Meridianin derivatives as potent Dyrk1A inhibitors and neuroprotective agents

Article abstract of DOI:10.1016/j.bmcl.2015.05.034

Meridianins are a group of marine-derived indole alkaloids which are reported to possess kinase inhibitory activities. In the present Letter, we report synthesis of N1-substituted and C-ring modified meridianin derivatives and their evaluation as Dyrk1A inhibitors and neuroprotective agents. Among the library of 52 compounds screened, morpholinoyl linked derivative 26b and 2-nitro-4-trifluoromethyl phenyl sulfonyl derivative 29v displayed potent inhibition of Dyrk1A with IC₅₀ values of 0.5 and 0.53 μM, respectively. The derivative 26b also inhibited Dyrk2 and Dyrk3 with IC₅₀ values of 1.4 and 2.2 μM, respectively showing 2.2 and 4.4 fold selectivity for Dyrk1A with respect to Dyrk2 and Dyrk3. The compound 26b was not cytotoxic to human neuroblastoma SH-SY5Y cells (IC₅₀ >100 μM) and it displayed significant neuroprotection against glutamate-induced neurotoxicity in these cells at 10 μM. Molecular modelling studies of compound 26b led to identification of key interactions in the binding site of Dyrk1A and the possible reasons for observed Dyrk1A selectivity over Dyrk2.

Full text of DOI:10.1016/j.bmcl.2015.05.034

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Meridianin derivatives as potent Dyrk1A inhibitors and
neuroprotective agents q
Rammohan R. Yadav a,b, Sadhana Sharma b,c, Prashant Joshi a,b, Abubakar Wani b,c, Ram A. Vishwakarma a,b
,
Ajay Kumar c, Sandip B. Bharate a,b,
⇑
a Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India
b Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India
c Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Meridianins are a group of marine-derived indole alkaloids which are reported to possess kinase inhibi-
tory activities. In the present Letter, we report synthesis of N1-substituted and C-ring modified meridi-
anin derivatives and their evaluation as Dyrk1A inhibitors and neuroprotective agents. Among the
library of 52 compounds screened, morpholinoyl linked derivative 26b and 2-nitro-4-trifluoromethyl
phenyl sulfonyl derivative 29v displayed potent inhibition of Dyrk1A with IC50 values of 0.5 and
Received 21 February 2015
Revised 17 April 2015
Accepted 14 May 2015
Available online xxxx
0.53
2.2
The compound 26b was not cytotoxic to human neuroblastoma SH-SY5Y cells (IC50 >100
played significant neuroprotection against glutamate-induced neurotoxicity in these cells at 10
l
l
M, respectively. The derivative 26b also inhibited Dyrk2 and Dyrk3 with IC50 values of 1.4 and
M, respectively showing 2.2 and 4.4 fold selectivity for Dyrk1A with respect to Dyrk2 and Dyrk3.
M) and it dis-
M.
Keywords:
Meridianins
Dyrk1A
l
l
Dyrk2
Molecular modelling studies of compound 26b led to identification of key interactions in the binding site
of Dyrk1A and the possible reasons for observed Dyrk1A selectivity over Dyrk2.
Ó 2015 Elsevier Ltd. All rights reserved.
Alzheimer’s disease
Neuroprotection
Dual-specificity Tyrosine-regulated Kinases (Dyrks) belong to
the CMGC family of eukaryotic protein kinase superfamily. This
group of kinases are further divided into two classes: (a) class 1
kinases (Dyrk1A and 1B) that has N-terminal nuclear localization
signal and a C-terminal PEST region and (b) class 2 kinases
(Dyrk2, 3 and 4), which lacks these motifs and are predominantly
cytosolic.1 Dyrk1A gets over-expressed in several neurodegenera-
tive diseases including Down syndrome and Alzheimer’s disease;
thus it has been considered as a molecular target for these dis-
eases.2–5 Considering the importance of Dyrk1A in Down syndrome
genesis and its role in signal transduction, many efforts have been
made to discover potent inhibitors of Dyrk1A. Harmine (1) is a
b-carboline alkaloid possessing potent Dyrk1A inhibitory activity
with IC50 value of 80 nM.6–8 Another natural product inhibitor
(IC50 330 nM) of Dyrk1A is epigallocatechin gallate (2), which is a
major catechin component of green tea.9,10 INDY (3) and its analog
4 are benzothiazoles possessing Dyrk1A inhibitory activity, with
Dyrk1A with IC50 of 0.034 l
M.14 A structurally similar azo-indole
7 is the most potent in vitro inhibitor of Dyrk1A reported till
date.15 Acridine derivative 8 displayed inhibition of Dyrk1A,
Dyrk2 and Dyrk3 enzymes with IC50 values of 0.1, 0.002,
0.019
possessing inhibition of Dyrk1A, Dyrk1B and Dyrk2 with IC50 val-
ues of 0.1, 0.07 and 0.04 M, respectively. The chemical structures
l
M.16 Schmitt et al.17 discovered a substituted thiophene 9
l
of compounds 1–9 are shown in Figure 1.
Meridianins18,19 are indole alkaloids substituted at the C-3 posi-
tion by 2-aminopyrimidine ring. The meridianins have been evalu-
ated against number of kinases such as Cdk1, Cdk2, Cdk5, PKA,
PKG, GSK-3b, CK1, KDR, IGF-1R, c-Met, RET, c-Src, c-Abl, HER-1,
Erk2 and Dyrk1A.14,20–22 Recently, Moreau and co-workers14 eval-
uated meridianin analogs against 5 kinases (Cdk5/p25, CK1d/
e,
GSK-3 /b, Dyrk1A, and CLK1) and for their in vitro antiproliferative
a
activities against human cancer cell lines (PC3, DU145, PA1, SH-
SY5Y, IMR-32 and MCF7). In the present study, our aim was to fur-
ther explore the SAR of meridianins for Dyrk1A inhibition and
investigate their neuroprotective activity.
Thus, herein we prepared a series of N-substituted meridianin
derivatives and screened for Dyrk1A inhibition. The selectivity of
key compound over other Dyrk’s (Dyrk2 and Dyrk3) was also
studied. The molecular modeling studies were carried out to
IC50 values of 0.24 and 0.93
l
M.11 A marine natural product leucet-
tine B derivative 5 possess potent Dyrk1A inhibition with IC50 of
0.04
l
M.12,13 Meridianin analog 6 displayed potent inhibition of
q
IIIM Communication number. IIIM/1786/2015.
⇑
Corresponding author. Tel.: +91 191 2585006; fax: +91 191 2586333.
E-mail address: sbharate@iiim.ac.in (S.B. Bharate).
http://dx.doi.org/10.1016/j.bmcl.2015.05.034
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Yadav, R. R.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.05.034

2
R. R. Yadav et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
OH
OH
O
HO
O
OH
O
O
O
MeO
S
N
NH
N
O
N
N
H
OH
OH
OH
RO
HN
O
1
5
2
OH
3: R = H Dyrk1A: IC50 = 0.24 µM
4: R = Me Dyrk1A: IC50 = 0.93 µM
Dyrk1A: IC50 = 0.04 µM
Dyrk1A: IC50 = 0.08 µM
Dyrk1A: IC50 = 0.33 µM
NH2
OH
H2N
N
HO
HO
N
S
N
OMe
N
I
MeO
N
S
S
N
N
N
Br
H
H
9
8
6
7
Dy1k1A: IC50 = 0.1 µM
Dyrk1B: IC50 = 0.07µM
Dyrk2: IC50 = 0.04 µM
Dy1k1A: IC50 = 0.1 µM
Dyrk2: IC50 = 0.002 µM
Dyrk3: IC50 = 0.019 µM
Dyrk1A: IC50 = 0.034 µM
Dyrk1A: IC50 = 0.003 µM
Figure 1. Chemical structures of Dyrk inhibitors.
H2N
N
N
understand the possible reason for selective Dyrk1A inhibition
over Dyrk2.
H2N
H2N
N
O
N
N
N
R1
Cl
R1
Cl
Meridianin C (19) and G (18) were synthesized in four steps
starting from commercially available indoles 10–11 as shown in
Scheme 123 The synthesized meridianins C and G were character-
ized by comparison of their spectral data with literature
values.18,19
24a-f
a
25a-d
R
R
N
R
a
N
H
N
26a-i
18: R = H
R1
R1
27a-g
O
19: R = 5-Br
The N-acyl and N-alkyl derivatives 26a–i and 27a–g were pre-
pared as described earlier24 and is depicted in Scheme 2.
Similarly, a library of N-sulfonyl derivatives 29a–ad were prepared
from meridianins C and G. Treatment of meridianins C and G with
different substituted sulfonyl chlorides 28a–t in presence of DIPEA
and DMAP produced N-sulfonyl products 29a–ad in 38–87% yield
(Scheme 3).25 The C-ring modified meridianin analogs 21–23 were
26a: R = H
N
N
O
R1
R1
=
O
N
27a: R = H
27b: R = 5-Br
26b: R = 5-Br
R1
=
26c: R = H
26d: R = 5-Br
N
=
27c: R = H
R1
R1
=
27d: R = 5-Br
Cl
S
26e: R = H
R1
R1
=
S
O
26f: R = H
26g: R = 5-Br
=
N
27e: R = H
=
O
O
O
CH3
26h: R = H, R1
=
CH3
27f: R = H
27g: R = 5-Br
R1
=
OMe
R
a
b
R
R
N
26i: R = H,
R1
=
N
H
N
Ts
H
EtO
10: R = H
12: R = H
14: R = H
11: R = 5-Br
13: R = 5-Br
15: R = 5-Br
Scheme 2. Synthesis of N1-substituted meridianin derivatives 26a–i and 27a–g.
Reagents and conditions: (a) K2CO3 (2 equiv), alkyl halide or acyl halide (1 equiv)
ACN, 12 h, rt, 32–86%.
c
CH3
N
H2N
N
H2N
N
H3C
O
N
N
d
Br
also prepared (structures shown in Scheme 1).24 All synthesized
derivatives were characterized by 1H, 13C NMR, IR, HRMS and melt-
ing point analysis.
R
R
N
N
H
N
Ts
OCH3
18: R = H
16: R = H
17: R = 5-Br
20
All derivatives were tested for Dyrk1A inhibition at 0.5 lM and
19: R = 5-Br
cytotoxicity in SH-SY5Y cells. Meridianin G (18) and C (19) along
with several derivatives showed significant Dyrk1A inhibition
activity. Based on the preliminary screening results, the IC50 was
determined for 6 derivatives viz. 20, 26b, 26f, 26g, 27b and 29v.
The N-morpholinoyl derivative 26b showed potent inhibition of
O
O
HN
NH
HN
N
I
R
Dyrk1A with IC50 value of 0.5
26g showed Dyrk1A inhibition with IC50 values of 3.1, 0.835
respectively. 2-Nitro-4-trifluoromethyl phenyl sulfonyl derivative
of meridianin C 29v showed IC50 value of 0.53 M (Table 2).
All compounds were screened for cytotoxicity in SH-SY5Y cells
at 30 M, wherein most of the compounds were not cytotoxic
lM. N-Benzoyl derivatives 26f and
N
H
lM,
N
H
21: R = H
22: R = 5-Br
23
l
Scheme 1. Synthesis of meridianin G (18) and meridianin C (19). Reagents and
conditions: (a) AcCl (2 equiv), SnCl4 (2 equiv), toluene, 0 °C, 2 h, 84–95%; (b) TsCl
(1.1 equiv), DIPEA (1.5 equiv), DMAP (0.05 equiv), DCM, rt, 20 h, 72–85%; (c) DMF-
DMA (1.5 equiv), DMF, 110 °C, 4 h; 50–55%; (d) guanidine HCl (1.5 equiv), 2-
methoxyethanol, K2CO3 (2 equiv), 120 °C, 24 h, 55–66%.
l
(Table 1). The cytotoxicity IC50 value of three compounds 26b,
26g and 29v, which exhibited better inhibition of Dyrk1A, was then
determined. Compounds 26b and 26g were not cytotoxic up to
Please cite this article in press as: Yadav, R. R.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.05.034

R. R. Yadav et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
H2N
H2N
N
N
N
N
+
R1-SO2Cl
28a-t
a
R
R
N
N
H
O
S
O
18: R = H
R1
19: R = 5-Br
29a-ad
29a: R = H
29o: R = H
R1
=
29x: R = H,
OMe
R1
R1
=
=
CF3
CF3
29b: R = 5-Br
R1
=
29p: R = 5-Br
OMe
OMe
29c: R = H
29d: R = 5-Br
29y: R = H,
R1
R1
=
=
29q: R = H
29r: R = 5-Br R1
=
29z: R = 5-Br,
29e: R = H
29f: R = 5-Br
NH
O
CF3
O
R1
R1
=
29s: R = H
29t: R = 5-Br
R1
=
29g: R = H
29h: R = 5-Br
29aa: R = H,
Cl
R1
R1
=
O
=
Cl
R1
=
OCF3
29u: R = 5-Br,
29v: R = 5-Br,
29i: R = H
29j: R = 5-Br
=
29ab: R = H,
29ac: R = H,
29ad: R = H,
Br
NO2
CN
R1
R1
=
O2N
29k: R = H
29l: R = 5-Br
R1
=
=
R1
R1
=
MeO
CF3
Br
=
F
CF3
=
I
29m: R = H
29n: R = 5-Br
29w: R = H,
R1
F
R1
=
Scheme 3. Synthesis of N1-substituted meridianin derivatives 29a–ad. Reagents and conditions: (a) R1-SO2Cl (1.1 equiv), DIPEA (1.5 equiv), DMAP (0.05 equiv), DCM, rt, 20 h,
38–87%.
Table 1
Table 2
Dyrk1A inhibition and SH-SY5Y cell viability of meridianin derivatives
IC50 values of selected compounds for Dyrk1A inhibition
Entry Dyrk1A
SH-SY5Y
Entry Dyrk1A
SH-SY5Y%
Entry
Dyrk1A (IC50, lM)
0.33a
1.3
0.5
3.1
0.83
1.8
0.53
(% inhibition)a (% viability)b
(% inhibition)a viabilityb
19
20
18
19
20
21
29.8
56.7
27.2
2
91.4
92.9
75.3
83.1
41.5
24
97.3
87
82
29e
29f
29g
29h
29i
29j
29k
29l
29m
29n
29o
29p
29q
29r
15.7
23.7
7.6
21.3
4.9
16.8
0
22.8
0
11
40
109
49
107
56
59
26b
26f
26g
27b
29v
22
9
23
20
26a
26b
26c
26d
26e
26f
26g
26h
26i
27a
27b
27c
27d
27e
27f
27g
29a
29b
29c
29d
1.4
56.7
0.4
110
106
76.1
38.8
95.6
85
72.4
76.4
59.4
112
74
15.2
99.1
61.6
127
71.6
55.4
91.4
96.2
57.5
Literature value.14
a
22.6
24.6
35.3
40.7
12.2
2.3
13.2
33.1
20
8.5
0
9.6
14.2
10.6
3.9
12.9
12.9
91.8
82
0
0
Table 3
106
65.1
94.6
46.6
88.5
83.1
115
24
101
96
79.8
58.8
99
Neuroprotective effect of compounds 26b and 26g in human neuroblastoma SH-SY5Y
cells
9.8
10.1
14.7
2.1
0
29s
29t
Compound
% viability ( SD) of SH-SY5Y cells
29u
29v
29w
29x
29y
29z
29aa
29ab
29ac
29ad
Control
100
36.9
0
Glutamate (250
Glutamate (250
Glutamate (250
Glutamate (250
Glutamate (250
l
l
l
l
l
M)
73.8 4.5
86.4 3.8
82.5 3.7
94.1 4.6
93.2 2.1
M) + 26b (50
M) + 26b (10
M) + 26g (50
M) + 26g (10
l
l
M)
M)
6.3
0
l
l
M)
M)
24.3
13.2
4.5
4.5
2.8
86.3
109
a
Compounds were tested toward Dyrk1A at 0.5
Compounds were tested for cytotoxicity in SH-SY5Y cell line at 30 lM.
l
M.
Table 4
Activity of compound 26b against three Dyrk’s
b
Dyrk enzyme
IC50
,
l
M
Fold selectivity for Dyrk1A
100
l
M (IC50 >100
l
M), however the sulfonyl linked derivative 29v
Dyrk1A
Dyrk2
Dyrk3
0.5
1.4
2.2
–
2.8
4.4
displayed cytotoxicity with IC50 value of 14
Based on the cytotoxicity results, next we selected compounds
26b and 26g for neuroprotective activity in human neuroblastoma
lM.
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R. R. Yadav et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
(a)
(b)
Figure 2. Interactions of meridianin derivative 26b with Dyrk1A (a) and Dyrk2 (b).
Table 5
The comparison of binding site residues of Dyrk1A and Dyrk2a
two factors: (a) difference in the binding orientation of 26b with
Dyrk1A and Dyrk2 and (b) hydrophobic interactions of 26b with
the conserved residues of Dyrk1A (Table 5)
Dyrk1A
Ile165
Dyrk2
Ille155
Lys178
Leu230
Leu231
Ile294
Asp295
Phe296
Gly297
The less activity towards Dyrk2 in comparison to Dyrk1A might
be due to the loss of interactions of 2-aminopyrimidine core with
Leu230 and Leu231 residues of hinge region. Instead of that, the
compound 26b orients differently and carbonyl group interacts at
ATP binding site. This change in orientation of 26b is might be
due to its interactions with the conserved Met240 and Val306 resi-
dues of Dyrk1A. The opposite orientation of compound 26b is sta-
bilized by its H-bonding interactions with the H2O-2018.
Lys188
Met240
Leu241
Val306
Asp307
Phe308
Gly309
a
The blue colored residues are key differences in these two
enzymes, which might be responsible for observed selectivity of
compound 26b towards one enzyme than other.
In conclusion, herein we have identified N1-substituted merid-
ianin derivative 26b as promising inhibitor of Dyrk1A and a neuro-
protective agent. Compound 26b displayed 3- and 4-fold
selectivity for Dyrk1A with respect to Dyrk2 and Dyrk3. The
promising neuroprotective activity in neuronal cells against gluta-
mate induced neurotoxicity further indicates promise of this iden-
tified lead for further development as an anti-Alzheimer agent.
SH-SY5Y cells against glutamate-induced neurotoxicity. The SH-
SY5Y cells were differentiated for one week with 10 M of retinoic
acid. Differentiated cells were used for neuroprotective effect
against glutamate induced toxicity. Both compounds at 10 as well
as 50 lM, provided significant protection against the toxicity
l
induced by glutamate. Results are shown in Table 3.
Acknowledgements
Compound 26b was further screened against a panel of 15
kinases including PKB-
Aurora A, Aurora B, AMPK, CK1, IKKb, Abl, IGF-1R, IR and VEGFR
at 0.5 M. It did not show significant inhibition of any of these
a, PKB-b, PKC-a, GSK-3b, CDK-2, CDk-9,
R.R.Y. thanks CSIR (India) for Senior Research Fellowship.
Authors are thankful to analytical department, IIIM for analytical
support. This work was supported by DST-SERB grant (no.
SR/FT/CS-168/2011).
l
kinases. It showed moderate inhibition (26%) of PKC-
a at this test
concentration.
The N-morpholinoyl derivative 26b was then investigated for
selectivity over Dyrk2 and Dyrk3. Compound 26b also showed
Supplementary data
inhibition of these Dyrk’s with IC50 values of 1.4 and 2.2 lM,
respectively. It showed 2.8 and 4.4-fold selectivity towards
Dyrk1A with respect to Dyrk2 and Dyrk3 (Table 4).
Supplementary data (experimental procedures and spectral
data scans) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.bmcl.2015.05.034.
In order to determine the mode of interaction and rationale for
selectivity of meridianin derivative 26b towards Dyrk1A, the
molecular modeling studies were carried out. Similar to parent
natural alkaloid meridianin C,14 derivative 26b also showed inter-
actions at the hinge region of Dyrk1A. The 2-aminopyrimidine core
mimics the ATP structure (adenine) interactions with the ATP
binding site of Dyrk’s. Secondary interactions were observed with
the bulkier bromo functionality of inhibitor 26b with Asp307 and
Lys188 side chain in terms of hydrophobic and ionic interactions.
Further, Val306 and DFG motif residues 307–309 displayed
hydrophobic interactions. These hydrophobic interactions could
be a plausible explanation for varying degree of Dyrk1A enzyme
inhibition for 26b (Fig. 2).
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follows: To the solution of meridianin G (18) or meridianin C (19) in
dichloromethane (5 ml) was added DMAP (0.05 equiv), aryl sulfonyl chloride
(1.1 equiv) and N,N-diisopropylethylamine (1.5 equiv). The mixture was stirred
at room temperature for 20 h. Reaction was then quenched by the addition of
10% HCl. This reaction mixture was extracted with dichloromethane
(50 ml  3), and combined organic layer was evaporated on rotary evaporator.
The crude products were purified by silica gel column chromatography (mesh
100–200) using dichloromethane–methanol (99:1 to 97:3) to get the titled
products 29a–ad. Spectral data of all compounds is provided in Supplementary
information. Data for representative compounds is provided here: (3-(2-
Aminopyrimidin-4-yl)-5-bromo-1H-indol-1-yl)(morpholino)
methanone
(26b): yield: 87%; yellow solid; mp 244–246 °C; 1H NMR (DMSO-d6,
400 MHz): d 8.86 (s, 1H), 8.44 (d, 1H, J = 1.6 Hz), 8.21–8.19 (m, 1H), 7.65–
7.63 (m, 1H), 7.46 (t, 1H, J = 6.8 Hz), 7.14–7.12 (m, 1H), 6.71 (s, 1H), 5.72 (d, 1H,
J = 2.0 Hz), 3.77 (s, 4H), 3.70 (s, 4H); 13C NMR (CD3OD+CDCl3, 125 MHz): d
162.35, 157.09, 156.14, 135.45, 131.47, 127.96, 127.05, 124.93, 123.92, 114.25,
114.03, 110.89, 106.40, 70.48, 58.43; IR (CHCl3): mmax 3306, 2955, 2925, 2858,
1739, 1688, 1578, 1544, 1491, 1449, 1419, 1401, 1362, 1342, 1273, 1248, 1082,
1015 cmÀ1; HRMS: m/z 402.0555 calcd for C17H16BrN5O2+H+ (402.0560). 4-(5-
Bromo-1-(2-nitro-4-(trifluoromethyl)phenyl sulfonyl)-1H-indol-3-yl)pyrim-
idin-2-amine (29v). Yield: 47%; yellow solid; mp 129–131 °C; 1H NMR
(CDCl3, 400 MHz): d 8.59 (d, 1H, J = 2.0 Hz), 8.24 (d, 1H, J = 5.6 Hz), 8.15 (s,
1H), 8.11 (d, 1H, J = 8.4 Hz), 7.95–7.91 (m, 2H), 7.70 (d, 1H, J = 8.8 Hz), 7.48 (dd,
1H, J = 8.8, 20 Hz), 7.01 (d, 1H, J = 5.6 Hz), 5.68 (s, 2H); 19F NMR (CDCl3,
376 MHz): d À63.50 (s, 3F); 13C NMR (CDCl3, 125 MHz): d 162.99, 160.23,
158.62, 148.03, 133.94, 131.20, 129.90, 129.53, 129.51,128.80 (d,
2JCF = 22.5 Hz), 126.20, 122.71, 120.39, 118.67, 114.48, 108.27; IR (CHCl3):
19. Seldes, A. M.; Brasco, M. F.; Franco, L. H.; Palermo, J. A. Nat. Prod. Res. 2007, 21,
555.
20. Gompel, M.; Leost, M.; De Kier Joffe, E. B.; Puricelli, L.; Franco, L. H.; Palermo, J.;
Meijer, L. Bioorg. Med. Chem. Lett. 2004, 14, 1703.
21. Rossignol, E.; Debiton, E.; Fabbro, D.; Moreau, P.; Prudhomme, M.; Anizon, F.
Anticancer Drugs 2008, 19, 789.
m
max 3401, 2955, 2924, 2854, 1738, 1573, 1553, 1459, 1439, 1398, 1362, 1323,
1269, 1188, 1084, 1020 cmÀ1; HRMS: m/z 543.9716 calcd for C19
H BrF3N5O4S
11
81
+ H+ (543.9740).
22. Akue-Gedu, R.; Debiton, E.; Ferandin, Y.; Meijer, L.; Prudhomme, M.; Anizon, F.;
Moreau, P. Bioorg. Med. Chem. 2009, 17, 4420.
26. Bahl, A.; Joshi, P.; Bharate, S.; Chopra, H. Med. Chem. Res. 2014, 23, 1925.
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Michaud, F.; Meijer, L. J. Heterocycl. Chem. 2007, 44, 793.
Please cite this article in press as: Yadav, R. R.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.05.034