Modification of imidazothiazole derivatives gives promising activity in B-Raf kinase enzyme inhibition; synthesis, in vitro studies and molecular docking

Article abstract of DOI:10.1016/j.bmcl.2020.127478

B-Raf mutation was identified as a key target in cancer treatment. Based on structural features of dabrafenib (potent FDA approved B-Raf inhibitor), the design of new NH₂-based imidazothiazole derivatives was carried out affording new highly potent derivatives of imidazothiazole-based scaffold with amino substitution on the terminal phenyl ring as well as side chain with sulfonamide group and terminal substituted phenyl ring. In vitro enzyme assay was investigated against V600E B-Raf kinase. Compounds 10l, 10n and 10o showed higher inhibitory activities (IC₅₀ = 1.20, 4.31 and 6.21 nM, respectively). In vitro cytotoxicity evaluation was assessed against NCI-60 cell lines. Most of tested derivatives showed cytotoxic activities against melanoma cell line. Compound 10k exhibited most potent activity (IC₅₀ = 2.68 μM). Molecular docking study revealed that the new designed derivatives preserved the same binding mode of dabrafenib with V600E B-Raf active site. It was investigated that the new modification in the synthesized derivatives (substituted with NH₂) had a significant inhibitory activity towards V600E B-Raf. This core scaffold is considered a key compound for further structural and molecular optimization.

Full text of DOI:10.1016/j.bmcl.2020.127478

Journal Pre-proofs
Modification of imidazothiazole derivatives gives promising activity in B-Raf
kinase enzyme inhibition; synthesis, in vitro studies and molecular docking
Usama M. Ammar, Mohammed S. Abdel-Maksoud, Karim I. Mersal, Eslam
M. H. Ali, Kyung Ho Yoo, Hong Seok Choi, Jae Kyun Lee, Sun Young Cha,
Chang-Hyun Oh
PII:
S0960-894X(20)30589-8
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127478
BMCL 127478
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Bioorganic & Medicinal Chemistry Letters
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Revised Date:
Accepted Date:
20 June 2020
3 August 2020
5 August 2020
Please cite this article as: Ammar, U.M., Abdel-Maksoud, M.S., Mersal, K.I., M. H. Ali, E., Ho Yoo, K., Seok
Choi, H., Kyun Lee, J., Young Cha, S., Oh, C-H., Modification of imidazothiazole derivatives gives promising
activity in B-Raf kinase enzyme inhibition; synthesis, in vitro studies and molecular docking, Bioorganic &
Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127478
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Modification of imidazothiazole derivatives gives promising activity in
B-Raf kinase enzyme inhibition; synthesis, in vitro studies and
molecular docking
Usama M. Ammara,b,c, Mohammed S. Abdel-Maksoud , Karim I. Mersal , Eslam M. H.
d
a,b
a,b
e
f
g
h
Ali , Kyung Ho Yoo , Hong Seok Choi , Jae Kyun Lee , Sun Young Cha , Chang-Hyun
Oha,b,*
aCenter for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu,
0
2792, Republic of Korea
b
University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea
c
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, Giza, 12566,
Egypt
d
Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research
Division, National Research Centre (NRC), Dokki, Giza, 12622, Egypt
e
Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea
f
College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
g
Center for Neuro-Medicine, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu,
0
2792, Republic of Korea
h
Department of Beauty Science, Hanseo University, Seosan 31962, Republic of Korea
Corresponding author
*
Abstract
B-Raf mutation was identified as a key target in cancer treatment. Based on structural
features of dabrafenib (potent FDA approved B-Raf inhibitor), the design of new NH2-
based imidazothiazole derivatives was carried out affording new highly potent derivatives
of imidazothiazole-based scaffold with amino substitution on the terminal phenyl ring as
well as side chain with sulfonamide group and terminal substituted phenyl ring. In vitro
enzyme assay was investigated against V600E B-Raf kinase. Compounds 10l, 10n and
1
0o showed higher inhibitory activities (IC = 1.20, 4.31 and 6.21 nM, respectively). In
50
vitro cytotoxicity evaluation was assessed against NCI-60 cell lines. Most of tested
derivatives showed cytotoxic activities against melanoma cell line. Compound 10k
exhibited most potent activity (IC = 2.68 µM). Molecular docking study revealed that the
50
new designed derivatives preserved the same binding mode of dabrafenib with V600E B-
Raf active site. It was investigated that the new modification in the synthesized derivatives

(
substituted with NH ) had a significant inhibitory activity towards V600E B-Raf. This core
2
scaffold is considered a key compound for further structural and molecular optimization.
Keywords
Antitumor agents; cancer; imidazo[2,1-b]thiazole; V600E B-Raf.
Cancer is one of the most prevalent diseases worldwide[1-6]. Both cell growth and
proliferation are controlled through MAPK signaling pathway[7-12]. B-Raf kinase enzyme
is considered an important element in MAPK cascade. Mutation of B-Raf lead to
[2]
uncontrolled cell proliferation and potentiation of cancer particularly melanoma . At
present, a number of small molecule-based inhibitors have been approved by FDA as B-
Raf kinase inhibitors such as vemurafenib (I)[13] and dabrafenib (II)[14] (Figure 1).
Figure 1. FDA approved V600E B-Raf inhibitors with their IC50 values.
However, these approved drugs have been acquired a number of resistances[15, 16]. As a
result, it is necessary to develop a more efficient and selective agents against mutated B-
Raf kinase enzyme. Imidazothiazole derivatives exhibit a wide range of biological
activities including anti-cancer, anti-inflammatory and anti-bacterial effect[17]. Recently,
the medicinal research era focus on the development of imidazothiazole-based
derivatives in the treatment of cancer[18-21]
.
In previous studies, we synthesized a number of imidazothiazole-based small molecules.
These derivatives exhibited inhibitory activities against V600E B-Raf kinase enzyme in a

range of nanomolar level[22]. In the present study, based on the structural features of
dabrafenib (II), we designed a number of new imidazothiazole-based derivatives in order
to enhance the potency towards V600E B-Raf kinase enzyme. Molecular docking
screening of dabrafenib has been identified to investigate the potential pharmacophores
which bind to conserved amino acids in B-Raf active site.
A new imidazothiazole derivatives was designed, where, the terminal phenyl ring was
substituted with NH group. In addition, the other key chemical features in dabrafenib
2
(sulphonamide group and terminal phenyl ring) were kept in the designed compounds in
order to afford the same binding mode of dabrafenib in B-Raf binding site (sulphonamide
group, Lys 483; terminal phenyl ring, Leu 505 and Phe 595) (Figure 2). The new
incorporated NH group affords both polarity as well as H-bond contribution (donor and
2
acceptor) with the biochemical environment of B-Raf active site. The new proposed
interactions (of NH group) was supposed to significantly contribute in the inhibitory
2
activity.
Figure 2. Rational design of new imidazothiazole derivatives (10a-p) in regard to dabrafenib (II). Both scaffolds maintained the
same binding mode with conserved amino acids in V600E B-Raf active site (Lys 483, Leu 505, Cys 532 and Phe 595).

The synthesis of new derivatives (10a-p) is shown in Scheme 1. The incorporated side
chain (3a-p) were prepared by reaction of appropriate diamines (1a,b) and different
substituted benzene sulfonyl chlorides (2a-h) though nucleophilic substitution reaction
mechanism[23]. Compound 6 was obtained by condensation of compound 4 with 2-
aminothiazole (5). Cross-coupling reaction of compound 6 with aryl halide compound (7)
is accomplished through Heck reaction[24, 25] to give compound 8. Treatment of compound
8
with oxone led to oxidation of SMe moiety to afford the key intermediate (9). Final target
compounds (10a-p) were provided by reaction of compound 9 with appropriate amine-
based side chain (3a-p) in presence of base followed by reduction of NO group in
2
presence of Pd/C under H atmosphere.
2
Cl
Ar
S
O O
H
NH2
2a-h
N
Ar
H N
2
n
H N
2
n
S
a
O O
1a,b
3a-p
Cl
N
S
S
S
H N
2
N
O
N
N
N
N
S
N
O N
2
Br
O N
2
O N
2
5
7
b
c
N
4
6
S
N
8
H
S
N
Ar
S
H N
2
n
S
N
N
O O
N
N
O N
H2N
2
3a-p
d
H
N
N
Ar
N
e,f
S
O
n
S
O
N
O
N
N
H
O
1
0a-p
9
Scheme 1. Reagents and conditions. a,TEA, DCM, 0 °C-rt, 8 h; b, EtOH, reflux, 18 h; c, Pd(OAc)
2
3 2 3
, Ph P, K CO , DMF, 80 °C,
8
h; d, Oxone, MeOH/H O, rt, 9 h; e, DIPEA, DMSO, 90 °C, 8 h; f, H , Pd/C, MeOH, rt,9 h.
2
2
In vitro inhibitory activity on mutated B-Raf kinase enzyme (V600E B-Raf) was evaluated
for the synthesized derivatives. The test was measured at 10 doses of tested compounds
with serial dilution (3-fold) at 1 µM. An IC value higher than 1 µM was estimated based
50
on the best curve fitting available. The IC values were summarized in Table 1.
50

The results showed that all the synthesized compounds exhibited potent inhibitory
activities against V600E B-Raf kinase enzyme in nanomolar level. Compounds 10l, 10n
and 10o exhibited more potent inhibitory activities (IC50 = 1.20, 4.31 and 6.21 nM,
respectively) than that of other synthesized derivatives as well as vemurafenib (I, IC =
50
3
1 nM). Moreover, they approached the inhibitory activity of dabrafenib (II, IC = 0.5 nM).
50
The results revealed that the new substituted group (NH ) has a potential biological
2
impact in inhibiting V600E B-Raf enzyme. Moreover, compounds with electron
withdrawing substitution in the terminal phenyl ring of side chain enhanced the enzyme
inhibitory effect (10e, 4-Cl; 10g, 4-F; 10i, 3-F; 10k, 4-CF 10n, 4-Br and 10o, 4-F). In
3;
addition, compounds with propylene spacer-based side chain (10i-p) showed higher
activities than that of ethylene linker-based derivatives (10a-h). It was suggested that the
propylene linker affords a proper molecular distance between the central scaffold and the
phenyl ring of side chain in order to be brought into the hydrophobic pocket of V600E B-
Raf kinase enzyme active site.
Table 1. In vitro enzyme assay data of target compounds.
Compound
n
1
1
1
1
1
1
1
1
2
2
2
2
2
Ar
V600E B-Raf IC50a
28.30
1
1
1
1
1
1
1
1
1
1
1
1
1
0a
0b
0c
0d
0e
0f
3-FPh
4-MePh
59.10
4-CF Ph
141.00
3
4-OMePh 23.40
4-ClPh
4-BrPh
4-FPh
16.70
73.70
12.70
152.00
13.50
NDb
0g
0h
0i
1-Naph
3-FPh
0j
4-MePh
0k
0l
4-CF Ph
11.40
3
4-OMePh 1.20
4-ClPh 20.40
0m

Compound
n
2
2
2
-
Ar
V600E B-Raf IC50a
10n
10o
10p
4-BrPh
4-FPh
1-Naph
-
4.31
6.21
24.50
31.00
Vemurafenib
I)
(
Dabrafenib (II)
-
-
0.50
a
nM
b
Not determined
In addition, the results revealed that the amino-based derivatives were more potent than
the previously reported imidazothiazole derivatives (fluoro-based[22] and nitro-based[26]
,
Table 2). The results showed that substitution at position 3 of terminal phenyl ring with
electron donating group (NH ) afforded greater inhibitory activities than electron
2
withdrawing groups (F and NO ). From these findings, it can be suggested that the
2
electron donation at that position is important in V600E B-Raf inhibition. Moreover, The
high activity of the most active compound (10l, IC = 1.20 nM) can be referred to the
50
propylene spacer along with 4-methoxy phenyl ring in the side chain which afford an
outstanding chemical environment for that compound to possess high affinity and stable
complex with B-Raf active site.

Table 2. In vitro enzyme assay data of most active compounds (10l, 10n and 10o) and
previously reported imidazothiazole derivatives with similar side chains against V600E
B-Raf kinase.
S
N
R1
N
O
O
N
S
N
R2
H
N
N
H
R2
V600E B-Raf IC (nM)
50
R1
NH2
Fa
NO2b
OMe
Br
1.20 (10l)
4.31 (10n)
6.21 (10o)
25.10
9.30
NDc
131.00
20.00
35.00
F
a[22]
b[26]
cNot determined
In vitro cellular activity was identified for the synthesized compounds. All target derivatives
were tested initially at a single high dose (10 µM) in the full NCI-60 cancer cell line panel.
The mean percent inhibition were summarized in Table 1s-10s.
All compounds showed relative cytotoxic activities over NCI-60 cancer cell lines. However,
a number of tested compounds exhibited potent values against melanoma cell line
(UACC-62,V600E B-Raf-based human cancer cell line, Table 3). In addition, derivatives
with propylene spacer exhibited better potencies than that of ethylene spacer (Figure 3).
Table 3. In vitro one-dose cytotoxic assay of most active compounds (10i-o) against
NCI-melanoma cell line (UACC-62).
Compound
UACC-62 (%)
78.07
1
0i
0j
1
59.62

Compound
UACC-62 (%)
100.00
47.03
1
1
1
1
1
1
0k
0l
0m
0n
0o
0p
13.40
3.91
77.80
57.39
Compound 10k showed the most potent cytotoxic activity among the tested compounds.
It showed mean percent inhibition value of 100% over melanoma cell lines. The relative
potencies of the synthesized compounds over NCI-60 cancer cell lines were suggested
to be referred to the polarity of the new substituted group (NH ) which may be
2
incorporated in the poor cell penetrating properties. This type of polarity can be masked
in a form of prodrug in future molecular and structural optimization.
Compound 10k (most potent derivative in single dose assay) was selected to be tested
in five-dose assay to evaluate its mean GI values against NCI-60 cell lines (Table 11s
50
and 4). The results showed that compound 10k showed high inhibitory activities in
micromolar level all over the NCI-60 cell lines. It exhibited higher inhibitory activities
against breast, leukemia, melanoma and prostate cancer (mean GI = 3.28, 3.03, 3.80
50
and 3.34 µM, respectively).

Figure 3. % Inhibition of compounds with ethylene spacer (blue color) and propylene spacer (red color) against NCI melanoma
cell line (UACC-62).
Table 4. In vitro five-dose cytotoxic assay (mean GI and mean TCI values in µM) of
50
compound 10k against NCI-60 cancer cell lines.
NCI-60 cell lines
Breast cancer
CNS cancer
Mean GI50
3.28
Mean TGI
28.46
29.77
32.17
17.41
19.70
52.43
44.42
23.75
44.05
5.58
Colon cancer
4.28
Leukemia
3.03
Melanoma
3.80
Non-small cell lung cancer
Ovarian cancer
Prostate cancer
Renal cancer
5.61
5.26
3.34
5.08
In order to investigate the binding mode of the new designed compounds in V600E B-Raf
kinase active site, molecular docking study was conducted for both dabrafenib (II) and
the most active derivatives (10i,k,l,n and 10o) into the V600E B-Raf pocket using
Molecular Operating Evnvironment (MOE 2014).

In molecular docking analysis, the X-ray structure of V600E B-Raf with dabrafenib (II) as
native ligand (PDB ID: 4XV2)[27] was used. The X-ray structure of B-Raf kinase domain
consists of two lobes, small N‐terminal lobe (orients the ATP molecule by antiparallel
β‐sheet structure) and large C‐terminal lobe (binds to MEK). The catalytic site is located
between these two lobes that were occupied by most B-Raf kinase inhibitors. Most B-Raf
kinase mutation (Val600Glu) occur in the activation segment (P-loop)[28]
.
The docking protocol of dabrafenib (II) in the enzyme active site was validated with route
mean square deviation (RMSD) of 1.8883 and virtual ligand screening (VLS) score of -
16.0501 kcal/mol.
The tested derivatives showed distinct interactions (arene and H-bonding interactions)
with the conserved amino acids (Lys 483, Leu 505, Cys 532, Phe 583 and Phe 595)
(Table 5).
Table 5. Molecular docking results of tested compounds and dabrafenib into V600E B-
Raf kinase domain
Compound
Binding scorea
Amino acidsb
Lys 483
Leu 505
Cys 532
NH (3.06 Å)
Phe 583
Phe 595
Dabrafenib (II)
-16.0501
SO
2
(2.88 Å)
DiFPh (π)
2
-
SO
2
(2.87 Å)
N Pyrimid (2.91 Å)
1
0i
-16.0956
-16.3698
-
-
-
-
-
-
SO
2
(2.98 Å)
10k
NH (3.43 Å)
SO (2.72 Å)
NH (3.27 Å)
Pyrimid (π)
3
4-CF Ph (π)
2
1
1
1
0l
-15.4919
-15.3194
-14.1222
4-OMePh (π)
NH
NH
-
2
2
(3.15 Å)
(2.94 Å)
-
4-OMePh (π)
SO
SO
SO
SO
2
2
2
2
(2.80 Å)
(3.50 Å)
(2.59 Å)
(2.78 Å)
0n
0o
-
-
4-BrPh (π)
4-FPh (π)
Pyrimid (π)
-
akcal/mol
bπ, arene interaction
The results showed that most of the tested compounds preserved the same binding mode
with that of dabrafenib. Most of compounds showed H-bond interactions between
sulfonamide moiety in the side chain and Lys 483 amino acid residue.

Figure 4. 2D ligand interaction of dabrafenib (II) and tested compounds (10l and 10n) with V600E B-Raf kinase domain.

In addition, the terminal phenyl ring of side chain exhibited hydrophobic interactions with
Leu 505 and Phe 595 amino acids in the active site. Moreover, the central pyrimidine ring
of the tested compounds contributed the molecular binding through arene interaction with
Cys 532. Furthermore, the most active compounds, 10l and 10n (IC = 1.20 and 4.31
50
nM, respectively), showed additional H-bond interaction between the new substitution
NH group) and Cys 532 amino acid residue of V600E B-Raf kinase active site (Figure
(
2
4). From the molecular docking study, it was revealed that the tested derivatives
conserved the binding interactions of dabrafenib.
In summary, a number of new series of NH -based imidazothiazole derivatives was
2
synthesized and evaluated for their in vitro enzyme inhibitory effect as well as in vitro
cytotoxic activity. It was investigated that the new NH -substituted derivatives preserved
2
the V600E B-Raf kinase enzyme inhibitory activity. Compounds 10l, 10n and 10o were
the most potent compounds against V600E B-Raf kinase enzyme. In addition, compound
1
0k (p-CF substituted phenyl ring with propylene linker-based side chain) was the most
3
active compounds among the synthesized derivatives against in vitro human cancer cell
lines. Both in vitro biological assays showed that derivatives with propylene spacer in the
incorporated side chain had a greater activities than that of ethylene spacer-based
derivatives. Moreover, derivatives with 4-OMe, 4-Br and 4-F substituted phenyl ring in
side chain (10l, 10n and 10o, respectively) had higher enzyme inhibitory activities among
the synthesized compounds. Furthermore, the potent enzyme inhibitory activities of new
NH -based derivatives were explained by the additional binding to V600E B-Raf kinase
2
enzyme active site via additional H-bond interaction(s) with Cys 532 amino acid residue.
Finally, these results afforded a new NH -based imidazothiazole derivatives for further
2
molecular and structural optimization.
Acknowledgements
This work was supported by Korea Institute of Science and Technology (KIST), and KIST
Project (2E29340). We are grateful to the National Cancer Institute (NCI), Bethesda,

Maryland, USA, for testing the antiproliferative activity of the target compounds against
0 cancer cell lines of nine different cancer types.
6
Conflict of Interest
The authors declare no conflict of interest.
Appendix A – Supplementary data
The supplementary data (the experimental details of synthesis, in vitro cytotoxicity assay,
in vitro enzyme assay, molecular docking and characterization data of all synthesized
compounds) related to this article can be found online at https://doi.org/××.××××/j.bmcl.×
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Highlights




New imidazothiazole derivatives were designed and synthesized.
In vitro enzyme inhibitory assay was evaluated on V600E B-Raf kinase.
In vitro cytotoxicity studies was performed over NCI-60 cancer cell lines.
Molecular docking was conducted to explore the mode of interactions with
enzyme.

Compounds 10l, 10n and 10o showed potent inhibitory activities.
Graphical abstract