Discovery of target based novel pyrrolyl phenoxy derivatives as antimycobacterial agents: An in silico approach

Article abstract of DOI:10.1016/j.ejmech.2015.03.013

A new series of pyrrolyl phenoxy derivatives bearing alkoxy linker were synthesized and evaluated for anti-tubercular activity (anti-TB) against Mycobacterium tuberculosis. Molecular modeling, pharmacophore constructed using GALAHAD to produce an effective alignment of data set and evaluated by Pareto ranking. The pharmacophore features were filtered by Surflex-dock study using enoyl ACP reductase from M. tuberculosis, which is one of the key enzymes involved in type II fatty acid biosynthesis pathway of M. tuberculosis. Compound 6a27 showed the H-bond with NAD⁺, whereas compound 6a26 showed H-bonds with Tyr158, Thr196, Met199 and NAD⁺ that fitted well into the binding pocket of target InhA. The alkoxy linker bridge and acceptor groups with benzene ring were advantageous for anti-TB activity, which merit further investigation.

Full text of DOI:10.1016/j.ejmech.2015.03.013

European Journal of Medicinal Chemistry 94 (2015) 317e339
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Discovery of target based novel pyrrolyl phenoxy derivatives as
antimycobacterial agents: An in silico approach
Uttam A. More a b, Shrinivas D. Joshi , Tejraj M. Aminabhavi , Venkatrao H. Kulkarni ,
,
a
,
*
a
a
c
d
Aravind M. Badiger , Christian Lherbet
Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T's College of Pharmacy, Sangolli Rayanna Nagar, Dharwad
80 002, India
Centre for Research and Development, Prist University, Thanjavur, Tamil Nadu 613 403, India
BDR Pharmaceuticals International Pvt. Ltd, Baroda, Gujarat, India
Universit ꢀe de Toulouse, UPS, Laboratoire de Synth ꢁe se et Physico-Chimie de Mol ꢀe cules d'Int ꢀe r ^e t Biologique, LSPCMIB, 118 Route de Narbonne, F-31062
a
5
b
c
d
Toulouse Cedex 9, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 September 2014
Received in revised form
A new series of pyrrolyl phenoxy derivatives bearing alkoxy linker were synthesized and evaluated for
anti-tubercular activity (anti-TB) against Mycobacterium tuberculosis. Molecular modeling, pharmaco-
phore constructed using GALAHAD to produce an effective alignment of data set and evaluated by Pareto
ranking. The pharmacophore features were filtered by Surflex-dock study using enoyl ACP reductase
from M. tuberculosis, which is one of the key enzymes involved in type II fatty acid biosynthesis pathway
4
March 2015
Accepted 5 March 2015
Available online 6 March 2015
þ
of M. tuberculosis. Compound 6a27 showed the H-bond with NAD , whereas compound 6a26 showed H-
þ
bonds with Tyr158, Thr196, Met199 and NAD that fitted well into the binding pocket of target InhA. The
Keywords:
alkoxy linker bridge and acceptor groups with benzene ring were advantageous for anti-TB activity,
which merit further investigation.
Pyrrolyl phenoxy derivatives
Anti-tubercular activity
Enoyl ACP reductase
Pharmacophore
© 2015 Elsevier Masson SAS. All rights reserved.
Surflex-docking
1. Introduction
tuberculosis-ENR is InhA that has been well validated. However,
complete genome sequence of TB bacteria helped to identify
Tuberculosis (TB) is caused by various strains of mycobacteria,
mainly by Mycobacterium tuberculosis (M. tuberculosis) and the
disease attacks lungs as well as other parts of the human system.
However, the unique structure of cell-wall allows it to be dormant
as a latent infection, which is a successful pathogen that overcomes
numerous challenges presented by the immune system of the host.
Furthermore, increase in immuno-suppressed individuals due to
AIDS are more susceptible to TB infection [1,2]. Over the past de-
cades, several anti-tuberculosis (anti-TB) drugs have been devel-
oped (Fig. 1), but drug-resistance issue is still increasing. There is
thus a demand to develop new anti-TB drugs that are active against
both acute and chronic growth phases of mycobacterium. Enoyl
ACP reductase (ENR) is an enzyme involved in the synthesis of
mycolic acids (MAs), which are essential structural components of
the mycobacterial cell-wall. As an anti-TB drug target, M.
several important drug targets that may have utility in prophylactic
and therapeutic interventions [3].
Mycobacteria possess both FAS-I and FAS-II systems; of these,
FAS-I for fatty acyl chains up to 16 carbons and FAS-II for the pro-
duction of long chains up to 56 carbons that are precursors of MAs,
indicating that FAS-II system utilizes the products of FAS-I system
as the primers to extend fatty acyl chain lengths even further. MAs
are long chain a-alkyl-b-hydroxy fatty acids, which are the major
components of mycobacterial cell-walls [4,5]. The protein encoded
by the inhA gene, referred to as InhA, has similar amino acid
sequence to the two previously characterized enoyl-ACP re-
ductases, 28% identical to FabI from Escherichia coli and 23% iden-
tical to ENR1 from Brassica napus [6,7]. Further analysis revealed
that InhA catalyzes NADH-dependent reduction of trans double
bond between the positions C2 and C3 of fatty acyl substrates. In
addition, InhA prefers fatty acyl substrates of C16 or even greater,
consistent with its being a member of the mycobacterial FAS-II
system [8].
*
Corresponding author.
E-mail address: shrinivasdj@rediffmail.com (S.D. Joshi).
The gene named inhA is deduced from isoniazid (INH), which is
http://dx.doi.org/10.1016/j.ejmech.2015.03.013
223-5234/© 2015 Elsevier Masson SAS. All rights reserved.
0

318
U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
Fig. 1. Milestones in TB drug research.
the first-line antibiotic for the treatment of TB for over 50 years that
is known to inhibit mycolic acid biosynthesis [9]. InhA is inhibited
by the active adduct of INH (INH-NAD), which is covalently formed
Recently, TCL and its derivatives are becoming important anti-
tubercular agents against Enoyl ACP reductase. This prompted us to
use phenoxy moiety as the core structure by employing computa-
tional strategies that include pharmacophore based on an auto-
mated computational alignment technique and molecular docking
studies to identify Enoyl ACP reductase as a potential target of
phenoxy pyrrole derivatives. Using these computational tech-
niques, we have demonstrated a quantitative pharmacophore
mapping tool that is valuable to identify physicochemical and
structural requirements for ligand binding and biological activity
[35] aspects along with the molecular docking investigations on 1-
(4-(2/3-aryloxyethoxy/propoxy)phenyl)-1H-pyrroles as inhibitors
of InhA and M. tuberculosis. No previous literature exists on these
aspects and hence, the study is novel.
þ
between NAD and the reactive acyl radical of INH generated by the
activation of catalase-peroxidase (KatG) [10]. More recently, tri-
closan (TCL) has been shown to inhibit InhA without the require-
ment for KatG-mediated activation [11]. For modifications in the
parent triclosan using structure-based drug design, three lipophilic
chlorine atoms of triclosan were removed, and one chlorine atom of
ring was replaced by an alkyl chain of varying length, resulting in
alkyl diphenyl ethers (5-hexyl-2-(2-methylphenoxy)phenol; PT70)
[12,13]. These are more potent than the parent compound TCL.
We have previously described the synthesis of potential in-
hibitors of InhA bearing pyrrole, aryloxy and eC]NeNHCOe
bridge as the core fragments compared to PT70 and TCL [14e16],
wherein we have synthesized these along with 2D and 3D-QSAR
studies [17e19]. During our studies on Paal-Knorr and Williamson
ether reactions on amine and phenol, we have focused our atten-
tion on pyrrole with aryloxy/ethoxy/propoxy fragments as the core
structures of the newly designed inhibitors. Molecules containing
aryloxy/ethoxy/propoxy and pyrrole as structural fragments have
been widely explored in drug design. For instance, TCL and its de-
rivatives, Epiroprim, LL-3858, Br-WR99210 are some of the
approved drugs as well as clinical drug candidates (Fig. 2). The
pyrrole ring is a part of many natural compounds [20e22] as well as
it is biologically active molecule [23]. Earlier, Yale [24] and Gazave
2. Computational details
2.1. General method
The crystal structure of M. tuberculosis InhA inhibited by PT70
were obtained from the Brookheaven Protein Databank as entries
X22 (2.1 Å, R-value 0.174%, R-free 0.216%). The 3D model of ENR
2
from M. tuberculosis was constructed previously [14]. In the
present case, biopolymer and each molecule in the data set
energetically minimized by employing Tripos force field [36],
Powell optimization method [37], Amber7FF9902 (biopolymer)
and MMFF94 (molecules) charges (NB cut-off 9.0 and
dielectric constant 4.0) with a convergence criterion set at
[25] have reported in vitro anti-TB pyrrole derivatives and later,
Cerreto et al. [26,27], reported some 1,5-diaryl-2-methyl-pyrrole
derivatives that exhibit potent anti-candida activity against Candida
albicans. Porretta, Deidda and Biava [28e30] also developed 1,5-
diaryl-2-methyl-3-(4-methylpiperazin-1-yl)-methyl-pyrrole
0
.001 kcal/mol Å. The pharmacophore models were generated
and analyzed using GALAHAD (Genetic Algorithm with Linear
Assignment of Hypermolecular Alignment of Datasets) module.
All the calculations were performed using the commercially
available SYBYL-X 2.0 software package (Tripos Associates, St.
Louis, MO, USA) [38].
Modeling proteineligand interactions is the key step in modern
drug designing. If the structure of a binding site is known, then
docking studies will provide valuable insights into such in-
teractions and, in favorable cases, tone can identify high-affinity
(
BM212) as a potent anti-TB drug and based on this approach, Lupin
Ltd. [31] developed LL-3858 that is currently used in clinical
development for the treatment of TB. Additionally, recent reports
on other scaffolds as anti-TB agents [32e34], encouraged us for the
discovery of new anti-TB agents.
Traditionally, however, it is difficult to select the best chemical
moiety that can play an effective role in treating or preventing TB.

U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
319
Fig. 2. Design concept for new molecular entities.
ligands by virtual high-throughput screening. The pharmacophore-
based 3D searching also proved particularly useful [39]. It is char-
acterized in terms of subgroups of two, three or four features, and
arrangement of particular characteristics that are necessary for
ligand binding as well as spatial relationship between them, thus
providing a fast and flexible tool for carrying out these searches.
Genetic Algorithm with Linear Assignment of Hypermolecular
Alignment of Database [40] was also utilized in the formulation of
pharmacophore hypothesis for the synthesized molecules, which is
a unique method as it does not require any template structure such
that it allows immediate and effective generation of partial-
coverage models with multiple partial match constraints [41].
Using more than four molecules from each series (i.e., >8) led to a
reduction in the quality of pharmacophore, while using a single
molecule, we could induce a non-specific feature set. The biological
activity of each compound was expressed as minimal inhibitory
concentration (MIC) against M. tuberculosis and the ꢀlog(MIC)
values were used in pharmacophore analysis.
Using flexible alignment, GALAHAD produced a set of probable
hypotheses (Table 3, 20 models). SPECIFICITY is a logarithmic in-
dicator of the expected discrimination for each query. The actual
number hit is given in the N_HITS column and the values in FEATS
column indicate the total number of features in the model query.
The next five columns are model score components from the ge-
netic algorithm. PARETO is a pareto rank of each model, where all
the models have a Pareto rank of zero. This means none of the
models are superior to any other when using all the four criteria in
columns 5e8 (ENERGY, STERICS, H_BOND, and MOL_QRY). ENERGY
calculates the total energy of the model; STERICS is a steric overlap
for the model; H_BOND, the pharmacophoric concordance and
MOL_QRY is an agreement between the query tuplet and phar-
macophoric tuplets for the ligands as a group. The last four columns
are the scores for individual ligands within each model. Thus, in
this case, every cell in each of the last four columns contains a list of
eight values.
In the second step, for rigid alignment of the remaining mole-
cules in data set, we need to select one best template model and the
selection of the model from obtained 20 models in the first stage
based on the model needed to “hit” all the 8 active molecules. The
model needed to have high sterics with low energy and pharma-
cophoric features. We have constructed a scatter plot (ENERGY vs
STERICS vs MOL_QRY) to visualize the Pareto surface and selected
2.2. Alignment and pharmacophore generation
A total of 66 newly synthesized pyrrolyl phenoxy anti-tuber-
cular compounds were used as data set in the identification of a
feature-based pharmacophore and docking analysis. The alignment
was performed in two steps. In the first step, eight compounds
(5a9/6a9, 5a12/6a12, 5a26/6a26, 5a27/6a27 labeled with asterisks
as shown in Table 1) were selected to carry out pharmacophore
hypothesis; the genetic algorithm was used here to create the
conformers for all molecules. The compounds that were selected to
generate pharmacophore hypothesis are highly active. All the
selected ligands were aligned flexibly by GALAHAD, completely
independent of a template, with a population size of 50 and a
maximum generation value of 70 with molecular required hitting
of 4. Twenty models were generated with default parameters and
using all the molecules in this stage to generate flexible alignment
that may lead to some features by neglecting the interaction [42].

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U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
Table 1
Anti-tubercular results of compounds 5a1e33 and 6a1e33 against Mycobacterium tuberculosis H37RV.
Compound
Ar
MIC
50
mg/mL
Compound
Ar
MIC
50
mg/mL
5a1
5a2
5a3
6a1
12.5
6a2
6a3
6.25
25
25
50
5a4
6a4
25
5
a5
a6
12.5
25
6a5
6a6
6.25
5
25
5a7
25
6a7
25
5
5
5
5
a8
12.5
6a8
12.5
a9*
a10
a11
6.25
6a9*
6a10
6a11
6.25
50
100
100
100
5
5
5
a12*
a13
a14
6.25
6a12*
6a13
6a14
6.25
12.5
12.5
6.25
3.125
3.125
5a15
3.125
6a15

U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
321
Table 1 (continued )
Compound
Ar
MIC
25
m
g/mL
Compound
Ar
MIC
m
g/mL
5
a16
a17
6a16
12.5
5
25
25
50
6a17
6a18
6a19
25
25
25
5
5
a18
a19
5
5
a20
a21
25
6a20
6a21
25
25
12.5
5
5
a22
a23
12.5
6a22
6a23
12.5
12.5
6.25
5
5
5
a24
a25
a26*
12.5
6a24
6a25
6a26*
12.5
6.25
6.25
3.125
3.125
3.125
5a27*
6a27*
1.6
5
5
a28
a29
3.125
6.25
6a28
6a29
3.125
6.25
(
continued on next page)

322
U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
Table 1 (continued )
Compound
Ar
MIC
mg/mL
Compound
Ar
MIC
mg/mL
5a30
6.25
6a30
3.125
5
a31
a32
100
6a31
6a32
50
5
100
100
100
100
10
5
a33
6a33
Isoniazid
e
0.25
Triclosan
e
Astringe (*) training set for pharmacophore generation.
the best pharmacophore model (Fig. 3). Considering the ENERGY,
STERICS and MOL_QRY criteria, the best model is shown in graph,
where the ENERGY is reasonably low and STERICS score is high.
Among the considered models, MODEL_04 (represented with a
black circle in Fig. 3) has the optimal position because it fulfills all
the three criteria and has better Specificity, N_hits and Feats values
hypermolecular alignment program LAMDA (Linear Assignment for
Molecular Dataset Alignment) [42].
2.3. Surflex-docking
In order to explore the interaction and illustrate accurate
binding model for the active site of ENR with ligands, molecular
docking was performed using the Surflex-dock module of another
advanced version of SYBYL package (X 2.0). This docking approach
aligns the ligand to a “protomol” (called also idealized ligand) in the
active site of the target. Surflex-dock that adopted an empirical
scoring function and a patented search engine [45,46] was
employed for molecular docking study of training set as well as test
set molecules into the active site of monomeric unit “A” of the
crystal structure of ENR catalytic core.
[40,43,44].
Finally, the associated pharmacophore (MODEL_04) was used as
a template to align all the molecules using GALAHAD's Align to
template procedure (Table 4). Here, model fitness evaluation starts
by applying the corresponding torsions to the specified base
configuration of each ligand. Pharmacophore and steric bitmaps
were created for each ligand, and (compressed) the count vectors
were then generated for the ensemble. Next, the post-processing
step in GALAHAD involves taking the genetic algorithm results
and producing the final models along with their alignments,
scoring of the models, and displaying their rank. In GALAHAD, the
needed frame of reference is generated via postprocessing using
3. Results and discussion
3.1. Chemistry
Compounds 5a1e5a33 and 6a1e6a33 were synthesized
through as per the steps outlined in Scheme 1. The Paal-Knorr re-
action was performed to synthesize 4-(1H-pyrrol-1-yl)phenol (2)
by
condensing
4-aminophenol
(1)
with
2,5-
dimethoxytetrahydrofuran. Then, Williamson ether synthesis
method was used to afford key intermediates viz., 1-(4-(2-
bromoethoxy)phenyl)-1H-pyrrole (3) and 1-(4-(3-bromopropoxy)
phenyl)-1H-pyrrole (4), by reacting 4-(1H-pyrrol-1-yl)phenol (2)
with excessive amounts of dihaloalkanes (1,2-dibromoethane and
1
2 3
,3-dibromopropane) in the presence of anhydrous K CO and a
ꢁ
catalytic amount of KI in acetone at 80 C. Next, different phenols
were reacted with intermediate 3 or 4 to get the final desired
diphenoxy derivatives 5a1e5a33 or 6a1e6a33 with good yields.
Catalytic amount of KI improved the reaction time and yield. The
final step also followed the Williamson ether synthesis method. All
the new compounds were purified by recrystallization or chroma-
tography and their spectroscopic data confirmed the structures.
1
All the synthesized compounds were characterized by FTIR, H
13
NMR, C NMR and mass spectroscopy. FTIR spectra of the com-
pounds showed absorption bands at 3143e2875 cm due to aro-
matic CeH stretching and C]C stretching at 1603e1514 cm
ꢀ
1
ꢀ
1
,
Fig. 3. Pareto scatter plot (energy vs sterics) from 20 models, black circled model_04
was selected for further alignment of all compounds.
while the characteristic ether linkage (CeOeC) asymmetric and

U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
323
Scheme 1. Synthetic route for pyrrolyl phenoxy derivatives.
ꢀ
1
symmetric stretches appeared in the regions 1260e1231 cm
,
3.2. Anti-tubercular and cytotoxicity studies
ꢀ
1
1
073e1058 cm , respectively confirming the formation of com-
pounds 5a1e5a33 and 6a1e6a33. The H NMR spectra of all the
compounds showed typical triplet signal for two protons of pyrrole
1
The anti-TB activity of the compounds was studied with
M. tuberculosis (Table 1). INH and TCL were used as references for
inhibitory activity against M. tuberculosis. The majority of com-
pounds showed quite moderate to good anti-TB activity. In the first
series of compounds viz., 5a9, 5a12, 5a14, 5a15, 5a23, 5a25,
5a26e30 showed a better activity with MIC values ranging from
at C
omatic proton signals (doublet, doublet of doublet, doublet of
triplet, triplet, triplet of doublet and multiplet) between of 6.16
and 8.73 ppm. The eOCH eCH Oe protons resonated as a triplet
between of 4.04 and 4.45 ppm. In case of compounds in the 6a
series, additional eCH e observed as a quintet (pentate) at of
.21e2.40 ppm. However, in both the series, multiplets also
3 4
and C positions with the d values of 6.22e6.36 ppm and ar-
d
2
2
d
3.125 to 6.25
mg/mL, while those from the second series of com-
2
d
pound 6a27 showed the highest activity with MIC value of 1.6 m
g/
2
mL. These results demonstrate the presence of an alkoxy group
bridge between the two benzene rings bearing one less carbon (in
series 5a1e5a33) is little detrimental for biological activity. Certain
therapeutic properties are required to be identified if an anti-
mycobacterial compound has the potential as a drug. Toxicity is one
of these important criteria. Hence, we have investigated the po-
tential toxicity of ten selected pyrrolyl phenoxy derivatives (5a15,
5a26e28, 6a14, 6a15, 6a26e28, and 6a30) towards the mammalian
Vero cell-lines and A549 (lung adenocarcinoma) cell-lines up to
13
observed. In the C NMR spectra, C
for both the aromatic rings (AreC eO and OeC
around of 154e158 ppm, while the remaining aromatic carbons
1
carbon resonance frequency
1
1
eAr) was observed
d
appeared around
appeared in the at
d
of 82e138 ppm and those of eCH
2
e groups
d
rang of 28e70 ppm. Furthermore, structures of
all the compounds were confirmed by EI-MS (Electron Impact
þ
Ionization) spectra that showed the molecular ion [Mþ] or [M þ1]
and all the spectroscopic measurements confirmed the structures
and their high purity.
concentrations of 62.5 mg/mL. Compounds showed a moderate

324
U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
cytotoxicity in comparison to the standard INH (see Table 2).
were chosen for this study. The compounds 5a23 and 6a26 were
selected as they have the basic structures of all the compounds of
this study and also catechol moiety mimics the standard drug PT70
or TCL and 6a27 was selected since it shows the highest activity
among all the compounds reported here.
3.3. Pharmacophore results
Total of 20 GALAHAD models were derived using 8 active ligands
with the MIC values of 1.6e6.25
m
g/mL (PMIC 5.796e5.204) against
According to the crystal structure of 6a27 (Fig. 7) with the ENR
(PDB ID 2X22, chain A), the ether functionality participates into H-
bond with the co-factor NAD of ENR-binding pocket. The com-
pound 6a26 (Fig. 8) contains a phenoxy-3,5-diol group instead of
naphthoxy group, the two hydroxyl groups makes six H-bonds, of
one which H-bond with Tyr158 (1.95 Å, hydrophilic residue), three
with NAD (1.73, 2.15, 2.67 Å, co-factor), one with Thr196 (2.22 Å,
hydrophilic residue) and one with Met199 (2.36 Å, hydrophobic/
alpha_helix10 residue). The third compound 5a23 (Fig. 9), which
contains 2-hydroxy phenoxy moiety makes two H-bonds i.e., one
with Tyr158 (1.97 Å, hydrophilic residue) and one with NAD (1.77 Å,
co-factor). The orientation and interactions of molecules are iden-
tical to PT70 or TCL (Fig. 10AeD). On the other hand, hydrophobic
(Ile95, Phe97, Met98, Met103, Ala154, Met155, Pro156, Trp160,
Met161, Pro193, Ile194, Leu197, Ala198, Ala201, Ile202, Val203,
Leu217, Leu218, Trp222, Trp230) and hydrophilic (Gly96, Gln100,
Gly104, Asp148, Asp150, Tyr158, Asn159, Thr162, Lys165, Gly192,
Arg195, Thr196, Ser200, Gly204, Gly208, Gln214, Glu219) amino
acid residues are surrounded to the representative compound 6a27
M. tuberculosis. All the models showed Pareto rank 0, which means
no one model was superior to any other (Table 3). Amongst the 20
models, MODEL_04 was selected, which showed better steric
values, features, hits and reasonably low energy than others. Hence,
MODEL_04 was considered for the final rigid alignment of the
remaining compounds. Two 5a series of molecules viz., 5a10, 5a14,
were not aligned by GALAHAD (low H_Bond, Mol_qury values; see
Table 4). The final MODEL_04 obtained from GALAHAD is displayed
in Fig. 4A and B that is comprised of 8 substructures, one conformer
for each molecule from the selected active 8 molecules as the
training set. This includes hydrophobes centered on benzene and
pyrrole rings as well as one on aliphatic linking chain, but the
acceptor atom centers on two oxygen atoms and at one end of the
benzene ring (opposite to pyrrole). The pharmacophore model
clearly shows the importance of hydrophobic phenyl rings with
polar oxygen to exhibit anti-TB activity. The hydrophobic linking
chain is also important for activity.
(Fig. 11A and B).
3.4. Molecular modeling: examination of ENR active site
The molecules showed consensus score in the range of
8.88e4.36, indicating the summary of all forces of interaction be-
The Ramachandran scatter plot for ENR model indicates that 0%
tween the ligands and the InhA. Charge and van der Waals in-
teractions between protein and ligands were found to vary
from ꢀ479.40 to ꢀ869.99 of Helmholtz free energies of interactions
for proteineligands atom pairs that range between ꢀ20.41
and ꢀ77.55 and its H-bonding, complex (ligand-protein), and in-
ternal (ligandeligand) energies range from ꢀ124.77 to ꢀ264.04,
while those ranging from ꢀ37.51 to ꢀ51.53 indicate the ligands
with respect to the reward for H-bonding, lipophilic contact, and
rotational entropy, along with the intercept terms. These scores
indicate that the molecules preferentially bind to InhA in compar-
ison to reference PT70 or TCL (Table 5).
violation (Fig. 5A) and Fig. 5B gives a clear idea of biding site for the
ligands (i.e., substrate-binding domain). After successful finding of
pharmacophore model and alignment, it is important to under-
stand how these interact with M. tuberculosis. Docking studies give
a fair idea related to drugereceptor interactions. For this study, ENR
has been chosen as it is assumed that the interaction of drug with
this enzyme is the important step during fatty acid elongation
system FAS-II, which is involved in the biosynthesis of MAs that are
the major and specific long-chain fatty acids of the cell envelope of
M. tuberculosis. The active pocket was considered to be the site
where PT70 complexes with enoyl-ACP reductase in 2X22. The
PT70 was re-docked to get its interactions and orientation at the
active site for comparison with other synthesized molecules. This
has shown two H-bond interactions i.e., through oxygen of hydroxy
group with the NAD þ ribose (1.8 Å), while hydrogen of hydroxy
group makes H-bonds with OH of the active site Tyr158 (1.9 Å)
3.5. Pharmacophore map correlation with the binding site
For a comparison between binding site residues and pharma-
cophoric features, the docked conformation (Figs. 7e9) was
correlated with the identified pharmacophore features. The in-
teractions identified by docking program were quite consistent
(Fig. 6). Three representative compounds viz., 5a23, 6a26 and 6a27
þ
with the outcome of pharmacophore modeling. The NAD co-factor
Table 2
of the receptor protein is mediating an H-bond with polar oxygen of
linker ether (acceptor interaction) of the most active compound
6a27. The acceptor feature (oxygen, fluorine, nitrile atoms or groups
with hydrophobic benzene ring at one end of the molecules) makes
a key H-bond with Thr196, Met199 (oxygen atom), and these amino
acid residues were well conserved in the ENR family, also called
substrate-binding site. Fluorine makes H-bond with Thr196, while
that of nitrile functionality makes H-bond with Gly104. This key
interaction was found to coherent with the outcome of pharma-
cophoric mapping because the same region of the ligand has
occupied favorable H-bond acceptor features. The hydrophobic
features of benzene and pyrrole ring helps the molecule for pene-
tration, but the crash score negative values indicate the extent of
penetration (Table 5; Crash score).
Cytotoxicity activity of selected pyrrolyl phenoxy derivatives.
Compound
IC50 (m
M)a
MV cell-linesb
c
A
549
5
5
5
5
6
6
6
6
6
6
a15
a26
a27
a28
a14
a15
a26
a27
a28
a30
211 ± 0.2
231 ± 0.3
220 ± 0.3
231 ± 0.3
212 ± 0.2
215 ± 0.4
220 ± 0.3
240 ± 0.3
238 ± 0.4
235 ± 0.3
>450
217 ± 0.2
237 ± 0.2
215 ± 0.2
233 ± 0.2
210 ± 0.3
223 ± 0.3
227 ± 0.2
243 ± 0.2
235 ± 0.3
237 ± 0.2
>450
Isoniazid
Cisplatin
1.29
9.90
a
Cytotoxicity is expressed as IC50 which is the concentration of compound
reduced by 50% of the optical density of treated cells with respect to untreated cells
using MTT assay. Values are the means ± SEM of three independent experiments.
4
. Experimental section
b
All the chemicals were commercially available and used without
Mammalian Vero cell-lines.
c
A549 (lung adenocarcinoma) cell-lines.
further purification unless otherwise stated. Melting points were

U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
325
Table 3
Different pharmacophore models proposed by GALAHAD.
SPECIFICITY
N_HITS
FEATS
PARETO
ENERGY
STERICS
H_BOND
MOL_QRY
MODEL_01
MODEL_02
MODEL_03
MODEL_04
MODEL_05
MODEL_06
MODEL_07
MODEL_08
MODEL_09
MODEL_10
MODEL_11
MODEL_12
MODEL_13
MODEL_14
MODEL_15
MODEL_16
MODEL_17
MODEL_18
MODEL_19
MODEL_20
4.867
3.208
5.265
4.725
4.873
5.188
4.871
5.228
5.292
4.923
3.497
4.844
5.256
4.871
4.649
5.195
4.179
5.213
5.178
3.087
7
7
6
8
8
5
5
6
7
5
7
7
7
8
8
8
4
4
8
8
7
5
6
8
7
6
7
6
6
7
7
7
6
7
8
6
5
6
6
9
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
10.94
10.80
12.69
16.25
11.44
18.11
16.33
11.65
11.69
12.78
9.56
13.05
10.63
12.60
16.15
12.66
16.53
10.16
9.35
587.80
564.80
588.20
873.50
633.40
680.20
608.80
641.00
604.10
729.10
406.30
662.20
485.30
628.30
510.50
592.60
707.50
535.00
460.80
685.50
49.70
46.80
44.40
37.70
33.00
41.80
57.30
39.00
43.90
34.60
36.00
34.70
40.70
33.70
53.90
39.20
40.70
35.00
36.10
31.40
38.82
16.96
21.08
20.53
22.09
27.80
20.87
14.56
14.08
17.68
20.98
18.78
15.93
18.98
21.70
17.34
15.56
14.45
15.32
20.35
13.67
IND_ENERGY
9.59
IND_STERICS
MODEL_01
MODEL_02
MODEL_03
MODEL_04
MODEL_05
MODEL_06
MODEL_07
MODEL_08
MODEL_09
MODEL_10
MODEL_11
MODEL_12
MODEL_13
MODEL_14
MODEL_15
MODEL_16
MODEL_17
MODEL_18
MODEL_19
MODEL_20
9.39
9.26
9.92
9.28
14.83
12.51
14.75
11.45
14.22
14.77
25.75
24.50
19.02
12.73
14.95
12.20
15.05
11.89
12.21
11.49
14.23
14.74
16.04
16.58
8.75
12.96
16.12
13.46
13.09
16.09
12.10
12.27
15.07
12.52
12.07
11.55
12.18
12.69
15.30
11.37
5.73
11.16
9.27
20,019.33
12,473.50
16,958.00
16,802.67
16,503.67
17,026.33
24,456.67
29,708.83
20,615.17
17,680.33
19,661.50
22,507.83
16,906.50
25,921.33
26,882.83
12,390.33
23,084.33
11,995.33
19,089.33
27,021.17
12,182.67
17,491.83
25,200.17
19,875.83
8842.17
19,041.50
19,100.50
23,024.00
17,148.33
16,263.83
14,338.00
25,090.00
23,495.17
22 701.00
13,267.83
17,988.00
12,513.83
13,423.00
14,906.67
25,812.33
19,976.33
16,048.83
19,844.00
17,526.33
19,525.33
14,823.17
27,122.33
32,553.83
23,867.17
20,275.83
20,650.83
22,540.33
18,854.33
25,360.83
27,800.17
8273.17
12,771.50
19,080.67
12,832.00
19,408.67
14,234.17
18,306.00
13,686.83
36,105.33
13,093.67
18,547.33
16,651.33
20,959.83
14,191.83
15,583.50
16,146.33
21,642.83
14,950.33
16,200.33
13,876.50
31,631.17
9970.00
15,607.67
15,738.00
17,742.83
13,931.50
18,195.67
15,757.17
19,560.83
12,383.83
15,425.50
12,478.83
17,618.67
16,938.83
22,186.67
10,659.83
21,734.00
13,005.67
15,926.50
13,621.83
23,447.00
16,656.33
13,015.17
15,204.33
14,098.33
18,565.67
14,373.17
22,907.67
29,740.00
19,065.17
14,776.00
12,010.83
18,993.83
16,283.00
16,845.33
24,948.83
19,080.83
17,396.67
13,447.83
22,683.00
24,205.67
10,965.33
12,477.83
20,186.50
14,891.33
15,245.67
13,008.50
11,617.33
17,695.00
15,685.00
16,009.33
12,913.83
15,801.83
18,967.50
16,311.17
16,547.83
15,354.67
14,509.00
15,326.83
14,431.17
20,695.17
1
.50
9.86
.05
12.29
.68
9.60
.25
10.06
.31
9.88
.82
14.70
.01
13.38
.75
10.97
.49
13.96
.14
10.16
.02
9.78
.16
12.95
.65
10.06
.82
9.89
11.15
10.95
12.16
18.42
26.58
10.09
9.88
10.46
21.15
55.81
36.51
19.09
11.65
11.86
10.62
18.32
9.06
9
11.40
8.57
13.27
10.98
9.26
10.82
13.11
9.00
11.00
13.40
11.61
12.24
11.61
8.57
17.08
10.98
10.08
8.97
9.27
10.99
9.61
9
9
9
8
9
8
23,861.17
14,308.33
9958.50
25,655.00
7949.50
4
9
9.44
9.66
10.86
25.69
9.95
5
16,392.33
26,205.83
22,396.83
14,404.33
18,823.00
19,828.67
23,652.50
17,977.83
17,004.50
15,656.17
25,670.17
25,461.17
24,912.17
15,502.83
18,453.50
14,580.00
16,011.67
18,149.83
26,985.50
9
9.02
2
8.86
9.97
8.83
12.77
20.92
17.82
36.52
13.98
14.54
18.76
25.91
10.22
11.17
9.55
8
18.18
13.00
11.72
11.08
37.88
11.07
9.41
8.53
10.48
9.24
10.08
12.40
9
.14
12.14
0.16
8.27
.72
11.93
.95
13.93
4.24
1
7
9.18
4
12.47
13.93
17.05
10.85
22.50
8.45
10.11
9.13
1
IND_H_BOND
1730.67
IND_MOL_QRY
MODEL_01
MODEL_02
MODEL_03
MODEL_04
MODEL_05
1997.33
2698.00
982.00
1905.00
1504.67
1719.00
616.00
1843.33
2759.33
1667.67
2570.33
2081.33
2209.67
991.00
1358.67
2131.33
1028.67
1827.67
1327.33
1282.33
694.00
ꢀ4.30
ꢀ3.60
ꢀ0.50
ꢀ0.60
ꢀ1.30
ꢀ1.40
¡4.30
¡3.80
ꢀ1.40
ꢀ4.30
ꢀ3.60
ꢀ0.50
ꢀ0.60
ꢀ1.30
ꢀ0.60
¡4.50
¡3.80
ꢀ1.40
ꢀ4.00
ꢀ3.50
ꢀ0.30
ꢀ0.60
ꢀ1.00
ꢀ0.50
¡4.40
¡3.80
ꢀ1.50
ꢀ4.30
ꢀ3.60
ꢀ0.30
ꢀ0.60
ꢀ1.30
ꢀ0.50
¡4.00
¡3.80
ꢀ0.80
2
431.33
868.67
791.67
1275.33
82.00
572.00
513.00
592.00
1
4
1
1525.00
705.33
1930.33
516.33
1518.33
956.67
(
continued on next page)

326
U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
Table 3 (continued )
SPECIFICITY
594.00
N_HITS
FEATS
PARETO
ENERGY
STERICS
H_BOND
MOL_QRY
1
1707.33
1601.33
2078.67
1090.67
2195.33
941.33
1358.33
701.33
1615.33
305.33
1685.33
573.33
1124.67
1104.00
1171.00
1328.00
1394.67
624.33
ꢀ0.30
ꢀ0.80
ꢀ0.30
ꢀ2.60
ꢀ2.40
ꢀ1.20
ꢀ1.60
ꢀ2.50
ꢀ2.40
ꢀ3.20
ꢀ2.10
ꢀ0.80
ꢀ0.20
ꢀ2.20
ꢀ1.20
ꢀ1.70
ꢀ0.90
ꢀ1.30
ꢀ0.60
ꢀ2.20
ꢀ1.80
ꢀ1.70
ꢀ0.60
ꢀ1.60
ꢀ1.00
ꢀ1.70
ꢀ1.00
ꢀ1.30
ꢀ0.90
ꢀ6.70
ꢀ6.50
ꢀ0.30
ꢀ0.80
ꢀ0.30
ꢀ2.80
ꢀ2.40
ꢀ1.20
ꢀ1.70
ꢀ2.50
ꢀ1.90
ꢀ2.90
ꢀ2.10
ꢀ1.10
ꢀ0.20
ꢀ2.20
ꢀ1.20
ꢀ1.70
ꢀ0.90
ꢀ1.30
ꢀ0.60
ꢀ2.40
ꢀ1.80
ꢀ1.70
ꢀ0.60
ꢀ1.60
ꢀ1.00
ꢀ1.30
ꢀ1.10
ꢀ1.60
ꢀ1.40
ꢀ6.80
ꢀ6.50
ꢀ0.70
ꢀ1.50
ꢀ0.30
ꢀ2.50
ꢀ2.40
ꢀ1.20
ꢀ1.40
ꢀ2.20
ꢀ1.80
ꢀ3.00
ꢀ2.10
ꢀ0.80
ꢀ0.20
ꢀ2.10
ꢀ1.50
ꢀ1.50
ꢀ0.90
ꢀ1.30
ꢀ0.60
ꢀ1.90
ꢀ2.10
ꢀ1.30
ꢀ0.60
ꢀ1.60
ꢀ0.90
ꢀ1.20
ꢀ1.50
ꢀ1.00
ꢀ1.20
ꢀ6.60
ꢀ6.50
ꢀ0.30
ꢀ1.50
ꢀ0.20
ꢀ2.70
ꢀ2.30
ꢀ1.20
ꢀ1.30
ꢀ2.10
ꢀ1.50
ꢀ2.90
ꢀ2.10
ꢀ1.00
ꢀ0.20
ꢀ2.00
ꢀ2.10
ꢀ1.20
ꢀ0.80
ꢀ1.40
ꢀ0.40
ꢀ2.30
ꢀ1.80
ꢀ1.50
ꢀ0.70
ꢀ1.30
ꢀ1.60
ꢀ1.20
ꢀ1.00
ꢀ1.60
ꢀ0.90
ꢀ7.20
ꢀ6.10
MODEL_06
MODEL_07
MODEL_08
MODEL_09
MODEL_10
MODEL_11
MODEL_12
MODEL_13
MODEL_14
MODEL_15
MODEL_16
MODEL_17
MODEL_18
MODEL_19
MODEL_20
1334.67
812.00
1345.67
966.00
929.33
87.33
1158.67
93.33
427.33
540.00
1245.67
885.33
658.67
195.67
178.67
891.67
755.33
553.00
1203.00
788.33
274.33
624.67
558.67
327.67
397.33
207.33
662.67
303.00
660.00
177.00
1
2201.33
2857.00
3294.00
1635.00
1676.33
1964.67
2338.00
799.67
1921.33
1706.00
1801.67
1305.67
1507.33
1658.00
2551.67
1008.67
1779.67
2646.33
2536.67
1845.00
2376.67
1856.67
1966.33
1198.00
850.67
1
6
382.67
1388.00
1847.33
202.67
1552.00
182.67
1897.33
764.00
1309.00
190.67
1903.67
868.67
1666.33
1017.33
2017.67
286.33
1636.67
672.00
1441.00
1230.67
1764.67
570.67
4
1
1545.33
529.33
1905.33
727.00
1
1
452.33
1159.00
1927.67
284.33
1453.67
537.33
1161.67
684.33
1179.00
868.33
399.00
879.00
1362.33
564.00
1478.67
342.67
1
1
1
1
1
1
1581.67
1557.33
931.00
1
589.33
762.67
1189.00
1
1505.00
1141.67
MODEL_04 given in bold was considered for the final rigid alignment of the remaining compounds.
Table 4
GALAHAD score for all aligned molecules using MODEL_04.
Compd
PMIC
ENERGY
STERICS
H_BOND
MOL_QRY
Compd
PMIC
ENERGY
STERICS
H_BOND
MOL_QRY
5a01
5a02
5a03
5a04
5a05
5a06
5a07
5a08
5a09
5a10
5a11
5a12
5a13
5a14
5a15
5a16
5a17
5a18
5a19
5a20
5a21
5a22
5a23
5a24
5a25
5a26
5a27
5a28
5a29
5a30
5a31
5a32
5a33
4.301
4.903
4.602
4.602
4.903
4.602
4.602
4.903
5.204
4.301
4.000
5.204
4.903
5.204
5.505
4.602
4.602
4.602
4.301
4.602
4.903
4.903
5.204
4.903
5.204
5.505
5.505
5.505
5.204
5.204
4.000
4.000
4.000
2.79
4.55
2.72
2.18
2.72
8.78
1.44
1.66
2.13
22.42
4.94
9.86
8.64
14.14
9.02
3.33
3.35
4.11
12.70
8.79
2.20
9.19
5.34
8.83
10.51
7.80
2.42
2.73
19.73
15.91
11.42
3.77
3.10
456.70
1056.50
565.30
537.90
1175.50
386.40
3.70
3.70
3.70
3.70
3.70
3.70
3.70
3.70
3.70
0.20
5.10
16.10
5.10
0.30
5.10
3.70
3.70
3.70
3.70
3.70
3.70
4.50
63.70
3.70
63.70
452.40
19.20
5.00
8.00
8.00
4.50
63.70
3.70
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
0.00
1.71
1.71
1.71
0.00
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
1.71
6a01
6a02
6a03
6a04
6a05
6a06
6a07
6a08
6a09
6a10
6a11
6a12
6a13
6a14
6a15
6a16
6a17
6a18
6a19
6a20
6a21
6a22
6a23
6a24
6a25
6a26
6a27
6a28
6a29
6a30
6a31
6a32
6a33
4.301
5.204
4.301
4.602
5.204
4.602
4.602
4.903
5.204
4.000
4.000
5.204
4.903
5.505
5.505
4.903
4.602
4.602
4.602
4.602
4.602
4.903
4.903
4.903
5.204
5.505
5.796
5.505
5.204
5.505
4.301
4.000
4.000
8.54
8.82
1.91
6.95
3.41
1.79
2.60
2.53
13.49
7.54
4.65
6.06
8.87
8.33
5.45
4.98
2.27
1.94
9.55
6.54
8.02
10.49
9.23
7.81
12.24
4.15
3.34
6.05
8.37
17.25
5.27
5.25
2.98
940.90
1535.20
849.30
940.90
1595.10
849.30
48.80
48.80
48.80
48.80
48.80
48.80
48.80
48.80
48.80
68.00
73.40
156.70
68.00
68.00
68.00
48.80
48.80
48.80
48.80
48.80
48.80
129.80
378.10
53.30
378.10
732.20
133.20
48.80
48.80
48.80
129.80
378.10
53.30
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
22.35
456.70
940.90
1056.50
1056.50
815.00
1713.70
1845.00
1444.80
236.30
1387.90
528.10
1038.10
488.50
1013.00
1057.70
562.60
702.70
1389.40
505.50
1258.30
1795.70
1261.80
1761.90
2095.70
2608.80
865.60
1595.10
1625.70
1982.30
2389.70
2647.80
2041.20
1903.40
2134.10
1091.30
1684.90
1016.30
3065.50
1207.10
1310.90
1108.50
1734.70
1291.00
1792.40
3198.50
3534.80
1812.10
1823.50
2980.30
1362.20
994.50
1259.20
589.40
1299.70

U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
327
Fig. 4. A) Final selected pharmacophore model and B) molecular alignment for InhA receptor ligands (total of 8 compounds), containing acceptor atoms (green) and hydrophobes
cyan). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
(
determined with capillary melting point apparatus (Shital-digital)
and are uncorrected. FTIR spectra were obtained on a Bruker FTIR
spectrophotometer in KBr disks. The H and C NMR spectra were
recorded on a Bruker AVANCE II 400 (400 and 100 MHz, respec-
added to the mixture, refluxed for 8 h, cooled, the reaction mixture
poured into ice-cold water (500 mL) and basified with Na CO
solution. The precipitated solid was filtered, washed with water,
dried and recrystallized using cyclohexane (200 mL) to afford pure
white crystals.
2
3
1
13
tively) in CDCl
The abbreviations used to describe the peak patterns are: (b) broad,
s) singlet, (d) doublet, (t) triplet, (q) quartet, (p) pentet and (m)
3 6
and DMSO-d using TMS as the internal standard.
ꢁ
(Yield 60%). mp 116e118 C; FTIR (KBr): 3393 (OH), 3142, 2923
1
(
(AreH), 1520 (C]C); H NMR (400 MHz, DMSO-d
6
)
d
ppm: 6.19 (t,
eH), 6.83, 6.85 (td, 2H, J ¼ 2.08, 2.08,
eH), 7.00 (t, 2H, J ¼ 2.08, pyrrole-C and C eH), 7.19,
and C eH), 9.29 (s, 1H, OH);
multiplet. Mass spectra (MS) were recorded on a JEOL GCMATE II
GC-Mass spectrometer. Elemental analysis data (performed on Leco
Tru Spec CHNS Analyzer) for C, H, and N were within ±0.4% of the
theoretical values. Analytical thin-layer chromatography (TLC) was
performed on the pre-coated TLC sheets of silica gel 60 F254 (Merck,
Darmstadt, Germany) visualized by long- and short-wavelength
ultraviolet (UV) lamps. Chromatographic purifications were per-
formed on Merck silica gel (70e230 mesh).
2H, J ¼ 2.12, pyrrole-C
3 4
and C
Ph-C and C
2
6
2
5
13
7.22 (td, 2H, J ¼ 2.12, 2.08, Ph-C
3
5
C
NMR (100 MHz, CDCl
3
)
d
ppm: 109.92, 116.17, 119.80, 122.46, 134.71,
þ
153.55; MS (EI): m/z ¼ found 159.07 [M ]; calcd.159.07. Anal. Calcd.
For C10
8.81.
9
H NO: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.01; H, 5.68; N,
4.2. General procedure for the synthesis of 1-(4-(2 or 3-
4.1. Synthesis of 4-(1H-pyrrol-1-yl)phenol (2)
bromoethoxy/propoxy)phenyl)-1H-pyrroles (3 or 4)
4
-Aminophenol (1.0 eq.) was added to warm glacial acetic acid
A round-bottom flask was charged with 4-(1H-pyrrol-1-yl)
(
25 mL). After 15 min, 2,5-dimethoxytetrahydrofuran (1.2 eq.) was
2 3
phenol (2) (1.0 eq.), anhydrous K CO (3.0 eq.) and catalytic amount
Fig. 5. A: Ramachandran scatter plot (PHI vs PSI) of ENR model; 92% of the residues were found in the most favored region; 7.5% were found in the additional allowed regions; 0.5%
were found in the generously allowed regions and 0% were found in the disallowed regions; B: The X-ray crystal of InhA (PDB: 2X22, Chain A). The protein is represented by ribbon
model with 1, substrate-binding domain; 2, NAD-binding domain; 3, N-terminus; 4, C-terminus; 5, the coenzyme NADH is shown in space filled model.

328
U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
Fig. 6. Crystal structure of PT70 in a complex with InhA and H-bonds are indicated by a dashed yellow line. (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)
of KI; the mixture were stirred for 20 min in dry acetone (25 mL) to
which 1,2-dibromoethane or 1,3-dibromopropane (1.2 eq.) was
added and stirred for 48 h at 80 C and the reaction was monitored
(100 MHz, CDCl
3
)
d
ppm: 29.08, 68.27, 110.03,115.64, 119.65,122.20,
þ
135.12, 156.12; MS (EI): m/z ¼ found 266.13 [M þ1]; calcd. 265.01.
ꢁ
Anal. Calcd. For C12
H12BrNO: C, 54.16; H, 4.54; N, 5.26. Found: C,
using TLC. After cooling to ambient temperature, acetone was filtered
over a pad of celite and further rinsed with acetone (60 mL). The
solvent was removed under reduced pressure and the residue was
purified by column chromatography on silica gel with diethyl ether/
petroleum ether (1:9) as eluent to afford the corresponding ethoxy
53.94; H, 4.56; N, 5.28.
4.2.2. 1-(4-(3-Bromopropoxy)phenyl)-1H-pyrrole (4)
ꢁ
(
Yield 70%). mp 68e70 C; FTIR (KBr): 3140, 2921 (AreH), 1520
asym
sym
ꢀ1 1
(
C]C), 1250 (CeOeC
NMR (400 MHz, CDCl
J ¼ 6.44, BrCH ), 4.09 (t, 2H, J ¼ 5.80, OCH
J ¼ 1.96, 2.08, pyrrole-C and C eH), 6.91e6.97 (m, 2H, Ph-C
eH), 6.98 (t, 2H, J ¼ 2.16, pyrrole-C and C eH), 7.26e7.30 (m, 2H,
eH); C NMR (100 MHz, CDCl ppm: 30.12, 32.99,
), 1023 (CeOeC ), 721 (CeBr) cm ; H
ppm: 2.31 (p, 2H, eCH e), 3.59 (t, 2H,
), 6.30, 6.31 (dd, 2H,
and
(3) or propoxy (4) derivatives in high purity with good yields.
3
)
d
2
2
2
4
.2.1. 1-(4-(2-Bromoethoxy)phenyl)-1H-pyrrole (3)
3
4
2
ꢁ
(
Yield 85%). mp 72e74 C; FTIR (KBr): 3129, 2926 (AreH), 1518
C
6
2
5
asym
sym
ꢀ1
1
13
(
C]C), 1255 (CeOeC
NMR (400 MHz, CDCl
OCH
), 6.32 (t, 2H, J ¼ 2.12, pyrrole-C
J ¼ 2.16, 3.44, Ph-C and C eH), 6.99 (t, 2H, J ¼ 2.16, pyrrole-C
eH), 7.29, 7.31 (td, 2H, J ¼ 2.20, 3.44, Ph-C
), 1071 (CeOeC ), 739 (CeBr) cm ; H
ppm: 3.64 (t, 2H, BrCH ), 4.29 (t, 2H,
and C eH), 6.94, 6.96 (td, 2H,
and
eH); C NMR
Ph-C
3
and C
5
3
) d
3
)
d
2
67.72, 110.06, 115.60, 117.93, 119.71, 122.18, 134.74, 156.80; MS (EI):
þ
2
3
4
m/z ¼ found 280.23 [M þ1]; calcd. 279.03. Anal. Calcd. For
2
6
2
13
C H14BrNO: C, 55.73; H, 5.04; N, 5.00. Found: C, 55.51; H, 5.06; N,
13
C
5
3
and C
5
4.98.
Fig. 7. Crystal structure of 6a27 in a complex with InhA and H-bond is indicated by a dashed yellow line. (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)

U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
329
Fig. 8. Crystal structure of 6a26 in a complex with InhA and H-bonds are indicated by a dashed yellow line. (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)
ꢀ1
4
.3. General procedure for the synthesis of 1-(4-(2-aryloxyethoxy)
1524 (C]C), 1238 (CeOeCasym), 1068 (CeOeCsym) cm ; 1H NMR
(400 MHz, DMSO-d
ppm: 4.33, 4.35 (td, 4H, J ¼ 4.52, 4.44,
2OCH and C eH), 6.93e6.97 (m,
), 6.26 (t, 2H, J ¼ 2.12, pyrrole-C
H, Ph-C , C eH and Ph-C ), 7.00e7.03 (m, 4H, Ph-C , C eH at
pyrrole and pyrrole-C and C eH), 7.27e7.35 (m, 4H, Ph-C , C eH
and Ph-C , C eH at pyrrole); C NMR (100 MHz, DMSO-d ppm:
phenyl)-1H-pyrroles (5a1e5a33) or 1-(4-(3-aryloxypropoxy)
phenyl)-1H-pyrroles (6a1e6a33)
6
) d
2
3
4
3
2
6
4
2
6
A round-bottom flask was charged with appropriate phenols
2
5
3
5
1
3
(
1.0 eq.), anhydrous K
the mixture were stirred for 20 min in dry acetone (25 mL). To this,
-(4-(2-bromoethoxy)phenyl)-1H-pyrrole (3) or 1-(4-(3-
2
CO
3
(3.0 eq.) and a catalytic amount of KI and
3
5
6
) d
66.06, 66.58, 109.76, 114.27, 115.23, 118.87, 120.60, 120.98, 129.28,
þ
1
133.83, 156.02, 158.18; MS (EI): m/z ¼ found 279.25 [M ]; calcd.
bromopropoxy)phenyl)-1H-pyrrole (4) (1.0 eq.) was added and
stirred for 48 h at 80 C, the reaction was monitored using TLC. After
279.13. Anal. Calcd. For C18
C, 77.71; H, 6.11; N, 4.99.
2
H17NO : C, 77.40; H, 6.13; N, 5.01. Found:
ꢁ
cooling to ambient temperature, acetone was filtered over a pad of
celite and further rinsed with acetone (60 mL). The solvent was
removed under reduced pressure and the residue was recrystal-
lized with ethyl acetate and diethyl ether mixture (7:3) or cyclo-
hexane to afford the corresponding diaryloxy derivatives in varying
yields.
4.3.2. 1-(4-(2-(4-Chlorophenoxy)ethoxy)phenyl)-1H-pyrrole (5a2)
ꢁ
(Yield 79%). mp 140e142 C; FTIR (KBr): 3141, 2928 (AreH),1525
asym
sym
ꢀ1 1
(C]C), 1237 (CeOeC
NMR (400 MHz, CDCl3)
2H, J ¼ 2.12, pyrrole-C and C eH), 6.87, 6.89 (td, 2H, J ¼ 2.12, 3.36,
), 1070 (CeOeC ), 825 (CeCl) cm ; H
d
ppm: 4.28e4.35 (m, 4H, 2OCH ), 6.32 (t,
2
3
4
Ph-C
role-C
7.32 (td, 2H, J ¼ 2.28, 3.00, Ph-C
2
and C
6
eH), 6.96e7.00 (m, 4H, chloroPh-C
2
, C
and C
3
eH); C NMR (100 MHz, CDCl )
6
eH and pyr-
4
.3.1. 1-(4-(2-Phenoxyethoxy)phenyl)-1H-pyrrole (5a1)
2
and C
5
eH), 7.22e7.26 (m, 2H, chloroPh-C
3
5
eH) 7.30,
ꢁ
13
(
Yield 87%). mp 156e158 C; FTIR (KBr): 3143, 2931 (AreH),
3
, C
5
Fig. 9. Crystal structure of 5a23 in a complex with InhA and H-bonds are indicated by a dashed yellow line. (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)

330
U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
Fig. 10. Superposition of the A) PT70 (magenta), TCL (cyan) with B) 6a27, C) 6a26, D) 5a23 (green) at active site of InhA. (For interpretation of the references to colour in this figure
legend, the reader is referred to the web version of this article.)
d
ppm: 66.85, 109.97, 115.50, 116.00, 119.65, 122.15, 126.10, 129.42,
Anal. Calcd. For C18
68.62; H, 5.16; N, 4.48.
2
H16ClNO : C, 68.90; H, 5.14; N, 4.46. Found: C,
þ
1
3
34.92, 156.60, 157.22; MS (EI): m/z ¼ found 313.75 [M ]; calcd.
2
13.09. Anal. Calcd. For C18H16ClNO : C, 68.90; H, 5.14; N, 4.46.
Found: C, 69.18; H, 5.12; N, 4.48.
4
.3.4. 1-(4-(2-(2-Chlorophenoxy)ethoxy)phenyl)-1H-pyrrole (5a4)
ꢁ
(
Yield 77%). mp 145e147 C; FTIR (KBr): 3137, 2941 (AreH), 1516
asym
sym
ꢀ1 1
4
.3.3. 1-(4-(2-(3-Chlorophenoxy)ethoxy)phenyl)-1H-pyrrole (5a3)
(C]C), 1239 (CeOeC
NMR (400 MHz, DMSO-d
J ¼ 1.44, pyrrole-C and C
7.03e7.07 (m, 5H, chloroPh-C
7.25 (t, 1H, chloroPh-C ) 7.32e7.37 (m, 3H, chloroPh-C
eH); C NMR (100 MHz, DMSO-d ppm: 66.59, 67.43, 109.72,
), 1070 (CeOeC ), 733 (CeCl) cm ; H
ppm: 4.40 (s, 4H, 2OCH ), 6.27 (d, 2H,
eH), 6.94 (t, 1H, J ¼ 7.64, chloroPh-C ),
, ph-C , C eH and pyrrole-C , C eH),
3
and Ph-C ,
ꢁ
(
Yield 77%). mp 138e140 C; FTIR (KBr): 3141, 2875 (AreH),1524
6
)
d
2
asym
sym
ꢀ1 1
(
C]C), 1240 (CeOeC
NMR (400 MHz, CDCl
and C
.99e7.04 (m, 6H, Ph-C , C
eH), 7.28 (q, 1H, chloroPh-C
, C
eH); 13C NMR (100 MHz, CDCl
09.98, 113.25, 115.12, 115.52, 119.66, 121.39, 122.16, 130.32, 134.95,
), 1071 (CeOeC ), 719 (CeCl) cm ; H
ppm: 4.35 (p, 4H, 2OCH ), 6.36 (t, 2H,
eH), 6.87e6.89 (m, 1H, chloroPh-C -H),
eH, chloroPh-C , C eH and pyrrole-C
-H) 7.34, 7.36 (dd, 2H, J ¼ 2.08,
ppm: 66.76, 66.80,
3
4
4
3
)
d
2
6
2
6
2
5
J ¼ 2.04, pyrrole-C
3
4
6
5
3
13
6
2
6
2
6
2
C
5
6
) d
and C
2
1
5
5
113.80, 115.36, 118.84, 121.04, 121.51, 121.87, 127.82, 129.81, 133.95,
þ
.16, Ph-C
3
5
3
)
d
153.69, 156.06; MS (EI): m/z ¼ found 313.78 [M ]; calcd. 313.09.
2
Anal. Calcd. For C18H16ClNO : C, 68.90; H, 5.14; N, 4.46. Found: C,
þ
156.59, 159.33; MS (EI): m/z ¼ found 313.15 [M ]; calcd. 313.09.
68.79; H, 5.16; N, 4.47.
Fig. 11. A) Hydrophobic and B) hydrophilic amino acid residues of active site surrounded to 6a27.

U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
331
Table 5
Surflex-dock scores (kcal/mol) of pyrrolyl phenoxy derivatives.
4.3.5. 1-(4-(2-(4-Bromophenoxy)ethoxy)phenyl)-1H-pyrrole (5a5)
ꢁ
(
Yield 80%). mp 168e170 C; FTIR (KBr): 3141, 2929 (AreH),1525
asym
sym
ꢀ1 1
Compd
C
Crash
Polar
D
PMF
score
G
Chem
score
(C]C), 1237 (CeOeC
), 1070 (CeOeC ), 824 (CeBr) cm ; H
ppm: 4.31e4.36 (m, 4H, 2OCH ), 6.22
and C
eH), 6.93, 6.94, (dd, 2H, J ¼ 2.16,
eH), 7.03, 7.04 (dd, 2H, J ¼ 2.16, 2.12, Ph-C
eH), 7.13 (t, 2H, J ¼ 2.16, pyrrole-C and C eH), 7.40e7.43 (m,
H, bromoPh-C , C eH and Ph-C , C eH); C NMR (100 MHz,
DMSO-d ppm: 66.43, 109.70, 112.33, 115.16, 116.33, 118.81,
scorea scoreb
scorec score
d
e
scoref
g
NMR (400 MHz, DMSO-d
(t, 2H, J ¼ 2.12, pyrrole-C
2.16, bromoPh-C and C
and C
6
)
d
2
PT70
13.54 ꢀ0.55
8.88 ꢀ1.89
8.59 ꢀ1.48
8.45 ꢀ0.84
8.27 ꢀ1.31
8.24 ꢀ1.17
8.20 ꢀ1.21
8.15 ꢀ1.34
8.02 ꢀ0.96
7.96 ꢀ1.28
7.89 ꢀ1.37
7.61 ꢀ1.08
6.88 ꢀ1.06
6.55 ꢀ1.40
6.54 ꢀ1.39
6.53 ꢀ0.82
6.48 ꢀ2.65
6.46 ꢀ1.38
6.41 ꢀ1.11
6.35 ꢀ0.35
6.34 ꢀ0.59
6.33 ꢀ1.40
6.32 ꢀ0.54
6.21 ꢀ1.25
6.17 ꢀ1.20
6.12 ꢀ1.04
6.11 ꢀ0.53
6.05 ꢀ0.31
6.04 ꢀ0.46
6.02 ꢀ1.32
6.01 ꢀ0.29
5.99 ꢀ0.66
5.97 ꢀ0.46
5.95 ꢀ0.97
5.92 ꢀ0.44
5.91 ꢀ1.59
5.88 ꢀ0.91
5.81 ꢀ1.13
5.80 ꢀ0.67
5.79 ꢀ0.97
5.79 ꢀ1.63
5.77 ꢀ1.99
5.73 ꢀ1.97
5.68 ꢀ0.54
5.66 ꢀ0.66
5.64 ꢀ0.58
5.61 ꢀ0.35
5.60 ꢀ0.80
5.59 ꢀ0.38
5.57 ꢀ0.88
5.55 ꢀ0.66
5.48 ꢀ0.47
5.45 ꢀ0.89
5.45 ꢀ0.33
5.44 ꢀ0.72
5.40 ꢀ0.82
5.39 ꢀ1.51
5.33 ꢀ1.32
5.30 ꢀ0.35
5.28 ꢀ0.66
5.26 ꢀ0.58
5.22 ꢀ1.01
5.22 ꢀ0.94
5.12 ꢀ1.12
4.99 ꢀ2.78
4.99 ꢀ0.66
4.77 ꢀ0.48
2.20
2.85
0.09
2.12
0.06
0.05
0.00
0.01
2.14
0.00
0.00
1.13
0.00
0.50
1.05
2.18
0.00
0.00
0.38
0.00
1.16
0.00
0.00
1.30
2.22
1.14
0.00
0.00
0.00
0.71
1.03
0.00
1.14
2.25
0.00
0.77
0.01
0.00
0.00
0.47
1.09
0.55
0.00
0.00
2.19
0.89
0.00
0.70
0.00
0.00
0.00
0.08
0.00
0.88
0.00
0.01
0.00
0.00
0.00
0.00
0.00
0.01
0.89
2.16
0.86
0.00
0.00
ꢀ356.647 ꢀ36.975 ꢀ225.068 ꢀ48.052
ꢀ687.186 ꢀ40.517 ꢀ151.376 ꢀ43.022
ꢀ501.676 ꢀ23.835 ꢀ211.838 ꢀ50.009
ꢀ593.566 ꢀ50.667 ꢀ128.347 ꢀ41.474
ꢀ515.999 ꢀ19.971 ꢀ208.209 ꢀ45.521
ꢀ712.488 ꢀ43.748 ꢀ219.403 ꢀ45.452
ꢀ638.570 ꢀ51.347 ꢀ219.866 ꢀ51.530
ꢀ476.605 ꢀ27.067 ꢀ211.658 ꢀ46.745
ꢀ685.785 ꢀ50.726 ꢀ132.902 ꢀ39.705
ꢀ641.980 ꢀ57.915 ꢀ216.269 ꢀ50.924
ꢀ509.127 ꢀ41.371 ꢀ218.670 ꢀ46.141
ꢀ575.951 ꢀ47.755 ꢀ173.728 ꢀ46.704
ꢀ588.935 ꢀ49.913 ꢀ217.666 ꢀ43.627
ꢀ781.271 ꢀ28.345 ꢀ185.190 ꢀ47.471
ꢀ562.662 ꢀ52.324 ꢀ208.465 ꢀ42.231
ꢀ598.044 ꢀ38.592 ꢀ153.925 ꢀ41.917
ꢀ541.399 ꢀ30.313 ꢀ264.035 ꢀ47.073
ꢀ543.901 ꢀ20.407 ꢀ162.225 ꢀ37.511
ꢀ602.340 ꢀ53.812 ꢀ236.516 ꢀ46.580
ꢀ529.494 ꢀ74.240 ꢀ166.448 ꢀ46.385
ꢀ628.213 ꢀ67.107 ꢀ171.774 ꢀ45.742
ꢀ534.955 ꢀ54.635 ꢀ218.778 ꢀ45.924
ꢀ524.786 ꢀ53.962 ꢀ183.780 ꢀ43.438
ꢀ583.773 ꢀ40.209 ꢀ169.459 ꢀ42.910
ꢀ322.294 ꢀ32.830 ꢀ176.909 ꢀ40.209
ꢀ591.019 ꢀ71.675 ꢀ198.380 ꢀ41.671
ꢀ515.080 ꢀ45.026 ꢀ160.744 ꢀ42.828
ꢀ524.736 ꢀ75.613 ꢀ184.828 ꢀ45.101
ꢀ571.843 ꢀ68.084 ꢀ169.150 ꢀ42.651
ꢀ582.961 ꢀ66.871 ꢀ209.940 ꢀ41.382
ꢀ633.877 ꢀ75.913 ꢀ145.350 ꢀ44.176
ꢀ528.537 ꢀ44.359 ꢀ193.164 ꢀ48.946
ꢀ624.742 ꢀ68.484 ꢀ179.632 ꢀ43.354
ꢀ613.798 ꢀ36.762 ꢀ124.769 ꢀ42.582
ꢀ607.934 ꢀ58.273 ꢀ192.958 ꢀ47.357
ꢀ507.481 ꢀ35.324 ꢀ201.677 ꢀ47.386
ꢀ602.931 ꢀ46.330 ꢀ195.100 ꢀ42.308
ꢀ517.930 ꢀ57.358 ꢀ186.273 ꢀ40.368
ꢀ524.262 ꢀ63.727 ꢀ185.178 ꢀ45.513
ꢀ639.352 ꢀ31.631 ꢀ168.660 ꢀ46.314
ꢀ636.041 ꢀ64.313 ꢀ195.096 ꢀ43.151
ꢀ553.070 ꢀ34.522 ꢀ213.528 ꢀ44.696
ꢀ611.893 ꢀ54.981 ꢀ214.155 ꢀ43.511
ꢀ519.420 ꢀ65.270 ꢀ191.935 ꢀ45.480
ꢀ586.362 ꢀ52.702 ꢀ159.829 ꢀ41.234
ꢀ561.066 ꢀ68.694 ꢀ167.052 ꢀ45.700
ꢀ520.905 ꢀ50.905 ꢀ161.246 ꢀ43.011
ꢀ555.662 ꢀ49.023 ꢀ166.760 ꢀ44.122
ꢀ517.349 ꢀ47.449 ꢀ154.983 ꢀ42.815
ꢀ517.214 ꢀ63.274 ꢀ209.723 ꢀ40.947
ꢀ539.315 ꢀ59.403 ꢀ180.297 ꢀ45.238
ꢀ509.237 ꢀ65.939 ꢀ180.018 ꢀ45.187
ꢀ479.396 ꢀ47.470 ꢀ186.385 ꢀ42.192
ꢀ547.037 ꢀ67.034 ꢀ157.940 ꢀ44.181
ꢀ522.813 ꢀ60.907 ꢀ196.414 ꢀ44.172
ꢀ707.284 ꢀ49.284 ꢀ174.374 ꢀ44.590
ꢀ751.595 ꢀ63.420 ꢀ217.026 ꢀ44.415
ꢀ500.591 ꢀ44.065 ꢀ185.046 ꢀ39.806
ꢀ525.192 ꢀ66.242 ꢀ172.742 ꢀ43.306
ꢀ524.734 ꢀ75.319 ꢀ180.856 ꢀ47.034
ꢀ548.686 ꢀ55.624 ꢀ173.063 ꢀ44.561
ꢀ525.253 ꢀ53.910 ꢀ199.952 ꢀ46.135
ꢀ519.826 ꢀ65.246 ꢀ188.962 ꢀ40.234
ꢀ718.086 ꢀ52.312 ꢀ136.104 ꢀ40.377
ꢀ713.447 ꢀ36.150 ꢀ212.885 ꢀ43.696
ꢀ530.053 ꢀ67.575 ꢀ185.943 ꢀ44.787
ꢀ869.990 ꢀ70.763 ꢀ180.450 ꢀ41.241
ꢀ860.936 ꢀ77.545 ꢀ170.835 ꢀ41.003
3
4
6
6
5
6
6
6
5
5
5
5
6
6
6
5
5
6
6
6
5
6
6
6
6
a26
a27
a23
a20
a15
a30
a27
a26
a30
a20
a12
a29
a14
a12
a25
a21
a9
2
6
2
6
2
5
13
4
3
5
3
5
6
) d
121.07, 131.84, 133.94, 155.99, 157.41; MS (EI): m/z ¼ found 358.22
þ
[M þ1]; calcd. 357.04. Anal. Calcd. For C18
2
H16BrNO : C, 60.35; H,
4
.50; N, 3.91. Found: C, 60.59; H, 4.52; N, 3.89.
4
.3.6. 1-(4-(2-(3-Bromophenoxy)ethoxy)phenyl)-1H-pyrrole (5a6)
ꢁ
(
Yield 80%). mp 142e144 C; FTIR (KBr): 3141, 2928 (AreH),1524
asym
sym
ꢀ1 1
(C]C), 1238 (CeOeC
NMR (400 MHz, CDCl
H, J ¼ 2.12, pyrrole-C
H), 7.01e7.04 (m, 4H, Ph-C
m, 3H, bromoPh-C , C and C
eH); C NMR (100 MHz, CDCl
09.99, 113.76, 115.51, 117.99, 119.66, 122.16, 122.87, 124.32, 130.66,
), 1071 (CeOeC ), 719 (CeBr) cm ; H
ppm: 4.33e4.38 (m, 4H, 2OCH ), 6.35 (t,
and C eH), 6.91e6.93 (m, 1H, bromoPh-C
,C eH and pyrrole-C , C eH), 7.13e7.21
eH), 7.34, 7.36 (dd, 2H, J ¼ 2.20, 2.16,
ppm: 66.76, 66.78,
3
)
d
2
2
3
4
6
-
2
6
2
5
a33
a19
a31
a7
a19
a32
(
2
4
5
1
3
Ph-C
1
3
and C
5
3
) d
þ
1
3
34.93, 156.58, 159.38; MS (EI): m/z ¼ found 358.24 [M þ1]; calcd.
57.04. Anal. Calcd. For C18 16BrNO : C, 60.35; H, 4.50; N, 3.91.
Found: C, 60.59; H, 4.48; N, 3.89.
H
2
TCL
a31
5
6
5
5
5
5
6
5
6
5
6
6
6
5
6
6
5
5
5
6
6
6
6
6
5
6
5
5
5
5
5
5
5
5
5
6
6
5
5
6
5
6
5
a16
a17
a9
4.3.7. 1-(4-(2-(2-Bromophenoxy)ethoxy)phenyl)-1H-pyrrole (5a7)
ꢁ
a33
a32
a28
a22
a23
a29
a18
a24
a17
a18
a13
a25
a24
a13
a6
a22
a3
a8
a2
a5
a1
a1
a4
a28
a3
(Yield 79%). mp 133e135 C; FTIR (KBr): 3131, 2937 (AreH), 1515
asym
sym
ꢀ1 1
(
C]C), 1241 (CeOeC
NMR (400 MHz, CDCl
.30e6.32 (m, 2H, pyrrole-C
J ¼ 1.40, 0.92, 1.36, bromoPh-C
H, Ph-C ,C eH and pyrrole-C , C
and Ph-C , C
eH), 7.54, 7.56 (dd, 1H, J ¼ 1.60, 1.52, bromoPh-C
H); C NMR (100 MHz, CDCl
), 1068 (CeOeC ), 732 (CeBr) cm ; H
ppm: 4.35e4.40 (m, 4H, 2OCH ),
and C eH), 6.85, 6.87, 6.89 (dt, 1H,
-H), 6.96e7.04 (m, 5H, bromoPh-C
3
)
d
2
6
3
4
6
4
-
-
2
6
2
5
eH), 7.23e7.33 (m, 3H, bromoPh-
C
5
3
5
3
13
3
)
d
ppm: 67.00, 68.03, 109.87, 109.96,
110.00, 112.65, 114.08, 115.56, 115.76, 116.13, 119.69, 122.17, 122.40,
122.58, 128.52, 133.57, 134.95, 155.18, 156.72; MS (EI): m/z ¼ found
þ
3
6
58.22 [M þ1]; calcd. 357.04. Anal. Calcd. For C18
2
H16BrNO : C,
0.35; H, 4.50; N, 3.91. Found: C, 60.43; H, 4.48; N, 3.93.
4
.3.8. 1-(4-(2-(4-Iodophenoxy)ethoxy)phenyl)-1H-pyrrole (5a8)
ꢁ
(
Yield 67%). mp 173e175 C; FTIR (KBr): 3141, 2929 (AreH), 1522
asym
sym
ꢀ1 1
(C]C), 1238 (CeOeC
), 1069 (CeOeC ), 719 (CeI) cm
ppm: 4.30e4.41 (m, 4H, 2OCH
and C eH), 6.80e6.83 (m, 2H, iodoPh-C
eH), 7.01e7.07 (m, 2H, Ph-C and C eH), 7.09e7.15 (m, 2H,
and C eH), 7.37e7.41 (m, 2H, Ph-C and C eH),
7.56e7.58 (dd, 2H, J ¼ 1.96, 1.92, iodoPh-C and C eH); C NMR
100 MHz, DMSO-d ppm: 66.36, 66.46, 82.83, 109.34, 109.72,
15.22, 117.00, 118.83, 121.05, 121.24, 134.60, 137.78, 156.85, 158.70;
; H
NMR (400 MHz, DMSO-d
6
)
d
2
), 6.22
(
t, 2H, J ¼ 1.84, pyrrole-C
3
4
2
and C
6
2
6
pyrrole-C
2
5
3
5
13
a7
3
5
a14
a15
a5
a16
a21
a6
(
1
6
) d
þ
MS (EI): m/z ¼ found 405.02 [M ]; calcd. 405.02. Anal. Calcd. For
C
18 2
H16INO : C, 53.35; H, 3.98; N, 3.46. Found: C, 53.56; H, 4.00; N,
3.47.
a4
a2
a10
a10
a8
a11
a11
c
Polar indicating the contribution of polar interactions to the total score.
D-score for charge and van der Waals interactions between the protein and the
d
ligand (work of Kuntz) [50].
e
4.36 ꢀ0.512 0.00
PMF-score indicating Helmholtz free energies of interactions for proteineligand
a
atom pairs (Potential of Mean Force, PMF) (work of Muegge and Martin) [51].
CScore (Consensus Score) integrates a number of popular scoring functions for
f
G-score showing hydrogen bonding, complex (ligand-protein), and internal
ranking the affinity of ligands bound to the active site of a receptor and reports the
(
ligandeligand) energies (work of Willett's group) [52].
Chem-score points for H-bonding, lipophilic contact, and rotational entropy,
output of total score.
g
b
Crash-score revealing the inappropriate penetration into the binding site. Crash
along with an intercept term (work of Eldridge, Murray, Auton, Paolini, and Mee)
53].
scores close to 0 are favorable. Negative numbers indicate penetration.
[

332
U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
þ
4
.3.9. 1-(4-(2-(4-Fluorophenoxy)ethoxy)phenyl)-1H-pyrrole (5a9)
132.52, 156.51, 168.33, 190.12; MS (EI): m/z ¼ found 307.52 [M ];
calcd. 307.12. Anal. Calcd. For C19 : C, 74.25; H, 5.58; N, 4.56.
Found: C, 74.55; H, 5.60; N, 4.58.
ꢁ
(
Yield 70%). mp 139e141 C; FTIR (KBr): 3142, 2929 (AreH), 1514
H17NO
3
asym
sym
ꢀ1 1
(
C]C), 1231 (CeOeC
NMR (400 MHz, DMSO-d
J ¼ 2.12, pyrrole-C and C
.99e7.03 (m, 4H, fluoroPh-C
J ¼ 2.08, pyrrole-C and C eH), 7.35, 7.38 (dd, 2H, J ¼ 3.32, 1.84, Ph-
and C ppm: 66.57, 66.81,
eH); 13C NMR (100 MHz, DMSO-d
09.75, 115.22, 115.43, 115.49, 115.57, 115.66, 118.85, 121.01, 133.88,
), 1071 (CeOeC ), 828 (CeF) cm
ppm: 4.30 (q, 4H, 2OCH ), 6.20 (t, 2H,
eH), 6.91e6.95 (m, 2H, Ph-C and C eH),
, C , C and C eH), 7.08 (t, 2H,
; H
6
)
d
2
3
4
2
6
4.3.14. 4-(2-(4-(1H-Pyrrol-1-yl)phenoxy)ethoxy)-3-
6
2
3
5
6
methoxybenzaldehyde (5a14)
ꢁ
2
5
(Yield 60%). mp 152e154 C; FTIR (KBr): 3143, 2925 (AreH),
asym
sym
C
1
3
5
6
)
d
1680 (C]O), 1522 (C]C), 1260 (CeOeC
), 1070 (CeOeC
)
),
ꢀ1
1
cm
4.36e4.47 (m, 4H, 2OCH
and C eH), 7.04e7.21 (m, 6H, Ph-C
aldehyde ph-C , C eH), 7.39e7.42 (m, 2H, ph-C
.51e7.54 (m, 1H, aldehyde Ph-C -H), 9.84 (s, 1H, CHO); C NMR
(100 MHz, DMSO-d ppm: 56.10, 66.40, 66.73, 109.29, 109.32,
;
H NMR (400 MHz, DMSO-d
6
)
d
ppm: 3.87 (s, 3H, OCH
3
þ
1
54.49, 155.45, 156.02, 157.80; MS (EI): m/z ¼ found 297.25 [M ];
calcd. 297.12. Anal. Calcd. For C18 16FNO : C, 72.71; H, 5.42; N, 4.71.
Found: C, 72.42; H, 5.44; N, 4.73.
2
), 6.23, 6.22 (dd, 2H, J ¼ 2.68, 2.16, pyrrole-
, C eH, pyrrole-C , C eH and
and C eH),
H
2
C
3
4
2
6
2
5
3
6
3
5
13
7
5
4.3.10. 1-(4-(2-(4-Nitrophenoxy)ethoxy)phenyl)-1H-pyrrole (5a10)
6
) d
ꢁ
(
Yield 65%). mp 98e100 C; FTIR (KBr): 3107, 2929 (AreH), 1594
109.40, 112.37, 115.57, 115.63, 118.77, 118.89, 124.03, 126.56, 126.26,
asym
sym
asym
(
(
4
(
NO
CeOeC ) cm ; H NMR (400 MHz, CDCl
H, 2OCH
), 6.37 (t, 2H, J ¼ 2.00, pyrrole-C
m, 6H, Ph-C , C eH, nitroPh-C , C
.32e7.42 (m, 2H, Ph-C and C
eH), 8.23, 8.25 (td, 2H, J ¼ 3.40, 3.40,
eH); C NMR (100 MHz, CDCl ppm: 66.59,
6.99, 110.83, 115.36, 115.45, 115.52, 115.69, 118.89, 122.31, 125.98,
26.19, 134.22, 141.85, 156.65, 163.65; MS (EI): m/z ¼ found 324.51
2
), 1515 (C]C), 1332 (NO
2
), 1249 (CeOeC
), 1067
ppm: 4.38e4.46 (m,
and C eH), 6.94e7.06
and C eH),
129.96, 133.00, 151.67, 155.33, 156.69, 190.10; MS (EI): m/z ¼ found
sym
ꢀ1
1
þ
3
)
d
337.52 [M ]; calcd. 337.13. Anal. Calcd. For C20
5.68; N, 4.15. Found: C, 71.48; H, 5.70; N, 4.17.
4
H19NO : C, 71.20; H,
2
3
4
2
6
2
6
eH and pyrrole-C
2
5
7
3
5
4.3.15. 4-(2-(4-(1H-Pyrrol-1-yl)phenoxy)ethoxy)-3-
13
nitroPh-C
6
1
3
and C
5
3
)
d
ethoxybenzaldehyde (5a15)
ꢁ
(Yield 58%). mp 148e150 C; FTIR (KBr): 2922 (AreH), 1601
asym
sym
ꢀ1
;
3
),
(C]O), 1522 (C]C), 1243 (CeOeC
), 1070 (CeOeC ) cm
ppm: 1.67 (s, 3H, OCH CH
), 4.09e4.42 (m, 4H, 2OCH ), 6.22,
.23 (dd, 2H, J ¼ 2.16, 2.12, pyrrole-C and C eH), 6.83e7.28 (m,
6H, Ph-C , C eH, pyrrole-C , C eH and aldehyde ph-C , C eH),
7.43e7.55 (m, 3H, ph-C , C eH and aldehyde Ph-C -H), 9.82 (s, 1H,
CHO); C NMR (100 MHz, DMSO-d ppm: 15.18, 64.91, 67.43,
þ
1
[M ]; calcd. 324.11. Anal. Calcd. For C18
H
16
N
2
O
4
: C, 66.66; H, 4.97; N,
H NMR (400 MHz, DMSO-d
3.24e3.25 (m, 2H, OCH CH
6
)
d
2
8
.64. Found: C, 66.39; H, 4.99; N, 8.61.
2
3
2
6
3
4
4.3.11. 1-(4-(2-(2,4-Dinitrophenoxy)ethoxy)phenyl)-1H-pyrrole
2
6
2
5
3
6
(5a11)
3
5
5
ꢁ
13
(
Yield 65%). mp 104e106 C; FTIR (KBr): 3143, 2918 (AreH),
6
) d
asym
sym
asym
1
559 (NO
2
), 1523 (C]C), 1330 (NO
2
), 1246 (CeOeC
ppm: 4.35e4.45
), 6.33 (t, 2H, J ¼ 2.04, pyrrole-C and C eH),
.93e6.97 (m, 2H, Ph-C and C
eH), 6.98 (t, 2H, J ¼ 2.12, pyrrole-C
eH), 7.20e724 (m, 1H, nitroph-C -H), 7.27e7.33 (m, 2H, ph-
eH), 8.35e8.64 (m, 2H, nitroPh-C
100 MHz, DMSO-d ppm: 66.55, 66.89, 110.81, 114.23, 115.43,
15.50, 115.63, 118.72, 122.34, 126.03, 132.18, 139.50, 141.85, 156.65,
), 1069
68.52, 109.83, 110.56, 112.35, 113.58, 115.16, 115.89, 118.35, 118.89,
122.51, 126.26, 126.37, 129.95, 133.08, 150.20, 155.65, 156.74,
sym
ꢀ1 1
(
CeOeC ) cm ; H NMR (400 MHz, DMSO-d
6
) d
þ
(
m, 4H, 2OCH
2
3
4
190.09; MS (EI): m/z ¼ found 351.33 [M ]; calcd. 351.15. Anal.
6
2
6
2
Calcd. For C21
6.04; N, 3.97.
4
H21NO : C, 71.78; H, 6.02; N, 3.99. Found: C, 71.49; H,
and C
C
(
1
5
6
13
3
and C
5
3 5
and C eH); C NMR
6
)
d
4.3.16. 1-(4-(2-(4-Tolyloxy)ethoxy)phenyl)-1H-pyrrole (5a16)
ꢁ
(Yield 83%). mp 176e178 C; FTIR (KBr): 3143, 2927 (AreH), 1519
þ
asym
sym
ꢀ1
1
1
58.23; MS (EI): m/z ¼ found 369.36 [M ]; calcd. 369.10. Anal.
Calcd. For C18 : C, 58.54; H, 4.09; N, 11.38. Found: C, 58.31;
H, 4.07; N, 11.33.
(C]C), 1235 (CeOeC
(400 MHz, CDCl ppm: 2.29 (s, 3H, CH
2OCH and C
), 6.32 (t, 2H, J ¼ 2.00, pyrrole-C
J ¼ 8.56, methylPh-C and C eH), 6.98e7.00 (m, 4H, Ph-C
and pyrrole-C , C and C
eH), 7.10 (d, 2H, J ¼ 8.20, methylPh-C
7.30e7.33 (m, 2H, Ph-C eH); C NMR (100 MHz, DMSO-d
ppm: 20.06, 66.14, 66.62, 109.73, 114.11, 115.20, 118.85, 121.00,
), 1072 (CeOeC ) cm
), 4.29e4.36 (m, 4H,
eH), 6.87, (d, 2H,
, C eH
eH)
;
H NMR
15
H N
3
O
6
3
)
d
3
2
3
4
2
6
2
6
4.3.12. 4-(2-(4-(1H-Pyrrol-1-yl)phenoxy)ethoxy)benzonitrile
2
5
3
5
13
(5a12)
3
and C
5
6
)
ꢁ
(
Yield 75%). mp 108e110 C; FTIR (KBr): 3139, 2945 (AreH),
d
asym
sym
ꢀ1
þ
2
221 (CN),1603 (C]C), 1252 (CeOeC
), 1068 (CeOeC ) cm
), 6.23
eH), 6.87e6.95 (m, 6H, Ph-C
eH and pyrrole-C , C eH) 7.20e7.25 (m, 2H,
eH), 7.49, 7.50 (dd, 2H, J ¼ 2.60, 1.84, nitrile Ph-C and
eH); C NMR (100 MHz, CDCl ppm: 66.62, 66.86, 104.32,
;
129.35, 129.62, 133.84, 156.06; MS (EI): m/z ¼ found 293.35 [M ];
1
H NMR (400 MHz, CDCl
3
)
d
ppm: 4.24e4.34 (m, 4H, 2OCH
and C
2
calcd. 293.14. Anal. Calcd. For C19
Found: C, 77.48; H, 6.50; N, 4.75.
2
H19NO : C, 77.79; H, 6.53; N, 4.77.
(
t, 2H, J ¼ 2.04, pyrrole-C
eH, nitrileph-C , C
ph-C and C
3
4
2
,
C
6
2
6
2
5
3
5
3
4.3.17. 1-(4-(2-(3-Tolyloxy)ethoxy)phenyl)-1H-pyrrole (5a17)
13
ꢁ
C
5
3
)
d
(Yield 80%). mp 151e153 C; FTIR (KBr): 3142, 2928 (AreH),1525
asym
sym
ꢀ1
1
109.83, 115.42, 115.61, 119.16, 121.75, 134.11, 134.21, 156.43, 161.96;
(C]C), 1244 (CeOeC
(400 MHz, CDCl ppm: 2.33 (s, 3H, CH
2OCH and C
), 6.32 (t, 2H, J ¼ 2.20, pyrrole-C
3H, methylPh-C , C and C eH), 6.97e7.01 (m, 4H, Ph-C
pyrrole-C , C -H), 7.28e7.33
eH), 7.18 (t, 1H, J ¼ 7.56, methylPh-C
(m, 2H, Ph-C eH); C NMR (100 MHz, DMSO-d ppm:
), 1070 (CeOeC ) cm
), 4.30e4.34 (m, 4H,
eH), 6.75e6.80 (m,
, C eH and
;
H NMR
þ
MS (EI): m/z ¼ found 304.23 [M ]; calcd. 304.12. Anal. Calcd. For
3
)
d
3
C
9
H
19 16
N
2
O
2
: C, 74.98; H, 5.30; N, 9.20. Found: C, 74.68; H, 5.28; N,
2
3
4
.24.
2
4
6
2
6
2
5
5
13
4.3.13. 4-(2-(4-(1H-Pyrrol-1-yl)phenoxy)ethoxy)benzaldehyde
3
and C
5
6
) d
(
5a13)
21.11, 65.98, 66.61, 109.77, 111.28, 114.97, 115.24, 118.88, 120.96,
ꢁ
(
Yield 60%). mp 146e148 C; FTIR (KBr): 3142, 2923 (AreH),
121.39, 129.03, 133.82, 138.86, 156.02, 158.20; MS (EI): m/z ¼ found
asym
sym
þ
1
678 (C]O), 1523 (C]C), 1243 (CeOeC
), 1070 (CeOeC
)
293.35 [M ]; calcd. 293.14. Anal. Calcd. For C19
6.53; N, 4.77. Found: C, 78.10; H, 6.50; N, 4.79.
2
H19NO : C, 77.79; H,
ꢀ
1 1
cm ; H NMR (400 MHz, CDCl
3
)
d
ppm: 4.32e4.43 (m, 4H, 2OCH
and C eH), 6.92e7.08 (m, 6H, Ph-C
eH and aldehyde ph-C , C eH), 7.30e7.33 (m,
eH), 7.50e7.52 (d, 2H, J ¼ 8.68, aldehyde Ph-C and
ppm: 66.45,
6.83, 109.77, 114.81, 115.25, 118.88, 120.96, 126.12, 129.97, 131.25,
2
),
6
C
2
C
6
.32 (t, J ¼ 1.96, 2H, pyrrole-C
eH, pyrrole-C , C
H, ph-C and C
eH), 9.90 (s, 1H, CHO); C NMR (100 MHz, CDCl
3
4
2
,
6
2
5
2
6
4.3.18. 1-(4-(2-(2-Tolyloxy)ethoxy)phenyl)-1H-pyrrole (5a18)
ꢁ
3
5
3
(Yield 80%). mp 123e125 C; FTIR (KBr): 3142, 2936 (AreH),1517
13
asym
sym
ꢀ1
1
5
3
)
d
(C]C), 1235 (CeOeC
), 1071 (CeOeC ) cm
;
H NMR
(400 MHz, CDCl ppm: 2.22 (s, 3H, CH
3
)
d
3
), 4.32e4.38 (m, 4H,

U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
333
2
OCH
J ¼ 7.52, methylPh-C
and pyrrole-C , C
eH), 7.16 (t, 2H, J ¼ 8.16, methylPh-C
.30, 7.32 (td, 2H, J ¼ 3.40, 3.28, Ph-C and C eH); C NMR
100 MHz, DMSO-d ppm: 15.87 66.45, 66.71, 109.69, 111.17,
15.26, 118.83, 120.36, 121.08, 126.56, 130.26, 133.89, 156.21, 156.27;
2
), 6.32 (t, 2H, J ¼ 2.12, pyrrole-C
and C eH), 6.99e7.03 (m, 4H, Ph-C
and C
3
and C
4
eH), 6.89 (t, 2H,
, C eH
eH),
18 3
C H17NO : C, 73.20; H, 5.80; N, 4.74. Found: C, 72.91; H, 5.78; N,
4.76.
5
6
2
6
2
5
3
4
1
3
7
(
1
3
5
4.3.23. 3-(2-(4-(1H-Pyrrol-1-yl)phenoxy)ethoxy)phenol (5a23)
ꢁ
6
)
d
(Yield 60%). mp 146e148 C; FTIR (KBr): 3311 (OH), 2930
asym
sym
ꢀ1 1
(AreH),1601 (C]C),1245 (CeOeC
NMR (400 MHz, DMSO-d ppm: 4.22e4.35 (m, 4H, 2OCH
(t, 2H, J ¼ 2.16, pyrrole-C and C eH), 6.37e7.26 (m, 8H, Phenol-C
, C , C eH, Ph-C , C eH and pyrrole-C , C eH), 7.35e7.37 (m, 2H,
Ph-C and C eH), 9.04 (s, 1H, OH); C NMR (100 MHz, DMSO-d
ppm: 66.00, 66.58, 102.50, 106.17, 108.11, 109.80, 110.00, 110.17,
),1070 (CeOeC ) cm ; H
þ
MS (EI): m/z ¼ found 293.35 [M ]; calcd. 293.14. Anal. Calcd. For
6
)
d
2
), 6.31
C
4
19
H
19NO
2
: C, 77.79; H, 6.53; N, 4.77. Found: C, 78.10; H, 6.56; N,
3
4
2
,
.79.
C
4
5
6
2
6
2
5
13
3
5
6
)
4
(
.3.19. 1-(4-(2-(3,5-Dimethylphenoxy)ethoxy)phenyl)-1H-pyrrole
5a19)
Yield 72%). mp 140e142 C; FTIR (KBr): 2921 (AreH), 1514 (C]
d
113.21, 115.23, 115.85, 120.90, 121.21, 129.44, 130.14, 133.83, 156.04,
ꢁ
þ
(
158.31, 159.40; MS (EI): m/z ¼ found 295.17 [M ]; calcd. 295.12.
asym
sym
ꢀ1 1
C), 1239 (CeOeC
CDCl ppm: 2.20e2.25 (m, 6H, 2CH
.31 (t, 2H, J ¼ 2.16, pyrrole-C and C
and C eH), 6.57 (s, 1H, methylph-C
and C
), 1071 (CeOeC ) cm ; H NMR (400 MHz,
3
Anal. Calcd. For C18H17NO : C, 73.20; H, 5.80; N, 4.74. Found: C,
3
)
d
3
), 4.09e4.17 (m, 4H, 2OCH ),
2
73.49; H, 5.82; N, 4.76.
6
3
4
eH), 6.53 (s, 2H, methylPh-C
-H), 6.91e6.95 (m, 2H, ph-C
2
2
6
4
4.3.24. 2-(2-(4-(1H-Pyrrol-1-yl)phenoxy)ethoxy)phenol (5a24)
ꢁ
6
eH), 6.97 (t, 2H, J ¼ 2.12, pyrrole-C
2
and C
5
eH), 7.25e7.28 (m,
ppm: 21.40,
(Yield 65%). mp 153e155 C; FTIR (KBr): 3425 (OH), 3142, 2926
13
asym
sym
ꢀ1 1
2
6
H, Ph-C
3
and C
5
eH); C NMR (100 MHz, CDCl
3
)
d
(AreH),1521 (C]C),1240 (CeOeC
NMR (400 MHz, CDCl ppm: 4.23e4.36 (m, 4H, 2OCH
1H, OH), 6.32 (t, 2H, J ¼ 2.12, pyrrole-C and C eH), 6.96e7.02 (m,
8H, Phenol-C , C , C , C eH, Ph-C , C eH and pyrrole-C , C eH),
7.26e7.33 (m, 2H, Ph-C and C eH); C NMR (100 MHz, CDCl
ppm: 65.68, 67.89, 109.08, 113.84, 114.47, 116.2, 117.53, 118.08,
), 1070 (CeOeC ) cm ; H
7.09, 67.89, 109.27, 112.55, 115.28, 119.57, 122.14, 122.49, 134.51,
3
)
d
2
), 5.75 (s,
þ
1
39.09, 156.89, 158.90; MS (EI): m/z ¼ found 307.51 [M ]; calcd.
3
4
3
07.16. Anal. Calcd. For C20
H21NO
2
: C, 78.15; H, 6.89; N, 4.56. Found:
3
4
5
6
2
6
2
5
1
3
C, 78.46; H, 6.92; N, 4.58.
3
5
3
)
d
4
.3.20. 1-(4-(2-(2,5-Dimethylphenoxy)ethoxy)phenyl)-1H-pyrrole
119.89, 120.19, 120.38, 131.79, 133.20, 144.72, 145.43, 147.43, 155.13;
þ
(5a20)
MS (EI): m/z ¼ found 295.21 [M ]; calcd. 295.12. Anal. Calcd. For
ꢁ
(
Yield 75%). mp 141e143 C; FTIR (KBr): 3142, 2925 (AreH),1521
18 3
C H17NO : C, 73.20; H, 5.80; N, 4.74. Found: C, 73.49; H, 5.82; N,
asym
sym
ꢀ1
1
(
(
CH
C]C), 1260 (CeOeC
400 MHz, CDCl
at C
), 1073 (CeOeC ) cm
at C position), 2.32 (s, 3H,
position), 4.33e4.36 (m, 4H, 2OCH ), 6.32, 6.33 (dd, 2H,
J ¼ 1.44, 2.08, pyrrole-C and C eH), 6.69e6.71 (m, 2H, methylPh-
and C eH), 7.00e7.03 (m, 5H, ph-C , C eH, pyrrole-C , C eH and
methylph-C -H), 7.30e7.33 (m, 2H, Ph-C and C eH); C NMR
100 MHz, DMSO-d ppm: 15.84, 21.41, 66.83, 67.20, 109.93,
12.58, 115.61, 119.70, 121.49, 122.18, 124.04, 130.58, 134.83, 136.59,
;
H NMR
4.76.
3
)
d
ppm: 2.17 (s, 3H, CH
3
2
3
5
2
4.3.25. 5-(2-(4-(1H-Pyrrol-1-yl)phenoxy)ethoxy)-2-chlorophenol
3
4
(5a25)
ꢁ
C
4
6
2
4
2
5
(Yield 60%). mp 92e94 C; FTIR (KBr): 3320 (OH), 2930 (AreH),
1
3
asym
sym
3
3
5
1601 (C]C), 1243 (CeOeC
), 1070 (CeOeC ), 721 (CeCl)
H NMR (400 MHz, DMSO-d ppm: 4.31e4.39 (m, 4H,
and C eH),
eH and pyrrole-C
ꢀ1
1
(
1
6
)
d
cm
2OCH
6.51e7.25 (m, 7H, Phenol-C
;
6
) d
2
), 6.32, 6.33 (dd, 2H, J ¼ 2.28, 2.20, pyrrole-C
3
4
þ
1
56.66, 156.90; MS (EI): m/z ¼ found 307.15 [M ]; calcd. 307.16.
2
, C
5
, C
and C
ppm: 66.48, 66.60, 102.00, 109.39,
6
eH, Ph-C
2
, C
6
2
,
C
13
Anal. Calcd. For C20 : C, 78.15; H, 6.89; N, 4.56. Found: C,
H21NO
2
C
5
eH), 7.25e7.33 (m, 2H, Ph-C
3
5
eH), 9.54 (s, 1H, OH);
7
8.46; H, 6.92; N, 4.54.
NMR (100 MHz, DMSO-d
6
)
d
1
10.13, 113.56, 115.81, 117.62, 118.53, 120.58, 121.22, 129.75, 132.35,
þ
4.3.21. 1-(4-(2-(2,4-Dimethylphenoxy)ethoxy)phenyl)-1H-pyrrole
154.24, 155.27, 156.08; MS (EI): m/z ¼ found 329.11 [M ]; calcd.
(
5a21)
3
329.08. Anal. Calcd. For C18H16ClNO : C, 65.56; H, 4.89; N, 4.25.
ꢁ
(
Yield 70%). mp 98e100 C; FTIR (KBr): 3132, 2924 (AreH), 1515
Found: C, 65.82; H, 4.91; N, 4.23.
asym
sym
ꢀ1
1
(
C]C), 1245 (CeOeC
), 1072 (CeOeC ) cm
ppm: 2.12 (s, 3H, CH at C position), 2.21 (s,
position), 4.26e4.35 (m, 4H, 2OCH ), 6.21 (t, 2H,
J ¼ 2.08, pyrrole-C and C eH), 6.83 (d, 1H, J ¼ 8.76, methylPh-C
H), 6.93 (d, 2H, J ¼ 5.52, methylph-C and C eH), 7.03e7.07 (m, 2H,
ph-C and C and C eH),
eH), 7.15 (t, 2H, J ¼ 2.36, pyrrole-C
eH); C NMR (100 MHz, DMSO-d
ppm: 16.17, 20.48, 67.15, 67.22, 109.91, 109.98, 111.76, 115.55,
15.60, 119.69, 122.17, 126.98, 127.06, 130.23, 131.68, 134.81, 154.69,
;
H NMR
(
3
400 MHz, DMSO-d
H, CH at C
6
)
d
3
2
4.3.26. 5-(2-(4-(1H-Pyrrol-1-yl)phenoxy)ethoxy)benzene-1,3-diol
3
4
2
(5a26)
ꢁ
3
4
6
-
(Yield 60%). mp 138e140 C; FTIR (KBr): 3429 (OH), 3143, 2930
asym
sym
ꢀ1 1
3
5
(AreH), 1518 (C]C), 1241 (CeOeC
NMR (400 MHz, CDCl ppm: 4.27e4.49 (m, 4H, 2OCH
2H, 2OH), 6.16 (s, 1H, phenol-C
and C eH), 6.87e6.95 (m, 3H, Ph-C
6.99e7.02 (m, 2H, pyrrole-C and C
-H); C NMR (100 MHz, CDCl
), 1069 (CeOeC ) cm ; H
2
6
2
5
3
)
d
2
), 6.10 (s,
1
3
7
d
.40e7.43 (m, 2H, Ph-C
3
and C
5
6
)
4
-H), 6.27e6.31 (m, 2H, pyrrole-C
3
4
2
, C
6
eH and phenol-C
2
-H),
1
1
2
5
eH), 7.21e7.34 (m, 3H, Ph-C
3
,
þ
13
56.90; MS (EI): m/z ¼ found 307.10 [M ]; calcd. 307.16. Anal. Calcd.
C
5
eH and phenol-C
6
3
) d
ppm: 68.65,
For C20 : C, 78.15; H, 6.89; N, 4.56. Found: C, 77.84; H, 6.86; N,
H
21NO
2
69.10, 90.03, 92.11, 97.21, 107.23, 113.15, 113.88, 118.01, 118.26,
4
.54.
119.54, 119.91, 132.01, 154.26, 154.49, 155.55, 158.03; MS (EI): m/
þ
z ¼ found 311.25 [M ]; calcd. 311.12. Anal. Calcd. For C18
4
H17NO : C,
4.3.22. 4-(2-(4-(1H-Pyrrol-1-yl)phenoxy)ethoxy)phenol (5a22)
69.44; H, 5.50; N, 4.50. Found: C, 69.16; H, 5.48; N, 4.48.
ꢁ
(
Yield 65%). mp 148e150 C; FTIR (KBr): 3423 (OH), 3143, 2927
asym
sym
ꢀ1 1
(
AreH),1520 (C]C),1239 (CeOeC
NMR (400 MHz, CDCl ppm: 4.27e4.49 (m, 4H, 2OCH
H, OH), 6.33e6.37 (m, 2H, pyrrole-C and C eH), 6.78e7.09 (m,
H, Phenol-C , C , C , C eH, Ph-C , C eH and pyrrole-C , C eH),
and C eH); C NMR (100 MHz, CDCl
ppm: 68.65, 69.10, 109.88, 110.00, 110.48, 113.23, 115.56, 116.29,
),1070 (CeOeC ) cm ; H
4.3.27. 1-(4-(2-(Naphthalen-1-yloxy)ethoxy)phenyl)-1H-pyrrole
3
)
d
2
), 5.76 (s,
(5a27)
ꢁ
1
8
3
4
(Yield 65%). mp 140e142 C; FTIR (KBr): 3143, 2945 (AreH),
asym
sym
ꢀ1 1
2
3
5
6
2
6
2
5
1523 (C]C), 1262 (CeOeC
(400 MHz, CDCl ppm: 4.46e4.51 (m, 4H, 2OCH
2H, J ¼ 1.96, 2.16, pyrrole-C and C
naphthyl-C -H), 6.97e7.05 (m, 4H, Ph-C
eH), 7.30e7.50 (m, 6H, Ph-C , C eH and naphthyl-C
), 1072 (CeOeC ) cm
; H NMR
1
3
7.31e7.38 (m, 2H, Ph-C
3
5
3
)
3
)
d
2
), 6.32, 6.33 (dd,
d
3
4
eH), 6.87 (d, 1H, J ¼ 6.88,
119.63, 119.69, 121.82, 122.45, 132.00, 155.67, 156.01, 156.67; MS
2
2
, C
6
eH and pyrrole-C
, C ,C
2
,
,
þ
(
EI): m/z ¼ found 295.10 [M ]; calcd. 295.12. Anal. Calcd. For
C
5
3
5
3
4
6

334
U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
C
7
eH), 7.80 (d, 1H, J ¼ 7.36, naphthyl-C
naphthyl-C
-H); 13C NMR (100 MHz, DMSO-d
05.06, 109.96, 110.47, 115.55, 115.67, 119.60, 119.70, 120.83, 122.11,
22.16, 122.22, 125.31, 125.72, 126.53, 127.47, 134.58, 134.92, 154.43,
5
-H), 8.27 (d, 1H, J ¼ 7.16,
4.3.34. 1-(4-(3-Phenoxypropoxy)phenyl)-1H-pyrrole (6a1)
ꢁ
8
6
)
d
ppm: 66.94, 67.08,
(Yield 85%). mp 95e97 C; FTIR (KBr): 3134, 2929 (AreH), 1520
asym
sym
ꢀ1
1
1
1
(C]C), 1237 (CeOeC
(400 MHz, CDCl ppm: 2.26 (p, 2H, eCH
J ¼ 3.00, 3.24, 2OCH ), 6.31 (t, 2H, J ¼ 2.16, pyrrole-C
6.89e6.97 (m, 5H, Ph-C , C , C eH and Ph-C , C eH at pyrrole), 6.98
(t, 2H, J ¼ 2.16, pyrrole-C and C eH), 7.25e7.30 (m, 4H, both ph-C
eH); C NMR (100 MHz, CDCl ppm: 29.42, 64.31, 64.93,
09.99, 114.61, 115.35, 119.74, 120.90, 122.20, 129.60, 134.62, 157.04,
), 1064 (CeOeC ) cm
e), 4.15, 4.18 (td, 4H,
and C eH),
;
H NMR
3
)
d
2
þ
1
56.87; MS (EI): m/z ¼ found 329.14 [M ]; calcd. 329.14. Anal. Calcd.
For C22 : C, 80.22; H, 5.81; N, 4.25. Found: C, 79.90; H, 5.79;
N, 4.27.
2
3
4
H19NO
2
2
4
6
2
6
2
5
3
13
and C
1
5
3
) d
4
(
.3.28. 1-(4-(2-(Naphthalen-2-yloxy)ethoxy)phenyl)-1H-pyrrole
5a28)
Yield 65%). mp 143e145 C; FTIR (KBr): 2920 (AreH), 1517 (C]
þ
1
58.93; MS (EI): m/z ¼ found 293.14 [M ]; calcd. 293.14. Anal. Calcd.
ꢁ
For C19
2
H19NO : C, 77.79; H, 6.53; N, 4.77. Found: C, 77.48; H, 6.56; N,
(
asym
sym
ꢀ1 1
4.79.
C), 1253 (CeOeC
CDCl ppm: 4.36e4.53 (m, 4H, 2OCH
pyrrole-C and C eH), 6.92e7.05 (m, 4H, Ph-C
eH), 7.19e7.25 (m, 2H, naphthyl-C and C
H, Ph-C , C eH and naphthyl-C
-H), 7.45 (t, 1H, J ¼ 7.04, naphthyl-
-H), 7.73e7.83 (m, 3H, naphthyl-C
ppm: 66.91, 67.01, 106.52, 109.79, 115.03, 118.75,
19.72, 122.21, 123.45, 126.27, 126.77, 127.53, 129.00, 129.32, 134.51,
), 1070 (CeOeC ) cm ; H NMR (400 MHz,
), 6.32 (t, 2H, J ¼ 2.04,
, C eH and pyrrole-
eH), 7.31e7.37 (m,
3
)
d
2
4
(
.3.35. 1-(4-(3-(4-Chlorophenoxy)propoxy)phenyl)-1H-pyrrole
6a2)
Yield 75%). mp 103e105 C; FTIR (KBr): 3141, 2926 (AreH),1525
3
4
2
6
C
3
C
2
, C
5
3
5
ꢁ
(
3
5
6
asym
sym
ꢀ1 1
13
(C]C), 1240 (CeOeC
NMR (400 MHz, CDCl
OCH
), 6.31 (t, 2H, J ¼ 2.16, pyrrole-C
2H, J ¼ 2.12, 3.40, Ph-C and C eH), 6.93, 6.95 (td, 2H, J ¼ 2.12, 3.36,
chloroPh-C and C eH) 6.99 (t, 2H, pyrrole-C and C eH), 7.21, 7.23
td, 2H, chloroPh-C and C
eH), 7.28, 7.30 (td, 2H, J ¼ 2.08, 3.32, Ph-
eH); C NMR (100 MHz, CDCl ppm: 29.26, 64.69, 109.89,
), 1063 (CeOeC ), 823 (CeCl) cm ; H
ppm: 2.26 (p, 2H, eCH e), 4.15 (p, 4H,
and C eH), 6.83, 6.85 (td,
7
4 5 8
, C and C eH); C NMR
3
)
d
2
(
3
100 MHz, CDCl ) d
2
2
3
4
1
þ
2
6
1
56.77, 156.86; MS (EI): m/z ¼ found 329.17 [M ]; calcd. 329.14.
2
6
2
5
Anal. Calcd. For C22 : C, 80.22; H, 5.81; N, 4.25. Found: C,
H19NO
2
(
C
3
5
8
0.54; H, 5.83; N, 4.27.
13
3
, C
5
3
) d
1
15.26, 115.53, 115.79, 119.68, 122.19, 125.67, 129.35, 134.62, 156.90,
4
.3.29. 1,2-Bis(4-(1H-pyrrol-1-yl)phenoxy)ethane (5a29)
þ
1
57.47; MS (EI): m/z ¼ found 327.78 [M ]; calcd. 327.10. Anal. Calcd.
For C19 18ClNO : C, 69.62; H, 5.53; N, 4.27. Found: C, 69.34; H, 5.55;
N, 4.25.
ꢁ
(
Yield 70%). mp 138e140 C; FTIR (KBr): 3147, 2923 (AreH),
H
2
asym
sym
ꢀ1 1
1
522 (C]C), 1241 (CeOeC
400 MHz, CDCl ppm: 4.40e4.42 (m, 4H, 2OCH
J ¼ 2.12, pyrrole-C and C eH), 6.93e7.05 (m, 8H, 2Ph-C
pyrrole-C , C eH), 7.31e7.36 (m, 4H, 2Ph-C and C eH); C NMR
100 MHz, CDCl ppm: 70.26, 109.43, 110.14, 115.20, 115.86,
17.63, 118.86, 121.01, 132.42, 155.31; MS (EI): m/z ¼ found 344.19
), 1070 (CeOeC ) cm
), 6.32 (t, 4H,
, C eH and
; H NMR
(
3
)
d
2
3
4
2
6
4.3.36. 1-(4-(3-(3-Chlorophenoxy)propoxy)phenyl)-1H-pyrrole
1
3
2
5
3
5
(6a3)
(
1
3
)
d
ꢁ
Yield 75%). mp 113e115 C; FTIR (KBr): 3143, 2922 (AreH), 1521
(
asym
sym
ꢀ1 1
(
C]C), 1241 (CeOeC
), 1071 (CeOeC ), 826 (CeCl) cm ; H
ppm: 2.27 (p, 2H, eCH e), 4.35 (p, 4H,
), 6.32 (t, 2H, J ¼ 2.16, pyrrole-C and C eH), 6.85e6.90 (m,
H, chloroPh-C -H), 7.01e7.06 (m, 6H, Ph-C , C eH, chloroPh-C
eH and pyrrole-C and C eH), 7.29 (q, 1H, chloroPh-C -H),
, C eH); C NMR (100 MHz, CDCl ppm:
þ
[M ]; calcd. 344.15. Anal. Calcd. For C22
20 2 2
H N O : C, 76.72; H, 5.85;
NMR (400 MHz, CDCl
3
)
d
2
N, 8.13. Found: C, 77.03; H, 5.87; N, 8.16.
2
1
C
OCH
2
3
4
6
2
6
2
,
4
.3.30. 1-(4-(2-(4-(1H-Pyrrol-1-yl)phenoxy)ethoxy)phenyl)-2,5-
dimethyl-1H-pyrrole (5a30)
Yield 72%). mp 126e128 C; FTIR (KBr): 3146, 2928 (AreH),
6
2
5
5
13
7.33e7.37 (m, 2H, Ph-C
3
5
3
) d
ꢁ
(
29.12, 64.77, 109.89, 113.12, 115.34, 115.97, 119.50, 121.38, 122.06,
asym
sym
ꢀ1
1
þ
1
520 (C]C), 1246 (CeOeC
400 MHz, CDCl ppm: 2.01 (s, 6H, 2CH
.88 (s, 2H, Dimethylpyrrole-C and C
eH), 6.32 (t, 4H, J ¼ 2.08,
pyrrole-C and C eH), 6.99e7.02 (m, 6H, 2Ph-C , C eH and pyrrole-
, C
and C
NMR (100 MHz, CDCl
15.52, 119.67, 122.17, 129.03, 129.34, 132.24, 134.94, 156.66, 157.91;
), 1071 (CeOeC ) cm
;
H NMR
130.30, 134.76, 156.77, 159.03; MS (EI): m/z ¼ found 327.10 [M ];
(
5
3
)
d
3
), 4.36 (s, 4H, 2OCH
2
),
2
calcd. 327.10. Anal. Calcd. For C19H18ClNO : C, 69.62; H, 5.53; N, 4.27.
3
4
Found: C, 69.90; H, 5.51; N, 4.25.
3
4
2
6
C
2
5
eH), 7.13, 7.14 (dd, 2H, J ¼ 2.16, 1.84, DimethylpyrrolePh-C
3
C
4.3.37. 1-(4-(3-(2-Chlorophenoxy)propoxy)phenyl)-1H-pyrrole
(6a4)
13
5
eH), 7.31, 7.33 (dd, 2H, J ¼ 2.16, 1.80, Ph-C
3
and C
5
eH),;
ꢁ
3
)
d
ppm: 66.76, 66.90, 105.38, 110.01, 114.97,
(Yield 73%). mp 136e138 C; FTIR (KBr): 3129, 2931 (AreH),
asym
sym
1
1521 (C]C), 1245 (CeOeC
), 1065 (CeOeC ), 729 (CeCl)
ppm: 2.31 (p, 2H, eCH e), 4.20,
4.22, 4.23 (dt, 4H, J ¼ 1.28, 1.48, 1.64, 2OCH ), 6.31 (t, 2H, J ¼ 2.16,
pyrrole-C and C
eH), 6.86, 6.88, 6.90 (dt, 2H, J ¼ 1.40, 1.32, 1.36,
chloroPh-C -H), 6.92e6.99 (m, 5H, Ph-C , C eH, chloroPh-C -H and
pyrrole-C , C
eH), 7.17, 7.19, 7.21 (dt, 1H, J ¼ 1.60, 1.44, 1.56, chlor-
oPh-C , C eH), 7.34, 7.36
-H), 7.27, 7.29 (td, 2H, J ¼ 3.40, 2.24, Ph-C
(dd, 1H, J ¼ 1.64, 1.60, chloroPh-C -H); C NMR (100 MHz, CDCl
ppm: 29.28, 64.69, 65.47, 109.91, 113.53, 115.53, 115.33, 119.71,
21.55, 122.19, 123.03, 127.78, 130.35, 134.59, 154.39, 156.96; MS
þ
ꢀ1 1
MS (EI): m/z ¼ found 372.45 [M ]; calcd. 372.18. Anal. Calcd. For
cm ; H NMR (400 MHz, CDCl
3
)
d
2
C
7.49.
24 24
H N
2
O
2
: C, 77.39; H, 6.49; N, 7.52. Found: C, 77.08; H, 6.52; N,
2
3
4
4
2
6
6
2
5
4
.3.31. 4-(2-(4-(1H-Pyrrol-1-yl)phenoxy)ethoxy)aniline (5a31)
ꢁ
5
3
5
(
Yield 63%). mp 98e100 C; FTIR (KBr): 3407 (NH
2
), 2922
13
asym
sym
ꢀ1
3
3
)
(
AreH), 1514 (C]C), 1237 (CeOeC
), 1069 (CeOeC ) cm
;
þ
d
MS (EI): m/z ¼ found 294.17 [M ]; calcd. 294.14.
1
þ
(
C
EI): m/z ¼ found 327.10 [M ]; calcd. 327.10. Anal. Calcd. For
4.3.32. 3-(2-(4-(1H-Pyrrol-1-yl)phenoxy)ethoxy)aniline (5a32)
19
2
H18ClNO : C, 69.62; H, 5.53; N, 4.27. Found: C, 69.90; H, 5.51; N,
ꢁ
(
Yield 60%). mp 145e147 C; FTIR (KBr): 3383 (NH
2
), 2924
4.29.
asym
sym
ꢀ1
(
AreH), 1517 (C]C), 1242 (CeOeC
), 1070 (CeOeC ) cm
;
þ
MS (EI): m/z ¼ found 294.17 [M ]; calcd. 294.14.
4
(
.3.38. 1-(4-(3-(4-Bromophenoxy)propoxy)phenyl)-1H-pyrrole
6a5)
(Yield 77%). mp 101e103 C; FTIR (KBr): 3140, 2944 (AreH),
ꢁ
4.3.33. 2-(2-(4-(1H-Pyrrol-1-yl)phenoxy)ethoxy)aniline (5a33)
ꢁ
asym
sym
(
Yield 60%). mp 140e142 C; FTIR (KBr): 3375 (NH
2
), 3140, 2932
1524 (C]C), 1241 (CeOeC
cm ; H NMR (400 MHz, CDCl
(p, 4H, 2OCH
), 1063 (CeOeC ), 820 (CeBr)
ppm: 2.26 (p, 2H, eCH e), 4.14
), 6.31 (t, 2H, J ¼ 2.16, pyrrole-C and C eH), 6.78, 6.80
asym
sym
ꢀ1
ꢀ1 1
(
AreH), 1521 (C]C), 1241 (CeOeC
), 1071 (CeOeC ) cm
;
3
)
d
2
þ
MS (EI): m/z ¼ found 294.17 [M ]; calcd. 294.14.
2
3
4

U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
335
(
td, 2H, J ¼ 2.04, 3.36, bromoPh-C
J ¼ 2.12, 3.48, Ph-C and C eH), 6.99 (t, 2H, J ¼ 2.12, pyrrole-C
eH), 7.28, 7.30 (td, 2H, J ¼ 2.12, 3.28, bromoPh-C and C
.35, 7.37 (td, 2H, J ¼ 2.08, 3.40, Ph-C and C eH); C NMR
100 MHz, CDCl ppm: 29.21, 64.60, 64.64, 109.86, 112.93, 115.22,
15.22, 115.50, 116.29, 119.67, 122.18, 132.27, 134.60, 156.87, 157.94;
2
and C
6
eH), 6.93, 6.95 (td, 2H,
and
eH),
115.57, 115.77, 115.99, 119.70, 122.18, 134.63, 155.03, 155.05, 156.15,
þ
2
6
2
156.97, 158.52; MS (EI): m/z ¼ found 311.13 [M ]; calcd. 311.13. Anal.
C
7
(
1
5
3
5
Calcd. For C19
2
H18FNO : C, 73.29; H, 5.83; N, 4.50. Found: C, 73.58; H,
13
3
5
5.81; N, 4.48.
3
) d
4.3.43. 1-(4-(3-(4-Nitrophenoxy)propoxy)phenyl)-1H-pyrrole
þ
MS (EI): m/z ¼ found 372.25 [M þ1]; calcd. 371.05. Anal. Calcd. For
(6a10)
ꢁ
C
3
19
H
18BrNO
2
: C, 61.30; H, 4.87; N, 3.76. Found: C, 61.05; H, 4.89; N,
(Yield 62%). mp 138e140 C; FTIR (KBr): 3076, 2934 (AreH),
asym
sym
asym
.78.
1592 (NO
2
), 1518 (C]C), 1338 (NO
2
), 1255 (CeOeC
CeOeC ) cm ; H NMR (400 MHz, CDCl ppm: 2.23 (p, 2H,
eCH near to pyrrole), 4.27 (t, 2H,
e), 4.19 (t, 2H, J ¼ 5.92, OCH
J ¼ 6.12, OCH near to nitro ph), 6.31 (t, 2H, J ¼ 2.16, pyrrole-C and
eH), 6.92e6.99 (m, 6H, Ph-C , C eH, nitroph-C , C eH and pyr-
role-C , C and C eH),
eH) 7.29, 7.31 (td, 2H, J ¼ 3.36, 3.48, ph-C
8.18, 8.20 (td, 2H, J ¼ 3.40, 3.32, nitroPh-C and C eH); C NMR
(100 MHz, CDCl ppm: 29.07, 64.33, 65.27, 109.88, 109.95, 114.47,
), 1059
sym
ꢀ1 1
(
3
) d
4
.3.39. 1-(4-(3-(3-Bromophenoxy)propoxy)phenyl)-1H-pyrrole
2
2
(6a6)
2
3
ꢁ
(
Yield 72%). mp 126e128 C; FTIR (KBr): 3140, 2944 (AreH),
C
4
2
6
2
6
asym
sym
1
523 (C]C), 1249 (CeOeC
), 1065 (CeOeC ), 718 (CeBr)
ppm: 2.25 (p, 2H, eCH e), 4.14
), 6.31 (t, 2H, J ¼ 2.16, pyrrole-C and C eH),
.81e6.84 (m, 1H, bromoPh-C
-H), 6.92, 6.93 (td, 2H, J ¼ 2.20, 2.24,
eH), 6.98 (t, 2H, J ¼ 2.12, pyrrole-C and C eH),
, C , C
eH), 7.27, 7.29 (td, 2H, J ¼ 2.16,
eH); C NMR (100 MHz, CDCl ppm: 29.27,
2
5
3
5
ꢀ
1
1
13
cm ; H NMR (400 MHz, CDCl
p, 4H, J ¼ 2OCH
3
)
d
2
3
5
(
6
2
3
4
3
) d
6
115.22, 119.65, 122.19, 125.96, 134.73, 141.58, 156.73, 163.89; MS
þ
Ph-C
2
and C
6
2
5
(EI): m/z ¼ found 338.13 [M ]; calcd. 338.13. Anal. Calcd. For
7
2
6
.05e7.13 (m, 3H, bromoPh-C
.16, Ph-C
2
4
5
19 18 2 4
C H N O : C, 67.44; H, 5.36; N, 8.28. Found: C, 67.71; H, 5.34; N,
13
3
and C
5
3
)
d
8.31.
4.70, 64.92, 109.85, 112.56, 115.45, 115.65, 116.57, 119.70, 122.20,
þ
1
32.87, 134.56,156.80,158.03; MS (EI): m/z ¼ found 372.25 [M þ1];
4.3.44. 1-(4-(3-(2,4-Dinitrophenoxy)propoxy)phenyl)-1H-pyrrole
calcd. 371.05. Anal. Calcd. For C19
3
H
18BrNO
2
: C, 61.30; H, 4.87; N,
(6a11)
ꢁ
.76. Found: C, 61.05; H, 4.89; N, 3.74.
(Yield 60%). mp 58e60 C; FTIR (KBr): 3141, 2951 (AreH), 1607
asym
sym
asym
(
NO
(CeOeC ) cm ; H NMR (400 MHz, CDCl
eCH ), 4.04 (t, 2H, J ¼ 5.80, OCH
e), 3.37 (t, 2H, J ¼ 6.80, OCH
(t, 2H, J ¼ 1.80, pyrrole-C and C eH), 6.92e6.95 (m, 2H, Ph-C
eH), 6.97e6.99 (m, 2H, pyrrole-C and C
eH), 7.21 (t, 1H, J ¼ 8.76,
nitroph-C and C eH),
-H), 7.28, 7.30 (dd, 2H, J ¼ 7.12, 3.20, ph-C
8.38, 8.40 (dd, 1H, J ¼ 2.40, 2.60, nitroPh-C -H), 8.73 (d, 1H, J ¼ 2.56,
ppm: 29.02, 64.66,
2
), 1522 (C]C), 1343 (NO
2
), 1253 (CeOeC
ppm: 2.27 (p, 2H,
), 6.31
and
), 1067
sym
ꢀ1 1
4
.3.40. 1-(4-(3-(2-Bromophenoxy)propoxy)phenyl)-1H-pyrrole
3
) d
(6a7)
2
2
2
ꢁ
(
Yield 70%). mp 138e140 C; FTIR (KBr): 3129, 2929 (AreH),
3
4
2
asym
sym
1
520 (C]C), 1249 (CeOeC
), 1064 (CeOeC ), 729 (CeBr)
ppm: 2.28 (p, 2H, eCH e), 4.19
), 6.30 (t, 2H, J ¼ 1.96, pyrrole-C and C eH), 6.80 (t,
H, J ¼ 7.52, bromoPh-C -H), 6.89 (d, 1H, J ¼ 8.20, bromoPh-C -H),
.93, 6.95 (dd, 2H, J ¼ 1.80, 1.76, Ph-C and C eH), 6.97 (t, 2H,
and C eH), 7.19e7.28 (m, 3H, bromoPh-C -H
eH), 7.50, 7.52 (dd, 1H, J ¼ 1.36, 1.28, bromoPh-C -H);
C NMR (100 MHz, CDCl ppm: 29.26, 29.76, 64.72, 65.48,
09.89, 112.34, 113.33, 115.33, 119.71, 122.03, 122.19, 128.53, 133.40,
C
6
2
5
ꢀ
1 1
cm ; H NMR (400 MHz, CDCl
p, 4H, 2OCH
3
)
d
2
6
3
5
(
1
6
2
3
4
5
13
6
4
3 3
nitroPh-C -H); C NMR (100 MHz, CDCl ) d
2
6
65.23, 110.76, 114.20, 115.35, 115.49, 115.61, 118.65, 122.42, 126.01,
J ¼ 2.00, pyrrole-C
2
5
5
132.17, 139.53, 141.87, 156.60, 158.20; MS (EI): m/z ¼ found 383.15
þ
and Ph-C , C
3
5
3
[M ]; calcd. 383.11. Anal. Calcd. For C19
H
17
N
3
O
6
: C, 59.53; H, 4.47; N,
1
3
3
)
d
10.96. Found: C, 59.29; H, 4.49; N, 11.00.
1
þ
1
3
34.58, 155.20, 156.96; MS (EI): m/z ¼ found 371.05 [M ]; calcd.
71.05. Anal. Calcd. For C19 18BrNO : C, 61.30; H, 4.87; N, 3.76.
Found: C, 61.55; H, 4.85; N, 3.74.
4.3.45. 4-(3-(4-(1H-Pyrrol-1-yl)phenoxy)propoxy)benzonitrile
H
2
(6a12)
ꢁ
(Yield 72%). mp 122e124 C; FTIR (KBr): 3138, 2922 (AreH),
asym
sym
ꢀ1
;
2
222 (CN),1525 (C]C), 1258 (CeOeC
), 1061 (CeOeC ) cm
ppm: 2.30 (p, 2H, eCH e), 4.17 (t, 2H,
near to pyrrole), 4.22 (t, 2H, J ¼ 6.08, OCH near to
nitrile ph), 6.31 (t, 2H, J ¼ 2.12, pyrrole-C and C eH), 6.93e6.99 (m,
6H, Ph-C , C eH, nitrileph-C , C eH and pyrrole-C , C eH) 7.28,
7.30 (td, 2H, J ¼ 3.44, 3.44, ph-C and C eH), 7.56, 7.58 (td, 2H,
J ¼ 2.64, 2.68, nitrile Ph-C and C
ppm: 28.41, 64.25, 64.73, 102.95, 109.76, 115.19, 115.37, 118.92,
1
4
.3.41. 1-(4-(3-(4-Iodophenoxy)propoxy)phenyl)-1H-pyrrole (6a8)
H NMR (400 MHz, CDCl
J ¼ 5.96, OCH
3
)
d
2
ꢁ
(
Yield 65%). mp 113e115 C; FTIR (KBr): 3141, 2951 (AreH), 1521
2
2
asym
sym
ꢀ1 1
(
C]C), 1245 (CeOeC
), 1065 (CeOeC ), 719 (CeI) cm
ppm: 2.24 (p, 2H, eCH e), 4.12 (p, 4H,
), 6.31 (t, 2H, J ¼ 2.04, pyrrole-C and C eH), 6.66, 6.69 (td,
H, J ¼ 3.04, 3.08, iodoPh-C and C eH), 6.91, 6.94 (td, 2H, J ¼ 3.40,
.32, Ph-C and C and C eH),
eH), 6.98 (t, 2H, J ¼ 2.08, pyrrole-C
.26, 7.29 (td, 2H, J ¼ 3.40, 3.32, Ph-C and C eH), 7.52, 7.54 (td, 2H,
J ¼ 2.96, 3.08, iodoPh-C and C eH); C NMR (100 MHz, CDCl
ppm: 29.23, 64.51, 64.68, 82.86, 109.92, 115.27, 116.96, 119.69,
22.19, 134.62, 138.27, 156.89, 158.75; MS (EI): m/z ¼ found 419.04
;
H
3
4
NMR (400 MHz, CDCl
3
)
d
2
2
6
2
6
2
5
2
2
3
OCH
2
3
4
3
5
13
2
6
3
5 3
eH); C NMR (100 MHz, CDCl )
2
6
2
5
d
7
3
5
120.94, 133.69, 133.94, 156.12, 161.86; MS (EI): m/z ¼ found 318.14
13
þ
3
5
3
)
[M ]; calcd. 318.14. Anal. Calcd. For C20
H
18
N
2
O
2
: C, 75.45; H, 5.70;
d
N, 8.80. Found: C, 75.15; H, 5.72; N, 8.76.
1
þ
[M ]; calcd. 419.04. Anal. Calcd. For C19
H18INO
2
: C, 54.43; H, 4.33;
4.3.46. 4-(3-(4-(1H-Pyrrol-1-yl)phenoxy)propoxy)benzaldehyde
N, 3.34. Found: C, 54.65; H, 4.31; N, 3.33.
(6a13)
ꢁ
(Yield 60%). mp 74e76 C; FTIR (KBr): 3142, 2940 (AreH), 1666
asym
sym
ꢀ1 1
4.3.42. 1-(4-(3-(4-Fluorophenoxy)propoxy)phenyl)-1H-pyrrole
(C]O), 1521 (C]C), 1245 (CeOeC
), 1062 (CeOeC ) cm ; H
e),
eH),
eH and aldehyde ph-
eH), 7.45e7.49 (m, 2H,
(
6a9)
NMR (400 MHz, CDCl
4.14e4.27 (m, 4H, 2OCH
6.88e7.02 (m, 6H, Ph-C
, C eH) 7.24e7.30 (m, 2H, ph-C
aldehyde Ph-C and C eH), 9.87 (s, 1H, CHO); C NMR (100 MHz,
CDCl ppm: 29.02, 64.56, 65.03, 109.70, 114.80, 115.22, 118.56,
3
)
d
ppm: 2.18e2.34 (m, 2H, eCH
), 6.30e6.31 (m, 2H, pyrrole-C and C
, C eH, pyrrole-C , C
and C
2
ꢁ
(
Yield 68%). mp 116e118 C; FTIR (KBr): 3122, 2939 (AreH), 1514
2
3
4
asym
sym
ꢀ1 1
(
C]C), 1243 (CeOeC
), 1062 (CeOeC ), 825 (CeF) cm
ppm: 2.25 (p, 2H, eCH e), 4.11, 4.14, 4.17
), 6.31 (t, 2H, J ¼ 2.12, pyrrole-C and
eH), 6.82e6.86 (m, 2H, Ph-C and C eH), 6.92e6.99 (m, 6H,
, C eH, pyrrole-C , C eH and ph-C and C eH), 7.27,
.30 (td, 2H, J ¼ 2.16, 3.44, fluoroPh-C and C
100 MHz, CDCl ppm: 29.38, 64.80, 65.03, 109.97, 115.31, 115.49,
;
H
2
6
2
5
NMR (400 MHz, CDCl
3
)
d
2
C
2
6
3
5
13
(
C
dt, 4H, J ¼ 6.08, 6.12, 2OCH
2
3
3
5
4
2
6
3
) d
fluoroPh-C
7
2
6
2
5
3
5
120.59, 126.00, 129.58, 131.05, 132.26, 156.50, 168.31, 190.10; MS
13
þ
3
5
eH); C NMR
(EI): m/z ¼ found 321.09 [M ]; calcd. 321.14. Anal. Calcd. For
(
3
)
d
20 3
C H19NO : C, 74.75; H, 5.96; N, 4.36. Found: C, 74.45; H, 5.98; N,

336
U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
4
.38.
(C]C), 1245 (CeOeCasym), 1061 (CeOeCsym) cmꢀ1
400 MHz, CDCl ppm: 2.22 (s, 3H, CH ), 2.29 (p, 2H, eCH
4.14-, 4.21 (m, 4H, 2OCH
), 6.31 (t, 2H, J ¼ 2.12, pyrrole-C
eH), 6.82e6.87 (m, 2H, methylPh-C and C eH), 6.93, 6.95 (td,
2H, J ¼ 2.12, 2.20, ph-C and C eH), 6.98 (t, 2H, J ¼ 2.16, pyrrole-C
and C and C eH), 7.7, 7.29
eH), 7.14 (t, 2H, J ¼ 7.52, methylph-C
(dd, 2H, J ¼ 2.16, 2.12, Ph-C eH); C NMR (100 MHz, CDCl
ppm: 16.32, 29.48, 64.26, 65.00, 109.91, 110.99, 115.29, 119.73,
;
1H NMR
e),
and
(
3
)
d
3
2
4.3.47. 4-(3-(4-(1H-Pyrrol-1-yl)phenoxy)propoxy)-3-
2
3
methoxybenzaldehyde (6a14)
C
4
5
6
ꢁ
(
Yield 60%). mp 86e88 C; FTIR (KBr): 3133, 2932 (AreH), 1689
2
6
2
asym
sym
ꢀ1 1
(
C]O), 1518 (C]C), 1261 (CeOeC
), 1064 (CeOeC ) cm ; H
e), 3.88 (t,
), 4.24e4.33 (m, 2H,
eH), 6.85e7.02 (m, 5H,
eH and aldehyde ph-C -H), 7.06e7.10
-H), 7.27e7.31 (m, 2H, ph-C and C eH),
-H), 9.84 (s, 1H, CHO); C NMR
ppm: 28.60, 29.03, 56.12, 64.63, 65.13, 109.15,
09.23, 109.25, 112.40, 115.01, 115.07, 118.63, 118.72, 124.29, 126.17,
26.23, 130.02, 132.96, 151.69, 155.26, 156.68, 190.25; MS (EI): m/
5
3
4
13
NMR (400 MHz, CDCl
H, J ¼ 11.44, OCH ), 4.17e4.22 (m, 2H, OCH
OCH and C
Ph-C
m, 1H, aldehyde ph-C
3
)
d
ppm: 2.29e2.38 (m, 2H, eCH
2
3
and C
5
3
)
3
3
2
d
2
), 6.31 (t, 2H, J ¼ 2.12, pyrrole-C
3
4
120.49, 122.21, 126.81, 126.87, 130.73, 134.58, 156.97, 157.03; MS
þ
2
, C
6
eH, pyrrole-C
2
, C
5
6
(EI): m/z ¼ found 307.16 [M ]; calcd. 307.16. Anal. Calcd. For
(
7
3
3
5
20 2
C H21NO : C, 78.15; H, 6.89; N, 4.56. Found: C, 77.84; H, 6.92; N,
1
3
.40e7.47 (m, 1H, aldehyde Ph-C
5
4.54.
(
100 MHz, CDCl
3
) d
1
1
4.3.52. 1-(4-(3-(3,5-Dimethylphenoxy)propoxy)phenyl)-1H-pyrrole
(6a19)
þ
ꢁ
z ¼ found 351.15 [M ]; calcd. 351.15. Anal. Calcd. For C21
H
21NO
4
: C,
(Yield 68%). mp 96e98 C; FTIR (KBr): 3138, 2926 (AreH), 1520
asym
sym
ꢀ1
1
71.78; H, 6.02; N, 3.99. Found: C, 71.49; H, 6.04; N, 3.97.
(C]C), 1250 (CeOeC
400 MHz, CDCl
4.11e4.16 (dt, 4H, J ¼ 6.08, 6.12, 2OCH
role-C and C eH), 6.54 (s, 2H, methylPh-C
methylph-C
-H), 6.93, 6.94 (dd, 2H, J ¼ 2.12, 2.12, ph-C
6.98 (t, 2H, J ¼ 2.16, pyrrole-C and C eH), 7.27, 7.29 (dd, 2H,
eH); C NMR (100 MHz, CDCl ppm:
), 1067 (CeOeC ) cm
ppm: 2.21e2.27 (m, 8H, 2CH
), 6.31 (t, 2H, J ¼ 2.12, pyr-
and C eH), 6.59 (s, 1H,
and C eH),
;
H NMR
(
3
)
d
3
, eCH e),
2
4.3.48. 4-(3-(4-(1H-Pyrrol-1-yl)phenoxy)propoxy)-3-
2
ethoxybenzaldehyde (6a15)
3
4
2
6
ꢁ
(
Yield 60%). mp 84e86 C; FTIR (KBr): 3141, 2946 (AreH), 1676
4
2
6
asym
sym
ꢀ1 1
(
C]O), 1521 (C]C), 1247 (CeOeC
), 1065 (CeOeC ) cm ; H
CH ), 2.24e2.31 (m,
), 4.13e4.26 (m, 4H,
and C eH), 6.87e7.02 (m,
eH and aldehyde ph-C , C eH),
eH), 7.44e7.49 (m, 1H, aldehyde Ph-
-H), 9.86 (s, 1H, CHO); C NMR (100 MHz, CDCl ppm: 15.16,
8.64, 29.36, 64.90, 65.33, 66.52, 109.34, 110.23, 112.26, 113.77,
2
5
1
3
NMR (400 MHz, CDCl
3
)
d
ppm: 1.72 (s, 3H, OCH
e), 3.23e3.24 (m, 2H, OCH CH
), 6.31 (t, 2H, J ¼ 2.08, pyrrole-C
H, Ph-C , C eH, pyrrole-C , C
.24e7.30 (m, 2H, ph-C and C
2
3
J ¼ 2.08, 2.16, Ph-C
3
and C
5
3
) d
2
2
6
7
C
2
H, eCH
OCH
2
2
3
21.46, 29.41, 64.14, 64.90, 109.84, 112.30, 115.27, 119.70, 122.18,
2
3
4
122.58, 134.53, 139.26, 157.00, 158.92; MS (EI): m/z ¼ found 321.17
þ
2
6
2
5
3
6
[M ]; calcd. 321.17. Anal. Calcd. For C21
4.36. Found: C, 78.78; H, 7.18; N, 4.34.
2
H23NO : C, 78.47; H, 7.21; N,
3
5
1
3
5
3
) d
4.3.53. 1-(4-(3-(2,5-Dimethylphenoxy)propoxy)phenyl)-1H-pyrrole
1
15.02, 115.77, 118.56, 118.88, 122.52, 126.06, 126.15, 129.23, 133.11,
(6a20)
þ
ꢁ
1
50.12, 155.67, 156.69, 190.12; MS (EI): m/z ¼ found 365.20 [M ];
(Yield 70%). mp 86e88 C; FTIR (KBr): 3138, 2928 (AreH), 1519
asym
sym
ꢀ1
1
calcd. 365.16. Anal. Calcd. For C22
4
H23NO : C, 72.31; H, 6.34; N, 3.83.
(C]C), 1250 (CeOeC
(400 MHz, CDCl ppm: 2.17 (s, 3H, CH
m, 5H, CH at C position and eCH
-), 4.15 4.18 (dt, 4H, J ¼ 5.96,
6.16, 2OCH and C eH), 6.67 (d, 2H,
), 6.31 (t, 2H, J ¼ 2.00, pyrrole-C
J ¼ 5.92, methylPh-C and C eH), 6.92, 6.94 (dd, 2H, J ¼ 3.28, 1.98,
ph-C and C eH), 6.97e7.01 (m, 3H, pyrrole-C , C eH and meth-
ylph-C
-H), 7.26, 7.28 (dd, 2H, J ¼ 3.20, 7.00, Ph-C
NMR (100 MHz, CDCl ppm: 15.91, 21.48, 29.54, 29.80, 64.26,
), 1061 (CeOeC ) cm
;
H NMR
Found: C, 72.60; H, 6.31; N, 3.81.
3
)
d
3
at C position), 2.26e2.30
2
(
3
5
2
4.3.49. 1-(4-(3-(4-Tolyloxy)propoxy)phenyl)-1H-pyrrole (6a16)
2
3
4
ꢁ
(
Yield 75%). mp 100e102 C; FTIR (KBr): 3126, 2923 (AreH),
4
6
asym
sym
ꢀ1 1
;
1
517 (C]C), 1248 (CeOeC
400 MHz, CDCl ppm: 2.22e2.27 (m, 5H, eCH
p, 4H, 2OCH and C
), 6.31 (t, 2H, J ¼ 2.20, pyrrole-C
dd, 2H, J ¼ 2.00, 2.08, methylPh-C and C eH), 6.93, 6.95 (dd, 2H,
and C and
eH), 6.98 (t, 2H, J ¼ 2.12, pyrrole-C
and C eH), 7.27, 7.29 (dd,
eH); C NMR (100 MHz, CDCl
), 1066 (CeOeC ) cm
e and CH
eH), 6.80, 6.82
H NMR
2
4
2
5
1
3
(
(
(
3
)
d
2
3
), 4.14
3
3
and C
5
eH);
C
2
3
4
3
) d
2
6
65.02, 69.20, 109.93, 109.95, 112.09, 115.09, 115.30, 115.58, 117.89,
119.73, 121.01, 122.16, 122.21, 123.61, 130.46, 133.19, 134.58, 136.64,
J ¼ 2.16, 2.24, ph-C
2
6
2
þ
C
2
d
5
eH), 7.08 (d, 2H, J ¼ 8.24, methylph-C
3
5
156.71, 156.86, 157.05; MS (EI): m/z ¼ found 321.18 [M ]; calcd.
1
3
H, J ¼ 2.20, 2.20, Ph-C
3
and C
5
3
)
321.17. Anal. Calcd. For C21
C, 78.78; H, 7.18; N, 4.38.
2
H23NO : C, 78.47; H, 7.21; N, 4.36. Found:
ppm: 20.49, 29.39, 29.74, 64.42, 64.92, 109.85, 114.40, 115.28,
1
19.70, 122.18, 129.95, 130.04, 134.54, 156.74, 157.01; MS (EI): m/
þ
z ¼ found 307.16 [M ]; calcd. 307.16. Anal. Calcd. For C20
H21NO
2
: C,
4.3.54. 1-(4-(3-(2,4-Dimethylphenoxy)propoxy)phenyl)-1H-pyrrole
7
8.15; H, 6.89; N, 4.56. Found: C, 78.46; H, 6.86; N, 4.58.
(6a21)
ꢁ
(Yield 70%). mp 93e95 C; FTIR (KBr): 3128, 2957 (AreH), 1522
asym
sym
ꢀ1
1
4
.3.50. 1-(4-(3-(3-Tolyloxy)propoxy)phenyl)-1H-pyrrole (6a17)
(C]C), 1252 (CeOeC
), 1067 (CeOeC ) cm
at C position), 2.31e2.38
e), 4.20, 4.26 (dt, 4H, J ¼ 5.96,
), 6.39 (t, 2H, J ¼ 2.16, pyrrole-C and C eH), 6.82 (d, 1H,
J ¼ 7.92, methylPh-C -H), 7.00e7.07 (m, 4H, methylph-C , C eH and
ph-C , C eH), 7.06 (t, 2H, pyrrole-C and C eH), 7.35, 7.38 (td, 2H,
J ¼ 2.16, 2.16, Ph-C eH); C NMR (100 MHz, CDCl ppm:
;
H NMR
ꢁ
(
Yield 73%). mp 88e90 C; FTIR (KBr): 3137, 2935 (AreH), 1523
(400 MHz, CDCl
(m, 5H, CH at C
6.20, 2OCH
3
)
d
ppm: 2.27 (s, 3H, CH
position and eCH
3
2
asym
sym
ꢀ1
1
(
C]C), 1254 (CeOeC
400 MHz, CDCl ppm: 2.24 (p, 2H, eCH
.13, 4.16 (dd, 4H, J ¼ 5.88, 6.00, 2OCH ), 6.30 (t, 2H, J ¼ 2.12, pyr-
role-C and C eH), 6.70e6.76 (m, 3H, methylPh-C , C and C eH),
.91, 6.93 (td, 2H, J ¼ 2.20, 2.16, ph-C and C eH), 6.97 (t, 2H,
J ¼ 2.12, pyrrole-C and C eH), 7.15 (t, 1H, J ¼ 7.68, methylph-C -H),
.26, 7.28 (td, 2H, J ¼ 2.16, 2.12, Ph-C eH); C NMR
100 MHz, CDCl ppm: 21.09, 28.73, 63.71, 64.36, 109.69, 111.17,
14.89, 115.06, 118.84, 121.03, 121.13, 128.91, 133.67, 138.76, 156.26,
), 1064 (CeOeC ) cm
;
H NMR
3
4
2
(
4
3
)
d
2
e), 2.31 (s, 3H, CH
3
),
2
3
4
2
6
3
5
3
4
2
4
6
2
4
2
5
1
3
6
2
6
3
and C
5
3
) d
2
5
5
16.24, 20.51, 29.52, 64.49, 65.03, 109.90, 111.11, 115.28, 119.73,
122.20, 126.58, 127.01, 129.68, 131.58, 134.54, 154.86, 157.05; MS
13
7
(
1
3 5
and C
þ
3
)
d
(EI): m/z ¼ found 321.17 [M ]; calcd. 321.17. Anal. Calcd. For
21 2
C H23NO : C, 78.47; H, 7.21; N, 4.36. Found: C, 78.78; H, 7.18; N,
þ
1
58.40; MS (EI): m/z ¼ found 307.16 [M ]; calcd. 307.16. Anal. Calcd.
4.34.
For C20 : C, 78.15; H, 6.89; N, 4.56. Found: C, 77.84; H, 6.92; N,
H21NO
2
4
.58.
4.3.55. 4-(3-(4-(1H-Pyrrol-1-yl)phenoxy)propoxy)phenol (6a22)
ꢁ
(
Yield 68%). mp 101e103 C; FTIR (KBr): 3416 (OH), 3143, 2927
asym
sym
ꢀ1 1
4.3.51. 1-(4-(3-(2-Tolyloxy)propoxy)phenyl)-1H-pyrrole (6a18)
(AreH),1520 (C]C),1239 (CeOeC
),1070 (CeOeC ) cm ; H
ꢁ
(
Yield 73%). mp 116e118 C; FTIR (KBr): 3125, 2930 (AreH), 1518
NMR (400 MHz, CDCl ) d ppm: 2.21e2.30 (m, 2H, eCH e),
3 2

U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
337
4
.12e4.29 (m, 4H, 2OCH
pyrrole-C and C eH), 6.81e7.20 (m, 8H, Phenol-C
Ph-C , C eH and pyrrole-C , C eH), 7.26e7.32 (m, 2H, Ph-C
eH); C NMR (100 MHz, CDCl
09.75, 110.01, 113.40, 115.35, 115.88, 118.80, 119.52, 120.01, 120.28,
2
), 5.76 (s, 1H, OH), 6.33 (t, 2H, J ¼ 2.12,
4.3.60. 1-(4-(3-(Naphthalen-1-yloxy)propoxy)phenyl)-1H-pyrrole
(6a27)
(Yield 63%). mp 132e134 C; FTIR (KBr): 3132, 2945 (AreH),1518
3
4
2
, C
3
, C
5
, C
6
eH,
ꢁ
2
6
2
5
3
and
1
3
asym
sym
ꢀ1
1
C
1
5
3
)
d
ppm: 28.76, 28.83, 64.62, 65.10,
(C]C), 1241 (CeOeC
(400 MHz, CDCl ppm: 2.40 (p, 2H, eCH
OCH
near to pyrrole ph), 4.33 (t, 2H, J ¼ 6.00, OCH
naphthyl), 6.30 (t, 2H, J ¼ 2.16, pyrrole-C and C eH), 6.83 (d, 1H,
J ¼ 6.88, naphthyl-C -H), 6.92e6.98 (m, 4H, Ph-C , C eH and pyr-
role-C , C and C eH),
eH), 7.26, 7.27 (td, 2H, J ¼ 2.24, 2.20, Ph-C
.35 (t, 1H, J ¼ 7.52, naphthyl-C -H), 7.42 (d, 1H, J ¼ 8.20, naphthyl-
C -H), 7.44e7.49 (m, 2H, naphthyl-C and C eH), 7.78, 7.79 (dd, 1H,
), 1069 (CeOeC ) cm
e), 4.25 (t, 2H, J ¼ 6.20,
near to
;
H NMR
3
)
d
2
1
22.36, 122.56, 132.03, 155.66, 156.13, 156.48; MS (EI): m/z ¼ found
2
2
þ
3
09.16 [M ]; calcd. 309.14. Anal. Calcd. For C19
H19NO
3
: C, 73.77; H,
3
4
6
.19; N, 4.53. Found: C, 74.07; H, 6.17; N, 4.55.
2
2
6
2
5
3
5
7
3
4.3.56. 3-(3-(4-(1H-Pyrrol-1-yl)phenoxy)propoxy)phenol (6a23)
ꢁ
(
Yield 60%). mp 98e100 C; FTIR (KBr): 3293 (OH), 2953 (AreH),
4
6
7
asym
sym
ꢀ1
1
J ¼ 3.04, 2.20, naphthyl-C -H), 8.26, 8.27 (dd, 1H, J ¼ 2.36, 2.64,
1
522 (C]C), 1249 (CeOeC
400 MHz, DMSO-d ppm: 2.14e2.20 (m, 2H, eCH
m, 4H, 2OCH ), 6.33e6.36 (m, 2H, pyrrole-C and C eH), 6.87e7.07
m, 8H, Phenol-C , C , C , C eH, Ph-C , C eH and pyrrole-C , C eH),
.32, 7.35 (dd, 2H, J ¼ 1.96, 2.00, Ph-C and C eH), 9.00 (s, 1H, OH);
ppm: 28.69, 29.40, 63.71, 64.39,
01.73, 102.49, 104.90, 106.15, 107.83, 109.73, 115.08, 118.86, 121.01,
29.40, 133.66, 156.25, 158.43, 159.62; MS (EI): m/z ¼ found 293.35
), 1067 (CeOeC ) cm
;
H NMR
5
13
naphthyl-C
4.62, 104.79, 109.71, 115.13, 118.89, 119.81, 121.01, 121.47, 125.94,
26.17, 127.21, 133.68, 133.96, 153.93, 156.25; MS (EI): m/z ¼ found
8 3
-H); C NMR (100 MHz, CDCl ) d ppm: 28.76, 64.35,
(
(
(
6
)
d
2
e), 4.04e4.13
6
1
3
2
3
4
2
4
5
6
2
6
2
5
þ
43.15 [M ]; calcd. 343.16. Anal. Calcd. For C23
2
H21NO : C, 80.44; H,
7
3
5
1
3
6.16; N, 4.08. Found: C, 80.76; H, 6.14; N, 4.10.
6
C NMR (100 MHz, DMSO-d ) d
1
1
4.3.61. 1-(4-(3-(Naphthalen-2-yloxy)propoxy)phenyl)-1H-pyrrole
þ
(6a28)
3
[M ]; calcd. 309.14. Anal. Calcd. For C19H19NO : C, 73.77; H, 6.19; N,
ꢁ
Yield 63%). mp 124e126 C; FTIR (KBr): 3141, 2948 (AreH), 1518
(
4
.53. Found: C, 73.47; H, 6.21; N, 4.55.
asym
sym
ꢀ1
1
(
(
C]C), 1251 (CeOeC
400 MHz, CDCl ) d ppm: 2.30 (p, 2H, eCH
3 2
), 1063 (CeOeC ) cm
e), 4.17 (t, 2H, J ¼ 6.12,
near to pyrrole ph), 4.25 (t, 2H, J ¼ 6.08, OCH near to
Naphthyl), 6.30 (t, 2H, J ¼ 2.16, pyrrole-C and C eH), 6.92, 6.94 (td,
H, J ¼ 2.16, 3.40, Ph-C and C eH), 6.97 (t, 2H, J ¼ 2.12, pyrrole-C
and C eH), 7.12e7.15 (m, 2H, naphthyl-C and C eH), 7.25, 7.27 (td,
and C
eH), 7.29, 7.31, 7.32 (dt, 1H, J ¼ 1.12,
;
H NMR
4.3.57. 2-(3-(4-(1H-Pyrrol-1-yl)phenoxy)propoxy)phenol (6a24)
OCH
2
2
ꢁ
(
Yield 60%). mp 104e106 C; FTIR (KBr): 3327 (OH), 3141, 2951
asym
sym
ꢀ1 1
3
4
(
AreH),1521 (C]C),1245 (CeOeC
NMR (400 MHz, CDCl ppm: 2.24e2.31 (m, 2H, eCH
.11e4.26 (m, 4H, 2OCH
), 5.77 (s, 1H, OH), 6.31 (t, 2H, J ¼ 2.16,
pyrrole-C and C eH), 6.80e6.99 (m, 8H, Phenol-C , C , C , C eH,
eH and pyrrole-C , C
eH), 7.27, 7.29 (td, 2H, J ¼ 2.36, 3.40,
and C ppm: 28.78, 28.86,
eH); 13C NMR (100 MHz, CDCl
),1063 (CeOeC ) cm ; H
2
2
6
2
3
)
d
2
e),
5
3
5
4
2
2
1
H, J ¼ 2.20, 3.44, Ph-C
3
5
3
4
3
4
5
6
.12, 1.08, naphthyl-C
6
-H), 7.39, 7.41, 7.43 (dt, 1H, J ¼ 1.20, 1.24, 1.24,
Ph-C
Ph-C
2
, C
6
2
5
13
naphthyl-C
7
4 5 8
-H), 7.71 (p, 3H, naphthyl-C , C and C eH); C NMR
3
5
3
) d
3
(100 MHz, CDCl ) d ppm: 29.33, 64.42, 64.91, 106.73, 109.86, 115.30,
6
1
4.43, 65.14, 109.72, 113.40, 114.22, 115.06, 115.15, 115.59, 118.83,
18.89, 119.08, 120.92, 120.99, 121.05, 121.16, 133.63, 146.56, 146.75,
1
18.88, 119.70, 122.20, 123.67, 126.41, 126.75, 127.67, 129.02, 129.44,
þ
1
34.58, 156.82, 156.98; MS (EI): m/z ¼ found 343.14 [M ]; calcd.
43.16. Anal. Calcd. For C23 : C, 80.44; H, 6.16; N, 4.08. Found:
C, 80.76; H, 6.14; N, 4.10.
þ
1
3
48.50, 156.25, 156.32; MS (EI): m/z ¼ found 309.14 [M ]; calcd.
09.14. Anal. Calcd. For C19 : C, 73.77; H, 6.19; N, 4.53. Found:
C, 73.47; H, 6.21; N, 4.51.
3
H21NO
2
H19NO
3
4
.3.62. 1,3-Bis(4-(1H-pyrrol-1-yl)phenoxy)propane (6a29)
4
.3.58. 5-(3-(4-(1H-Pyrrol-1-yl)phenoxy)propoxy)-2-chlorophenol
ꢁ
(
Yield 65%). mp 140e142 C; FTIR (KBr): 3141, 2948 (AreH),1523
(6a25)
asym
sym
ꢀ1
1
(
(
2
4
C]C), 1254 (CeOeC
400 MHz, CDCl ppm: 2.28 (p, 2H, eCH
), 6.31 (t, 4H, J ¼ 2.12, pyrrole-C and C
H, J ¼ 2.12, 3.40, 2Ph-C and C eH), 6.98 (t, 4H, J ¼ 2.16, pyrrole-C
), 1068 (CeOeC ) cm
e), 4.17 (t, 4H, J ¼ 6.08,
eH), 6.93, 6.96 (td,
;
H NMR
ꢁ
Yield 58%). mp 70e72 C; FTIR (KBr): 3425 (OH), 3110, 2917
(
3
)
d
2
asym
sym
ꢀ1 1
(
AreH),1531 (C]C),1253 (CeOeC
),1053 (CeOeC ) cm ; H
e),
), 5.51 (s, 1H, OH), 6.37e6.42 (m, 2H, pyr-
, C , C eH, Ph-C
eH), 7.32e7.35 (m, 2H, Ph-C and C eH);
C NMR (100 MHz, CDCl ppm: 29.15, 29.78, 64.71, 65.38, 101.84,
08.28, 109.94, 113.77, 115.33, 115.59, 117.93, 119.69, 122.09, 130.31,
33.15, 134.64, 155.01, 156.64, 156.91; MS (EI): m/z ¼ found 343.76
OCH
2
3
4
NMR (400 MHz, CDCl
.17e4.28 (m, 4H, 2OCH
role-C and C
eH and pyrrole-C
3
) d ppm: 2.29e2.36 (m, 2H, eCH
2
2
6
2
C
4
2
13
and C
5
eH), 7.28, 7.30 (td, 4H, J ¼ 2.16, 3.44, 2Ph-C
3
and C
5
eH);
3
4
eH), 6.99e7.06 (m, 7H, Phenol-C
, C
2
5
6
2
,
NMR (100 MHz, CDCl
)
d
ppm: 29.34, 64.75, 109.90, 115.28, 119.69,
3
C
6
2
5
3
5
þ
1
3
22.20, 134.62, 156.94; MS (EI): m/z ¼ found 358.17 [M ]; calcd.
1
3
3
) d
22 2 2
58.17. Anal. Calcd. For C23H N O : C, 77.07; H, 6.19; N, 7.82.
1
1
Found: C, 76.76; H, 6.21; N, 7.85.
þ
[M ]; calcd. 343.10. Anal. Calcd. For C19
3
H18ClNO : C, 66.38; H, 5.28;
4.3.63. 1-(4-(3-(4-(1H-Pyrrol-1-yl)phenoxy)propoxy)phenyl)-2,5-
N, 4.07. Found: C, 66.65; H, 5.26; N, 4.05.
dimethyl-1H-pyrrole (6a30)
ꢁ
Yield 60%). mp 88e90 C; FTIR (KBr): 3140, 2943 (AreH), 1523
(
asym
sym
ꢀ1
1
4.3.59. 5-(3-(4-(1H-Pyrrol-1-yl)phenoxy)propoxy)benzene-1,3-diol
(C]C), 1250 (CeOeC
), 1066 (CeOeC ) cm
), 2.39 (p, 2H, eCH
), 5.98 (s, 2H, Dimethylpyrrole-C and C eH),
6.41 (t, 4H, J ¼ 2.12, pyrrole-C and C eH), 7.03e7.09 (m, 6H, 2Ph-
, C eH and pyrrole-C , C
eH), 7.20, 7.22 (dd, 2H, J ¼ 2.16, 2.16,
DimethylpyrrolePh-C and C
eH), 7.38, 7.39 (td, 2H, J ¼ 2.16, 2.24,
eH); C NMR (100 MHz, CDCl ppm: 13.08, 29.39,
;
H NMR
(6a26)
(400 MHz, CDCl
3
)
d
ppm: 2.11 (s, 6H, 2CH
3
2
e),
ꢁ
(
Yield 58%). mp 108e110 C; FTIR (KBr): 3334 (OH), 3140, 2928
4.31 (q, 4H, 2OCH
2
3
4
asym
sym
ꢀ1 1
(
AreH),1521 (C]C),1256 (CeOeC
),1068 (CeOeC ) cm ; H
e), 4.13 (p,
-H), 6.29e6.32
eH), 6.89e6.96 (m, 3H, Ph-C , C eH and
-H), 6.98e7.00 (m, 2H, pyrrole-C and C eH), 7.19e7.31
-H); C NMR (100 MHz, CDCl
3
4
NMR (400 MHz, CDCl
H, 2OCH ), 6.11 (s, 2H, 2OH), 6.17 (s, 1H, phenol-C
m, 2H, pyrrole-C and C
phenol-C
3
)
d
ppm: 2.21e2.28 (m, 2H, eCH
2
C
2
6
2
5
4
(
2
4
3
5
13
3
4
2
6
Ph-C
3
and C
5
3
) d
2
2
5
64.62, 64.75, 105.41, 110.01, 114.82, 115.31, 115.59, 119.72, 122.16,
122.21, 129.06, 129.34, 131.91, 134.64, 156.97, 158.22; MS (EI): m/
13
(
m, 3H, Ph-C
3
, C
5
eH and phenol-C
6
3
)
þ
d
ppm: 26.87, 27.31, 62.04, 62.38, 89.77, 91.75, 97.58, 107.48, 112.65,
13.12, 117.20, 117.27, 119.68, 119.80, 132.17, 154.35, 154.52, 155.67,
z ¼ found 386.20 [M ]; calcd. 386.20. Anal. Calcd. For C25
26 2 2
H N O :
1
C, 77.69; H, 6.78; N, 7.25. Found: C, 77.38; H, 6.81; N, 7.22.
þ
1
58.36; MS (EI): m/z ¼ found 325.13 [M ]; calcd. 325.13. Anal. Calcd.
For C19 : C, 70.14; H, 5.89; N, 4.31. Found: C, 70.42; H, 5.87; N,
.33.
H19NO
4
4.3.64. 4-(3-(4-(1H-Pyrrol-1-yl)phenoxy)propoxy)aniline (6a31)
ꢁ
4
(Yield 60%). mp 94e96 C; FTIR (KBr): 3385 (NH
2
), 3137, 2924

338
U.A. More et al. / European Journal of Medicinal Chemistry 94 (2015) 317e339
ꢀ1
(
AreH), 1516 (C]C), 1239 (CeOeCasym), 1067 (CeOeCsym) cm
;
for developing InhA inhibitors.
þ
MS (EI): m/z ¼ found 308.17 [M ]; calcd. 308.15.
Acknowledgments
4
.3.65. 3-(3-(4-(1H-Pyrrol-1-yl)phenoxy)propoxy)aniline (6a32)
ꢁ
(
Yield 58%). mp 107e109 C; FTIR (KBr): 3366 (NH
2
), 3133, 2950
Authors appreciate the financial support from the Indian
Council of Medical Research, New Delhi (File No. 64/4/2011-BMS,
IRIS Cell No. 2010-08710). We thank Mr. H. V. Dambal, President,
S.E.T's College of Pharmacy for the encouragement and, Dr. K.G.
Bhat of Maratha Mandal's Dental College, Hospital and Research
Centre, Belgaum, for providing anti-tubercular and cytotoxic ac-
tivities. Director, SAIF, Indian Institute of Technology, Chennai,
Tamilnadu, India and the Director, SAIF, Panjab University, Chan-
digarh, Panjab, India for providing some of the NMR and mass
spectral data. The authors also appreciate the technical assistance
from Mr. S. A. Tiwari and Mr. Ravi Nadagir.
asym
sym
ꢀ1
(
AreH), 1520 (C]C), 1252 (CeOeC
), 1058 (CeOeC ) cm ;
þ
MS (EI): m/z ¼ found 308.17 [M ]; calcd. 308.15.
4
.3.66. 2-(3-(4-(1H-Pyrrol-1-yl)phenoxy)propoxy)aniline (6a33)
ꢁ
(
Yield 58%). mp 98e100 C; FTIR (KBr): 3351 (NH
2
), 3137, 2933
asym
sym
ꢀ1
(
AreH), 1520 (C]C), 1240 (CeOeC
), 1065 (CeOeC ) cm
;
þ
MS (EI): m/z ¼ found 308.21 [M ]; calcd. 308.15.
5
. Biological activity
5
.1. Anti-tubercular studies
Appendix A. Supplementary data
All the synthesized compounds were tested for inhibition of
M. tuberculosis strain H37RV using Microplate Alamar Blue Assay
MABA) as described earlier [47]. The 96 wells plate received 100 mL
of Middlebrook 7H9 broth and serial dilution of compounds were
made directly on the plate with drug concentrations of 0.2, 0.4, 0.8,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2015.03.013. These data include MOL
files and InChiKeys of the most important compounds described in
this article.
(
1
.6, 3.125, 6.25, 12.5, 25, 50 and 100
m
g/mL. Plates were covered and
ꢁ
sealed with parafilm and incubated at 37 C for 5 days. Then, 25
mL
References
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color was scored as growth. The MIC was defined as the lowest drug
concentration, which prevented color change from blue to pink.
Table 1 reveals the anti-tubercular activity (MIC) data.
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