Design, synthesis, and biological evaluation of novel imidazole derivatives possessing terminal sulphonamides as potential BRAFV600E inhibitors

Article abstract of DOI:10.1016/j.bioorg.2020.104508

BRAF^V600E mutation has been detected in various malignant tumours. Developing of potent BRAF^V600E inhibitors is considered a leading step in the way to cure different cancer types. In the current work, a series of 38 4-(1H-imidazol-5-yl)pyridin-2-amine derivatives was designed and synthesized using Dabrafenib as a lead compound for structural-guided optimization. The target compounds were evaluated as potential anticancer agents against NCI 60 human cancer cell lines. In 5-dose testing mode, two compounds 14h and 16e were tested to determine their IC₅₀ values over each of the 60 cell lines. The selected candidates exhibited promising activity with mean IC₅₀ values of 2.4 μM and 3.6 μM, respectively. Melanoma cancer cell lines exhibited the highest sensitivity after the treatment with the tested compounds 14h and 16e. The mean IC₅₀ values of compounds 14h and 16e against Melanoma cancer cell lines are 1.8 μM and 1.88 μM, respectively. In addition, BRAF^V600E kinase inhibitory activity was determined for each derivative. Compounds 15i, 15j, 16a, and 16d were the most potent inhibitors against BRAF^V600E with IC₅₀ 76 nM, 32 nM, 35 nM, and 68 nM. The newly developed compounds represent a therapeutically promising approach for the treating various cancer types.

Full text of DOI:10.1016/j.bioorg.2020.104508

Bioorganic Chemistry xxx (xxxx) xxx
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Design, synthesis, and biological evaluation of novel imidazole derivatives
possessing terminal sulphonamides as potential BRAFV600E inhibitors
a
,
b
,
c
d
a,
b
,
e
a,b
Eslam M.H. Ali
, Mohammed S. Abdel-Maksoud , Usama M. Ammar
, Karim I. Mersal
,
f
g
a,b,*
Kyung Ho Yoo , Park Jooryeong , Chang-Hyun Oh
a
Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seongbuk-gu, Seoul 02792, Republic of Korea
University of Science & Technology (UST), Yuseong-gu, Daejeon 34113, Republic of Korea
b
c
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University of Technology and Information (MTI), Cairo 12055, Egypt
d
Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre NRC (ID: 60014618), Dokki,
Giza 12622, Egypt
e
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza 12566, Egypt
f
Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea
g
Department of Beauty Science, Hanseo University, Seosan 31962, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
BRAFV600E mutation has been detected in various malignant tumours. Developing of potent BRAFV600E inhibitors
is considered a leading step in the way to cure different cancer types. In the current work, a series of 38 4-(1H-
imidazol-5-yl)pyridin-2-amine derivatives was designed and synthesized using Dabrafenib as a lead compound
for structural-guided optimization. The target compounds were evaluated as potential anticancer agents against
NCI 60 human cancer cell lines. In 5-dose testing mode, two compounds 14h and 16e were tested to determine
their IC50 values over each of the 60 cell lines. The selected candidates exhibited promising activity with mean
IC50 values of 2.4 µM and 3.6 µM, respectively. Melanoma cancer cell lines exhibited the highest sensitivity after
Keywords:
Protein kinase inhibitors
V600E
BRAF
inhibitors
Anticancer
Imidazole
SAR
the treatment with the tested compounds 14h and 16e. The mean IC50 values of compounds 14h and 16e against
V600E
Melanoma cancer cell lines are 1.8 µM and 1.88 µM, respectively. In addition, BRAF
kinase inhibitory ac-
tivity was determined for each derivative. Compounds 15i, 15j, 16a, and 16d were the most potent inhibitors
V600E
against BRAF
with IC50 76 nM, 32 nM, 35 nM, and 68 nM. The newly developed compounds represent a
therapeutically promising approach for the treating various cancer types.
1
. Introduction
The mitogen-activated protein kinase (MAPK) signaling is a key
signaling transduction to the MEK resulting in the activation of down-
stream MEK1/2 and ERK1/2 [8,9]. Amid the three RAF kinases, BRAF
has higher basal activity and is a major activator of MEK1/2Compared to
ARAF and CRAF [10,11]. The pathological mutation in RAF kinases
regulator for basic cellular processes such as growth, proliferation, dif-
ferentiation, migration and apoptosis [1,2]. Signal transmission is acti-
vated by a phosphorylation cascade of intracellular protein kinases
usually occurs to the BRAF subtype [12]. The most common mutation
V600E
observed is BRAF
, when the valine residue at site 600 substituted
(
MKKK, MKK and MAPK) [3]. The aberrant regulation of MAPK cascades
with glutamate residue [13,14]. This mutation mimics the active phos-
V600E
have been elucidated to trigger the process of diverse severe diseases
including Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyo-
trophic lateral sclerosis (ALS), and various types of cancers [4,5]. Dis-
turbing of the Ras-Raf-MEKERK signaling pathway is widely associated
with human tumorigenesis [6]. Raf kinases (ARAF, BRAF and CRAF) is a
key component in ERK signaling branch of MAPK cascade [7]. RAF ki-
nases bind with RAS as upstream activator, and mediate the MAPK
phorylation state, hence the BRAF
protein persistently trigger
downstream pathways without regulation [15]. BRAF mutation has
been detected in various malignant tumours, for instance, 60% mela-
V600E
noma cases are caused by the BRAF
mutation [16,17]. Other so-
matic tumours, such as colorectal carcinomas, papillary thyroid
carcinoma, hairy cell leukemia, and lung cancer, are also validated to be
involved with the mutated BRAF kinase [18–21]. In this regard,
*
Corresponding author at: Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seongbuk-gu, Seoul 02792, Republic of Korea.
E-mail address: choh@kist.re.kr (C.-H. Oh).
https://doi.org/10.1016/j.bioorg.2020.104508
Received 8 June 2020; Received in revised form 16 November 2020; Accepted 19 November 2020
Available online 24 November 2020
0
045-2068/© 2020 Elsevier Inc. All rights reserved.
Please cite this article as: Eslam M.H. Ali, Bioorganic Chemistry, https://doi.org/10.1016/j.bioorg.2020.104508

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
BRAFV600E inhibitors become one of the most essential classes of anti-
cancer agents [22–26]. Several drugs have already been approved for
the treatment of Raf-related diseases. U.S. Food and Drug Administra-
tion (FDA) approved Vemurafenib (PLX4032, Fig. 1) and Dabrafenib
developing potent analogues of Dabrafenib might be a promising step
for developing more potent and selective drug candidates for treatment
V600E
of BRAF
mutation related cancers. In our previous study on BRAF
mutation inhibition, compound I that contains pyrazole backbone and
terminal urea side chain showed a mild activity aganist mutated BRAF
with an IC50 770 nM and potent cellular activity over NCI 60 cell lines as
it showed 100% mean percent inhibition at 10 uM. In the current work,
(
GSK2118436, Fig. 1) for late-stage melanoma. Both are selective-
V600E
BRAF
inhibitors through the activation of programmed cell death
in melanoma cell lines with high potency [27–29]. Sorafenib (Nex-
avar™, Fig. 1) is small molecule inhibitor for treatment of hepatocel-
lular carcinoma, advanced renal cancer, and differentiated thyroid
V600E
the X-ray crystal structure of Dabrafenib in complex with BRAF
(PDB: 4XV2) was used as a guide for structural optimization of our lead
compound I. According to the crystal structure, Dabrafenib shows a
unique binding behaviour. As a type 1 1/2 inhibitor, Dabrafenib binds
not only in the ATP binding site, but also extends to Ras-Pocket that has
a significant role in enzyme regulation. Dabrafenib bonds to Cys 532 in
V600E
carcinoma. Sorafenib is a multi-kinase inhibitor includingBRAF
V600E
[
30]. Encorafenib (Braftovi™, Fig. 1) is FDA approved BRAF
in-
hibitor for treatment of metastatic melanoma incombination with
Binimetinib [31]. In our previous work, we identified compound I as
V600E
3
mild inhibitor for BRAF
[32]. Based on compound I structure and
the adenine hinge binding area by two hydrogen bonds with N , and 2-
structures of known BRAFV600E inhibitors, especially Dabrafenib,
structure modifications were applied to compound I.
2
NH Pyrimidine at position 5 of the thiazole ring. Besides, the 2-fluoro-
phenyl group at position 4 of the imidazole ring occupies the hydro-
phobic pocket. The central thiazole ring embeds into the ribose pocket,
and possesses Arene-H interaction with Val 471. While, the terminal 2,6-
difluorphenyl sulfonamide group extended to the Ras-Pocket where, the
sulfonamide oxygen formed H-bonds to the backbone NH of Phe 595 and
Dabrafenib (GSK2118436) is a selective inhibitor of BRAFV600E [33].
FDA has approved Dabrafenib as a single agent treatment for metastatic
V600E
melanoma in patients with BRAF
mutation. Also, Dabrafenib has
granted a favourable opinion in the EU in this indication [33,34]. Thus,
Fig. 1. Structures of reported BRAF inhibitors, compound I and new compound 15j.
2

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
the side chain of Lys 594. While, the nitrogen atom of the sulfonamide
moiety formed H-bonding with the main chain NH of Asp594. In addi-
tion 2,6-difluorphenyl ring formed Arene-H interaction with Leu 505
amino acid. Phe 595 and Leu 505 amino acids are two of the four amino
acids (Leu505, Phe516, His574, and Phe595) that compose the regula-
tory spine of kinases by distortion of the spine responsible for the
transition to an inactive state [35,36]. In this work, Imidazole scaffold
bought our attention as a beginning for a subsequent structural modi-
fication of Dabrafenib. The Imidazole scaffold was used instead of pyr-
azole in compound I as many research papers reported Imidazole-based
derivatives as BRAF inhibitors [37–39]. Principal modifications in the
new compounds focused on the ribose binding moiety, bioisosteric
replacement of Thiazole ring by 1H-imidazole, where the free NH was
expected to enhance the binding affinity by formation of extra hydrogen
bond. The hinge binding moiety 2-amino pyrimidine was replaced by 2-
amino pyridine. The 2-flouro phenyl group in the hydrophobic pocket
was replaced by a linear ethyl or propyl chain. The sulphonamide moiety
in Dabrafenib was reserved in the new compounds in order to keep
molecular interaction with Phe 595 and Lys 483 that subsequently ori-
ents the terminal hydrophobic rings to Ras selective pocket. A variety of
substituted hydrophobic phenyl rings were introduced to the sulpho-
namide instead of the 2,6-diflouro phenyl ring in Dabrafenib, so as to
improve the binding affinity in the Ras-Pocket. Besides, the tertiarybutyl
in the solvent area was replaced by a rigid phenyl moiety in position 2 of
Imidazole ring. Furthermore, the new compounds possessed substitution
at position 4 of the imidazole ring with 3-methoxy phenyl or 3-hydroxy
phenyl groups in attempt to boost the molecular interaction with
enzyme pocket Fig. 2. As a result, a series of 38 novel derivatives were
designed and synthesized. The synthesized candidates 13a-i, 14a-i, 15a-
j, and 16a-j were evaluated for theirantiproliferative activities against
NCI-60 human cancer cell lines. Several compounds showed prominent
antitumor activities against the majority of tested 60 cancer lines and
compounds 14h and 16ewere further tested in 5-dose testing mode to
determine theirIC50 values over each of the 60 cell lines. The highest
inhibitory activity of the tested compounds 14h and 16e was exhibited
synthesized using the reactions adopted in Scheme 1. Esterification of
the 3-methoxy-4-chlorobenzoic acid 1with methanol in the presence of
sulphuric acid produced the corresponding methyl ester 2. In a basic
media of lithium bis(trimethylsilyl)amide (LiHMDS), the methyl group
of2-bromo-4-methylpyridine 3 was activated by stirring for 30 min,
followed by drop wise addition of the methyl ester 2 produced the 2-(2-
bromopyridin-4-yl)-1-(3-methoxyphenyl)ethan-1-one intermediate 4.
Cyclization of the Imidazole compound 7 was carried out by oxidation of
4 by hydrobromic acid in DMSO to produce 1-(2-bromopyridin-4-yl)-2-
(3-methoxyphenyl)ethane-1,2-dione 5, and subsequent reaction of 5
with benzaldehyde 6 in presence of ammonium acetate and acetic acid
afforded 2-bromo-4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-5-yl)
pyridine 7. The ethyl and propyl sulphonamide terminals were added
by the reaction of the bromo compound 7 with ethylene diamine or
propylene diamine producing 10 or11, respectively. Coupling of 10 or
11 with different aromatic sulfonyl chlorides in THF using N,N-diiso-
propylethylamine as a base affording the final target compounds 13a-i
◦
and 14a-i. Boron tribromide was added drop wise at ꢀ 70 C to a solution
of 13a-i or 14a-I in presence of catalytic amount of Tetrabutylammo-
nium iodide in anhydrous dichloromethane under nitrogen resulting of
demethylation of 13a-i or 14a-i, affording the hydroxyl moiety de-
rivatives 15a-j and 16a-j. Structures of the final target compounds are
illustrated in Table 1.
2
2
.2. Pharmacological screening
.2.1. Anticancer activity
In vitro cytotoxicity of the final target compounds 13, 14, 15 and 16
was assessed by testing their antiproliferative activities against NCI60
human cancer cell lines panel belonging to nine cancer types (leukemia,
non-small cell lung cancer, colon cancer, CNS cancer, melanoma,
ovarian cancer, renal cancer, prostate cancer and breast cancer). All the
subjected compounds were selected for one-dose 60 cell line assay. The
tested compounds showed a wide spectrum of antiproliferative activity
against the different human cancer cell lines. The mean inhibition
percent for each compound over the 60 cell lines is presented in Fig. 3.
The data attained in Fig. 3 revealed that most of the tested compounds
showed inhibitory effect over the 60 cell lines. It was notable that
compounds 13a-i and 14a-i, possessing 3-methoxyphenyl group at po-
sition 4 of imidazole emerged to be more potent inhibitor than com-
pounds 15a-j and 16a-j with 3-hydroxy phenyl group at position 4 of
imidazole ring. Among the NCI cell lines, Leukemia (RPMI-8226), Non-
Small Cell Lung Cancer (NCI-H522), Colon Cancer (HT29), CNS Cancer
over Melanoma cell lines with mean IC50 values of 1.8 µM and 1.88 µM.
V600E
The BRAF
enzyme inhibitory activity were determined, as well.
Compounds 15j and 16a were the most potent inhibitors with IC50
values of 32 nM and 35 nM, respectively.
2
. Results and discussion
2
.1. Chemistry
(
SF-295), Renal cancer (A498 and RXF 393), and Melanoma (LOX
The designed compounds 13a-i, 14a-i, 15a-j, and 16a-j were
IMVI, M14, and SK-MEL-2) exhibited high sensitivity towards the tested
Fig. 2. Principle Dabrafenib structural modifications for design the new Imidazole-based derivatives 13a-i, 14a-i, 15a-j, and 16a-j. A) Dabrafenib molecular in-
V600E
V600E
teractions into BRAF
kinase domain; B) Proposed binding behaviour of the new synthesised Imidazole derivatives into BRAF
kinase domain.
3

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
◦
◦
◦
Scheme 1. Reagents and conditions: i) MeOH, Conc.H
2
SO
4
, 80 C, 12 h.; ii) LiHMDS, THF, ꢀ 70 C, 18 h.; iii) HBr, DMSO, 55 C , 2 h.; iv) NH
4 3
OAC, CH COOH,
◦
◦
, TBAI, DCM, ꢀ 70 ◦C, 6 h.
1
00 C, 4 h.; v) 100 C, 12 h.; vi) DCM, DIPEA, rt, 12 h.; vii) BBr
3
compounds. The inhibition percent was summarized in Table 2. Leu-
kemia (RPMI-8226) was the most sensitive cell line that was completely
inhibited by the treatment with compounds 13d, 13e, 13g, 13h, 14b,
activities over Melanoma, Colon Cancer, Non-Small Cell Lung Cancer,
Leukemia, CNS Cancer, and Renal Cancer cell lines (Fig. 4). Apparently,
amongst the compounds bearing 3-hydroxy phenyl group at position 4
of imidazole ring15a-j and 16a-j, compound 16e possessing terminal 3-
Chloro phenyl sulfonamide and propylene linker exhibited a wide
spectrum inhibitory activity over the whole 60 cell lines. The mean in-
hibition percent of compound 16e was 100%, 92%, 100%, 100%, 67%,
94%, 86%, and 100% over Leukemia, Non-Small Cell Lung Cancer,
Colon Cancer, CNS Cancer, Melanoma, Ovarian Cancer, Renal Cancer,
Prostate Cancer, and Breast Cancer cell lines, respectively (Fig. 5). Out of
the tested series, two compounds 14h and 16e were selected by the NCI
to be tested in 5-dose testing mode to determine their IC50 values over
each of the 60 cell lines (Table 3, Fig. 6). The mean IC50 values over the
60 cell lines were 2.4 µM and 3.6 µM for 14h and 16e, respectively.
Obviously, the highest inhibitory activity of compounds 14h and 16e
were against Melanoma nine cell lines with mean IC50 values of 1.8 µM
and 1.88 µM, respectively. Moderate inhibitory activity of compounds
14h and 16e were exhibited over the rest of the tested cell lines (leu-
kemia, non-small cell lung cancer, colon cancer, CNS cancer, ovarian
cancer, renal cancer, prostate cancer, and breast cancer) with IC50
values ranging from 2 µM to 2.4 µM. However, compound 16e showed
weak activity against Ovarian (NCI/ADR-RES) cell line with IC50 value
1
4h, and 16h (Table 2). Differently, renal cancer (A498) that was 100%
inhibited by the treatment with compounds 13b, 13c, 13d, 13f, 13h,
4h, and 16e (Table 2). Interestingly, CNS Cancer (SF-295) showed high
1
sensitivity towards the treatment with most of the tested compounds
especially 13d, 13e, 13g, 13h, 14h, and 16e(Table 2). In addition, the
growth of Non-Small Cell Lung Cancer (NCI-H522) and Colon Cancer
(
HT29) were suppressed by compounds 13e, 13h, and 16e (Table 2).
Obviously, most of the evaluated compounds showed moderate to high
inhibitory effect (70%ꢀ 100%) over variable Melanoma sub-types. In
particular, compound 13h which attained 100% mortality to four Mel-
anoma sub-types (LOX IMVI, MALME-3M, M14, and SK-MEL-5) and
compound 16e that achieved 100% inhibition over seven Melanoma
sub-types (LOX IMVI, MALME-3M, M14, SK-MEL-2, SK-MEL-28, SK-
MEL-5, and UACC-257).
The data obtained in Fig. 3 and Table 2 revealed that compounds
1
3b, 13d, 13e, 13h, 14b, 14h, and 16e occurred to be the highest
effective inhibitors for the 60 cell lines with mean inhibition percent
6%, 62%, 70%, 88%, 60%, 74%, and 100%, respectively (Fig. 3 and
Table 2). The above-mentioned compounds shared the high inhibitory
6
4

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
activity against BRAFV600E Kinase using ELISA technique (enzyme-
linked immunosorbent assay). As reported in (Table 4), the tested
Table 1
Structure of the final target compounds 13a-i, 14a-i, 15a-j, and 16a-j.
compounds exhibited a wide range of inhibition activity against
V600E
BRAF
Kinase. The preliminary % inhibition data of the tested de-
rivatives revealed that, compounds installing 3-hydroxyl group 15a-j
and 16a-j at position 4 of imidazole have a significant inhibitory activity
compared to that with 3-methoxyl group at position 4 of imidazole 13a-i
and 14a-i. Furthermore, the inhibitory activity of the compounds with
propylene spacer 14a-i and 16a-j is quite higher than the ethylene
spacer containing compounds 13a-i and 15a-j.
ID
R
n
Ar
ID
R
n
Ar
For more elucidation of the structural activity relationship of the
synthesized compounds, ten compounds 14h, 15a, 15d, 15h, 15i, 15j,
1
1
3a
3b
CH
3
3
3
3
1
15b
OH
1
1
6a, 16d, 16e, and 16f with variable substituents were subjected to
enzyme IC50 assay. All the tested candidates showed nanomolar IC50
CH
CH
CH
1
1
1
15c
15d
15e
OH
OH
OH
1
1
1
V600E
V600E
againstBRAF
from32 nM to 630 nM. From the data obtained in (Table 5), Compound
6a with unsubstituted phenyl terminal and propylene spacer showed
Kinase. The IC50 over BRAF
Kinase was ranging
1
1
3c
3d
1
V600E
higher potency against BRAF
Kinase with IC50 = 35 nM than
compound 15a with the ethylene spacer which has IC50 = 53 nM. The
para-substitution on the terminal phenyl sulfonamide with either elec-
tron withdrawing groups in compounds 15d, 15h, and 16d or electron
1
1
3e
3f
CH
CH
CH
3
3
3
1
1
1
15f
OH
OH
OH
1
1
1
donating group in compound 15i reduced the inhibitory activity (IC50
=
91 nM, 480 nM, 68 nM, and 76 nM, respectively) compared to the
unsubstituted derivatives 15a and 16a. A remarkable activity reduction
was noticed in the meta-substituted derivatives 16e and 16f with IC50
values of 120 nM and 190 nM, respectively compared to the para-
substituted derivatives. Compound 15j possessing para-hydroxyl sub-
15g
15h
1
3g
stitution on the terminal phenyl sulfonamide recorded the most poten-
V600E
tial inhibitory effect against BRAF
kinase (IC50 = 32 nM).
Meanwhile, compound 14h bearing 3-methoxy phenyl at position 4 of
imidazole ring was the lowest active (IC50 = 630 nM) derivative among
the tested compounds, the IC50 values of the tested compounds are
demonstrated in (Table 5).
1
1
1
1
1
1
1
3h
3i
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
1
1
2
2
2
2
2
15i
OH
OH
OH
OH
OH
OH
OH
1
1
2
2
2
2
2
15j
4a
4b
4c
4d
4e
16a
16b
16c
16d
16e
2
.2.3. Cell-cycle analysis and apoptotic modifications
Compound 16e exhibited its higher activity over MDA-MB-468 and
T-47D. Therefore, the effect of compound 16e was investigated to check
its effect on both cell cycle and apoptosis and necrosis in T-47D. Cell
cycle is the events occur to produce two cells from single cell. The cell
cycle is compose of four distinct phases; G1 phase, M phase (nuclear
division), S phase (DNA synthesis), and G2 phase. In addition to these
four phases another phase G0 which is the rest phase in which the cell in
non-multiplication state. Cells were treated with compound 16e (1 uM)
for 24 h and cell analysis for DNA contents was performed by using flow
cytometer (Fig. 7 A). Compound 16e showed increased in cell popula-
tion in G1 phase from 50.63% to 58.74% and S phase from 26.51% to
32.81% and decrease in population in G2 phase from 18.03% to 6.12%.
The effect of 16e on both apoptosis and necrosis was adopted by using
Annexin- V flow cytometry Kit/BD (Fig. 7 B). Compound 16e showed
increase in early apoptotic stage (Q2) from 1.99% to 4.04% and late
apoptotic stage from 3.75% to 7.57%.
1
1
1
4f
CH
CH
3
2
2
16f
OH
OH
2
2
4g
4h
3
16g
CH
3
3
2
2
1
16h
16i
16j
OH
OH
OH
2
2
2
1
1
4i
CH
2.3. Docking study
5a
OH
In attempt to correlatethe newly synthesized compoundsvariable
potency and structural features, Molecular docking was performed using
(
MOE) software. Target compounds 13a-i, 14a-i, 15a-j, and 16a-jwere
V600E
docked inside the active site ofBRAF
Kinase in complex with Dab-
above 100 µM (Table 3). The data revealed in (Table 3) explained the
rafenib (PDB ID: 4XV2) [41] so as to explore their potential binding
upcoming enzymatic assay results of the tested compounds. Melanoma
progression is commonly related to BRAFV600E mutation, as reported,
V600E
pattern. The docking results revealed that the Dabrafenib-BRAF
V600E
kinase domaincomplex had low root mean square deviation, RMSD
6
0% melanoma cases are caused by the BRAF
mutation [40].
(
0.1925) thatproved valid docking protocol with dock score (ꢀ 10.71
.2.2. BRAFV600E kinase inhibition assay
kcal/mol, Table 6). The native ligand (Dabrafenib) bound in the ATP
2
3
2
pocket by formation of two H-bonds between N , and 2-NH Pyrimidine
Further investigational studies were conducted through testing the
synthesized candidates 13a-i, 14a-i, 15a-j, and 16a-j for their inhibitory
at position 5 of the imidazole ring and Cys 532 amino acidin the hinge
binding area. Besides, the 2-fluorophenyl group at position 4 of the
5

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
1
1
20
00
8
6
4
2
0
0
0
0
0
Fig. 3. Mean Inhibition percent of NCI-60 cell line panel after treatment with compounds (13a-i, 14a-i, 15a-j, and 16a-j) at single dose (10 uM).
Table 2
Inhibitory effect of the target compounds 13a-i, 14a-i, 15a-j and 16a-j against the most sensitive cell lines using single dose (10 uM).
Comp.
Cell line
a
b
c
d
e
e
f
f
f
RPMI-8226
NCI-H522
HT29
SF-295
A498
RXF 393
LOX IMVI
M14
SK-MEL-2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
3a
3b
3c
3d
3e
3f
90
98
88
100
100
84
100
100
86
87
100
95
91
87
75
88
100
73
60
0
40
36
88
100
100
40
52
95
30
30
34
25
42
43
32
26
50
15
12
5
79
69
65
83
96
72
85
100
78
70
71
66
74
66
67
43
79
60
17
0
82
94
93
100
100
88
97
100
84
65
81
80
75
66
56
68
100
44
12
0
74
72
94
85
99
100
94
78
100
96
56
83
83
64
52
54
50
100
36
18
0
61
64
58
70
92
65
74
100
50
65
56
62
70
64
46
47
89
20
37
3
54
68
65
75
94
49
68
100
67
62
70
63
72
68
47
63
78
30
25
1
33
40
35
60
90
38
44
94
25
43
40
33
56
46
36
42
46
13
12
0
100
100
100
100
88
3g
3h
3i
97
100
84
4a
4b
4c
4d
4e
4f
65
81
96
99
76
79
4g
4h
4i
62
100
66
5a
5b
5c
5d
5e
5f
30
24
67
78
88
80
72
2
7
38
22
48
48
35
2
19
35
52
51
28
1
48
33
33
49
45
34
0
40
63
63
50
50
4
35
53
61
55
43
6
14
32
33
30
29
0
27
35
34
20
2
47
46
33
5g
6b
6c
6d
6e
6g
6h
6i
49
32
77
89
96
97
100
63
100
14
25
100
47
50
18
100
62
67
100
74
70
62
100
78
43
100
82
77
23
100
87
92
40
100
59
92
34
91
67
40
100
65
62
33
100
59
56
100
56
75
39
100
15
34
100
40
40
16
100
99
100
93
84
68
Comp. I
95
a: Leukemia, b: Non-small cell lung cancer, c: Colon cancer, d: CNS cancer, e: Renal cancer f: Melanoma.
imidazole ring occupied the hydrophobic pocket. In the ribose pocket,
the central Thiazole ring possessed Arene-H interaction with Val 471.
Likewise, the terminal 2,6-difluorphenyl sulfonamide group extended to
the allosteric binding site where, the sulfonamide oxygen formed H-
bonds to the backbone NH of Phe595 and the side chain of Lys594.
While, the nitrogen atom of the sulfonamide moiety formed H-bonding
with the main chain NH of Asp594. In addition, 2,6-difluorphenyl ring
formed Arene-H interaction with Leu 505 amino acid. Phe 595 and Leu
distortion of the spine responsible for the transition to an inactive state
[42].
Accordingly, the target compounds were designed to conserve the
essential binding features of Dabrafenib. Analysis of thedocking results
in Table 6 revealed that the binding conformation of most compounds
showed well alignment of Imidazole scaffold with Dabrafenib thiazole.
Imidazole was embedded in the ribose pocket by Arene-H interaction
with Val 471, the same binding behavior of thiazole Fig. 8. Moreover,
most of the target compounds keep a quite similar molecular in-
teractions of the native ligand by forming different bonds with the
5
05 amino acids are two of the four amino acids (Leu505, Phe516,
His574, and Phe595) that compose the regulatory spine of kinases by
6

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
1
00
100
9
9
9
9
9
9
9
8
7
6
5
4
80
60
40
20
0
1
3b 13d 13e 13h 14b 14h 16e
13b 13d 13e 13h 14b 14h 16e
1
00
1
00
80
60
40
20
0
8
6
4
2
0
0
0
0
0
1
3b 13d 13e 13h 14b 14h 16e
13b 13d 13e 13h 14b 14h 16e
1
00
1
00
8
6
4
2
0
0
0
0
0
80
60
40
20
0
1
3b 13d 13e 13h 14b 14h 16e
13b 13d 13e 13h 14b 14h 16e
Fig. 4. Mean percent inhibition of compounds (13b, 13d, 13e, 13h, 14b, 14h, and 16e) over a) Leukemia (RPMI-8226); b) Non-Small Cell Lung Cancer (NCI-
H522); c)Colon Cancer (HT29); d) CNS Cancer (SF-295); e) Renal cancer (A498); f) Renal cancer (RXF 393); g) Melanoma (LOX IMVI); h) Melanoma (M14); i)
Melanoma (SK-MEL-2) at single dose 10 uM.
essential amino acids Asp 594, Cys 532, Leu 505, Lys 483, Leu 514, Phe
95, and Val 471. In compound 15a and 15c, nitrogen of Pyridine ring
3. Conclusion
5
and its NH substituent formed hydrogen bond with Cys532, and imid-
azole ring bonded with Val 471 by Arene-H interaction, additionally, 3-
hydroxyphenyl ring bonded with Lys 483 by Arene-H interaction. These
three amino acids interactions are considered as the fundamental
interaction in the binding mode Fig. 8. The sulfonamide oxygen and the
In this study, a series 38 imidazole-based derivatives have been
designed and synthesized. Dabrafenib was used as leading compound,
several structural modifications have occurred in attempt to produce
candidates that are more potent. All target compounds were evaluated
for their in vitro cytotoxic activity against NCI 60 human cancer cell
lines, most of the tested compounds exhibited moderate to high inhib-
itory activity to most of cell lines. Compounds 14h and 16e demon-
strated the highest potency over Melanoma cell lines with mean IC50
values of 1.8 µM and 1.88 µM, respectively.
2
-phenyl ring of 16a, the most active derivative, formed H-bonding with
Phe 595 and Arene-H interaction with Leu 505, respectively. Bonding
with these two amino acids is of a great importance to keep the enzyme
in its inactive form [36] Fig. 8. Apparently, some of the docked com-
pounds (13g, 16b, and 16j) with a high docking score showed extra
molecular interactions with the BRAFV600E active site different from the
native ligand Table 6, Fig. 8.
In addition, the inhibitory activity of all the synthesized derivatives
V600E
was determined against BRAF
, and compounds 15a-j and 16a-j
bearing 3-hydroxy phenyl moiety in position 4 of Imidazole exhibited
higher activity than 13a-i and 14a-I with 3-methoxy phenyl in the same
7

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
1
00
100
80
60
40
20
0
8
6
4
2
0
0
0
0
0
1
3b 13d 13e 13h 14b 14h 16e
13b 13d 13e 13h 14b 14h 16e
g
h
1
00
80
60
40
20
0
1
3b 13d 13e 13h 14b 14h 16e
i
Fig. 4. (continued).
4
. Experimental
Breast Cancer
Prostate Cancer
Renal Cancer
Ovarian Cancer
Melanoma
4
.1. Chemistry
The intermediate compounds as well as the target compounds were
purified by flash column chromatography using silica gel 60
0.040–0.063 mm, 230–400 meshASTM) and technical grade solvents.
(
1
13
H NMR and C NMR analyses were carried out on a Bruker Avance 400
CNS Cancer
spectrometer using tetramethylsilane (TMS) as an internal standard.
Melting points were measured on a Walden Precision Apparatus Elec-
trothermal 9300 apparatus and were uncorrected. LC-MS analysis was
conducted using the following system: Waters 2998 photodiode array
detector, Waters 3100 mass detector, Waters SFO system fluidics orga-
nizer, Waters 2545 binary gradient module, Waters reagent manager,
Colon Cancer
Non-Small Cell Lung Cancer
Leukemia
0
10 20 30 40 50 60 70 80 90 100
1
8
Fig. 5. Mean percent inhibition of compound 16e over Leukemia, Non-Small
Cell Lung Cancer, Colon Cancer, CNS Cancer, Melanoma, Ovarian Cancer,
Renal Cancer, Prostate Cancer, and Breast Cancer cell lines at single dose
Waters 2767 sample manager, Sunfire™ C column (4.6 × 50 mm, 5
μm
particle size); Solvent gradient = 95% A at 0 min, 1% A at 5 min; solvent
A: 0.035% trifluoroacetic acid (TFA) in water; solvent B: 0.035% TFA in
MeOH; flow rate = 3.0 mL/min; the AUC was calculated using Waters
MassLynx 4.1 software. The solvents and liquid reagents were trans-
ferred using hypodermic syringes. All the solvents and reagents were
purchased from commercial companies, and used as such.
(
10 uM).
position. The IC50 of the most potent inhibitors has been determined;
compounds 15i, 15j, 16a, and 16d were the most potent inhibitors with
IC50 values of 76 nM, 32 nM, 35 nM and 68 nM, respectively. The
V600E
designed compounds were docked into BRAF
(PDB ID: 4XV2)
4.1.1. Methyl 3-methoxybenzoate (2)
active site, most the docked candidates conserved the essential molec-
ular interaction of Dabrafenib.
A mixture of 3-methoxybenzoic (1, 4.24 g, 0.002 mol) and methanol
(40 mL) were heated under reflux until the benzoic acid was dissolved in
methanol then few drops of concentrated sulphuric acid was added to
the mixture and refluxed for 8 h. The resulting mixture was cooled to
room temperature, diluted with water and a saturated solution of so-
dium bicarbonate was added to the mixture to neutralize the benzoic
acid, extracted with ethyl acetate, dried and evaporated to get the
required ester compound 2.
Together, the antiproliferative activity, along with enzyme inhibi-
tion results, illustrated that this series of Imidazole-based derivatives
V600E
bearing 2-amino pyridinyl moiety is promising BRAF
inhibitors
with potential anticancer activity and good leads for further structural
optimization.
◦
1
Yield: 90%. m.p.: 110 C. H NMR (400 MHz, CDCl
3
) δ 7.61 (m, 1H,
Ar-H), 7.54 (m, 1H, Ar-H), 7.31 (t, J = 8 Hz, 1H, Ar-H), 7.07 (m, 1H, Ar-
8

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
Table 3
IC50 values of compounds 14h and 16e and lead compound I as positive standard over 60 human cancer lines.
Cell line
14h
16e
Compound I
IC50(µM)
Mean IC50(µM)
IC50(µM)
Mean IC50(µM)
IC50(µM)
Mean IC50(µM)
Leukemia
CCRF-CEM
HL-60(TB)
K-562
2.3
3.25
2.57
2.58
1.85
2.16
2.33
2.4
2.91
2.55
2.51
1.97
1.87
1.61
2.2
3.18
2.51
2.38
1.95
2.13
1.73
MOLT-4
RPMI-8226
SR
Non-small cell lung cancer
A549/ATCC
EKVX
3.04
2.92
2.63
3.38
2.39
2.21
3.42
2.07
2.23
2.7
3.08
2.47
2.32
2.05
2.04
1.79
2.39
1.90
2.04
2.2
3.79
3.51
3.23
2.32
5.61
3.16
2.71
3.76
ND
3.51
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
2.48
2.15
1.72
1.99
2.83
2.81
2.54
2.4
1.97
1.76
1.81
1.97
1.87
1.99
2.24
2
1.78
2.17
2.33
2.40
2.55
2.75
3.02
2.4
HT29
KM12
SW-620
CNS cancer
SF-268
2.24
1.88
1.89
3.59
1.75
2.03
2.2
2.16
1.79
1.78
2.43
1.68
2.11
2
2.32
2.38
2.25
4.01
2.52
3.10
2.9
SF-295
SF-539
SNB-19
SNB-75
U251
Melanoma
LOX IMVI
MALME-3M
M14
1.75
1.69
1.76
1.97
2.21
2.13
1.60
2.08
1.85
1.8
1.75
1.51
1.83
1.85
2.09
1.63
1.54
1.99
1.92
1.88
1.64
1.86
1.97
2.01
1.92
1.93
1.75
2.05
1.91
1.89
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
Ovarian cancer
IGROV1
1.83
2.70
2.23
3.69
3.15
2.42
3.73
2.8
1.84
2.33
2.02
2.28
2.73
ND
2.29
4.24
4.57
3.55
3.53
3.22
2.19
4.92
3.74
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
2.66
Renal cancer
7
86–0
2.53
2.33
3.06
2.54
2.05
3.08
3.01
1.66
2.5
2.13
1.61
2.86
2.76
1.71
2.34
2.72
1.89
2.3
1.82
2.15
4.23
3.16
1.80
5.73
4.51
1.78
3.14
A498
ACHN
CAKI-1
RXF 393
SN12C
TK-10
UO-31
Prostate cancer
PC-3
2.50
3.32
2.9
2
2.30
2.43
2.4
1.9
3.96
5.47
4.17
2.69
DU-145
Breast cancer
MCF7
1.82
2.54
2.24
1.60
1.88
1.87
1.51
2.83
2.46
1.77
1.41
1.21
1.94
1.97
2.35
3.20
2.41
1.92
MDA-MB-231/ATCC
HS 578 T
BT-549
T-47D
MDA-MB-468
9

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
3
2
1
0
.5
3
.5
2
.5
1
.5
0
1
4h 16e
Fig. 6. Mean IC50 of compounds 14h and 16e over Leukemia, Non-Small Cell Lung Cancer, Colon Cancer, CNS Cancer, Melanoma, Ovarian Cancer, Renal Cancer,
Prostate Cancer, and Breast Cancer cell lines.
H), 3.89 (s, 1H, OOCH3), 3.81 (s, 1H, OCH3). 13C NMR (100 MHz,
Table 4
CDCl3) δ 166.85 (Ar-C), 159.86 (Ar-C), 131.41 (Ar-C), 129.6 (Ar-C),
122.16 (Ar-C), 119.36 (Ar-C), 114.22 (Ar-C), 55.29 (OOCH3), 52.04
Enzyme % inhibition activity of the final target compounds 13a-i, 14a-i, 15a-j,
V600E
and 16a-j over BRAF
10 uM.
(
OCH3).
Comp.
BRAF (V600E) % inhibition
Comp.
BRAF (V600E) % inhibition
at (10 µM)
at (10 µM)
4
.1.2. 2-(2-Bromopyridin-4-yl)-1-(3-methoxyphenyl)ethan-1-one (4)
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
3a
3b
3c
3d
3e
3f
52.92 ± 0.21
55.81 ± 0.55
56.84 ± 0.61
57.01 ± 0.24
55.42 ± 0.44
65.50 ± 0.72
60.21 ± 0.25
58.49 ± 0.57
50.61 ± 0.88
54.02 ± 0.92
60.72 ± 0.78
50.29 ± 0.47
67.03 ± 0.63
60.41 ± 0.29
65.60 ± 0.41
64.61 ± 0.22
59.68 ± 0.46
68.10 ± 0.17
99.72 ± 0.13
90.44 ± 0.18
15b
15c
15d
15e
15f
15g
15h
15i
98.34 ± 0.20
97.94 ± 0.11
98.13 ± 0.32
97.61 ± 0.36
98.13 ± 0.28
98.78 ± 0.69
97.95 ± 0.87
99.05 ± 0.16
99.99 ± 0.10
100 ± 0.09
A solution of compound 2 (1.0 g, 5.0 mmol) and 2-bromo-4-picoline
◦
(
0.5 mL, 5.6 mmol) in THF (5 mL) was cooled to ꢀ 25 C, and LiHMDS
◦
(
3.7 mL, 1.0 M solution in THF, 19.9 mmol) was slowly added at ꢀ 25 C
◦
to the reaction mixture maintaining the temperature at ꢀ 25 C. The
resulting mixture was stirred overnight at room temperature. The
3g
3h
3i
4
mixture was quenched with saturated aqueous NH Cl (15 mL), and
ethylacetate (20 mL) was added. The organic layer was separated, and
the aqueous layer was extracted with ethyl acetate (3–10 mL). The
combined organic layer was washed with saline and dried over anhy-
drous sodium sulphate. The organic solvent was evaporatedunder vac-
uum and the residue was purified by flash column chromatography
15j
4a
4b
4c
4d
4e
4f
16a
16b
16c
16d
16e
16f
16g
16h
16i
98.63 ± 0.19
97.78 ± 0.20
99.84 ± 0.15
97.66 ± 0.31
98.26 ± 0.24
98.64 ± 0.44
97.59 ± 0.32
96.71 ± 0.42
97.87 ± 0.51
(
silica gel, hexane ethyl acetate 1:1 v/v then switching to hexane–ethyl
acetate 1:5 v/v) to yield the title compound 4, which was subjected to
the next step without further purification.
4g
4h
4i
5a
16j
4
.1.3. 1-(2-bromopyridin-4-yl)-2-(3-methoxyphenyl)ethane-1,2-dione (5)
Comp
I
A solution of compound 4 (2.0 g, 6.8 mmol) in DMSO (10 mL) was
◦
heated to 55 C. Hydrobromic acid (2.5 mL, 20.4 mmol, 3 eq.) was added
◦
dropwise to the reaction mixture. The reaction was stirred at 55 C for 2
h. The reaction mixture was poured carefully to a saturated solution of
sodium bicarbonate, extracted with ethyl acetate, dried and evaporated
to get the required compound 5.
Table 5
IC50 values of compounds 14h, 15a, 15d, 15h, 15i, 15j, 16a,
V600E
1
6d, 16e, and 16f against BRAF
kinase.
◦
1
Yield: 80%. m.p.: 115 C. H NMR (400 MHz, CDCl
3
) δ 8.63 (d, J =
Comp.
IC50 (nM) BRAF (V600E))
5
7
.2 Hz, 1H, Ar-H), 7.97 (s, 1H, Ar-H), 7.75 (d, J = 1.2 Hz, 1H, Ar-H),
1
1
1
1
1
1
1
1
1
1
4h
5a
5d
5h
5i
630 ± 5.61
.74 (d, J = 1.2 Hz, 1H, Ar-H), 7.48 (m, 2H, Ar-H), 7.26 (m, 1H, Ar-
53.80 ± 1.25
91.70 ± 2.33
485.00 ± 6.24
76.60 ± 2.11
32.90 ± 1.02
35.60 ± 1.53
68.80 ± 2.05
120.00 ± 2.37
190.00 ± 3.46
770 ± 5.24
13
3 3
H), 3.9 (s, 3H, OCH ). C NMR (100 MHz, CDCl ) δ 191.71 (Ar-C),
1
91.01 (Ar-C), 160.26 (Ar-C), 151.57 (Ar-C), 143.47 (Ar-C), 141.19 (Ar-
C), 133.25 (Ar-C), 130.3 (Ar-C), 127.24 (Ar-C), 123.39 (Ar-C), 122.65
Ar-C), 121.26 (Ar-C), 113.08 (Ar-C), 55.61 (OCH ).
5j
(
3
6a
6d
6e
6f
4
.1.4. 2-bromo-4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-5-yl)
pyridine (7)
Comp I
To a solution of compound 5 (1.23 g, 4 mmol) and Benzaldehyde 6
(
0.4 mL, 4 mmol) in acetic acid (10 mL), ammonium acetate (3.1 g, 40
◦
mmol, 10 eq.) was added. The reaction mixture was heated to 100 C for
1
0

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
Fig. 7. Effect of compound 16e on cell cycle (A) and apoptosis and necrosis (B).
h. The reaction mixture was poured in Ammonia solution with crushed 4.1.6. N-(2-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-5-yl)
4
ice. The resulted precipitate was filtered, washed with water three times,
pyridin-2 yl)amino)ethyl(propyl))substituted benzenesulfonamide (13–14)
To a solution of compound 10 or 11 (0.3 mmol) in anhydrous
and dried under vacuum to get the titled compound 7.
◦
1
◦
Yield: 75%. m.p.: 125 C. H NMR (400 MHz, CDCl
3
) δ 10.45 (s, 1H,
dichloromethane (6 mL), DIPEA (0.6 mmol, 2 eq.) was added at 0 C,
Ar-H), 8.15 (d, J = 5.2 Hz, 1H, Ar-H), 7.94 (d, J = 7.2 Hz, 2H, Ar-H),
stirred for 15 min, then benzenesulfonyl chlorides(0.36 mmol, 1.2 eq.)
was added drop wise. The reaction mixture was stirred at room tem-
perature for 24 h. When the reaction completed, the solvent was
removed and the residue was partitioned between ethyl acetate and
water. The organic layer was separated and the aqueous layer was
extracted with ethyl acetate (3–10 mL). The combined organic layer was
washed with brine two times and the organic solvent was evaporated
under reduced pressure. The residue was purified by column chroma-
tography (silica gel, hexane–ethyl acetate2:1 v/v) to give the required
products 13 and 14 as solid.
7
1
.45 (m, 4H, Ar-H), 7.36 (t, J = 8 Hz, 1H, Ar-H), 7.04 (d, J = 7.6 Hz,
13
H, Ar-H), 6.98 (d, J = 8.8 Hz, 2H, Ar-H), 3.08 (s, 3H, OCH
) δ 160.03 (Ar-C), 149.7 (Ar-C), 142.49 (Ar-C), 130.3
Ar-C), 129.42 (Ar-C), 129.22 (Ar-C), 129.01 (Ar-C), 125.53 (Ar-C),
25.32 (Ar-C), 120.32 (Ar-C), 120.24 (Ar-C), 114.83 (Ar-C), 113.83 (Ar-
C), 55.41 (OCH ).
3
). C NMR
(
(
100 MHz, CDCl
3
1
3
4
.1.5. N1-(4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-5-yl)pyridin-2-
yl)ethane(propan)- diamine (10–11)
A solution of compound 7 (2.0 g, 5 mmol) in ethylenediamine (8, 3
mL, 50 mmol, 10 eq.) or propylenediamine (9, 3.7 mL, 50 mmol, 10 eq.)
was heated under reflux for 12 h. The reaction mixture was evaporated
under vacuum producing the title compounds 10 and 11, respectively.
The produced compounds were subjected to the next step reaction
without further purification.
4.1.6.1. N-(2-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-5-yl)pyr-
idin-2-yl)amino)ethyl)benzenesulfonamide (13a):. Yield: 65%. m.p.:
◦
1
139 C. H NMR (400 MHz, CDCl ) δ 7.92 (d, J = 4.8 Hz, 2H, Ar-H), 7.73
3
(d, J = 5.16 Hz, 1H, Ar-H), 7.66 (d, J = 8.16 Hz, 2H, Ar-H), 7.33 (q, J =
8.75 Hz, 5H, Ar-H), 7.19 (t, J = 7.52 Hz, 1H, Ar-H), 7 (s,2H, Ar-H), 6.83
(
d, J = 7.4 Hz, 1H, Ar-H), 6.66 (s,1H, Ar-H), 6.6 (d, J = 3.48 Hz, 1H, Ar-
3 2 2 2
H), 4.96 (s,1H, NH), 3.69 (s,3H, OCH ), 3.3 (s,2H, CH CH NHSO ), 3.02
1
1

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
Table 6
V600E
Docking results of target compounds 13a-i, 14a-i, 15a-j, and 16a-j inBRAF
kinase (PDB ID: 4XV2).
Comp.
Energy score (Kcal/mol)
Amino acid
Binding group
Interaction
Hydrogen bond length (Å)
Dabrafenib
ꢀ 10.71
Asp 594
Cys 532
SO2
H-bond
H-bond
H-bond
Arene-H
3.11
3.4
NH2-Pyrimidine
N-Pyrimidine
2,6-diflouro phenyl ring
2.9
Leu 505
2
,6-diflouro phenyl
Lys 483
Phe 595
Val 471
Ile 463
SO2
H-bond
H-bond
Arene-H
Arene-H
2.6
Imidazole ring
3.38
1
3a
ꢀ 8.31
3-methoxyphenyl ring
Phenyl ring
Lys 483
Ser 536
Val 471
Asn 580
Gly 466
Lys 483
Val 471
Asn 580
Lys 578
Phe 583
Ser 465
Val 471
SO2
Arene-H
H-bond
Arene-H
H-bond
Arene-H
Arene-H
Arene-H
H-bond
H-bond
Arene-H
H-bond
Arene-H
3.06
3.11
Imidazole ring
1
1
3b
3c
ꢀ 8.94
ꢀ 8.76
NH
Pyridine ring
Phenyl ring
Imidazole ring
NH
2.93
3.16
NH
Imidazole ring
CH
3.51
3.14
3-methoxyphenyl ring
1
3d
ꢀ 8.95
Cys 532
Gly 466
Lys 483
N-Pyridine ring
Phenyl ring
H-bond
Arene-H
Arene-H
3-methoxyphenyl ring
Imidazole ring
Val 471
Gly 466
Lys 483
Val 471
Asp 594
Lys 483
Phe 595
Val 471
Leu 514
Lys 483
Phe 595
Val 471
Asn 580
Lys 483
Asn 580
Lys 578
Asn 580
Lys 483
Val 471
Leu 514
Lys 483
Phe 595
Val 471
Lys 483
Lys 578
Val 471
Leu 514
Phe 595
Ser 465
Arene-H
Arene-H
Arene-H
Arene-H
H-bond
H-bond
H-bond
Arene-H
Arene-H
H-bond
Arene-H
Arene-H
H-bond
Arene-H
Arene-H
Arene-H
H-bond
Arene-H
Arene-H
Arene-H
H-bond
H-bond
Arene-H
Arene-H
H-bond
Arene-H
Arene-H
Arene-H
H-bond
1
1
3e
3f
ꢀ 8.81
ꢀ 8.05
Pyridine ring
Phenyl ring
Imidazole ring
SO2
3.04
3.18
2.93
SO2
SO2
Pyridine ring
4-F-Phenyl ring
SO2
1
3g
ꢀ 9.25
3.09
3.07
4-F-Phenyl ring
Imidazole ring
NH
1
1
1
3h
3i
ꢀ 8.47
ꢀ 8.23
ꢀ 8.97
4-CF3-Phenyl ring
Imidazole ring
Phenyl ring
NH
4a
2.91
Imidazole ring
Phenyl ring
4-Cl-Phenyl ring
SO2
1
4b
ꢀ 8.31
3.15
2.84
SO2
Imidazole ring
Phenyl ring
SO2
1
1
4c
4d
ꢀ 9.35
3.15
Imidazole ring
4-F-Phenyl ring
4-F-Phenyl ring
3-methoxyphenyl ring
ꢀ 8.765
3.33
1
1
4e
4f
ꢀ 8.15
ꢀ 8.58
Asp 594
Lys 483
Gly 464
Phe 583
Phe 595
Ser 465
Asn 580
Lys 483
Val 471
Ile463
NH
H-bond
H-bond
Arene-H
Arene-H
H-bond
Arene-H
H-bond
Arene-H
Arene-H
Arene-H
Arene-H
H-bond
Arene-H
Arene-H
Arene-H
H-bond
Arene-H
3.52
3.35
SO2
Phenyl ring
Pyridine ring
SO2
3.07
3.34
Phenyl ring
NH
1
4g
ꢀ 8.16
Phenyl ring
Imidazole ring
4-CF3- Phenyl ring
Imidazole ring
SO2
1
1
4h
4i
ꢀ 8.49
ꢀ 8.42
Lys 483
Lys 483
Phe 583
Ser 535
Val 471
Cys 532
Gly 466
2.75
3.17
Imidazole ring
Phenyl ring
Pyridine ring
N-Pyridine ring
Phenyl ring
1
5a
ꢀ 8.85
(
continued on next page)
1
2

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
Table 6 (continued)
Comp.
Energy score (Kcal/mol)
Amino acid
Binding group
Interaction
Hydrogen bond length (Å)
Gly 534
Lys 483
Val 471
Gln 530
Ile 463
NH
H-bond
Arene-H
Arene-H
H-bond
Arene-H
Arene-H
H-bond
Arene-H
Arene-H
H-bond
H-bond
Arene-H
Arene-H
2.93
3-hydroxyphenyl ring
Imidazole ring
3-hydroxyphenyl ring
Imidazole ring
4-Cl-Phenyl ring
SO2
1
5b
ꢀ 8.82
3.03
2.99
Leu 514
Lys 483
Phe 595
Ser 535
Cys 532
4-Cl-Phenyl ring
Phenyl ring
1
1
5c
5d
ꢀ 9.07
ꢀ 8.41
NH
3.37
3.07
N-Pyridine ring
3-hydroxyphenyl ring
Imidazole ring
Lys 483
Val 471
Gly 466
Lys 483
Ser 536
Val 471
Lys 483
Phe 583
Ser 535
Asn 580
Lys 483
Val 471
Asp 594
Pyridine ring
Phenyl ring
SO2
Arene-H
Arene-H
H-bond
Arene-H
H-bond
Arene-H
Arene-H
H-bond
Arene-H
Arene-H
H-bond
H-bond
H-bond
Arene-H
Arene-H
Arene-H
Arene-H
Arene-H
Arene-H
Arene-H
Arene-H
Arene-H
3.33
3.04
Imidazole ring
SO2
1
1
1
5e
5f
ꢀ 8.44
ꢀ 7.73
ꢀ 8.44
Imidazole ring
Phenyl ring
NH
3.24
Phenyl ring
Imidazole ring
SO2
5g
2.99
2.97
2.96
NH
Lys 483
SO2
Pyridine ring
NH
Phe 595
Val 471
Phe 583
Imidazole ring
Pyridine ring
Imidazole ring
3-hydroxyphenyl ring
Phenyl ring
Imidazole ring
4-methoxyphenyl ring
SO2
1
1
1
1
1
5h
5i
ꢀ 8.81
ꢀ 8.28
ꢀ 8.95
ꢀ 9.12
ꢀ 9.08
Ser 465
Ser 535
Gly 466
Leu 514
Lys 483
Gly 466
H-bond
H-bond
Arene-H
Arene-H
Arene-H
H-bond
Arene-H
Arene-H
H-bond
H-bond
Arene-H
Arene-H
Arene-H
H-bond
Arene-H
H-bond
H-bond
H-bond
Arene-H
H-bond
Arene-H
Arene-H
H-bond
H-bond
Arene-H
Arene-H
Arene-H
Arene-H
Arene-H
Arene-H
Arene-H
H-bond
H-bond
Arene-H
Arene-H
H-bond
Arene-H
Arene-H
2.86
3.03
5j
4-hydroxyphenyl
Pyridine ring
Phenyl ring
Imidazole ring
SO2
Lys 483
Val 471
Asp 594
Leu 505
Phe 583
Phe 595
Lys 483
Phe 583
Phe 595
Ser 535
Thr 508
Val 471
Asp 594
Lys 483
Phe 583
Phe 595
Asp 594
Phe 595
Ser 535
Lys 483
6a
6b
3.17
Phenyl ring
Imidazole ring
SO2
3.24
2.94
SO2
Imidazole ring
4-Cl-Phenyl ring
Phenyl ring
4-Cl-Phenyl ring
Pyridine ring
SO2
2.8
1
6c
ꢀ 8.42
3.11
2.99
2.81
SO2
SO2
Imidazole ring
3-hydroxyphenyl ring
4-F-Phenyl ring
Phenyl ring
SO2
1
1
6d
6e
ꢀ 8.89
ꢀ 8.83
2.87
3.02
3.25
NH
Phe 583
Val 471
Lys 483
Ser 465
Arg 462
Phe 583
Ser 535
Lys 483
Imidazole ring
Pyridine ring
2,4-dichlorophenyl
Imidazole ring
Phenyl ring
Imidazole ring
Phenyl ring
SO2
1
6f
ꢀ 8.42
1
1
6g
6h
ꢀ 8.98
ꢀ 8.38
3.11
3.37
NH
Phe 583
Ser 535
Asn 580
Lys 483
Lys578
Imidazole ring
Phenyl ring
NH
1
6i
ꢀ 8.82
3.06
Phenyl ring
4-methoxyphenyl ring
Imidazole ring
(
continued on next page)
1
3

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
Table 6 (continued)
Comp.
Energy score (Kcal/mol)
Amino acid
Binding group
Interaction
Hydrogen bond length (Å)
Val 471
Leu 514
Arene-H
H-bond
Arene-H
H-bond
Arene-H
H-bond
Arene-H
Arene-H
1
6j
ꢀ 8.85
4-hydroxyphenyl
2.86
3.31
2.92
4
-hydroxyphenyl ring
Lys 483
Phe 595
Ser 465
Ser 535
Ser 436
SO2
4-hydroxyphenyl ring
3-hydroxyphenyl
Phenyl ring
Phenyl ring
V600E
Fig. 8. 2D representation of docking study output (PDB ID: 4XV2). a) 2D interaction of Dabrafenib (native ligand) with BRAF
kinase enzyme domain; b) 2D
V600E
V600E
interaction of 15c with BRAF
V600E
kinase enzyme domain; c) 2D interaction of 16a with BRAF
kinase enzyme domain; d) 2D interaction of 16j with BRAF-
kinase enzyme domain.
(
s,2H, CH
58.48 (Ar-C), 147.05 (Ar-C), 146.59 (Ar-C), 138.85 (Ar-C), 138.43 (Ar-
C), 129.66 (Ar-C), 129.55 (Ar-C), 129.27 (Ar-C), 129.03 (Ar-C), 128.79
Ar-C), 125.73 (Ar-C), 120.99 (Ar-C), 113.95 (Ar-C), 113.85 (Ar-C),
2
CH
2
NHSO
2
). 13C NMR (100 MHz, CDCl
3
) δ 159.62 (Ar-C),
H), 4.94 (s,1H, NH), 3.75 (s,3H, OCH
CH CH NHSO
), 3.08 (t, J = 5.32 Hz, 2H, CH
(100 MHz, CDCl ) δ 159.73 (Ar-C), 158.41 (Ar-C), 146.89 (Ar-C), 146.43
3
), 3.38 (t, J = 4.84 Hz, 2H,
13
1
2
2
2
2 2 2
CH NHSO ). C NMR
3
(
(Ar-C), 139.03 (Ar-C), 132.25 (Ar-C), 129.79 (Ar-C), 129.51 (Ar-C),
1
3 2 2 2
12.24 (Ar-C), 105.92 (Ar-C), 55.25 (OCH ), 44.01 (CH CH NHSO ),
129.12 (Ar-C), 128.87 (Ar-C), 127.34 (Ar-C), 125.63 (Ar-C), 120.93 (Ar-
4
1.63 (CH
2
CH
2
NHSO
2
). LC/MS 526 (M + 1)+.
C), 113.93 (Ar-C), 112.26 (Ar-C), 105.95 (Ar-C), 55.32 (OCH
3
), 44.31
+
(
CH
2
CH
2
NHSO
2
), 41.68 (CH
2
CH
2
NHSO
2
). LC/MS 560.4 (M) .
4
5
.1.6.2. 4-chloro-N-(2-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-
-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (13b):. Yield: 60%. m.
4.1.6.3. 4-bromo-N-(2-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-
◦
1
p.: 130 C. H NMR (400 MHz, CDCl
3
) δ 7.95 (d, J = 6.6 Hz, 2H, Ar-H),
5-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (13c):. Yield: 71%. m.
◦
1
7
7
7
.79 (d, J = 5.52 Hz, 1H, Ar-H), 7.64 (s,1H, Ar-H), 7.61 (s,1H, Ar-H),
p.: 127 C. H NMR (400 MHz, CDCl
3
) δ 7.96 (d, J = 6.8 Hz, 2H, Ar-H),
.57 (s,1H, Ar-H), 7.55 (d, J = 1.72 Hz, 2H, Ar-H), 7.38 (m,3H, Ar-H),
.25 (d, J = 8 Hz, 1H, Ar-H), 7.05 (d, J = 5.92 Hz, 2H, Ar-H), 6.88
7.79 (m,3H, Ar-H), 7.39 (m,3H, Ar-H), 7.25 (d, J = 8.12 Hz, 1H, Ar-H),
7.11 (t, J = 8.48 Hz, 2H, Ar-H), 7.06 (d, J = 4 Hz, 2H, Ar-H), 6.88 (dd, J
= 1.72 Hz, 1H, Ar-H), 6.73 (s,1H, Ar-H), 6.66 (d, J = 4.88 Hz, 1H, Ar-H),
(
dd, J = 1.75 Hz, 1H, Ar-H), 6.71 (s,1H, Ar-H), 6.67 (d, J = 4 Hz, 1H, Ar-
1
4

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
4
.98 (s,1H, NH), 3.76 (s,3H, OCH
CH CH NHSO
), 3.09 (t, J = 5.28 Hz, 2H, CH
100 MHz, CDCl ) δ 166.16 (Ar-C), 163.64 (Ar-C), 159.74 (Ar-C), 158.4
Ar-C), 146.38 (Ar-C), 136.03 (Ar-C), 129.79 (Ar-C), 129.65 (Ar-C),
29.52 (Ar-C), 128.87 (Ar-C), 125.62 (Ar-C), 120.92 (Ar-C), 116.31 (Ar-
C), 116.09 (Ar-C), 113.92 (Ar-C), 112.23 (Ar-C), 105.92 (Ar-C), 55.31
3
), 3.39 (d, J = 4.64 Hz, 2H,
(CH
2
CH
2
NHSO
2
), 41.63 (CH
2
CH
2
NHSO
2
). LC/MS 544.3 (M + 1)+.
1
3
2
2
2
2 2 2
CH NHSO ). C NMR
(
(
3
4.1.6.8. N-(2-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-5-yl)pyr-
idin-2-yl)amino)ethyl)-4-(trifluoromethyl)benzenesulfonamide (13h):.
◦
1
1
Yield: 60%. m.p.: 110 C. H NMR (400 MHz, CDCl ) δ 7.95 (d, J = 6.6
3
Hz, 2H, Ar-H), 7.79 (d, J = 5.52 Hz, 1H, Ar-H), 7.64 (s,1H, Ar-H), 7.61
(
OCH
3
), 44.21 (CH
2
CH
2
NHSO
2
), 41.68 (CH
2
CH
2
NHSO
2
). LC/MS 605.8
(s,1H, Ar-H), 7.57 (s,1H, Ar-H), 7.55 (d, J = 1.72 Hz, 2H, Ar-H), 7.38
(m,3H, Ar-H), 7.25 (d, J = 8 Hz, 1H, Ar-H), 7.05 (d, J = 5.92 Hz, 2H, Ar-
H), 6.88 (dd, J = 1.75 Hz, 1H, Ar-H), 6.71 (s,1H, Ar-H), 6.67 (d, J = 4 Hz,
+
(
M + 1) .
4
5
.1.6.4. 4-fluoro-N-(2-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-
1H, Ar-H), 4.94 (s,1H, NH), 3.75 (s,3H, OCH
3
), 3.38 (t, J = 4.84 Hz, 2H,
13
-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (13d):. Yield: 65%. m.
CH
2
CH
2
NHSO
2
), 3.08 (t, J = 5.32 Hz, 2H, CH
2 2 2
CH NHSO ). C NMR
◦
1
p.: 133 C. H NMR (400 MHz, CDCl
3
) δ 7.94 (d, J = 6.76 Hz, 2H, Ar-H),
(100 MHz, CDCl
3
) δ 159.73 (Ar-C), 158.41 (Ar-C), 146.89 (Ar-C), 146.43
7
.79 (t, J = 1.84 Hz, 2H, Ar-H), 7.65 (d, J = 7.84 Hz, 1H, Ar-H), 7.48 (dd,
(Ar-C), 139.03 (Ar-C), 132.25 (Ar-C), 129.79 (Ar-C), 129.51 (Ar-C),
129.12 (Ar-C), 128.87 (Ar-C), 127.34 (Ar-C), 125.63 (Ar-C), 120.93 (Ar-
J = 0.92 Hz, 1H, Ar-H), 7.38 (m,4H, Ar-H), 7.25 (t, J = 8.12 Hz, 1H, Ar-
H), 7.05 (d, J = 5.8 Hz, 2H, Ar-H), 6.87 (dd, J = 1.76 Hz, 1H, Ar-H), 6.71
3
C), 113.93 (Ar-C), 112.26 (Ar-C), 105.95 (Ar-C), 55.32 (OCH ), 44.31
(
(
s,1H, Ar-H), 6.66 (d, J = 4.64 Hz, 1H, Ar-H), 4.93 (s,1H, NH), 3.74
(CH
2
CH
2
NHSO
2
), 41.68 (CH
2
CH
2
NHSO
2
). LC/MS 594.2 (M + 1)+.
s,3H, OCH
.96 Hz, 2H, CH
C), 158.44 (Ar-C), 146.45 (Ar-C), 141.76 (Ar-C), 135.11 (Ar-C), 132.54
3
), 3.38 (d, J = 4.68 Hz, 2H, CH
2
CH
2
NHSO
2
), 3.09 (t, J =
1
3
4
2
CH
2
NHSO
2
). C NMR (100 MHz, CDCl
3
) δ 159.71 (Ar-
4.1.6.9. 4-methoxy-N-(2-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imida-
zol-5-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (13i):. Yield: 64%.
◦
1
(
(
Ar-C), 130.35 (Ar-C), 129.76 (Ar-C), 129.51 (Ar-C), 128.86 (Ar-C), 127
Ar-C), 125.63 (Ar-C), 124.96 (Ar-C), 120.94 (Ar-C), 113.97 (Ar-C),
m.p.: 101 C. H NMR (400 MHz, CDCl ) δ 7.97 (d, J = 6.8 Hz, 2H, Ar-H),
3
7.74 (d, J = 5.6 Hz, 1H, Ar-H), 7.69 (d, J = 8.84 Hz, 2H, Ar-H), 7.33
1
4
12.28 (Ar-C), 105.97 (Ar-C), 55.31 (OCH
3
), 44.4 (CH
2
CH
2
NHSO
2
),
(m,3H, Ar-H), 7.2 (t, J = 7.8 Hz, 1H, Ar-H), 7.03 (d, J = 7.88 Hz, 2H, Ar-
H), 6.87 (d, J = 8.88 Hz, 2H, Ar-H), 6.83 (dd, J = 1.16 Hz, 1H, Ar-H),
1.72 (CH
2
CH
2
NHSO
2
). LC/MS 544.2 (M + 1)+.
6
.68 (s,1H, Ar-H), 6.59 (d, J = 8 Hz, 1H, Ar-H), 5.04 (s,1H, NH), 3.78
4
5
.1.6.5. 3-chloro-N-(2-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-
-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (13e):. Yield: 74%. m.
(s,3H, OCH
CH CH NHSO
(100 MHz, CDCl
3
), 3.71 (s,3H, OCH
3
), 3.33 (d,
J
=
4.48 Hz, 2H,
2
2
2
), 3.03 (t, J = 5.08 Hz, 2H, CH
2
CH
2
NHSO
2
). 13C NMR
◦
1
p.: 120 C. H NMR (400 MHz, CDCl
3
) δ 7.97 (d, J = 7.28 Hz, 2H, Ar-H),
3
) δ 162.75 (Ar-C), 159.59 (Ar-C), 158.52 (Ar-C), 147.04
7
2
6
.82 (d, J = 5.48 Hz, 1H, Ar-H), 7.42 (m,5H, Ar-H), 7.28 (q, J = 3.2 Hz,
(Ar-C), 146.65 (Ar-C), 131.32 (Ar-C), 129.63 (Ar-C), 129.01 (Ar-C),
H, Ar-H), 7.08 (d, J = 6.96 Hz, 2H, Ar-H), 6.9 (t, J = 1.72 Hz, 1H, Ar-H),
128.94 (Ar-C), 128.77 (Ar-C), 125.74 (Ar-C), 121 (Ar-C), 114.22 (Ar-C),
.76 (s,1H, Ar-H), 6.69 (s,1H, Ar-H), 4.95 (s,1H, NH), 3.77 (s,3H,
113.82 (Ar-C), 112.13 (Ar-C), 105.83 (Ar-C), 55.55 (OCH
(OCH ), 43.7 (CH CH NHSO ), 41.55 (CH CH NHSO
3
), 55.25
+
OCH
3
), 3.47 (q, J = 5.24 Hz, 2H, CH
2
CH
). C NMR (100 MHz, CDCl
58.37 (Ar-C), 146.53 (Ar-C), 135.45 (Ar-C), 134.91 (Ar-C), 132.27 (Ar-
2
NHSO
2
), 3.22 (q, J = 5.48 Hz,
3
2
2
2
2
2
2
). LC/MS (M) .
1
3
2
H, CH
2
CH
2
NHSO
2
3
) δ 159.74 (Ar-C),
1
4.1.6.10. N-(3-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-5-yl)pyr-
C), 131.55 (Ar-C), 131.37 (Ar-C), 129.8 (Ar-C), 129.53 (Ar-C), 128.87
Ar-C), 125.61 (Ar-C), 120.93 (Ar-C), 114.03 (Ar-C), 113.86 (Ar-C),
idin-2-yl)amino)propyl)benzenesulfonamide (14a):. Yield: 65%. m.p.:
◦
1
(
105 C. H NMR (400 MHz, CDCl ) δ 7.96 (d, J = 6.76 Hz, 2H, Ar-H), 7.8
3
1
12.28 (Ar-C), 105.78 (Ar-C), 55.34 (OCH
3
), 44.3 (CH
2
CH
2
NHSO
2
),
(m,3H, Ar-H), 7.51 (t, J = 4.8 Hz, 1H, Ar-H), 7.43 (t, J = 7.76 Hz, 2H, Ar-
+
4
1.72 (CH
2
CH
2
NHSO
2
). LC/MS 560.1 (M) .
H), 7.36 (m, J = 6.8 Hz, 3H, Ar-H), 7.24 (t, J = 8.04 Hz, 1H, Ar-H), 7.05
(
d, J = 5.75 Hz, 2H, Ar-H), 6.87 (t, J = 4 Hz, 1H, Ar-H), 6.68 (s,1H, Ar-
4
.1.6.6. 2,6-dichloro-N-(2-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imida-
H), 6.62 (d, J = 3.72 Hz, 1H, Ar-H), 4.74 (s,1H, NH), 3.73 (s,3H, OCH
3.28 (t, J = 5.92 Hz, 2H, CH CH CH NHSO ), 2.92 (t, J = 5.76 Hz, 2H,
CH CH CH NHSO
), 1.6 (t, J = 5.8 Hz, 2H, CH
NMR (100 MHz, CDCl ) δ 159.66 (Ar-C), 158.77 (Ar-C), 146.9 (Ar-C),
3
),
zol-5-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (13f):. Yield: 75%.
2
2
2
2
◦
1
13
m.p.: 109 C. H NMR (400 MHz, CDCl
3
) δ 7.92 (d, J = 6.24 Hz, 2H, Ar-
2
2
2
2
2
2
CH CH
2
NHSO
2
).
C
H), 7.75 (d, J = 5.52 Hz, 1H, Ar-H), 7.55 (d, J = 7.88 Hz, 1H, Ar-H), 7.47
3
(
(
dd, J = 2.04 Hz, 1H, Ar-H), 7.38 (m,4H, Ar-H), 7.2 (m,2H, Ar-H), 7.01
d, J = 7.08 Hz, 2H, Ar-H), 6.84 (t, J = 1.92 Hz, 1H, Ar-H), 6.66 (s,1H,
146.69 (Ar-C), 140.08 (Ar-C), 132.41 (Ar-C), 129.59 (Ar-C), 129.03 (Ar-
C), 128.83 (Ar-C), 126.86 (Ar-C), 125.68 (Ar-C), 120.95 (Ar-C), 113.96
Ar-H), 6.61 (d, J = 5.08 Hz, 1H, Ar-H), 4.94 (s,1H, NH), 3.71 (s,3H,
(Ar-C), 113.82 (Ar-C), 111.73 (Ar-C), 55.29 (OCH
3
), 40.17
OCH
3
), 3.33 (d, J = 4.48 Hz, 2H, CH
2
CH
2
NHSO
2
), 3.06 (t, J = 5.12 Hz,
(CH
(CH
2
CH
2
CH
2
NHSO
NHSO
2
),
38.37
(CH CH CH NHSO ), 29.91
2 2 2 2
1
3
+
2
1
1
H, CH
2
CH
2
NHSO
2
). C NMR (100 MHz, CDCl
3
) δ 163.57 (Ar-C),
2
CH
2
CH
2
2
). LC/MS (M) .
61.08 (Ar-C), 159.64 (Ar-C), 158.49 (Ar-C), 146.99 (Ar-C), 142 (Ar-C),
30.88 (Ar-C), 129.69 (Ar-C), 129.06 (Ar-C), 128.82 (Ar-C), 125.68 (Ar-
4.1.6.11. 4-chloro-N-(3-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-
C), 120.96 (Ar-C), 119.53 (Ar-C), 114.36 (Ar-C), 113.9 (Ar-C), 112.26
5-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide (14b):. Yield: 65%.
◦
1
(
Ar-C), 105.96 (Ar-C), 55.26 (OCH
3
), 44.22 (CH
2
CH
2
NHSO
2
), 41.67
m.p.: 108 C. H NMR (400 MHz, CDCl ) δ 7.95 (d, J = 6.52 Hz, 2H, Ar-
3
+
(
CH
2
CH
2
NHSO
2
). LC/MS 593.9 (M) .
H), 7.82 (d, J = 5.52 Hz, 1H, Ar-H), 7.7 (d, J = 8.64 Hz, 2H, Ar-H), 7.39
(
q, J = 6.72 Hz, 4H, Ar-H), 7.29 (d, J = 2.36 Hz, 1H, Ar-H), 7.25 (d, J =
4
5
.1.6.7. 3-fluoro-N-(2-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-
8.04 Hz, 1H, Ar-H), 7.05 (d, J = 6.8 Hz, 2H, Ar-H), 6.89 (t, J = 1.76 Hz,
1H, Ar-H), 6.71 (s,1H, Ar-H), 6.63 (d, J = 4.76 Hz, 1H, Ar-H), 4.73 (s,1H,
-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (13 g):. Yield: 70%. m.
◦
1
p.: 112 C. H NMR (400 MHz, CDCl
.73 (d, J = 5.16 Hz, 1H, Ar-H), 7.66 (d, J = 8.16 Hz, 2H, Ar-H), 7.33 (q,
J = 8.75 Hz, 5H, Ar-H), 7.19 (t, J = 7.52 Hz, 1H, Ar-H), 7 (s,2H, Ar-H),
.83 (d, J = 7.4 Hz, 1H, Ar-H), 6.66 (s,1H, Ar-H), 6.6 (d, J = 3.48 Hz, 1H,
Ar-H), 4.96 (s,1H, NH), 3.69 (s,3H, OCH ), 3.3 (s,2H, CH CH NHSO ),
.02 (s,2H,CH CH NHSO ) δ 159.62 (Ar-
). 13C NMR (100 MHz, CDCl
C), 158.48 (Ar-C), 147.05 (Ar-C), 146.59 (Ar-C), 138.85 (Ar-C), 138.43
Ar-C), 129.66 (Ar-C), 129.55 (Ar-C), 129.27 (Ar-C), 129.03 (Ar-C),
28.79 (Ar-C), 125.73 (Ar-C), 120.99 (Ar-C), 113.95 (Ar-C), 113.85 (Ar-
C), 112.24 (Ar-C), 105.92 (Ar-C), 55.25 (OCH ), 44.01
3
) δ 7.92 (d, J = 4.8 Hz, 2H, Ar-H),
NH), 3.75 (s,3H, OCH
3
), 3.31 (q, J = 5.64 Hz, 2H, CH
2
CH
), 1.62 (t, J = 5.8 Hz, 2H,
). C NMR (100 MHz, CDCl ) δ 159.7 (Ar-C), 158.71
2 2 2
CH NHSO ),
7
2.91 (t, J = 5.68 Hz, 2H, CH
2 2 2 2
CH CH NHSO
1
3
CH
2
CH
2
CH
2
NHSO
2
3
6
(Ar-C), 146.87 (Ar-C), 138.73 (Ar-C), 129.77 (Ar-C), 129.54 (Ar-C),
129.26 (Ar-C), 129.08 (Ar-C), 128.85 (Ar-C), 128.36 (Ar-C), 125.65 (Ar-
C), 120.93 (Ar-C), 113.92 (Ar-C), 111.74 (Ar-C), 105.81 (Ar-C), 55.3
3
2
2
2
3
2
2
2
3
(OCH
3
), 40.1 (CH
2
CH
2 2 2 2 2 2 2
CH NHSO ), 38.34 (CH CH CH NHSO ), 29.93
+
(
(CH CH
2
2
CH NHSO
2
2
). LC/MS (M) .
1
3
1
5

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
4
5
.1.6.12. 4-bromo-N-(3-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-
4.1.6.16. 3-fluoro-N-(3-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-
-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide (14c):. Yield: 70%.
5-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide (14g):. Yield: 72%.
◦
1
◦
1
m.p.: 120 C. H NMR (400 MHz, CDCl
3
) δ 7.96 (d, J = 6.72 Hz, 2H, Ar-
m.p.: 101 C. H NMR (400 MHz, CDCl
3
) δ 7.94 (d, J = 6.56 Hz, 2H, Ar-
H), 7.82 (d, J = 5.56 Hz, 1H, Ar-H), 7.64 (d, J = 8.6 Hz, 2H, Ar-H), 7.57
H), 7.82 (d, J = 5.52 Hz, 1H, Ar-H), 7.57 (d, J = 7.88 Hz, 1H, Ar-H), 7.5
(m,1H, Ar-H), 7.4 (m,4H, Ar-H), 7.23 (t, J = 8.28 Hz, 1H, Ar-H), 7.2 (dd,
J = 1.92 Hz, 1H, Ar-H), 7.04 (d, J = 6.84 Hz, 2H, Ar-H), 6.88 (t, J = 1.96
Hz, 1H, Ar-H), 6.71 (s,1H, Ar-H), 6.63 (d, J = 5.2 Hz, 1H, Ar-H), 4.72
(
d, J = 8.6 Hz, 2H, Ar-H), 7.4 (d, J = 7.4 Hz, 2H, Ar-H), 7.29 (q, J = 5.16
Hz, 2H, Ar-H), 7.06 (d, J = 7.24 Hz, 2H, Ar-H), 6.91 (t, J = 1.76 Hz, 1H,
Ar-H), 6.74 (s,1H, Ar-H), 6.66 (d, J = 4.96 Hz, 1H, Ar-H), 4.84 (s,1H,
NH), 3.76 (s,3H, OCH
3
), 3.33 (q, J = 5.8 Hz, 2H, CH
2
CH
), 1.64 (m,2H,
) δ 159.74 (Ar-C),
2
CH
2
NHSO
2
),
(s,1H, NH), 3.74 (s,3H, OCH
CH CH CH NHSO
), 2.93 (t, J = 5.88 Hz, 2H, CH
(t, J = 5.92 Hz, 2H, CH
3
), 3.3 (q,
J
=
5.88 Hz, 2H,
CH NHSO ), 1.62
) δ
2
.93 (t,
J
=
5.6 Hz, 2H, CH
2
CH
2
CH
2
NHSO
2
2
2
2
2
2
CH
2
2
2
). 13C NMR (100 MHz, CDCl
CH
2
NHSO
). C NMR (100 MHz, CDCl
13
CH CH CH
2
2
2
NHSO
2
3
2
CH
2
2
3
1
58.57 (Ar-C), 139.31 (Ar-C), 132.24 (Ar-C), 129.83 (Ar-C), 129.51 (Ar-
C), 129.12 (Ar-C), 128.88 (Ar-C), 128.48 (Ar-C), 127.2 (Ar-C), 125.63
Ar-C), 120.92 (Ar-C), 114.03 (Ar-C), 113.93 (Ar-C), 111.71 (Ar-C),
161.1 (Ar-C), 159.68 (Ar-C), 158.74 (Ar-C), 146.87 (Ar-C), 142.33 (Ar-
C), 130.86 (Ar-C), 130.79 (Ar-C), 129.53 (Ar-C), 128.85 (Ar-C), 125.64
(Ar-C), 122.62 (Ar-C), 120.94 (Ar-C), 119.4 (Ar-C), 114.36 (Ar-C),
(
5
5.33 (OCH
3
), 40.09 (CH
CH NHSO
2
CH
2
CH
2
NHSO
2
), 38.35 (CH
2
CH
2
CH
2
NHSO
2
),
113.87
(Ar-C),
111.75
38.31
). LC/MS 557.64 (M) .
(Ar-C),
55.29
CH CH
(OCH
NHSO ),
3
),
40.13
29.98
+
2
9.93 (CH CH
2
2
2
2
). LC/MS (M) .
(CH
CH
2
CH
2
CH
2
NHSO
NHSO
2
),
(CH
2
+
2
2
2
(
2
CH
2
CH
2
2
4
5
.1.6.13. 4-fluoro-N-(3-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-
-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide (14d):. Yield: 72%.
4.1.6.17. N-(3-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-5-yl)pyr-
idin-2-yl)amino)propyl)-4-(trifluoromethyl)benzenesulfonamide (14h):.
◦
1
m.p.: 112 C. H NMR (400 MHz, CDCl
3
) δ 7.94 (t, J = 1.8 Hz, 2H, Ar-H),
.77 (m,3H, Ar-H), 7.35 (d, J = 6.76 Hz, 3H, Ar-H), 7.22 (t, J = 8.04 Hz,
H, Ar-H), 7.08 (t, J = 8.56 Hz, 1H, Ar-H), 7.02 (d, J = 5.68 Hz, 2H, Ar-
◦
1
7
1
Yield: 65%. m.p.: 110 C. H NMR (400 MHz, CDCl
3
) δ 7.92 (t, J = 2.16
Hz, 2H, Ar-H), 7.88 (d, J = 8 Hz, 2H, Ar-H), 7.68 (d, J = 8.32 Hz, 2H, Ar-
H), 7.34 (t, J = 1.36 Hz, 3H, Ar-H), 7.23 (t, J = 8.08 Hz, 1H, Ar-H), 7.01
(d, J = 6.08 Hz, 2H, Ar-H), 6.86 (t, J = 4 Hz, 1H, Ar-H), 6.7 (s,1H, Ar-H),
H), 6.86 (t, J = 1.84 Hz, 1H, Ar-H), 6.67 (s,1H, Ar-H), 6.59 (d, J = 5.04
Hz, 1H, Ar-H), 4.7 (s,1H, NH), 3.71 (s,3H, OCH
), 3.25 (d, J = 8 Hz, 2H,
CH CH CH NHSO CH CH NHSO ), 1.58
), 2.88 (t, J = 5.64 Hz, 2H, CH
t, J = 8 Hz, 2H, CH ). C NMR (100 MHz, CDCl ) δ
66.08 (Ar-C), 163.55 (Ar-C), 159.63 (Ar-C), 158.84 (Ar-C), 146.96 (Ar-
C), 146.72 (Ar-C), 136.2 (Ar-C), 129.69 (Ar-C), 129.03 (Ar-C), 128.81
Ar-C), 125.71 (Ar-C), 120.96 (Ar-C), 116.07 (Ar-C), 113.91 (Ar-C),
3
2
2
2
2
2
2
2
2
6.6 (d, J = 5.16 Hz, 1H, Ar-H), 4.68 (s,1H, NH), 3.71 (s,3H, OCH
3
), 3.27
1
3
(
2
2
CH CH
2
NHSO
2
3
(d, J = 4 Hz, 2H, CH
CH CH CH NHSO
), 1.59 (t, J = 5.08 Hz, 2H, CH
NMR (100 MHz, CDCl ) δ 159.66 (Ar-C), 158.85 (Ar-C), 146.94 (Ar-C),
2 2 2 2
CH CH NHSO
), 2.92 (t, J = 4.08 Hz, 2H,
1
3
1
2
2
2
2
2
CH
2
CH
2
NHSO
2
).
C
3
(
143.95 (Ar-C), 134.1 (Ar-C), 129.72 (Ar-C), 128.82 (Ar-C), 127.35 (Ar-
1
11.77
(Ar-C),
105.75
38.33
(Ar-C),
(CH
55.25
CH CH
(OCH
NHSO ),
3
),
40.12
29.86
C), 126.16 (Ar-C), 125.69 (Ar-C), 124.61 (Ar-C), 121.9 (Ar-C), 120.95
(
CH
CH
2
CH
2
CH
2
2
NHSO
NHSO
2
),
). LC/MS (M) .
2
2
2
2
(Ar-C), 113.97 (Ar-C), 111.81 (Ar-C), 105.88 (Ar-C), 55.24 (OCH
3
),
+
(
2
CH
2
CH
2
40.12 (CH
CH CH CH
2
CH
2
CH
2
NHSO
2
), 38.31 (CH
2
CH
2
CH
2
NHSO
2
), 29.98
+
(
2
2
2
NHSO
2
). LC/MS 607.65 (M) .
4
5
.1.6.14. 3-chloro-N-(3-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imidazol-
-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide (14e):. Yield: 71%.
4.1.6.18. 4-methoxy-N-(3-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imida-
◦
1
m.p.: 113 C. H NMR (400 MHz, CDCl
3
) δ 7.94 (t, J = 1.36 Hz, 2H, Ar-
zol-5-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide
(14i):. Yield:
◦
1
H), 7.78 (m,2H, Ar-H), 7.64 (d, J = 7.8 Hz, 1H, Ar-H), 7.47 (q, J = 0.8
Hz, 1H, Ar-H), 7.35 (m,4H, Ar-H), 7.22 (t, J = 8.04 Hz, 1H, Ar-H), 7.02
60%. m.p.: 100 C. H NMR (400 MHz, CDCl
3
) δ 7.97 (d, J = 6.84 Hz,
2H, Ar-H), 7.81 (d, J = 5.52 Hz, 1H, Ar-H), 7.36 (q, J = 6.12 Hz, 3H, Ar-
H), 7.23 (t, J = 8.08 Hz, 1H, Ar-H), 7.06 (d, J = 5.2 Hz, 2H, Ar-H), 6.87
(m,3H, Ar-H), 6.67 (s,1H, Ar-H), 6.61 (s,1H, Ar-H), 4.76 (s,1H, NH),
(
d, J = 6.12 Hz, 2H, Ar-H), 6.86 (t, J = 1.8 Hz, 1H, Ar-H), 6.67 (s,1H, Ar-
H), 6.61 (d, J = 5.04 Hz, 1H, Ar-H), 4.71 (s,1H, NH), 3.71 (s,3H, OCH
.27 (d, J = 5.76 Hz, 2H, CH CH CH NHSO ), 2.9 (t, J = 5.6 Hz, 2H,
CH CH CH NHSO
), 1.59 (t, J = 5.72 Hz, 2H, CH
NMR (100 MHz, CDCl ) δ 159.63 (Ar-C), 158.81 (Ar-C), 146.67 (Ar-C),
41.98 (Ar-C), 135.1 (Ar-C), 132.46 (Ar-C), 130.36 (Ar-C), 129.55 (Ar-
C), 128.83 (Ar-C), 126.95 (Ar-C), 125.69 (Ar-C), 124.93 (Ar-C), 120.97
Ar-C), 113.89 (Ar-C), 111.77 (Ar-C), 105.79 (Ar-C), 55.27 (OCH ),
), 29.94
3
),
3
2
2
2
2
3.81 (s,3H, OCH
CH CH CH NHSO
3
), 3.72 (s,3H, OCH
3
), 3.27 (q, J = 5.84 Hz, 2H,
CH CH NHSO ), 1.6 (t,
). C NMR (100 MHz, CDCl ) δ
1
3
2
2
2
2
2
2
CH CH
2
NHSO
2
).
C
2
2
2
2
), 2.88 (t, J = 5.4 Hz, 2H, CH
2
2
2
2
1
3
3
J = 5.88 Hz, 2H, CH
2
CH
2
CH
2
NHSO
2
3
1
162.69 (Ar-C), 159.63 (Ar-C), 158.8 (Ar-C), 146.79 (Ar-C), 129.63 (Ar-
C), 129.02 (Ar-C), 128.8 (Ar-C), 125.71 (Ar-C), 120.97 (Ar-C), 114.19
(
3
(Ar-C), 113.95 (Ar-C), 113.79 (Ar-C), 111.74 (Ar-C), 55.55 (OCH
3
),
),
4
0.14 (CH
2
CH
2
CH
2
NHSO
2
), 38.32 (CH
2
CH
2
CH
2
NHSO
2
55.27 (OCH3), 40.19 (CH
29.77 (CH CH CH NHSO
2
CH
2
CH
2
NHSO
2
), 38.45 (CH
2
CH
2
CH
2
NHSO
2
+
+
(
CH CH CH
2
2
2
NHSO
2
). LC/MS 574.1 (M) .
2
2
2
2
). LC/MS 570.3 (M) .
4
.1.6.15. 2,6-dichloro-N-(3-((4-(4-(3-methoxyphenyl)-2-phenyl-1H-imi-
4.1.7. N-(2-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-5-yl)pyridin-
2 yl)amino)ethyl(propyl))substituted benzenesulfonamide (15–16)
To a solution of compound 13 or 14 (0.3 mmol) in methylene
dazol-5-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide (14f):. Yield:
◦
1
6
2
3%. m.p.: 117 C. H NMR (400 MHz, CDCl
3
) δ 7.94 (d, J = 6.84 Hz,
H, Ar-H), 7.82 (d, J = 5.36 Hz, 1H, Ar-H), 7.41 (d, J = 7.88 Hz, 2H, Ar-
chloride (3 mL), BBr
3
(3 mL of a 1Msolution in methylene chloride) was
◦
H), 7.35 (d, J = 7.52 Hz, 2H, Ar-H), 7.26 (m,3H, Ar-H), 7.02 (s,2H, Ar-
H), 6.84 (d, J = 7.56 Hz, 1H, Ar-H), 6.63 (d, J = 15.2 Hz, 2H, Ar-H), 4.66
added drop wise at ꢀ 78 C under N
2
. The reaction mixture was stirred at
the same temperature for 1 h, and then allowed to warm to room tem-
perature and stirred for another 3 h. The mixture was quenched with
(
s,1H, NH), 3.71 (s,3H, OCH
3
), 3.3 (d,
J
=
5.44 Hz, 2H,
CH NHSO ), 1.59
). C NMR (100 MHz, CDCl ) δ
59.6 (Ar-C), 158.92 (Ar-C), 147.05 (Ar-C), 144.68 (Ar-C), 135.97 (Ar-
C), 134.76 (Ar-C), 132.23 (Ar-C), 131.39 (Ar-C), 129.63 (Ar-C), 128.79
Ar-C), 125.71 (Ar-C), 120.98 (Ar-C), 117.23 (Ar-C), 113.96 (Ar-C),
CH
2
CH
2
CH
2
NHSO
2
), 3.04 (d, J = 4.6 Hz, 2H, CH
2
CH
2
2
2
2 3
saturated aqueous Na CO . Ethyl acetate (5 mL) was added and the
1
3
(
d, J = 5.04 Hz, 2H, CH
2
CH
2
CH
2
NHSO
2
3
organic layer was separated. The aqueous layer was extracted with ethyl
acetate (X 2). The combined organic layer extracts were washed with
1
2 4
brine, and dried over anhydrous Na SO . After evaporation of the
(
organic solvent, the residue was purified by short column chromatog-
raphy (silica gel, using ethylacetate then switching to ethyl aceta-
te–methanol 4:1 v/v) to yield the title compound.
1
11.81
(Ar-C),
105.69
38.31
). LC/MS 608.54 (M) .
(Ar-C),
55.27
CH CH
(OCH
NHSO ),
3
),
40.22
30.29
(
CH
CH
2
CH
2
CH
2
2
NHSO
NHSO
2
),
(CH
2
+
2
2
2
(
2
CH
2
CH
2
4
.1.7.1. N-(2-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-5-yl)pyr-
idin-2-yl)amino)ethyl)benzenesulfonamide (15a):. Yield: 68%. m.p.:
1
6

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
◦
1
1
80 C. H NMR (400 MHz, MeOH) δ 7.98 (d, J = 7.2 Hz, 2H, Ar-H), 7.82
C), 129.55 (Ar-C), 128.56 (Ar-C), 126.48 (Ar-C), 125.69 (Ar-C), 124.93
(Ar-C), 119.84 (Ar-C), 115.46 (Ar-C), 115 (Ar-C), 111.48 (Ar-C), 106.13
(
q, J = 1.6 Hz, 3H, Ar-H), 7.51 (m,1H, Ar-H), 7.46 (m,4H, Ar-H), 7.39 (t,
J = 2.4 Hz, 1H, Ar-H), 7.23 (t, J = 8 Hz, 1H, Ar-H), 6.98 (t, J = 2.4 Hz,
(Ar-C), 42.37 (CH
2
CH
2
NHSO
2
), 41.02 (CH
2
CH
2
NHSO
2
). LC/MS 545.8
+
1
H, Ar-H), 6.83 (dd, J = 2.4 Hz, 1H, Ar-H), 6.7 (d, J = 5.2 Hz, 2H, Ar-H),
CH NHSO
). C NMR (100 MHz, MeOD) δ 158.69 (Ar-C), 157.37
(M) .
3
.32 (q, J = 4 Hz, 2H, CH
2
2
2
), 3.03 (t, J = 6 Hz, 2H,
1
3
CH
2
CH
2
NHSO
2
4.1.7.6. 2,6-dichloro-N-(2-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imida-
(
Ar-C), 147.18 (Ar-C), 146.43 (Ar-C), 140.25 (Ar-C), 132.28 (Ar-C),
29.63 (Ar-C), 129.58 (Ar-C), 128.86 (Ar-C), 128.58 (Ar-C), 126.57 (Ar-
C), 125.7 (Ar-C), 119.8 (Ar-C), 115.43 (Ar-C), 115 (Ar-C), 111.48 (Ar-C),
zol-5-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (15f):. Yield: 64%.
◦
1
1
m.p.: 141 C. H NMR (400 MHz, MeOD) δ 7.98 (d, J = 7.6 Hz, 2H, Ar-
H), 7.78 (d, J = 5.6 Hz, 1H, Ar-H), 7.41 (m,5H, Ar-H), 7.27 (m,2H, Ar-
H), 6.98 (t, J = 6.8 Hz, 2H, Ar-H), 6.83 (dd, J = 2 Hz, 1H, Ar-H), 6.7 (d, J
= 5.6 Hz, 1H, Ar-H), 6.65 (s,1H, Ar-H), 3.33 (q, J = 5.6 Hz, 2H,
1
06.22 (Ar-C), 42.35 (CH
2
CH
2
NHSO
2
), 41.06 (CH
2
CH
2
NHSO
2
). LC/MS
+
5
12 (M) .
1
3
CH
2
CH
2
NHSO
2
), 3.18 (t, J = 6 Hz, 2H, CH
2 2 2
CH NHSO ). C NMR (100
4
5
.1.7.2. 4-chloro-N-(2-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-
MHz, MeOD) δ 158.58 (Ar-C), 157.37 (Ar-C), 147.16 (Ar-C), 146.44 (Ar-
C), 135.55 (Ar-C), 134.45 (Ar-C), 132.47 (Ar-C), 131.28 (Ar-C), 129.63
(Ar-C), 128.81 (Ar-C), 128.59 (Ar-C), 125.7 (Ar-C), 119.85 (Ar-C),
-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (15b):. Yield: 74%. m.
◦
1
p.: 115 C. H NMR (400 MHz, MeOD) δ 8.01 (t, J = 1.2 Hz, 2H, Ar-H),
7
.8 (t, J = 6.44 Hz, 3H, Ar-H), 4.89 (m, 4H, Ar-H), 7.4 (t, J = 7.28 Hz,
H, Ar-H), 7.25 (m,1H, Ar-H), 7 (q, J = 1.84 Hz, 2H, Ar-H), 6.85 (dd, J =
.36 Hz, 1H, Ar-H), 6.71 (t, J = 5.68 Hz, 2H, Ar-H), 3.33 (t, J = 8 Hz, 2H,
115.47 (Ar-C), 115 (Ar-C), 111.51 (Ar-C), 106.24 (Ar-C), 42.34
+
1
(CH
2
CH
2
NHSO
2
), 40.9 (CH
2
CH
2
NHSO
2
). LC/MS 579.9 (M) .
1
1
3
CH
2
CH
2
NHSO
2
), 3.07 (t, J = 5.88 Hz, 2H, CH
2
CH
2
NHSO
2
). C NMR
4.1.7.7. 3-fluoro-N-(2-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-
(
100 MHz, MeOD) δ 158.62 (Ar-C), 157.36 (Ar-C), 147.17 (Ar-C),
46.41 (Ar-C), 139.1 (Ar-C), 138.38 (Ar-C), 129.64 (Ar-C), 129.58 (Ar-
C), 129.04 (Ar-C), 128.82 (Ar-C), 128.59 (Ar-C), 128.3 (Ar-C), 125.72
Ar-C), 119.85 (Ar-C), 115.48 (Ar-C), 115.03 (Ar-C), 111.45 (Ar-C),
5-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (15g):. Yield: 74%. m.
◦
1
1
p.: 118 C. H NMR (400 MHz, MeOD) δ 8 (d, J = 7.32 Hz, 2H, Ar-H),
7.82 (d, J = 6.04 Hz, 1H, Ar-H), 7.66 (d, J = 8 Hz, 1H, Ar-H), 7.58 (d,
J = 8.24 Hz, 1H, Ar-H), 7.53 (t, J = 8.08 Hz, 1H, Ar-H), 7.46 (m,2H, Ar-
H), 7.39 (t, J = 7.16 Hz, 1H, Ar-H), 7.28 (m,2H, Ar-H), 6.99 (d, J = 6.88
Hz, 2H, Ar-H), 6.85 (t, J = 1.68 Hz, 1H, Ar-H), 6.72 (d, J = 4.64 Hz, 2H,
(
1
5
06.14 (Ar-C), 42.39 (CH
2
CH
2
NHSO
2
), 40.98 (CH
2
CH
2
NHSO
2
). LC/MS
+
46.3 (M) .
Ar-H), 3.35 (t, J = 5.92 Hz, 2H, CH
2
CH
2
NHSO
2
), 3.08 (t, J = 6 Hz, 2H,
1
3
4
5
.1.7.3. 4-bromo-N-(2-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-
CH CH NHSO ). C NMR (100 MHz, MeOD) δ 163.65 (Ar-C), 161.17
2 2 2
-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (15c):. Yield: 72%. m.
(Ar-C), 158.58 (Ar-C), 147.18 (Ar-C), 146.26 (Ar-C), 142.58 (Ar-C),
142.51 (Ar-C), 131.05 (Ar-C), 130.98 (Ar-C), 129.67 (Ar-C), 128.67 (Ar-
C), 125.72 (Ar-C), 122.57 (Ar-C), 119.86 (Ar-C), 115.48 (Ar-C), 113.81
◦
1
p.: 145 C. H NMR (400 MHz, MeOD) δ 8 (d, J = 1.2 Hz, 1H, Ar-H), 7.98
(
(
s,1H, Ar-H), 7.82 (d, J = 5.52 Hz, 1H, Ar-H), 7.71 (s,1H, Ar-H), 7.69
s,1H, Ar-H), 7.64 (d, J = 8 Hz, 2H, Ar-H), 7.45 (m,3H, Ar-H), 7.25 (t, J
(Ar-C), 111.49 (Ar-C), 104.19 (Ar-C), 42.41 (CH
2
CH
2
NHSO
2
), 41.05
+
=
8 Hz, 1H, Ar-H), 6.98 (t, J = 1.2 Hz, 2H, Ar-H), 6.83 (m,1H, Ar-H),
(CH
2
CH
2
NHSO
2
). LC/MS 530.1 (M) .
6
.72 (dd, J = 1.08 Hz, 1H, Ar-H), 6.67 (s,1H, Ar-H), 3.33 (q, J = 1.64
13
Hz, 2H, CH
2
CH
2
NHSO
2
), 3.06 (t, J = 5.96 Hz, 2H, CH
2
2
CH NHSO
2
).
C
4.1.7.8. N-(2-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-5-yl)pyr-
idin-2-yl)amino)ethyl)-4-(trifluoromethyl)benzenesulfonamide (15 h):.
NMR (100 MHz, MeOD) δ 158.61 (Ar-C), 157.36 (Ar-C), 147.16 (Ar-C),
46.44 (Ar-C), 139.63 (Ar-C), 132.03 (Ar-C), 129.65 (Ar-C), 129.55 (Ar-
C), 128.78 (Ar-C), 128.55 (Ar-C), 128.33 (Ar-C), 126.73 (Ar-C), 125.7
Ar-C), 119.82 (Ar-C), 115.45 (Ar-C), 114.98 (Ar-C), 111.42 (Ar-C),
◦
1
1
Yield: 65%. m.p.: 117 C. H NMR (400 MHz, MeOD) δ 8 (q, J = 2.16 Hz,
4H, Ar-H), 7.81 (d, J = 7.92 Hz, 3H, Ar-H), 7.46 (t, J = 7.68 Hz, 2H, Ar-
H), 7.39 (m,1H, Ar-H), 7.24 (t, J = 8.08 Hz, 1H, Ar-H), 6.99 (m, J = 2.08
Hz, 2H, Ar-H), 6.84 (dd, J = 1.44 Hz, 1H, Ar-H), 6.71 (t, J = 4 Hz, 2H, Ar-
(
1
5
2 2 2 2 2 2
06.11 (Ar-C), 42.33 (CH CH NHSO ), 40.94 (CH CH NHSO ). LC/MS
92 (M + 2)+.
H), 3.33 (m,2H, CH CH NHSO ), 3.1 (t,
2
2
2
J
=
5.92 Hz, 2H,
1
3
2 2 2
CH CH NHSO ). C NMR (100 MHz, MeOD) δ 158.65 (Ar-C), 157.34
4
5
.1.7.4. 4-fluoro-N-(2-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-
(Ar-C), 147.19 (Ar-C), 146.48 (Ar-C), 144.34 (Ar-C), 133.63 (Ar-C),
133.3 (Ar-C), 129.62 (Ar-C), 128.55 (Ar-C), 127.37 (Ar-C), 125.98 (Ar-
C), 124.86 (Ar-C), 122.15 (Ar-C), 119.84 (Ar-C), 115.46 (Ar-C), 115 (Ar-
-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (15d):. Yield: 74%. m.
◦
1
p.: 143 C. H NMR (400 MHz, MeOD) δ 7.99 (d, J = 7.2 Hz, 2H, Ar-H),
.87 (m,2H, Ar-H), 7.82 (d, J = 4 Hz, 1H, Ar-H), 7.47 (t, J = 7.08 Hz, 2H,
7
C), 111.51 (Ar-C), 106.13 (Ar-C), 42.41 (CH
2
CH
2
NHSO
2
), 41.07
+
Ar-H), 7.41 (t, J = 7.24 Hz, 1H, Ar-H), 7.23 (m,3H, Ar-H), 7.98 (t, J =
(CH
2
CH
2
NHSO
2
). LC/MS 580.1 (M) .
6
.48 Hz, 2H, Ar-H), 6.83 (m,1H, Ar-H), 6.71 (t, J = 3.72 Hz, 2H, Ar-H),
CH NHSO
). C NMR (100 MHz, MeOD) δ 166.16 (Ar-C), 163.65
3
.33 (t, J = 6 Hz, 2H, CH
2
2
2
), 3.05 (t, J = 6 Hz, 2H,
4.1.7.9. N-(2-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-5-yl)pyr-
1
3
CH
2
CH
2
NHSO
2
idin-2-yl)amino)ethyl)-4-methoxybenzenesulfonamide (15i):. Yield: 55%.
◦
1
(
Ar-C), 158.66 (Ar-C), 157.35 (Ar-C), 147.17 (Ar-C), 146.42 (Ar-C),
36.56 (Ar-C), 129.63 (Ar-C), 129.45 (Ar-C), 128.78 (Ar-C), 128.55 (Ar-
C), 125.69 (Ar-C), 119.81 (Ar-C), 115.92 (Ar-C), 115.43 (Ar-C), 114.98
m.p.: 120 C. H NMR (400 MHz, MeOD) δ 7.99 (d, J = 7.36 Hz, 2H, Ar-
H), 7.82 (d, J = 5.48 Hz, 1H, Ar-H), 7.75 (d, J = 8.8 Hz, 2H, Ar-H), 7.48
(t, J = 8.76 Hz, 2H, Ar-H), 7.42 (t, J = 7.36 Hz, 1H, Ar-H), 7.25 (t, J =
8.16 Hz, 1H, Ar-H), 6.98 (t, J = 6.64 Hz, 4H, Ar-H), 6.85 (dd, J = 5.36
1
(
Ar-C), 111.45 (Ar-C), 106.15 (Ar-C), 42.31 (CH
2
CH
2
NHSO
2
), 41
+
(
CH
2
CH
2
NHSO
2
). LC/MS 530 (M) .
Hz, 1H, Ar-H), 6.7 (t, J = 5.64 Hz, 2H, Ar-H), 3.7 (s,3H, CH ), 3.32 (t, J
3
=
6.56 Hz, 2H, CH
2
CH
2
NHSO
2
), 3.02 (t, J = 6 Hz, 2H, CH
2 2 2
CH NHSO ).
1
3
4
5
.1.7.5. 3-chloro-N-(2-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-
C NMR (100 MHz, MeOD) δ 162.92 (Ar-C), 158.68 (Ar-C), 157.36 (Ar-
-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (15e):. Yield: 73%. m.
C), 147.15 (Ar-C), 146.42 (Ar-C), 131.66 (Ar-C), 129.54 (Ar-C), 128.78
(Ar-C), 128.55 (Ar-C), 125.68 (Ar-C), 119.8 (Ar-C), 115.42 (Ar-C),
115.26 (Ar-C), 114.96 (Ar-C), 113.9 (Ar-C), 111.37 (Ar-C), 106.11 (Ar-
◦
1
p.: 138 C. H NMR (400 MHz, MeOD) δ 7.98 (d, J = 7.2 Hz, 2H, Ar-H),
.83 (q, J = 2.04 Hz, 2H, Ar-H), 7.73 (d, J = 7.76 Hz, 1H, Ar-H), 7.53
dd, J = 0.76 Hz, 1H, Ar-H), 7.46 (m,3H, Ar-H), 7.39 (t, J = 7.24 Hz, 1H,
7
(
C), 54.75 (CH
3
), 42.26 (CH
2
CH
2
NHSO
2
), 40.92 (CH
2
CH
2
NHSO
2
). LC/
+
Ar-H), 7.24 (m,1H, Ar-H), 6.99 (t, J = 2.24 Hz, 2H, Ar-H), 6.84 (dd, J =
MS 542 (M) .
1
2
.48 Hz, 1H, Ar-H), 6.71 (t, J = 5.56 Hz, 2H, Ar-H), 3.33 (t, J = 5.92 Hz,
13
H, CH
2
CH
2
NHSO
2
), 3.06 (t, J = 5.96 Hz, 2H, CH
2
CH
2
NHSO
2
).
C
4.1.7.10. 4-hydroxy-N-(2-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imida-
NMR (100 MHz, MeOD) δ 158.65 (Ar-C), 157.35 (Ar-C), 147.16 (Ar-C),
46.48 (Ar-C), 142.28 (Ar-C), 134.73 (Ar-C), 132.2 (Ar-C), 130.46 (Ar-
zol-5-yl)pyridin-2-yl)amino)ethyl)benzenesulfonamide (15j):. Yield: 55%.
◦
1
1
m.p.: 122 C. H NMR (400 MHz, MeOD) δ 8 (d, J = 8.4 Hz, 1H, Ar-H),
1
7

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
7
8
.69 (d, J = 8.8 Hz, 1H, Ar-H), 7.48 (t, J = 6.8 Hz, 1H, Ar-H), 7.42 (t, J =
.4 Hz, 1H, Ar-H), 7.25 (t, J = 8.4 Hz, 1H, Ar-H), 6.99 (d, J = 3.2 Hz, 1H,
(d, J = 5.2 Hz, 1H, Ar-H), 6.68 (s,1H, Ar-H), 3.22 (t, J = 6.8 Hz, 2H,
CH
2
CH
2
CH
2
NHSO
2
), 2.93 (t, J = 6.4 Hz, 2H, CH
2 2 2 2
CH CH NHSO ), 1.67
1
3
Ar-H), 6.88 (d, J = 8.8 Hz, 1H, Ar-H), 6.84 (dd, J = 6 Hz, 2H, Ar-H), 6.72
(m,2H, CH
2
CH CH NHSO ). C NMR (100 MHz, MeOD) δ 166.16 (Ar-
2
2 2
(
d, J = 5.6 Hz, 1H, Ar-H), 1.64 (brs, 2H, CH
2
CH
2
NHSO
2
), 1.40 (brs,2H,
C), 163.66 (Ar-C), 158.95 (Ar-C), 157.54 (Ar-C), 136.67 (Ar-C), 129.65
(Ar-C), 129.46 (Ar-C), 128.78 (Ar-C), 128.56 (Ar-C), 125.69 (Ar-C),
119.8 (Ar-C), 115.96 (Ar-C), 115.44 (Ar-C), 114.97 (Ar-C), 111.07 (Ar-
1
3
CH
2
CH
2
NHSO
2
). C NMR (100 MHz, MeOD) δ 161.44 (Ar-C), 158.7
(
Ar-C), 157.35 (Ar-C), 147.18 (Ar-C), 146.36 (Ar-C), 130.07 (Ar-C),
29.63 (Ar-C), 128.93 (Ar-C), 128.8 (Ar-C), 128.57 (Ar-C), 125.69 (Ar-
C), 119.8 (Ar-C), 115.4 (Ar-C), 115.29 (Ar-C), 114.97 (Ar-C), 111.43
1
C),
105.96
(Ar-C),
40.28
CH
(CH
2
CH
2
CH
2
NHSO
2
),
38.33
(CH
2
CH CH NHSO
2
2
2
), 29.37 (CH
2
2
CH NHSO
2
2
). LC/MS 544.1 (M +
+
(
Ar-C), 106.21 (Ar-C), 42.29 (CH
2
CH
2
NHSO
2
), 41.06 (CH
2
CH
2
NHSO
2
).
1) .
+
LC/MS 527.9 (M) .
4
.1.7.15. 3-chloro-N-(3-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-
4
.1.7.11. N-(3-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-5-yl)pyr-
5-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide (16e):. Yield: 70%.
◦
1
idin-2-yl)amino)propyl)benzenesulfonamide (16a):. Yield: 65%. m.p.:
m.p.: 142 C. H NMR (400 MHz, MeOD) δ 7.99 (d, J = 1.36 Hz, 1H, Ar-
H), 7.98 (s,1H, Ar-H), 7.84 (m,2H, Ar-H), 7.76 (dt, J = 1.04 Hz, 1H, Ar-
H), 7.57 (m,1H, Ar-H), 7.48 (m,3H, Ar-H), 7.41 (m,1H, Ar-H), 7.25 (t, J
= 7.84 Hz, 1H, Ar-H), 6.98 (m,2H, Ar-H), 6.84 (dd, J = 1.72 Hz, 1H, Ar-
H), 6.72 (dd, J = 1.12 Hz, 1H, Ar-H), 6.68 (s,1H, Ar-H), 3.23 (t, J = 6.68
◦
1
1
23 C. H NMR (400 MHz, MeOD) δ 7.98 (d, J = 7.32 Hz, 2H, Ar-H),
.83 (q, J = 7.12 Hz, 3H, Ar-H), 7.53 (, J = 7.04 Hz, 3H, Ar-H), 7.46
7
(
q, J = 4.04 Hz, 2H, Ar-H), 7.38 (t, J = 7.2 Hz, 1H, Ar-H), 7.24 (t, J =
8
.04 Hz, 1H, Ar-H), 6.99 (t, J = 2.02 Hz, 2H, Ar-H), 6.84 (dd, J = 1.28
Hz, 1H, Ar-H), 6.72 (d, J = 5.52 Hz, 1H, Ar-H), 6.68 (s,1H, Ar-H), 3.21 (t,
J = 6.56 Hz, 2H, CH CH CH NHSO ), 2.92 (t, J = 6.6 Hz, 2H,
CH CH CH NHSO
), 1.66 (t, J = 6.6 Hz, 2H, CH
NMR (100 MHz, MeOD) δ 158.78 (Ar-C), 157.35 (Ar-C), 147.19 (Ar-C),
46.28 (Ar-C), 140.26 (Ar-C), 132.26 (Ar-C), 129.6 (Ar-C), 128.88 (Ar-
C), 128.58 (Ar-C), 126.58 (Ar-C), 125.71 (Ar-C), 119.85 (Ar-C), 115.47
Hz, 2H, CH
2
CH
2
CH
2
NHSO
2
), 2.95 (t,
J
=
6.76 Hz, 2H,
1
3
2
2
2
2
CH CH CH NHSO
2
2
2
2
), 1.68 (m, 2H, CH
2
CH CH NHSO ). C NMR (100
2
2 2
1
3
2
2
2
2
2
2
CH CH
2
NHSO
2
).
C
MHz, MeOD) δ 158.85 (Ar-C), 157.36 (Ar-C), 147.16 (Ar-C), 146.36 (Ar-
C), 142.35 (Ar-C), 134.77 (Ar-C), 132.17 (Ar-C), 130.5 (Ar-C), 129.56
(Ar-C), 128.55 (Ar-C), 126.46 (Ar-C), 125.68 (Ar-C), 124.95 (Ar-C),
119.81 (Ar-C), 115.44 (Ar-C), 111.07 (Ar-C), 105.96 (Ar-C), 40.3
1
(
(
(
Ar-C), 115.04 (Ar-C), 111.11 (Ar-C), 105.96 (Ar-C), 40.3
(CH
(CH
2
CH
2
CH
2
NHSO
NHSO
2
),
38.32
(CH
2
CH
2
CH
2
NHSO
2
),
28.99
+
CH
CH
2
CH
2
CH
2
2
NHSO
NHSO
2
),
38.39
(CH
2
CH
2
CH
2
NHSO
2
),
28.97
2
CH
2
CH
2
2
). LC/MS 560.2 (M) .
+
2
CH
2
CH
2
). LC/MS 526.2 (M) .
4
.1.7.16. 2,6-dichloro-N-(3-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imi-
4
5
.1.7.12. 4-chloro-N-(3-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-
-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide (16b):. Yield: 62%.
dazol-5-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide (16f):. Yield:
◦
1
75%. m.p.: 138 C. H NMR (400 MHz, MeOD) δ 7.99 (d, J = 6.48 Hz,
2H, Ar-H), 7.83 (d, J = 4.28 Hz, 1H, Ar-H), 7.48 (d, J = 6.88 Hz, 4H, Ar-
H), 7.39 (dd, J = 6.56 Hz, 2H, Ar-H), 7.24 (d, J = 7.2 Hz, 1H, Ar-H), 6.99
(d, J = 8.08 Hz, 2H, Ar-H), 6.84 (d, J = 6.48 Hz, 1H, Ar-H), 6.7 (m,2H,
◦
1
m.p.: 130 C. H NMR (400 MHz, MeOD) δ 7.99 (t, J = 6.92 Hz, 2H, Ar-
H), 7.82 (m,3H, Ar-H), 7.53 (t, J = 2.36 Hz, 1H, Ar-H), 7.51 (t, J = 1.8
Hz, 1H, Ar-H), 7.47 (q, J = 7.68 Hz, 2H, Ar-H), 7.41 (m,1H, Ar-H), 7.25
(
t, J = 7.88 Hz, 1H, Ar-H), 6.99 (t, J = 2.04 Hz, 2H, Ar-H), 6.83 (m,1H,
Ar-H),
CH CH
3.23
CH NHSO
(s,2H,
CH
2
CH
2
CH
CH
2
NHSO 3.07
2
),
(s,2H,
Ar-H), 6.73 (dd, J = 1.24 Hz, 1H, Ar-H), 6.69 (s,1H, Ar-H), 3.22 (t, J =
2
2
2
2
), 1.69 (s,2H, CH
2
2
CH NHSO
2
2
). 13C NMR (100
6
.64 Hz, 2H, CH
2
CH
2
CH
2
NHSO
2
), 2.95 (t,
J
=
6.72 Hz, 2H,
MHz, MeOD) δ 158.84 (Ar-C), 157.36 (Ar-C), 147.15 (Ar-C), 146.41 (Ar-
C), 135.76 (Ar-C), 134.51 (Ar-C), 131.32 (Ar-C), 129.59 (Ar-C), 128.79
(Ar-C), 125.69 (Ar-C), 119.82 (Ar-C), 115.44 (Ar-C), 115 (Ar-C), 111.09
CH CH CH NHSO ), 1.67 (m,2H, CH
2
2
2
2
2
CH CH NHSO
2
2
2
). 13C NMR (100
MHz, MeODMeOH) δ 158.81 (Ar-C), 157.37 (Ar-C), 147.17 (Ar-C),
46.31 (Ar-C), 139.17 (Ar-C), 138.35 (Ar-C), 129.63 (Ar-C), 129.04 (Ar-
C), 128.78 (Ar-C), 128.55 (Ar-C), 128.29 (Ar-C), 125.69 (Ar-C), 119.82
Ar-C), 115.45 (Ar-C), 114.99 (Ar-C), 111.06 (Ar-C), 105.94 (Ar-C),
1
(Ar-C),
(CH CH
105.99
CH NHSO
(Ar-C),
40.06
CH CH
(CH
2
CH
2
CH
2
NHSO
2
),
38.28
+
2
2
2
2
), 29.4 (CH
2
2
2
NHSO
2
). LC/MS 594.2 (M) .
(
4
0.28 (CH
2
CH
2
CH
2
NHSO
2
), 38.32 (CH
2
CH
2
CH
2
NHSO
2
), 28.94
4.1.7.17. 3-fluoro-N-(3-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-
+
(
CH CH CH
2
2
2
NHSO
2
). LC/MS 560.1 (M) .
5-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide (16g):. Yield: 60%.
◦
1
m.p.: 140 C. H NMR (400 MHz, MeOD) δ 7.99 (d, J = 6.88 Hz, 2H, Ar-
H), 7.83 (d, J = 4.8 Hz, 1H, Ar-H), 7.67 (d, J = 7.24 Hz, 1H, Ar-H), 7.56
(m,2H, Ar-H), 7.43 (m,3H, Ar-H), 7.32 (dt, J = 6.96 Hz, 2H, Ar-H), 6.98
(s,2H, Ar-H), 6.84 (d, J = 7.28 Hz, 1H, Ar-H), 6.7 (m,2H, Ar-H), 3.23
4
5
.1.7.13. 4-bromo-N-(3-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-
-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide (16c):. Yield: 60%.
◦
1
m.p.: 128 C. H NMR (400 MHz, MeOD) δ 8 (d, J = 7.28 Hz, 2H, Ar-H),
7
.85 (d, J = 5.44 Hz, 1H, Ar-H), 7.72 (q, J = 8.66 Hz, 4H, Ar-H), 7.49 (t,
(s,2H, CH
2
CH
2
CH
2
NHSO CH
2
), 2.96 (s,2H, CH
2
2 2 2
CH NHSO ), 1.68 (t, J
1
3
J = 7.08 Hz, 2H, Ar-H), 7.43 (t, J = 6.28 Hz, 1H, Ar-H), 7.26 (t, J = 7.84
Hz, 1H, Ar-H), 6.99 (t, J = 6.4 Hz, 2H, Ar-H), 6.84 (t, J = 1.48 Hz, 1H,
Ar-H), 6.73 (d, J = 5.2 Hz, 1H, Ar-H), 6.68 (s,1H, Ar-H), 3.23 (t, J = 6.64
= 5.68 Hz, 2H, CH
2
CH CH NHSO ). C NMR (100 MHz, MeOD) δ
2 2 2
163.7 (Ar-C), 161.22 (Ar-C), 158.8 (Ar-C), 157.35 (Ar-C), 147.18 (Ar-C),
142.64 (Ar-C), 131.03 (Ar-C), 130.95 (Ar-C), 129.59 (Ar-C), 128.56 (Ar-
C), 125.7 (Ar-C), 122.59 (Ar-C), 119.07 (Ar-C), 115.46 (Ar-C), 113.78
Hz, 2H, CH
2
CH
2
CH
2
NHSO
2
), 2.95 (t,
CH CH
J
=
6.76 Hz, 2H,
). 13C NMR (100
CH CH CH NHSO
2
2
2
2
), 1.68 (m,2H, CH
2
2
2
NHSO
2
(Ar-C), 111.1 (Ar-C), 105.97 (Ar-C), 40.32 (CH
2
CH
2 2 2
CH NHSO ), 38.35
MHz, MeOD) δ 158.95 (Ar-C), 157.4 (Ar-C), 147.14 (Ar-C), 146.54 (Ar-
C), 139.73 (Ar-C), 132.06 (Ar-C), 129.67 (Ar-C), 128.75 (Ar-C), 128.37
(CH
2
CH
2
CH
2
NHSO
2
), 28.99 (CH
2
CH
2
2
CH NHSO
2
). LC/MS 544.2 (M +
+
1) .
(
Ar-C), 126.67 (Ar-C), 125.67 (Ar-C), 119.77 (Ar-C), 115.42 (Ar-C),
1
14.97
(Ar-C),
111.02
38.26
). LC/MS 606 (M + 2) .
(Ar-C),
105.91
(Ar-C),
NHSO ),
40.28
28.95
4.1.7.18. N-(3-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-5-yl)pyr-
idin-2-yl)amino)propyl)-4-(trifluoromethyl)benzenesulfonamide (16 h):.
(
(
CH
CH
2
CH
2
CH
2
2
NHSO
NHSO
2
),
(CH
2
CH CH
2
2
2
+
1
◦
2
CH
2
CH
2
Yield: 70%. m.p.: 118 C. H NMR (400 MHz, MeOD) δ 8.03 (d, J = 8.2
Hz, 2H, Ar-H), 8 (d, J = 7.2 Hz, 2H, Ar-H), 7.87 (s,1H, Ar-H), 7.83 (t, J =
4.36 Hz, 2H, Ar-H), 7.47 (t, J = 8 Hz, 2H, Ar-H), 7.41 (t, J = 7.2 Hz, 1H,
Ar-H), 7.25 (t, J = 7.8 Hz, 1H, Ar-H), 7 (d, J = 8 Hz, 2H, Ar-H), 6.84 (dd,
J = 1.72 Hz, 1H, Ar-H), 6.72 (t, J = 4.2 Hz, 2H, Ar-H), 3.24 (t, J = 6.64
4
5
.1.7.14. 4-fluoro-N-(3-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-
-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide (16d):. Yield: 75%.
◦
1
m.p.: 147 C. H NMR (400 MHz, MeOD) δ 7.98 (d, J = 7.2 Hz, 2H, Ar-
H), 7.88 (m,2H, Ar-H), 7.83 (d, J = 5.6 Hz, 1H, Ar-H), 7.46 (t, J = 7.2 Hz,
Hz, 2H, CH
2
CH
2
CH
2
NHSO
2
), 2.98 (t, 6.72 Hz, 2H,
J
=
2
6
H, Ar-H), 7.4 (t, J = 7.2 Hz, 1H, Ar-H), 7.26 (q, J = 2 Hz, 3H, Ar-H),
.99 (d, J = 8.4 Hz, 2H, Ar-H), 6.83 (dd, J = 1.6 Hz, 1H, Ar-H), 6.71
CH CH CH NHSO
2
2
2
2
), 1.69 (m,2H, CH
2
CH CH NHSO
2
2 2
). 13C NMR (100
MHz, MeOD) δ 158.7665 (Ar-C), 157.3769 (Ar-C), 147.1943 (Ar-C),
1
8

E.M.H. Ali et al.
Bioorganic Chemistry xxx (xxxx) xxx
1
1
1
4
44.4041 (Ar-C), 133.6514 (Ar-C), 129.6259 (Ar-C), 127.3952 (Ar-C),
26.0172 (Ar-C), 125.9802 (Ar-C), 124.8846 (Ar-C), 122.1808 (Ar-C),
19.814 (Ar-C), 115.4464 (Ar-C), 111.0724 (Ar-C), 105.9958 (Ar-C),
CA, USA).
4.2.4. Apoptosis effect
0.3301 (CH
CH CH
2
CH
2
CH
2
NHSO
2
), 38.3261 (CH
2
CH
2
CH
2
NHSO
2
), 29.0156
Apoptosis and necrosis cell populations are determined using
Annexin V-FITC apoptosis detection kit (Abcam Inc., Cambridge Science
Park, Cambridge, UK) coupled with 2 fluorescent channels flowcy-
+
(
CH
2
2
2
NHSO
2
). LC/MS 594.1 (M + 1) .
5
4
.1.7.19. N-(3-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imidazol-5-yl)pyr-
(16i):. Yield:
0%. m.p.: 120 C. H NMR (400 MHz, MeOD) δ 8 (d, J = 7.24 Hz, 2H,
Ar-H), 7.84 (d, J = 5.16 Hz, 1H, Ar-H), 7.77 (d, J = 8.6 Hz, 2H, Ar-H),
tometry. After treatment with test compounds for 24, cells (10 cells) are
idin-2-yl)amino)propyl)-4-methoxybenzenesulfonamide
collected by trypsinization and washed twice with ice-cold PBS (pH 7.4).
Then, cells are incubated in dark with 0.5 mL of Annexin V-FITC/PI
solution for 30 min in dark at room temperature according to manu-
facturer protocol. After staining, cells are injected via ACEA Novocyte™
flowcytometer (ACEA Biosciences Inc., San Diego, CA, USA) and
analyzed for FITC and PI fluorescent signals using FL1 and FL2 signal
detector, respectively (λex/em 488/530 nm for FITC and λex/em 535/
617 nm for PI). For each sample, 12,000 events are acquired and positive
FITC and/or PI cells are quantified by quadrant analysis and calculated
using ACEA NovoExpress™ software (ACEA Biosciences Inc., San Diego,
CA, USA).
◦
1
7
7
.49 (t, J = 7.04 Hz, 2H, Ar-H), 7.43 (d, J = 6.92 Hz, 1H, Ar-H), 7.26 (t,
J = 7.68 Hz, 1H, Ar-H), 7.01 (t, J = 8.8 Hz, 4H, Ar-H), 6.84 (d, J = 8.4
Hz, 1H, Ar-H), 6.73 (d, J = 5 Hz, 1H, Ar-H), 6.69 (s,1H, Ar-H), 2.83
(
s,3H, OCH
.4 Hz, 2H, CH
CH CH CH NHSO
3
), 3.23 (t, J = 6.04 Hz, 2H, CH
2
CH
2
CH
2
NHSO
2
), 2.91 (t, J =
6
2
CH
2
2
CH NHSO
2
), 1.67 (t,
J
=
6.4 Hz, 2H,
). 1 C NMR (100 MHz, MeOD) δ 162.9251 (Ar-C),
3
2
2
2
2
1
1
1
5
58.8438 (Ar-C), 147.1582 (Ar-C), 131.7538 (Ar-C), 129.5501 (Ar-C),
28.904 (Ar-C), 128.5467 (Ar-C), 125.6733 (Ar-C), 119.7921 (Ar-C),
15.4281 (Ar-C), 114.9691 (Ar-C), 110.9773 (Ar-C), 105.9006 (Ar-C),
4.7721
CH
(OCH
3
),
40.2178
(CH
2
CH
2
CH
2
NHSO
2
),
38.3466
4.3. Docking study
(
CH
2
2
CH
2
NHSO
2
), 28.9007 (CH
2
CH CH
2
2
NHSO
2
). LC/MS 556.1 (M
+
+
1) .
The X-ray crystal structure of BRAF Kinase V600E oncogenic mutant
in complex with dabrafenib (PDB ID: 4XV2) was downloaded from the
protein data bank (www.rcsb.org) in PDB format. The 2D structure of
the target compounds were assembled using ChemDraw software. Mo-
lecular Operating Environment (MOE) software was used for the mo-
4
.1.7.20. 4-hydroxy-N-(3-((4-(4-(3-hydroxyphenyl)-2-phenyl-1H-imida-
zol-5-yl)pyridin-2-yl)amino)propyl)benzenesulfonamide (16j):. Yield:
0%. m.p.: 130 C. H NMR (400 MHz, MeOD) δ 7.97 (d, J = 7.2 Hz, 2H,
Ar-H), 7.8 (d, J = 5.6 Hz, 1H, Ar-H), 7.68 (d, J = 8.4 Hz, 2H, Ar-H), 7.44
◦
1
6
lecular docking operation of the target compounds 13a-i, 14a-i, 15a-j,
V600E
(
t, J = 4.6 Hz, 2H, Ar-H), 7.38 (t, J = 7.2 Hz, 1H, Ar-H), 7.24 (t, J = 8.4
and 16a-j with BRAF
kinase enzyme domain (PDB ID: 4XV2). The
Hz, 1H, Ar-H), 6.99 (d, J = 6.4 Hz, 2H, Ar-H), 6.89 (d, J = 8.8 Hz, 2H, Ar-
H), 6.84 (dd, J = 1.2 Hz, 1H, Ar-H), 6.71 (t, J = 2.8 Hz, 2H, Ar-H), 3.21
enzyme was prepared for the molecular docking procedure by applying
3D protonation of both enzyme amino acids and the native ligand
(
t, J = 6.4 Hz, 2H, CH
CH CH CH NHSO
NMR (100 MHz, MeOD) δ 161.39 (Ar-C), 158.44 (Ar-C), 157.33 (Ar-C),
47.27 (Ar-C), 145.63 (Ar-C), 130.11 (Ar-C), 129.66 (Ar-C), 128.97 (Ar-
C), 128.59 (Ar-C), 125.73 (Ar-C), 119.89 (Ar-C), 115.47 (Ar-C), 115.35
2
CH
2
CH
2
NHSO
2
), 2.89 (t, J = 6.4 Hz, 2H,
(dabrafenib). In addition, water of crystallization was removed from
1
3
V600E
), 1.66 (t, J = 6.4 Hz, 2H, CH
2
CH
2
CH
2
NHSO
2
).
C
both BRAF
kinase enzyme domains. The BRAF kinase enzyme
2
2
2
2
active site was isolated. The docking simulation of native ligand (dab-
V600E
1
rafenib) with the BRAF
kinase enzyme active site (PDB ID: 4XV2)
was investigated in order to validate the docking protocol. Both 3D
protonation and energy minimization were performed for the target
compounds using MOE software.
(
Ar-C), 111.08 (Ar-C), 106.05 (Ar-C), 40.24 (CH
2
CH
2 2 2
CH NHSO ), 38.47
(
CH
2
CH
2
CH
2
NHSO
2
), 28.84 (CH
2
CH
2
CH
2
NHSO
2
). LC/MS 542.1 (M +
+
1
) .
Declaration of Competing Interest
4
4
1
.2. Pharmacological screening
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
.2.1. Anticancer activity
Screening against the cancer cell lines was carried out for compounds
3a-i, 14a-i, 15a-j, and 16a-j at the National Cancer Institute (NCI),
Acknowledgments
Bethesda, Maryland, USA, applying the standard protocol of the NCI
43].
[
This work was supported by Korea Institute of Science and Tech-
nology (KIST), and KIST Project (2E29340). We are grateful to the Na-
tional Cancer Institute (NCI), Bethesda, Maryland, USA, for testing the
antiproliferative activity of the target compounds against 60 cancer cell
lines of nine different cancer types.
4
.2.2. In vitro kinase assay
Reaction Biology Corp. Kinase HotSpotSM service was used for
screening of final compounds. Assay protocol: as reported on Reaction
Biology Corp. website using 1 M concentration of ATP.
μ
Appendix A. Supplementary material
4
.2.3. Cell cycle analysis
After treatment with test compounds for 24 cells (105 cells)
including untreated cells as negative control- were collected by tryp-
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bioorg.2020.104508.
–
sinization and washed twice with ice-cold PBS (pH 7.4). Cells are re-
suspended in two milliliters of 60% ice-cold ethanol and incubated at
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37C, cells are analyzed for DNA contents using flow cytometry analysis
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2
0