-dihydro-1-ary1–8-alkyl pyrazolo (3, 4-b) Indoles. Acta Pharm.
2
010, 60, 73–88. DOI: 10.2478/v10007-010-0009-8.
20] Rádl, S.; Hezký, P.; Urbánková, J.; Váchal, P.; Krejčí, I. Synthesis and Analgesic Activity of
Some 1-Benzofurans, 1-Benzothiophenes and Indoles. Collect. Czech. Chem. Commun. 2000,
65, 280–296. DOI: 10.1135/cccc20000280.
21] Aghaei, P.; Mashayekhi, V.; Tehrani, K. H. M. E.; Kobarfard, F.; Faizi, M. Analgesic Activity of
Novel Anti-Platelet Indole-Based Hydrazones; Data Reveals New Clues to the Mechanism of
Action of the Studied Analogues. Res. Pharm. Sci. 2012, 7, 25.
22] Kale, M.; Narute, A.; Kalyankar, T. Synthesis and Pharmacological Studies of Novel
3
-Substituted Indole Derivatives as Potential Anti-Inflammatory and Analgesic Agents. Clin.
Anti-Inflammatory Anti-Allergy Drugs 2014, 1, 39–44. DOI: 10.2174/221270380166613
209232632.
1
[
23] Siddiqui, N.; Andalip, S.-B.; Ali, R.; Afzal, O.; Akhtar, M.-J.; Azad, B.; Kumar, R. Antidepressant
Potential of Nitrogen-Containing Heterocyclic Moieties: An Updated Review. J. Pharm.
BioAllied Sci. 2011, 3, 194. DOI: 10.4103/0975-7406.80765.

SYNTHETIC COMMUNICATIONS®
9
[
[
[
[
24] Patil, P.-O.; Bari, S.-B. Synthesis, Characterization and Screening for Antidepressant and
Anticonvulsant Activity of 4, 5-Dihydropyrazole Bearing Indole Derivatives. Arabian J. Chem.
2
016, 9, 588–595. DOI: 10.1016/j.arabjc.2013.08.027.
25] Saini, T.; Kumar, S.; Narasimhan, B. Central Nervous System Activities of Indole Derivatives:
An Overview. Cent. Nerv. Syst. Agents Med. Chem. (Formerly Curr. Med. Chem.-Central
Nervous Syst. Agents) 2016, 16, 19–28. DOI: 10.2174/1871524915666150608103224.
26] Tehrani, K. H. M. E.; Zadeh, M.-E.; Mashayekhi, V.; Hashemi, M.; Kobarfard, F.; Gharebaghi,
F.; Mohebbi, S. Synthesis, Antiplatelet Activity and Cytotoxicity Assessment of Indole-Based
Hydrazone Derivatives. Iran. J. Pharm. Res. 2015, 14, 1077.
27] Mirfazli, S. S.; Kobarfard, F.; Firoozpour, L.; Asadipour, A.; Esfahanizadeh, M.; Tabib, K.;
Shafiee, A.; Foroumadi, A. N-Substituted Indole Carbohydrazide Derivatives: Synthesis and
Evaluation of their Antiplatelet Aggregation Activity. Daru. J. Pharm. Sci. 2014, 22, 65. DOI:
1
0.1186/s40199-014-0065-6.
[
28] Kalhor, N.; Mardani, M.; Abdollahzadeh, S.; Vakof, M.; Zadeh, M.-E.; Tehrani, K. H. M. E.;
Kobarfard, F.; Mohebbi, S. Novel N‐Substituted ((1H‐indol‐3‐yl) methylene) Benzohydrazides
and ((1H‐indol‐3‐yl) methylene)‐2‐Phenylhydrazines: Synthesis and Antiplatelet Aggregation
Activity. Bull. Korean Chem. Soc. 2015, 36, 2632–2639. DOI: 10.1002/bkcs.10531.
[
29] Mashayekhi, V.; Tehrani, K. H. M. E.; Amidi, S.; Kobarfard, F. Synthesis of Novel Indole
Hydrazone Derivatives and Evaluation of Their Antiplatelet Aggregation Activity. Chem.
Pharm. Bull. 2013, 61, 144–150. DOI: 10.1248/cpb.c12-00597.
[
30] Kreighbaum, W.-E.; Matier, W.-L.; Dennis, R.-D.; Minielli, J.-L.; Deitchman, D.; Perhach, J.-L.
Jr; Comer, W.-T. Antihypertensive Indole Derivatives of Phenoxypropanolamines with. Beta-
adrenergic receptor antagonist and Vasodilating Activity. J. Med. Chem. 1980, 23(3),
2
85–289. DOI: 10.1021/jm00177a015.
[
31] Borgati, T. F.; Boaventura, M. A. D. Effects of Indole Amides on Lettuce and Onion
Germination and Growth. Z. Nat. C. 2011, 66, 485–490. DOI: 10.5560/znc.2011.66c0485.
32] Cardellina, J.-H.; Nigh, D.; Van Wagenen, B.-C. Plant Growth Regulatory Indoles from the
Sponges Dysidea etheria and Ulosa ruetzleri. J. Nat. Prod. 1986, 49, 1065–1067. DOI:
[
1
0.1021/np50048a015.
[
[
[
[
[
33] Ishida, Y.; Akamura, A.; Mitani, Y.; Suzuki, M.; Soeno, K.; Asami, T.; Shimada, Y. Comparison
of Indole Derivatives as Potential Intermediates of Auxin Biosynthesis in Arabidopsis. Plant
Biotechnol. 2013, 30, 185–190. DOI: 10.5511/plantbiotechnology.13.0128c.
34] Ummadi, N.; Gundala, S.; Padmavathi, V.; Padmaja, A. Synthesis and Antioxidant Activity of
a New Class of Pyrazolyl Indoles, Thiazolyl Pyrazolyl Indoles. Med. Chem. Res. 2017, 26,
1
574–1584. DOI: 10.1007/s00044-017-1827-8.
35] El-Mekabaty, A.; Hassan A. E., Mosbah, A. Synthesis of Some New Fused Pyrazole Derivatives
Bearing Indole Moiety as Antioxidant Agents. J. Heterocycl. Chem. 2013, 53, 894–900.
DOI: 10.1002/jhet.2218.
36] Ekhlass, N.; Yaser, A.; Afaf, M. E.; Rezek, R. A. Synthesis and Antiproliferative Activity of
1
-(4-(1H-Indol-3-Yl)-6-(4-Methoxyphenyl)Pyrimidin-2-yl)Hydrazine and Its Pyrazolo
Pyrimidine Derivatives. Med. Chem. 2016, 6, 224–233. DOI: 10.4172/2161-0444.1000350.
37] Sidhu, J.; Singla, R.; Mayank, Jaitak, V. Indole Derivatives as Anticancer Agents for Breast
Cancer Therapy: A Review. Adv. Anticancer Agents Med. Chem. 2015, 16, 160–173.
DOI: 10.2174/1871520615666150520144217.
[
38] Gokce, U.; Gultaz, C. Synthesis and Evaluation of Functionalized Indoles as Antimycobacterial
and Anticancer Agents. Mol. Diver. 2012, 16, 525–539. DOI: 10.1007/s11030-012-9385-y.
39] Narsidas, J.-P.; Hitesh, A.-B.; Bhavesh, R. P.; Navin, P.-T. A Highly Efficient, Rapid One-Pot
Synthesis of Some New Heteroarylpyrano[2,3-c]Pyrazoles in Ionic Liquid Under Microwave-
Irradiation. RSC Adv. 2013, 3, 8064–8072. DOI: 10.1039/c3ra00068k.
[