Design, synthesis and anti-mycobacterial activity of 1,2,3,5- tetrasubstituted pyrrolyl-N-acetic acid derivatives

Article abstract of DOI:10.1016/j.ejmech.2014.06.075

A novel synthesis of highly substituted pyrrole-N-acetic derivatives is described through the coupling of 1,4-diketones with amino acids following Paal-Knorr's approach. These pyrrole-N-acetic acid derivatives are found to exhibit potent anti-mycobacterial activity against Mycobacterium smegmatis and Mycobacterium tuberculosis strain H37Rv. In particular, 5n, 5q & 5r are found to display excellent anti-mycobacterial activity against M. tuberculosis strain H37Rv with MIC values in the range of 2.97 μM. Conversely, these compounds showed low cytotoxicity (selectivity index: >16.83) against HEK-293T cell line.

Full text of DOI:10.1016/j.ejmech.2014.06.075

Accepted Manuscript
Design,synthesis and anti-mycobacterial activity of 1,2,3,5-tetrasubstituted pyrrolyl-N-
acetic acid derivatives
P. Lakshmi Reddy, M. Lakshmi Devi, S. Satyanarayana, Ashita Singh, T. Veera
Reddy, J. Padma Sridevi, G. Raja Sekhar, P. Yogeeswari, D. Sriram, U.S.N. Murty,
Ramesh Ummanni, B.V. Subba Reddy, R. Narender
PII:
S0223-5234(14)00604-7
10.1016/j.ejmech.2014.06.075
EJMECH 7118
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 27 March 2014
Revised Date: 27 June 2014
Accepted Date: 30 June 2014
Please cite this article as: P. Lakshmi Reddy, M. Lakshmi Devi, S. Satyanarayana, A. Singh, T. Veera
Reddy, J. Padma Sridevi, G. Raja Sekhar, P. Yogeeswari, D. Sriram, U.S.N. Murty, R. Ummanni, B.V.
Subba Reddy, R. Narender, Design,synthesis and anti-mycobacterial activity of 1,2,3,5-tetrasubstituted
pyrrolyl-N-acetic acid derivatives, European Journal of Medicinal Chemistry (2014), doi: 10.1016/
j.ejmech.2014.06.075.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Research Highlights
•
•
•
•
•
A novel tetrasubstituted-1H-pyrrol-1-yl-N-acetic acid derivatives were
prepared.
Products were screened against M. tuberculosis H37Rv and
Mycobacterium smegmatis.
The cyctotoxicity of TB active compounds were evaluated against HEK-
2
93Tcell line.
5n, 5q & 5r showed significant anti-TB activity against M. tuberculosis
H37Rv.
5d, 5g, 5i & 5j exhibited moderate activity against Mycobacterium
smegmatis.

ACCEPTED MANUSCRIPT
Graphical abstract
Design, synthesis and anti-mycobacterial activity of 1,2,3,5-tetrasubstituted
pyrrolyl-N-acetic acid derivatives.
1

ACCEPTED MANUSCRIPT
Design,synthesis and anti-mycobacterial activity of 1,2,3,5-tetrasubstituted
pyrrolyl-N-acetic acid derivatives.
a
c
a
b
P. Lakshmi Reddy, M. Lakshmi Devi, S. Satyanarayana, Ashita Singh, T.
c
d
f
d
d
Veera Reddy, J. Padma Sridevi, G. Raja Sekhar, P. Yogeeswari, D. Sriram,
f
b
e
a
U.S.N.Murty, Ramesh Ummanni, * B. V. Subba Reddy,* R. Narender,*
a
Crop Protection Chemicals, Indian Institute of Chemical Technology, Tarnaka,
Hyderabad -500 007, India.
b
Chemical Biology, Indian Institute of Chemical Technology, Tarnaka,
Hyderabad -500 007, India.
c
Department of Chemistry, Vikrama Simhapuri University, Nellore- 524001.
d
Department of Pharmacy, Birla Institute of Technology & Science-Pilani,
Hyderabad Campus.
e
Natural Product Chemistry, Indian Institute of Chemical Technology, Tarnaka,
Hyderabad -500 007, India.
f
Biology Division Indian Institute of Chemical Technology, Tarnaka,
Hyderabad -500 007, India.
CORRESPONDING AUTHOR FOOTNOTE
Email: ravindra@iict.res.in Fax: (+91) 40-27193382
2

ACCEPTED MANUSCRIPT
ABSTRACT
A novel synthesis of highly substituted pyrrole-N-acetic derivatives is
described through the coupling of 1,4-diketones with amino acids following
Paal-Knorr’s approach. These pyrrole-N-acetic acid derivatives are found to
exhibit potent anti-mycobacterial activity against Mycobacterium smegmatis
and Mycobacterium tuberculosis strain H37Rv. In particular, 5n, 5q & 5r are
found to display excellent anti-mycobacterial activity against M. tuberculosis
strain H37Rv with MIC values in the range of 2.97 ꢀM. Conversely, these
compounds showed low cytotoxicity (selectivity index: >16.83) against HEK-
2
93T cell line.
Keywords: Stetter reaction; Paal-Knorr pyrrole synthesis; Anti-mycobacterial
activity
3

ACCEPTED MANUSCRIPT
1
. Introduction
Tuberculosis (TB) is a dreadful disease with high morbidity caused by
infection with Mycobacterium tuberculosis. The World Health Organization
WHO) estimates 11.4 million people worldwide are infected with both
Mycobacterium tuberculosis (Mtb) and HIV. Currently, there are approximately
million new infections and 3 million deaths attributed to M. tuberculosis
(
8
annually [1-3]. To date, several anti-tubercular agents in different combinations
are in clinical application for the treatment. However, patients often develop
resistance to commonly used regimen. The expansion of multidrug-resistant TB
(MDR-TB) and the emergence of drug-resistant TB (XDR-TB) cause new
tackle for the prevention, cure and manage of this lethal disease [4-5].
Therefore, the development of new drugs with enhanced activity against MDR-
TB and XDR-TB is highly appreciated for the prevention of disease.
Pyrrole has a long history since from its discovery as it presents in many
naturally occurring chlorophyll, vitamine-B12, and bilirubine. Many of the
pyrrole derivatives possess a wide range of biological activities such as anti-
mycobacterial [6]. anti-bacterial, anti-inflammatory, anti-oxidant, anti-tumor,
CNS depressive, HIV inhibiting and anti-fungal behavior [7]. The
Mycobacterial tuberculosis activity of pyrrole derivative BM212 was first
reported by Deidda et al in 1998 [8]. Later on, several analogues of BM212
have been prepared by Biava and co-workers [9]. In particular, substituted
4

ACCEPTED MANUSCRIPT
pyrrole derivatives (LL-3858) are known to exhibit promising MTB activity
(
Fig. 1). Currently LL-3858 is in phase-II clinical trials in India for the
treatment of TB. Thus, 1,2,3,5-tetrasubstituted pyrrole derivatives are very
important for drug discovery.
In addition to pyrrole pharmacopore, benzothiazole and thiadiazole derivatives
(
Fig. 1) are also an important class of heterocyclic compounds, which display a
broad spectrum of biological activities such as anti-mycobacterial, antibacterial,
antifungal, analgesic, anti-inflammatory, antioxidant and antitumor activity [10-
1
1]. Based on the pharmcological importance of pyrrole, benzothiazole and
thiadiazole derivatives in medicinal chemistry, we report the design, synthesis
and anti-mycobacterial activity of novel tetrasubstituted pyrrolyl-N-acetic acid
and acetamide derivatives (Fig. 2). Preliminary analysis of the structure-activity
relationship indicates that the presence of benzothiazole, thiadiazole, pyridine,
benzyl nucleus and the position of the substituent on pyrrole ring plays a key
role in biological activity.
Fig. 1
Fig. 2
2
. Results and Discussion
2
.1 Synthesis
5

ACCEPTED MANUSCRIPT
As a part of our research program on biologically active heterocycles [12].
we herein report an efficient method for the synthesis of tetrasubstituted
pyrrolyl-N-acetic acid and acetamide scaffolds. The starting 1,4-diketones were
prepared through the hydroacylation of α,β-unsaturated ketones (1 mmol) with
aromatic or heterocyclic aldehydes (1.2 mmol) in ethanol using 20 mol % of
bis-thiazolium salt (0.2 mmol) in the presence of triethyl amine (1 mmol). The
reaction proceeded smoothly under reflux conditions to afford the
corresponding 1,4-diketones (Scheme 1) [13]. These 1,4-diketones were then
successfully condensed with amino acids to produce the pyrrole derivatives
under Paal-Knorr conditions [14-17]. Accordingly, treatment of 1,4-diketone
(
1) with amino acid (2) in acetic acid under reflux conditions gave the 1,2,3,5-
tetrasubstituted-1H-pyrrol-1-yl acetic acid derivatives 4a-4k in good yields.
This method works well not only with glycine but also with other amino acids
such as valine and leucine and the results are presented in Table 1. Inspired by
their anti-mycobacterial activity, we next attempted the coupling of pyrrolyl-N-
acetic acids with heteroaryl amines. Accordingly, a variety of heteroaryl amines
such as benzothiazole, 5-ethyl-1,3,4-thiadiazole, tryptamine, and 2-
aminopyridine were successfully coupled with pyrrolyl-N-acetic acids under
amide coupling conditions [18] to produce the corresponding 1,2,3,5-
tetrasubstituted-1H-pyrrol-1-yl-N-acetamide derivatives 5a, 5b, 5d-o, 5q-t in
good yields. Similarly, benzyl amine also coupled with pyrrolyl-N-acetic acid to
6

ACCEPTED MANUSCRIPT
produce the corresponding benzamide derivatives 5c and 5p and the results are
presented in Table 2
Scheme 1
Table 1
Table 2
2
.2 Biology
The anti-mycobacterial activity of the 1,2,3,5-tetrasubstituted pyrrolyl-N-
acetamide derivatives 5a-5r was evaluated against Mycobacterium smegmatis,
which is a fast growing non-pathogenic strain to assess the activity of the
compounds in primary screening. It is known in literature that M. smegmatis
based screens shows 100% specificity and 78% sensitivity in comparison to
MDR Mycobacterium tuberculosis [19-22] The screening results of compounds
5
a-5r (Table 3) reveal that all the tested compounds showed moderate to good
activity against M.smegmatis. For test compounds, the GI is varying largely
5
0
against M.smegmatis, which is a surrogate model system for identifying new
anti-tubercular agents. To determine their exact anti-tubercular potential, all the
compounds were further screened against M.tuberculosis (H37Rv).
All newly synthesized tetrasubstituted pyrrole derivatives (4a-4k & 5a-5r) were
screened in vitro anti-mycobacterial activity against M.tuberculosis H37Rv
7

ACCEPTED MANUSCRIPT
(ATCC27294) by agar dilution method [23]. The MIC is defined as the
minimum concentration of the compound, which is required to completely
inhibit the bacterial growth. The MIC values (µg/mL) of all the compounds (4a-
4
k & 5a-5r) were measured with respect to five standard anti-tubercular drugs
at pH 7.4 and the screening results are presented in Table 3 & 4. All new
compounds 4a-4k & 5a-5r were screened for in vitro activity against MTB with
MIC values ranging from 2.97 to 129.87 µM. Among them, sixteen
tetrasubstituted pyrrole derivatives 4a, 4c, 4g and 5a, 5c, 5e, 5f, 5g, 5h, 5j, 5k,
5
m, 5n, 5o, 5q, 5r displayed the MIC values below 24.80 µm. Remarkably,
three of them 5n, 5q and 5r inhibited the MTB with MIC value of 3.10 µM,
another seven compounds 4c, 4g, 5c, 5e, 5f, 5h, and 5m inhibited the MTB with
MIC value of 7.95 µM. When compared to first-line TB drug ethambutol (MIC
2
7.50 µM), ten of these compounds 4c, 4g, 5c, 5e, 5f, 5h, 5m, 5n, 5q and 5r
were found to be more potent, albeit, they were less effective than other TB
drugs including isoniazid (5.25 µM) and rifampicin (0.29 µM).
The structure reactivity relationship of tested compounds with respect to
their anti-tubercular activity reveals that tetrasubstituted pyrrole derivatives 5n,
5
q and 5r are highly active due to the presence of naphthalene and two
heteroaryl moieties like furan and benzothiazole or thiadiazole. However, the
molecules bearing furan and benzothiazole or thiadiazole are not effective (5a,
5
b, 5i and 5j) without the naphthalene ring. Similarly, the molecules with
8

ACCEPTED MANUSCRIPT
benzothiazole alone are not effective (5f, 5g, 5k and 5l) without furan and
naphthalene rings. Furthermore, the molecule with furanyl and 2-naphthyl
moieties without heteroaryl ring is also not effective (5p). Conversely, the
molecule with all three core groups like furan, naphthalene and thiadiazole is
also not active. The above study indicates that the position of the substituent on
pyrrole ring also plays a crucial role in the observed activity. Next we tested the
in vitro cytotoxicity of all newly synthesized compounds by 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) against
HEK-293Tcell line at 50 µg/mL concentration [24]. The percentage of
cytotoxicity at 50 ꢀM of test compound is provided in Table 5. The compounds
which exhibits selectivity index (SI) [25] values greater than 25 in HEK-
2
3
93Tcells are considered as nontoxic. Compounds 5n, 5q and 5r showed
8.32%, 68.83% and 59.68% inhibition at 50 µM/mL with selectivity index of
>
16. Compounds 5b, 5g and 5k were less cytotoxic at 50 µM/mL with
favorable selectivity index. These results indicate that compounds 5n, 5q, and
r display high activity against M. tuberculosis (2.97, 3.10 µM) and low
cytotoxicity against HEK-293Tcell line.
Table 3
5
Table 4
Table 5
9

ACCEPTED MANUSCRIPT
3
. Conclusion
In summary, we have developed a simple method for the synthesis of 2,3,4-
tetraubstituted-1H-pyrrol-1-ylacetic acid derivatives by means of Paal-Knorr
approach. The condensation of 1,4-diketone with an excess of amino acid in
acetic acid under reflux conditions provides a novel class of 1,2,3,5-
tetrasubstituted-1H-pyrrol-1-yl-N-acetic acid derivatives. This method also
describes the synthesis of 1,2,3,5-tetrasubstituted-1H-pyrrol-1-yl acetamide
derivatives. Among the tested compounds, 5n, 5q & 5r displayed an excellent
anti-mycobacterial activity against M. tuberculosis H37Rv using MABA assay,
whereas compounds 4c, 4g, 5c, 5e, 5f, 5h, and 5m showed moderate anti-
mycobacterial activity. These pyrrole derivatives showed an interesting anti-
mycobacterial activity laying the foundation for developing new lead molecules,
which may be useful for the drug discovery.
4
4
. Experimental protocols
.1 Synthesis
All chemicals used possess a purity of >95%. Yield refers to pure products
after purification and are unoptimized. Melting points were determined in open
capillaries on Gallenkamp apparatus and are uncorrected. IR spectra were
1
recorded on a Buck Scientific IR M-500 spectrophotometer in KBr pellets, H
13
and C NMR spectra for analytical purpose were recorded in CDCl DMSO-d
3
,
6
1
0

ACCEPTED MANUSCRIPT
on a Bruker instrument at 300 MHz and 75 MHz, respectively; chemical shifts
are expressed in δ-scale downfield from TMS as an internal standard. Silica gel
6
0 (230–400 mesh) was used for the column chromatography. TLC plates
Silica Gel 60 F254) were used for thin-layer chromatography (TLC).
.1. General procedure for the preparation of 1,2,3,5-tetrasubstituted
(
4
pyrrolyl-N-acetic acid derivatives.
Following the Paal-Knorr conditions, to a solution of diketone (1 g) in acetic
acid (10 mL) was added amino acid (2 eq). The resulting mixture was heated in
o
an oil bath at 120 C. After completion, the mixture was cooled to room
temperature and concentrated in vacuo. The residue was dissolved in equal
amount of ethyl acetate and water. The combined organic layers were dried over
Na SO and concentrated in vacuo. The crude material was purified by column
2
4
chromatography
.1.1 (Table 1): 2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1-yl)acetic acid
4a).
White solid, mp: 143-145 °C; Yield: 95%; H NMR (300 MHz, CDCl ): δ 7.48-
.
4
(
1
3
7
.33 (m, 5H, Ar-H), 7.28 (t, J = 6.7 Hz, 3H, Ar-H), 7.22 (d, J = 8.8 Hz, 2H, Ar-
H ), 7.15 (t, J = 6.7 Hz, 1H, Furan-H), 6.40 (s, 1H, Pyrrole- H), 6.38 (d, J = 3.2
1
3
Hz, 1H, Furan-H), 6.25 (d, J = 3.2 Hz, 1H, Furan-H) 4.63 (s, 2H, CH2); C
NMR (75 MHz, CDCl ): δ 47.2, 109.8, 111.1, 111.4, 121.3, 126.1, 126.4, 127.8,
3
1
1

ACCEPTED MANUSCRIPT
1
27.9, 128.1, 128.7, 129.0, 132.2, 135.4, 136.8, 142.6, 145.6, 175.4; IR (KBr):
-1
+
υ 760, 1069, 1239, 1483, 1728, 2939, 3069 cm ; ESI-MS: m/z: 366 [M+Na] ;
+
HRMS (ESI) calcd for C H NO Na, 366.1106 [M+Na] , found: 366.1103.
2
2
17
3
4
.1.2
(Table
1):
2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1yl)-3-
methylbutan oic acid (4b).
1
White solid, mp: 121-123 °C; Yield: 69%; H NMR (300 MHz, CDCl ): δ 7.56
3
(
t, J=6.7 Hz, 1H, Ar-H) 7.49-7.37(m, 4H, Ar-H), 7.30-7.19 (m, 5H, Ar-H), 7.17
d, J = 3.0 Hz, 1H, Furan-H), 6.46 (s, 1H Pyrrole-H), 6.42 (t, J = 3.1 Hz, 1H,
(
Furan-H), 6.38 (d, J = 3.1 Hz, 1H, Furan-H), 4.45 (d, J = 10.5 Hz, 1H, CH),
.05-1.92 (m, 1H, CH), 0.88 (d, J = 6.2 Hz, 3H, CH ), 0.50 (d, J = 6.6 Hz, 3H,
2
3
1
3
CH ); C NMR (75MHz, CDCl ): δ 18.6, 21.8, 64.5, 109.0, 111.3, 113.2,
3
3
1
19.4, 125.9, 127.3, 127.6, 127.9, 128.1, 128.5, 129.8, 132.9, 135.4, 138.3,
-1
1
42.6, 145.1, 176.4; IR (KBr): υ 761, 852, 1232, 1510, 1708, 2843, 3026 cm ;
+.
ESI-MS: m/z: 386 [M+H]
4
.1.3 (Table 1): 2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1yl)-3-methyl pent
anoic acid (4c).
1
Brown solid, m.p: 112-114 °C; Yield: 61%; H NMR (300 MHz, CDCl ): δ 7.50
3
(
t, J = 7.5 Hz, 3H, Ar-H), 7.42 -7.34 (m, 2H, Ar-H), 7.29 -7.17 (m, 5H, Ar-H),
.13 (d, J=6.7 Hz, 1H, Furan-H), 6.42 (t, J = 3.0 Hz, 1H, Furan-H), 6.39 (s, 1H,
Pyrrole- H), 6.29 (d, J = 3.0 Hz, 1H, Furan-H), 4.91 (dd, J = 4.5, 11.3 Hz, 1H,
7
1
2

ACCEPTED MANUSCRIPT
CH), 1.61-1.45 (m, 2H, CH ), 0.92-0.81 (m, 1H, CH), 0.61 (d, J = 6.7 Hz, 3H),
2
1
3
0
5
1
3
.48 (d, J = 6.0 Hz, 3H); C NMR (75MHz, CDCl ): δ 20.9, 22.8, 24.0, 38.9,
3
7.2, 109.4, 111.5, 112.1, 125.9, 127.5, 127.9, 128.1, 128.6, 128.6, 129.4,
32.9, 137.8, 142.2, 174.7; IR (KBr): υ 759, 1033, 1248, 1511, 1710, 2955,
-1
+
+
420 cm ; ESI-MS: m/z: 400 [M+H] , 422 [M+Na] .
4
.1.4 (Table 1): 2-(2-3di(furan-2-yl)-5-phenyl-1H-pyrrol-1-yl)acetic acid
(
4d).
1
Brown solid, m.p: 125-127 °C; Yield: 79%; H NMR (300 MHz, CDCl ): δ 7.49
3
(
d, J = 1.5 Hz, 1H, Furan-H), 7.42-7.32 (m, 5H, Ar-H), 7.31 (d, J = 1.5 Hz, 1H,
Furan-H), 6.55 (d, J = 3.7 Hz, 1H, Furan-H), 6.52 (s, 1H, Pyrrole-H), 6.48 (t, J
5.2 Hz, 1H, Furan-H), 6.29 (t, J = 5.2 Hz, 1H, Furan-H), 6.08 (d, J = 3.7 Hz,
=
1
3
1
1
1
1
H, Furan-H), 4.56 (s, 2H, CH ); C NMR (75 MHz, CDCl ): δ 47.0, 104.5,
2
3
07.8, 109.0, 109.1, 110.9, 111.1, 111.9, 123.2, 127.3, 127.9, 128.4, 128.6,
28.8, 128.9, 129.0, 136.8, 140.4, 142.8, 174.2; IR (KBr): υ 670, 836, 1017,
-1
+
238, 1486, 1724, 2972, 3059 cm ; ESI-MS: m/z: 334 [M+H] ; HRMS (ESI)
+
calcd for C H O N 334.1079 [M+H] , found: 334.1086.
20
16
4
4
.1.5
(Table
1):
2-(2-3-di(furan-2-yl)5-phenyl-1H-pyrrol-1yl)-3-
methylbutano ic acid (4e).
1
Brown solid, m.p: 110-112 °C; Yield: 75%; H NMR (300 MHz, CDCl ): δ
3
7
.54 (d, J = 6.3 Hz, 2H, Furon-H) 6.49-6.33 (m, 5H, Ar-H), 6.58 (d, J = 4.7 Hz,
1
3

ACCEPTED MANUSCRIPT
1
H, Furan-H), 6.57 (s, 1H, Pyrrole-H), 6.49 (t, J = 3.1 Hz, 1H, Furan-H), 6.31
(
t, J = 3.1 Hz, 1H, Furan-H), 5.88 (d, J = 3.1 Hz, 1H, Furan-H), 4.41 (s, 1H,
CH), 1.98-1.87 (m, 1H, CH), 0.85 (d, J = 6.2 Hz, 3H, CH ), 0.50 (d, J = 6.6 Hz,
3
1
3
3
1
1
H,CH ); C NMR (75MHz, CDCl ): δ 18.7, 21.7, 64.5, 104.0, 107.0, 111.0,
3
3
11.2, 113.4, 118.4, 118.6, 128.1, 128.6, 129.9, 132.6, 138.4, 140.3, 142.9,
-1
44.4, 149.9, 176.2; IR (KBr): υ 753, 865, 1246, 1615, 1721, 2867, 3015 cm ;
+
+
ESI-MS: m/z: 376 [M+H] , 398 [M+Na] .
4
1
.1.6 (Table 1): 2-(2-(furan-2-yl)-5-(naphthalene-1-yl)-3-phenyl-1H-pyrrol-
-yl)acetic acid (4f).
1
White solid, m.p: 138-140 °C; Yield: 85%; H NMR (300 MHz, CDCl ): δ 7.97
3
(
d, J = 8.3 Hz, 1H, Ar-H ), 7.81 (d, J = 9.0 Hz, 1H, Ar-H), 7.76 (t, J = 4.5 Hz,
H, Ar-H), 7.50 (d, J = 6.7 Hz, 2H, Ar-H), 7.46-7.30 (m, 7H, Ar-H), 7.25 (d, J
1.5 Hz, 1H, Furan-H), 6.39 (s, 1H, Pyrrole-H), 6.10 (dd, J = 1.5, J = 3.0 Hz,
1
=
13
1
H, Furan-H) 5.63 (d, J = 3.7 Hz, 1H, Furan-H), 4.87 (s, 2H, CH ); C NMR
2
(
75 MHz, CDCl ): δ 47.3, 110.3, 111.2, 111.4, 121.7, 126.1, 126.3, 126.5,
3
1
1
3
4
26.6, 126.8, 127.7, 127.8, 127.9, 128.0, 128.2, 128.4, 129.6, 132.6, 133.3,
35.5, 136.8, 142.7, 145.6, 174.6; IR (KBr): υ 709, 802, 1221, 1602, 1726,
-1
+
054 cm ; ESI-MS: m/z: 416 [M+Na] ; HRMS (ESI) calcd for C H O NNa
26
19
3
+
16.1262 [M+Na] , found: 416.1244.
1
4

ACCEPTED MANUSCRIPT
4
1
.1.7 (Table 1): 2-(2-(furan-2-yl)-3-(naphthalene-1-yl)-5-phenyl-1H-pyrrol-
-yl)acetic acid (4g).
1
White solid, m.p: 145-147 °C; Yield: 84%; H NMR (300 MHz, CDCl ): δ 7.89
3
(
s, 1H, Ar-H), 7.86 (d, J = 8.9 Hz, 1H, Ar-H), 7.85-7.81 (m, 2H, Ar-H), 7.55 (d,
J = 8.9 Hz, 1H, Furan-H), 7.50-7.47 (m, 3H, Ar-H), 7.31 (d, J = 7.9 Hz, 2H),
.24 (t, J = 7.9 Hz, 3H, Ar-H), 7.15 (t, J = 6.9 Hz, 1H, Ar-H), 6.50 (s, 1H,
Pyrrole-H), 6.37 (t, J = 2.9 Hz, 1H, Furan-H ), 6.27 (d, J = 2.9 Hz, 1H, Furan-
7
13
H), 4.70 (s, 2H, CH ); C NMR (75 MHz, CDCl ): δ 47.9, 109.1, 111.0, 112.4,
2
3
1
1
1
3
23.6, 123.7, 125.3, 125.5, 125.7, 126.4, 127.1, 127.7, 127.8, 127.9, 128.7,
28.9, 129.0, 133.6, 141.3, 146.1, 175.3; IR (KBr): υ 761, 864, 1247, 1449,
-1
503, 1602, 1725, 2926, 3056 cm ; HRMS (ESI) calcd for C H O N
26
20
3
+
94.1443 [M+H] , found: 394.1440.
4
.1.8 (Table 1): 2-(2,3,5-triphenyl-1H-pyrrol-1-yl)acetic acid (4h).
1
White solid, mp: 135-137 °C; Yield: 74%; H NMR (300 MHz, CDCl ): δ 7.39
3
(d, J = 7.7 Hz, 2H, Ar-H), 7.37 (t, J = 9.8 Hz, 1H, Ar-H), 7.34-7.26 (m, 7H, Ar-
H), 7.06 (t, J = 8.0 Hz, 4H, Ar-H), 6.99 (t, J = 6.9 Hz, 1H, Ar-H), 6.47 (s, 1H,
13
Pyrrole-H), 4.50 (s, 2H, CH ); C NMR (75MHz, CDCl ): δ 46.6, 109.5, 123.3,
2
3
1
1
25.3, 127.6, 128.0, 128.2, 128.6, 128.8, 129.0, 131.2, 132.2, 132.5, 132.7,
35.6, 135.7, 174.8; IR(KBr): υ 703, 777, 1008, 1223, 1346, 1478, 1722, 3054
-1
+
cm ; HRMS (ESI) calcd for C H O N 354.1494 [M+H] , found: 354.1503.
2
4
20
2
1
5

ACCEPTED MANUSCRIPT
4
.1.9 (Table 1): 2-(3,5diphenyl-2-p-tolyl-1H-pyrrol-1-yl)acetic acid (4i).
1
White solid, mp: 124-126 °C Yield: 86%; H NMR (300 MHz, CDCl ): δ 7.37-
3
7
.30, (m, 4H, Ar-H), 7.24 (t, J = 8.8 Hz, 6H, Ar-H), 7.19 (d, J = 6.9 Hz, 4H, Ar-
1
3
H) 6.50 (s, 1H, Pyrrole-H), 4.51 (s, 2H), 2.41 (s, 3H, CH ); C NMR (75MHz,
3
CDCl ): δ 21.2, 46.9, 109.3, 109.5, 123.8, 127.4, 128.6, 129.0, 129.3, 129.4,
3
1
29.5, 130.0, 130.9, 130.9, 133.0, 136.6, 136.9, 137.4, 139.9, 175.1; IR (KBr):
-1
+
υ 755, 824, 1223, 1601, 1706, 2822, 3028 cm ; ESI-MS: m/z: 390 [M+Na] .
.1.10 (Table 1): 2-(2-(4-bromophenyl)-3,5-diphenyl-1H-pyrrol-1-yl)acetic
acid (4j).
White solid, mp: 194-196 °C; Yield: 83%; H NMR (300 MHz, CDCl ): δ 7.49
4
1
3
(d, J = 8.3 Hz, 2H, Ar-H) 7.45-7.40 (m, 4H, Ar-H), 7.39-7.35 (m, 1H, Ar-H)
7
4
1
1
.20 (t, J = 4.1 Hz, 6H, Ar-H), 7.13-7.09 (m, 1H, Ar-H) 6.45 (s, 1H, Pyrrole-H),
13
.49 (s, 2H, CH ); C NMR (75MHz, CDCl ): δ 46.7, 108.8, 121.5, 122.4,
2
3
25.3, 127.1, 127.3, 128.1, 128.3, 128.6, 130.4, 131.5, 131.6, 132.3, 132.8,
-1
35.2, 135.4, 170.4; IR (KBr): υ 743, 842, 1234, 1591, 1721, 2923, 3034 cm ;
+
HRMS (ESI) calcd for C H O NNa 454.0414 [M+Na] , found: 454.0416.
2
4
18
2
4
.1.11 (Table 1): 2-(2-(4-chlorophenyl)-3,5-diphenyl-1H-pyrrol-1-yl)acetic
acid (4k).
1
6

ACCEPTED MANUSCRIPT
1
White solid, mp:143-145 °C; Yield: 90%; H NMR: (300 MHz, CDCl ): δ
3
7
.77-7.69 (m, 1H, Ar-H), 7.49 (d, J = 4.5 Hz, 1H, Ar-H), 7.44 (t, J = 8.3 Hz,
H, Ar-H), 7.39-7.31 (m, 5H, Ar-H), 7.19 (d, J = 6.2 Hz, 5H, Ar-H), 7.10 (t, J =
1
6
1
3
.2 Hz, 1H, Ar-H), 6.49 (s, 1H, Pyrrole-H), 4.43 (s, 2H, CH ); C NMR (75
2
MHz, CDCl +DMSO-d ): δ 46.7, 109.1, 122.8, 124.9, 125.7, 126.0, 126.3,
3
6
1
1
1
26.7, 127.0, 127.1, 127.4, 127.7, 128.4, 129.6, 130.6, 130.7, 131.8, 132.1,
32.7, 133.2, 135.2, 135.2, 170.6; IR (KBr): υ 699, 768, 1043, 1204, 1452,
-1
+
708, 3018 cm ; ESI-MS: m/z: 387 [M+] 389 [M+2H] .
4
.2. General procedure for the preparation of 1,2,3,5-tetrasubstituted
pyrrolyl-N-acetamide derivatives
Compound 4 (1 mmol) was dissolved in freshly dry dichloromethane under
nitrogen atmosphere. Then HOBt (1.1 mmol), EDC.HCl (1.1 mmol) were added
to the above solution. The resulting mixture was stirred for 5 min, and then
4
amine (R ) (1.2 mmol) was added slowly followed by N,N-
diisopropylethylamine (DIPEA) (1.2 mmol). The mixture was allowed to stir for
3
h at room temperature. The progress of the reaction was monitored by TLC.
After completion, the reaction mixture was quenched with water (10-15 mL)
and extracted with dichloromethane. The organic layer was collected and dried
over anhydrous Na SO . The solvent was removed under reduced pressure and
2
4
the resultant crude material was purified by column chromatography.
1
7

ACCEPTED MANUSCRIPT
4
.2.1 (Table 2): N-(benzo[d]thiazol-2yl)-2-(furan-2-yl)-3,5-diphenyl-1H-
pyrrol -1-yl)acetamide (5a).
White solid, m.p: 113-115 ºC; Yield: 78%; H NMR (300 MHz, CDCl ): δ 7.78
1
3
(d, J = 7.5 Hz, 1H, Ar-H) 7.53 (d, J = 8.3 Hz, 1H, Ar-H), 7.45-7.17 (m, 13H,
Ar-H, Furan-H), 6.52 (s, 1H, Pyrrole-H), 6.34 (t, J = 3.0 Hz, 1H, Furan-H ),
1
3
6
.28 (d, J = 3.0 Hz, 1H, Furan-H), 4.75 (s, 2H, CH ); C NMR (75 MHz,
2
CDCl ): δ 49.4, 110.9, 111.3, 112.0, 120.8, 121.4, 124.2, 126.4, 127.6, 127.9,
3
1
28.3, 128.9, 131.5, 132.0, 135.0, 137.1, 143.1, 144.9, 147.8, 157.4, 167.5; IR
-
1
(
[
[
KBr): υ 758, 1271, 1545, 1703, 2924, 3060, 3351 cm ; ESI-MS: m/z: 476
+
+
M+H] , 498 [M+Na] ; HRMS (ESI) calcd for C H N O NaS, 498.1252
29
21
3
2
+
M+Na] , found: 498.1258.
.2.2 (Table 2): N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2-(furan-2-yl)-3,5-
dipheny l-1H-pyrrol-1-yl)acetamide (5b).
4
1
White solid, m.p: 236-238 °C; Yield: 81%; H NMR (300 MHz, CDCl ) δ 8.03
3
(
d, J = 7.5 Hz, 1H, Ar-H),7.80 (d, J = 7.7 Hz, 1H, Ar-H), 7.75 (d, J = 3.0 Hz,
H, Ar-H), 7.56 (d, J = 6.7 Hz, 2H, Ar-H), 7.45-7.27 (m, 5H, Ar-H), 7.01 (d, J
3.3 Hz, 1H, Furan-H), 6.44 (s, 1H, Pyrrole-H), 5.99 (t, J = 3.0 Hz, 1H, Furan-
H), 5.65 (d, J = 3.0 Hz, 1H, Furan-H), 5.21. (s, 2H, CH ), 3.02 (qt, 2H, CH ),
1
=
2
2
1
3
1
1
.40 (t, J = 7.5 Hz, 3H, CH ); C NMR (75 MHz, CDCl ): δ 13.6, 22.5, 47.8,
3
3
08.6, 111.2, 111.7, 121.0, 125.3, 125.7, 126.7, 127.6, 128.1, 128.4, 128.6,
1
8

ACCEPTED MANUSCRIPT
1
1
31.8, 135.0, 136.4, 143.6, 144.6, 157.5. 165.6. 166.9; IR (KBr): υ 761, 1307,
-1
+
570, 1707, 2872, 3055 cm ; ESI-MS: m/z: 477 [M+Na] ; HRMS (ESI) calcd
+
for C H N O NaS, 477.1361 [M+Na] , found: 477.1369.
26
22
4
2
4
.2.3 (Table 2): N-benzyl-2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1-
yl)aceta mide (5c).
1
White solid, m.p: 178-180 °C; Yield: 80%; H NMR (300 MHz, CDCl ): δ
3
7
6
.43-7.34 (m, 6H, Ar-H),7.32-7.25 (m, 7H, Ar-H), 7.22-7.16 (m, 3H, Ar-H),
.51 (s, 1H, Pyrrole-H), 6.39 (dd, J = 1.8, 3.3 Hz, 1H, Furan-H), 6.25 (d, J = 3.0
Hz, 1H, Furan-H), 5.99-5.92. (m, 1H, Ar-H), 4.63 (s, 2H, CH ), 4.44 (d, J = 7.5
2
1
3
Hz, 2H, CH ); C NMR (75 MHz, CDCl ): δ 43.2, 49.3, 110.3, 111.1, 111.9,
2
3
1
1
1
20.2, 121.3, 125.1, 126.2, 127.2, 127.4, 127.5, 127.6, 128.0, 128.2, 128.5,
28.7, 131.6, 135.0, 136.9, 137.6, 142.9, 144.9, 168.7; IR (KBr): υ 759, 1248,
-1
+
557, 1661, 2924, 3064 cm ; ESI-MS: m/z: 433 [M+H] ; HRMS (ESI) calcd
+
for C H N O , 433.1916 [M+ H] , found: 433.1931.
2
9
25
2
2
4
2
.2.4 (Table 2): 2-(2-(furan-2-yl)-3,5-diphenyl-1H-pyrrol-1-yl)-N-(pyridin-
-yl)acetamide (5d).
1
White solid, m.p: 118-120 °C; Yield:74%; H NMR (300 MHz, CDCl ): δ 8.18
3
(d, J = 6.7 Hz, 2H, Pyridine-H), 7.66 (t, J = 7.5 Hz, 1H, Ar-H), 7.45 (d, J = 7.5
Hz, 3H, Ar-H), 7.38 (t, J = 7.5 Hz, 2H, Pyridine-H), 7.35-7.29 (m, 3H, Ar-H,
Furan-H), 7.25 (t, J = 6.7 Hz, 2H, Ar-H), 7.16 (t, J = 7.5 Hz, 1H, Ar-H), 7.00 (t,
1
9

ACCEPTED MANUSCRIPT
J = 6.0 Hz, 1H, Ar-H), 6.54 (s, 1H, Pyrrole-H), 6.35 (t, J = 3.7 Hz, 1H, Furan-
1
3
H), 6.29 (d, J = 3.7 Hz, 1H, Furan-H). 4.65 (s, 2H, CH ); C NMR (75 MHz,
2
CDCl ): δ 49.9, 110.6, 111.2, 112.0, 114.0, 120.2, 126.2, 127.7, 128.0, 128.2,
3
1
28.8, 128.9, 131.7, 135,1, 137.0, 138.3, 143.0, 145.0, 147.8, 150.5, 167.4; IR
-1
(
KBr): υ 778 , 1306, 1447, 1571, 1712, 2926, 3054 cm ; ESI-MS: m/z: 420
+
+
[
M+H] , HRMS (ESI) calcd for C H N O , 420.1712 [M+H] , found:
27
22
3
2
4
20.1707.
4
1
.2.5 (Table 2): N-(2-(1H-indol-3-yl)ethyl)-2-(2-(furan-2-yl)-3,5-diphenyl-
H-pyrrol-1-yl)acetamide (5e).
1
Orange solid, m.p: 105-107 °C; Yield: 88%; H NMR (300 MHz, CDCl ): δ
3
7
.77 (s, 1H, Indole-H), 7.48 (d, J = 7.5 Hz, 1H, Ar-H), 7.28 (t, J = 3.1 Hz, 6H,
Ar-H), 7.21 (d, J = 7.3 Hz, 2H, Ar-H), 7.15 (t, J = 8.1 Hz, 3H, Ar-H), 7.03 (t, J
=
7.9 Hz, 1H, Ar-H), 6.71 (d, J = 1.5 Hz, 1H, Ar-H), 6.41, (s, 1H, Pyrrole-H),
.29. (t, J = 1.7 Hz, 1H, Furan-H), 6.00 (d, J = 3.0 Hz, 1H, Furan-H), 5.60 (t, J
4.3 Hz, 1H, Furan-H). 4.42 (s, 2H, CH ), 3.51 (qt, 2H, CH ), 2.86 (t, J = 6.4
6
=
2
2
1
3
Hz, 2H, CH ); C NMR (75 MHz, CDCl ): δ 24.8, 38.8, 49.2, 109.8, 111.1,
2
3
1
1
11.2, 111.9, 112.0, 118.5, 119.3, 120.9, 122.2, 126.3, 126.8, 126.9, 127.3,
27.9, 128.4, 128.7, 128.7, 131.5, 135.1, 136.4, 136.7, 143.0, 144.6, 168.6; IR
-1
(
KBr): υ 698, 1228, 1526, 1663, 2925, 3025, 3296 cm ; ESI-MS: m/z: 486
2
0

ACCEPTED MANUSCRIPT
+
+
[
M+H] , 508 [M+Na] ; HRMS (ESI) calcd for C H N O Na, 508.2000
32
27
3
2
+
[
M+Na] , found: 508.1993.
.2.6 (Table 2): N-(benzo[d]thiazol-2yl)-2-(2,3,5-triphenyl-1H-pyrrol-1-yl)
ac etamide (5f).
White solid, m.p: 129-131 °C; Yield: 76%; H NMR (300 MHz, CDCl ): δ 7.76
4
1
3
(d J = 7.9 Hz, 1H, Ar-H), 7.49 (t, J = 7.9 Hz, 3H, Ar-H), 7.40-7.25 (m, 11H, Ar-
H), 7.18 (t, J = 7.1Hz, 2H, Ar-H), 7.14 (d, J = 7.5 Hz, 1H, Ar-H), 7.07 (t, J =
1
3
6
.7 Hz 1H, Ar-H), 6.57 (s, 1H, Pyrrole-H), 4.67 (s, 2H, CH ); C NMR (75
2
MHz, CDCl ): δ 48.7, 110.5, 120.6, 121.4, 124.2, 124.3, 125.6, 126.4, 127.7,
3
1
1
28.0, 128.1, 128.4, 128.9, 129.1, 131.9, 132.1, 132.2, 135.3, 135.7, 147.7,
-1
57.8, 157.9, 167.5; IR (KBr): υ 756, 1271, 1555, 1601, 1709, 2925, 3057 cm ;
+
+
ESI-MS: m/z: 486 [M+H] , 508 [M+Na] ; HRMS (ESI) calcd for C H N OS,
31
24
3
+
4
86.1640 [M+H] , found: 486.1655.
.2.7 (Table 2): N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2,3,5-triphenyl-1H-
4
pyrrol-1-yl)acetamide (5g).
White solid, m.p: 182-184 °C; Yield: 82%; H NMR (300 MHz, CDCl ): δ 7.50
1
3
(d, J = 6.9 Hz, 2H, Ar-H), 7.39 (t, J = 7.3 Hz, 1H, Ar-H), 7.30 (t, J = 6.6 Hz,
3
7
H, Ar-H ), 7.25 (d, J = 8.3 Hz, 1H, Ar-H), 7.21 (d, J = 7.5 Hz, 1H, Ar-H),
.17-7.08 (m, 6H, Ar-H ), 7.02 (t, J = 6.9 Hz, 1H, Ar-H), 6.52 (s, 1H, Pyrrole-
1
3
H), 4.86 (s, 2H, CH ), 2.99 (qt, 2H, CH ), 1.40 (t, J = 7.5 Hz, 3H, CH ); C
2
2
3
2
1

ACCEPTED MANUSCRIPT
NMR (75 MHz, CDCl ): δ 13.7, 22.6, 47.7, 108.8, 122.1, 125.2, 127.0, 127.4,
3
1
1
28.1, 128.3, 128.4, 128.7, 130.9, 132.0, 132.2, 132.4, 135.2, 135.6, 157.6,
-1
65,8, 167.4; IR (KBr): υ 754, 1303, 1560, 1717, 2922, 3050 cm ; ESI-MS:
+
+
m/z: 465 [M+H] ; HRMS (ESI) calcd for C H ON S, 465.17592 [M+H] ,
2
8
25
4
found: 465.17436.
.2.8 (Table
yl)acetamide (5h).
4
2):
N-(pyridin-2-yl)-2-(2,3,5-triphenyl-1H-pyrrol-1-
1
White solid, mp: 103-105 °C Yield: 75%; H NMR (300 MHz, CDCl ): δ 8.12
3
(t J=8.6Hz,1H, Ar-H), 7.68 (t, J = 7.3 Hz, 1H, Ar-H), 7.48 (d, J = 6.6 Hz, 1H,
Ar-H), 7.41 (t, J = 6.6 Hz, 1H, Ar-H), 7.37-7.26 (m, 9H, Ar-H), 7.15 (t, J = 8.6
Hz, 4H, Ar-H), 7.06 (d, J = 6.7 Hz, 1H, Ar-H), 7.01 (t, J = 7.3 Hz, 1H, Ar-H),
1
3
6
1
1
1
.57 (s, 1H, Pyrrole-H), 4.59 (s, 2H, CH ); C NMR (75 MHz, CDCl ): δ 48.7,
2
3
10.5, 120.6, 121.4, 124.2, 124.3, 125.6, 126.4, 127.7, 128.0, 128.1, 128.4,
28.8, 128.9, 129.1, 131.0, 131.9, 132.1, 132.2, 135.3, 135.7, 147.7, 157.8,
-1
67.5; IR (KBr): υ 755, 1191, 1303, 1561, 1716, 2934, 3050 cm . ESI-MS:
+
+
m/z: 430 [M+H] , 452[M+Na] ; HRMS (ESI) calcd for C H N O, 430.1919
2
9
24
3
+
[
M+H] , found: 430.1900.
4
.2.9 (Table 2): N-(benzo[d]thiazol-2-yl)-2-(2,3-di(furan-2-yl)-5-phenyl-1H-
pyrrol-1-yl)acetamide (5i).
2
2

ACCEPTED MANUSCRIPT
1
Brown solid, m.p: 112-114 °C; Yield: 79%, H NMR (300 MHz, CDCl ) δ 7.82
3
(
d, J = 7.5 Hz, 1H, Furan-H), 7.70 (d, J = 7.5 Hz, 1H, Furan-H), 7.50-7.28 (m,
H, Ar-H), 6.68 (s, 1H, Pyrrole-H), 6.62 (d, J = 3.7 Hz, 1H, Furan-H), 6.47 (t, J
3.0 Hz, 1H, Furan-H), 6.38 (t, J = 3.0 Hz, 1H, Furan-H), 6.20 (d, J = 3.0 Hz,
9
=
1
3
1
1
1
1
H, Furan-H), 4.76 (s 2H, CH ); C NMR (75 MHz, CDCl ): δ 49.3, 105.1,
2
3
09.0, 111.0, 111.3, 112.2, 118.2, 120.4, 120.9, 121.4, 124.2, 126.4, 126.6,
28.4, 128.9, 129.0, 131.2, 137.1, 140.8, 143.3, 144.2, 147.9, 149.3, 157.2,
-1
67.2; IR (KBr): υ 761, 1306, 1567, 1709, 2934, 3050 cm ; ESI-MS: m/z: 465
+
[
M+H] .
4
.2.10 (Table 2): N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2,3-di(furan-2-yl)-5-
phenyl -1H-pyrrol-1-yl)acetamide (5j).
Brown solid, mp: 117-119 °C Yield: 83%; H NMR (300 MHz, CDCl ): δ 7.47
1
3
(
d, J = 6.7 Hz, 1H, Furan-H), 7.37-7.26 (m, 5H, Ar-H), 6.77 (t, J = 3.5 Hz, 1H,
Furan-H) 6.58 (s, 1H, Pyrrole-H) 6.51 (d, J = 3.1 Hz, 1H, Furon-H), 6.28 (t, J =
.2 Hz, 2H, Furan-H), 6.05 (d, J= 3.0 Hz, 1H Furan-H), 4.92 (s, 2H, CH ), 3.00
2
2
13
(
qt, 2H, CH ), 1.39 (t, J = 7.5 Hz, 3H, CH ); C NMR (75 MHz, CDCl ): δ
2
3
3
1
1
1
3.6, 22.5, 48.5, 109.4, 110.9, 111.5, 122.8, 123.3, 125.3, 125.5, 125.7, 126.9,
27.4, 127.6, 127.9, 128.4, 128.7, 131.7, 131.8, 133.2, 133.6, 136.1, 142.5,
-1
45.2, 165.6, 167.2; IR (KBr): υ 702, 1214, 1338, 1603, 1718, 2926 cm ; ESI-
2
3

ACCEPTED MANUSCRIPT
MS: m/z: 445 [M+H] ; HRMS (ESI) calcd for C H N O S, 445.1328 [M+H] ,
+
+
24
21
4
3
found: 445.1329.
.2.11 (Table 2): N-(benzo[d]thiazol-2-yl)-2-(2-(4-bromophenyl)-3,5-
diphenyl-1H-pyrrol-1-yl) acetamide (5k).
4
1
White solid, m.p: 111-113 °C; Yield:80%, H NMR (300 MHz, CDCl ): δ 7.79
3
(
d, J = 5.2 Hz, 1H, Ar-H), 7.52 (d, J = 8.3 Hz, 1H, Ar-H) 7.45 (t, J = 8.3 Hz,
H, Ar-H), 7.36 (t, J = 6.7 Hz, 2H, Ar-H), 7.32-7.29 (m, 2H, Ar-H), 7.25-7.17
m, 7H, Ar-H), 7.12 (t, J = 4.5 Hz, 1H, Ar-H) 6.62 (s, 1H, Pyrrole-H), 4.65 (s,
4
(
1
3
2
1
1
2
H, CH ); C NMR (75 MHz, CDCl ): δ 48.7, 110.9, 120.6, 121.5, 122.8,
2
3
24.3, 125.9, 126.5, 127.8, 128.1, 128.2, 128.9, 129.0, 130.8, 131.9, 132.2,
32.6, 135.0, 136.2, 147.6, 157.7, 167.3; IR (KBr): υ 757, 1270, 1553, 1709,
-1
+
926, 3057 cm ; ESI-MS: m/z: 564 [M] , HRMS (ESI) calcd for
+
C H ON BrS, [M] , 564.07397 found:564.07579.
3
1
23
3
4
.2.12 (Table 2): N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2-(4-bromophenyl)-3,5-
diphenyl-1H-pyrrol-1-yl) acetamide (5l).
1
White solid, m.p: 226-228 °C; Yield: 74%; H NMR (300 MHz, CDCl ): δ 7.44
3
(
d, J = 7.9 Hz, 4H, Ar-H), 7.37 (t, J = 6.9 Hz, 2H, Ar-H), 7.29 (t, J = 6.9 Hz,
H, Ar-H), 7.22 (d, J = 7.9 Hz, 2H, Ar-H), 7.16 (d, J = 4.9 Hz, 4H, Ar-H), 7.07
t, J = 4.9 Hz, 1H, Ar-H), 6.44 (s, 1H, Pyrrole-H), 4.61 (s, 2H, CH ), 3.02 (qt,
1
(
2
1
3
2
H, CH ), 1.41 (t, J = 7.9 Hz, 3H, CH ); C NMR (75 MHz, CDCl ): δ 13.6,
2
3
3
2
4

ACCEPTED MANUSCRIPT
2
1
1
2.6, 47.7, 106.4, 109.0, 109.7, 119.7, 121.6, 122.6, 125.3, 127.1, 127.4, 128.2,
28.4, 128.6, 129.0, 130.6, 131.4, 131.7, 132.2, 132.9, 135.4, 135.6, 142.7,
-1
57.4, 165.7, 167.2; IR (KBr): υ 758, 1131, 1574, 1709, 2924, 3051 cm ; ESI-
+
MS: m/z: 545 [M+2H] ; HRMS (ESI) calcd for C H BrN OS, 545.0826
2
8
25
4
+
[
M+2H] , found: 545.07805.
4
.2.13 (Table 2): 2-(2-(4-bromophenyl)-3,5-diphenyl-1H-pyrrol-1-yl)-N-
(pyri din-2-yl)acetamide (5m).
1
White solid, m.p: 175-177 °C; Yield: 69%; H NMR (300 MHz, CDCl ): δ 8.15
3
(d, J = 4.1 Hz, 1H, Pyridine-H ), 8.05 (d, J = 8.1 Hz, 1H, Pyridine-H), 7.64 (t, J
=
8.3 Hz, 1H, Pyridine-H), 7.46 (d, J = 7.9 Hz, 3H, Ar-H), 7.39 (t, J = 6.9 Hz,
1
7
4
1
1
2
H, Ar-H), 7.31 (t, J = 7.1 Hz, 1H, Ar-H), 7.25-7.15 (m, 8H, Ar-H), 7.11 (t, J =
.9 Hz, 1H, Pyridine-H), 7.00 (t, J = 6.2 Hz, 1H, Ar-H), 6.59 (s, 1H, Pyrrole-H),
13
.58 (s, 2H, CH ); C NMR (75 MHz, CDCl ): δ 48.2, 108.7, 113.4, 119.6,
2
3
21.5, 122.3, 125.2, 127.0, 127.3, 128.1, 128.3, 128.5, 130.6, 131.5, 132.3,
32.9, 135.5, 138.2, 147.9, 151.1, 167.5; IR (KBr): υ 756, 1300, 1482, 1689,
-1
+
+
941, 3294 cm ; ESI-MS: m/z: 508 [M] , 510 [M+2H] ; HRMS (ESI) calcd for
C H BrN O 510.1908, found: 510.1203.
2
9
24
3
4
2
.2.14 (Table 2): N-(benzo[d]thiazol-2-yl)-2-(2-(furan-2-yl)-5-(naphthalen-
-yl)-3-phenyl-1H-pyrrol-1-yl)acetamide (5n).
2
5

ACCEPTED MANUSCRIPT
1
White solid, m.p:122-124 °C; Yield: 79%; H NMR (300 MHz, CDCl ): δ 7.90
3
(d J = 8.3 Hz, 1H, Ar-H), 7.88 (s, 1H, Ar-H), 7.85-7.79 (m, 3H, Ar-H), 7.72 (d,
J = 7.5 Hz, 1H, Ar-H), 7.55 (dd, J = 6.7, 8.3 Hz, 1H, Furan-H), 7.51-7.47 (m,
2
7
6
2
1
1
2
H, Ar-H), 7.45 (t, J = 3.0 Hz, 2H, Ar-H), 7.40 (d, J = 7.1 Hz, 2H, Ar-H), 7.37-
.30 (m, 3H, Ar-H), 7.24 (t, J = 6.7 Hz, 1H, Ar-H), 6.68 (s, 1H, Pyrrole-H),
.37 (t, J = 3.0 Hz, 1H, Furan-H), 6.33 (d, J = 3.0 Hz, 1H, Furan-H), 4.89 (s,
1
3
H, CH ); C NMR (75 MHz, CDCl ): δ 49.5, 111.4, 112.0, 120.9, 121.4,
2
3
21.6, 124.2, 126.4, 126.4, 126.5, 126.6, 127.6, 127.8, 127.9, 128.0, 128.3,
28.7, 132.7, 135.0, 143.1, 157.4, 167.4; IR (KBr): υ 758, 1259, 1576, 1710,
-1
+
935, 3051 cm ; ESI-MS: m/z: 548 [M+Na] . HRMS (ESI) calcd for
+
C H N O NaS, 548.1408 [M+Na] , found: 548.2970.
3
3
23
3
2
4
.2.15 (Table 2): N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(2-(furan-2-yl)-5-
(naphth alen-2-yl)-3-phenyl-1H-pyrrol-1-yl)acetamide (5o).
1
White solid, mp: 153-155 °C; Yield: 83%; H NMR (300 MHz, CDCl ): δ 7.93
3
(s, 1H, Ar-H), 7.89-7.74 (m, 3H, Ar-H), 7.59 (d, J = 8.3 Hz, 1H, Ar-H), 7.49-
7
.41 (m, 3H, Ar-H), 7.25 (t, J = 6.9 Hz, 4H, Ar-H), 7.14 (t, J = 6.6 Hz, 1 H, Ar-
H), 6.54 (s, 1H, Pyrrole-H), 6.42 (t, J = 3.0 Hz,1H, Furan-H), 6.35 (d, J = 3.2
Hz, 1H, Furan-H), 4.81 (s, 2H, CH ), 3.04 (qt, 2H, CH ), 1.42 (t, J = 7.5 Hz, 3H,
2
2
1
3
CH ); C NMR (75 MHz, CDCl ): δ 13.5, 22.5, 47.9, 109.2, 111.2, 111.8,
3
3
1
21.3, 125.4, 125.6, 125.8, 126.2, 126.4, 126.4, 126.7, 127.0, 127.4, 127.8,
2
6

ACCEPTED MANUSCRIPT
1
28.1, 129.0, 129.3, 132.0, 132.7, 135.0, 136.4, 143.7, 144.6, 166.9; IR (KBr):
-1
+
υ 756, 1215, 1340, 1605, 1720, 2926 cm ; ESI-MS: m/z: 505 [M+H] ; HRMS
+
(
ESI) calcd for C H N O S, 505.16927 [M+H] , found: 505.16940.
30
25
4
2
4
1
.2.16 (Table 2): N-benzyl-2-(2-(furan-2-yl)-5-(naphthalen-2-yl)-3-phenyl-
H-pyrrol-1-yl)acetamide (5p).
1
White solid, m.p: 147-149 °C; Yield: 74%; H NMR (300 MHz, CDCl ): δ 7.81
3
(
t, J = 8.3 Hz, 2H, Ar-H), 7.77 (s, 1H) 7.71 (d, J = 3.0 Hz, 1H, Ar-H), 7.48 (t, J
3.7 Hz, 3H, Ar-H), 7.38 (d, J = 1.5 Hz, 1H, Furan-H), 7.25-7.20 (m, 7H, Ar-H
, 7.19-7.12 (m, 2H, Ar-H ), 6.62 (s, 1H, Pyrrole-H ), 6.38 (dd, J = 2.2, 5.2 Hz,
H, Furan-H), 6.22 (d, J = 3.7 Hz, 1H, Furan-H), 6.06 (t, J = 6.0 Hz, 1H, Ar-H),
=
)
1
4
4
1
1
3
.70 (s, 2H, CH ), 4.45 (d, J = 6.0 Hz, 2H, CH ); C NMR (75 MHz, CDCl ): δ
2
2
3
3.3, 49.6, 110.8, 111.2, 112.0, 121.7, 126.3, 126.4, 126.5, 127.4, 127.6, 128.1,
28.3, 128.5, 129.0, 132.6, 133.2, 135.1, 136.9, 137.6, 143.0, 144.9, 168.7; IR
-1
+
(
KBr): υ 761, 1250, 1543, 1671, 2920, 3062 cm ; ESI-MS: m/z: 483 [M+H] .
4
5
.2.17 (Table 2): N-(benzo[d]thiazol-2-(2-(furan-2-yl)-3-(naphthalen-2-yl)-
-phenyl-1H-pyrrol-1-yl)acetamide (5q).
1
White solid, m.p: 119-121°C; Yield: 78%; H NMR (300 MHz, CDCl ): δ 7.77
3
(d, J = 7.5 Hz, 1H, Ar-H ), 7.55 (d, J = 7.5 Hz, 1H, Ar-H ), 7.45-7.34 (m, 11H,
Ar-H), 7.29 (d, J = 6.7 Hz, 2H, Ar-H ), 6.63 (s, 1H, Pyrrole-H), 6.58 (d, J = 3.0
Hz, 1H, Furan-H), 6.43 (t, J = 3.0 Hz, 1H, Ar-H), 6.31 (t, J = 3.0 Hz, 1H, Furan-
2
7

ACCEPTED MANUSCRIPT
1
3
H), 6.11 (d, J = 3.7 Hz, 1H, Furan-H), 4.71 (s, 2H, CH ); C NMR (75 MHz,
2
CDCl ): δ 50.2, 110.1, 111.2, 113.7, 120.9, 121.4, 124.2, 125.4, 125.6, 125.9,
3
1
1
2
26.2, 126.4, 127.5, 127.9, 128.1, 128.2, 128.9, 131.4, 132.3, 133.4, 133.7,
36.9, 142.0, 148.1, 157.3, 157.4, 167.8; IR (KBr): υ 758, 1270, 1546, 1708,
-1
+
923, 3056 cm ; ESI-MS: m/z: 526 [M+H] , HRMS (ESI) calcd for
+
C H N O S, 526.1583 [M+H] , found: 526.1579.
3
3
24
3
2
4
.2.18 (Table 2): N-(5-ethylthiazol-2-yl)-2-(2-(furan-2-yl)-3-(naphthalen-2-
yl)-5-phenyl-1H-pyrrol-1-yl)acetamide (5r).
1
White solid, m.p: 161-163°C; Yield: 83%; H NMR (300 MHz, CDCl ): δ 8.03
3
(
d, J = 7.5 Hz, 1H, Ar-H), 7.80 (d, J = 7.5 Hz, 1H, Ar-H), 7.74 (d, J = 3.0 Hz,
H, Ar-H ), 7.56 (d, J = 6.7 Hz, 2H, Ar-H), 7.45-7.27 (m, 7H, Ar-H), 7.00 (d, J
1.5 Hz, 1H, Furan-H), 6.45 (s, 1H, Pyrrole-H), 5.98 (t, J = 3.0 Hz, 1H, Furan-
H), 5.65. (d, J = 3.0 Hz, 1H, Furan-H), 5.20 (s, 2H, CH ), 3.01 (qt, 2H, CH ),
1
=
2
2
1
3
1
1
1
1
.40 (t, J = 7.5 Hz, 3H, CH ); C NMR (75 MHz, CDCl ): δ 12.1, 21.3, 46.6,
3
3
07.6, 109.5, 110.0, 119.9, 124.0, 124.1, 124.5, 124.8, 124.9, 125.3, 125.6,
25.8, 126.2, 126.5, 127.8, 130.6, 131.3, 133.5, 135.0, 141.4, 141.5, 143.3,
-1
56.2, 164.1, 165.7; IR (KBr): υ 752, 1273, 1550, 1698, 2921, 3056 cm ; ESI-
+
+
MS: m/z: 505 [M+H] , 527 [M+Na] .
5
. Acknowledgments
2
8