Click chemistry based rapid one-pot synthesis and evaluation for protease inhibition of new tetracyclic triazole fused benzodiazepine derivatives

Article abstract of DOI:10.1016/j.bmcl.2009.06.107

We describe herein a one-pot synthesis of novel tetracyclic scaffolds that incorporate a fusion of a proline, 1,2,3-triazole ring with [1,4]-benzodiazepin-8(4H)-one ring systems following click chemistry. The expected peptide bond formation followed by in

Full text of DOI:10.1016/j.bmcl.2009.06.107

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5241–5245
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Click chemistry based rapid one-pot synthesis and evaluation for protease
inhibition of new tetracyclic triazole fused benzodiazepine derivatives
a
b
b
Debendra K. Mohapatra a,c, , Pradip K. Maity , M. Shabab , M. I. Khan
*
a Organic Chemistry Division, National Chemical Laboratory (CSIR), Pune 411 008, India
b Biochemistry Division, National Chemical Laboratory (CSIR), Pune 411 008, India
c Organic Chemistry Division-I, Indian Institute of Chemical Technology (CSIR), Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein a one-pot synthesis of novel tetracyclic scaffolds that incorporate a fusion of a proline,
1,2,3-triazole ring with [1,4]-benzodiazepin-8(4H)-one ring systems following click chemistry. The
expected peptide bond formation followed by in situ 1,3-dipolar cycloaddition in absence of any catalyst
led to the formation of new triazole fused benzodiazepine derivatives.
Received 7 May 2009
Revised 23 June 2009
Accepted 26 June 2009
Available online 21 July 2009
Ó 2009 Published by Elsevier Ltd.
The development of new therapeutic agents, as well as the iden-
tification of molecular probes for the study of the chemical/biolog-
ical interfaces, is one of the major goals in biomedical research. In
this context, the availability of libraries of small molecules, which
depend heavily on the availability of synthetic transformations
that allow the rapid assembly of complex molecular frameworks
providing maximum diversity and covering as much chemical
space as possible, is seen as the only means which guarantees po-
tential modulation of the many biological targets that are ulti-
mately being unveiled by genomics.1 The design of such libraries
may involve novel scaffolds to which diverse side chains are
attached, the trajectories of which seek to explore three-dimen-
sional space. An important overlapping principle is the concept
of privileged structures, recently updated by Patchett et al.2 One
of the privileged structure 1,4-benzodiazepine derivative display
tranquilizing, muscular relaxant, anti-convulsant and sedative
effects.3,4 The use of this class of compounds with therapeutic pur-
poses is not only limited to anxiety and stress conditions, seem-
ingly minor changes in their structures can produce a host of
different biological activities, such as central nervous system
receptors,5 G-proteins coupled receptors6 and central nervous sys-
tem diseases.7 It has also found applications for the synthesis of
peptidomimetics,8 peptide antagonists,9 inhibitors of DNA interac-
tions,10 antiviral or antimalarial activity,11 and many other poten-
tially active molecules.12 Currently there is a considerable interest
in the discovery and development of small molecules such as pyr-
rolo[2,1-c][1,4]-benzodiazepines (PBD’s) that have to be used as
potential antitumor and gene targeted drugs.13 Anthramycin (1),
DC-81 (2) and Neothramycin (3) are well-known and promising
members of the PBD class (Fig. 1).14 A number of pyrrolo[2,1-
c][1,4]-benzo-diazepin-5-ones constitute a new class of anthramy-
cin antibiotics, a typical example of which is abbeymycin (4).
Recently, the tetracyclic compound 5, referred to as bretazenil,15
has emerged due to its potential usage against neurodegenerative
diseases.
In the context of our ongoing effort directed towards the synthe-
sis of 1,4-benzodiazepine derivatives of pharmacological interest,
we turned our attention to new classes of tetracyclic compounds,
namely benzo[e]pyrrolo[1,2-a][1,2,3]triazolo[5,1-c][1,4]diaze-pin-
8(4H)-one (6), 5-(benzyloxy)-benzo[e]pyrrolo[1,2-a][1,2,3]triazol-
o[5,1-c][1,4]diazepine-8(4H)-one (7) and their derivatives (Fig. 2).
In developing a strategy toward the synthesis of these compounds,
we perceived the usefulness of intramolecular azide-alkyne 1,3-
dipolar cycloaddition in order to construct simultaneously the se-
ven-membered heterocycle, the triazole and pyrazole and report
OH
OMe
N
HO
N
MeO
H
N
MeO
N
NH2
O
O
O
Anthramycin (1)
DC-81 (2)
N
CO2tBu
N
H
HO
H
OMe
H
N
N
H
N
MeO
N
N
O
OH
HO
Br
O
O
Neothramycin (3)
Bretazenil (5)
Abbeymycin (4)
* Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160512.
E-mail address: mohapatra@iict.res.in (D.K. Mohapatra).
Figure 1. Structures of promising members of PBD class.
0960-894X/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2009.06.107

5242
D. K. Mohapatra et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5241–5245
N
N
N
R1
N
R1
R2
R3
R2
R3
N
H
N
H
N
N
OBn
R4
R4
O
O
6
7
Figure 2. Structures of new tetracyclic triazole fused benzodiazepines.
TFA
ref. 16
OH
Figure 3. ORTEP diagram of compound 14.
N
H
CH2Cl2
N
H
N
O
.TFA
Boc
8
10
9
The corresponding aromatic azido acid 12 was prepared from
anthranilic acid (11) by diazotization reaction using NaNO2 and
dil. HCl in Et2O at 0 °C followed by treatment with NaN3 at the
same temperature in good yield (Scheme 2).17
Scheme 1. Synthesis of alkyne 10.
Coupling between aromatic azido acid 12 and TFA salt of
amine 10 was carried out in the presence of EDCI, HOBT and DI-
PEA in dry DMF expecting to isolate azido-alkyne 13. To our
pleasant surprise, the isolated product was resultant of a further
1,3-dipolar cycloaddition reaction to afford very interesting tet-
racyclic compound 14 in 82% yield (Scheme 2),18 which was fully
characterized by spectral and analytical data.19 In addition, the
herein the facile assembly of a library of triazole fused tetracyclic
compounds.
Naturally occurring L-proline (8) was converted to alkyne 9 in
80% overall yield following literature known procedure (Scheme
1).16 Boc deprotection of alkyne 18 was carried out with TFA in
CH2Cl2 to afford the TFA salt of amine 10.
Table 1
One-pot amide coupling and intramolecular 1,3-dipolar cycloaddition reaction under catalyst free condition
S.No.
2
Acid
Amine (10)
Product (14)
Time (h)
08
Yield (%)
87
R1 = H; R2 = Cl; R3 = H; R4 = H.
N
14a
H
H
. TFA
3
4
R1 = H; R2 = H; R3 = Br; R4 = H.
R1 = H; R2 = H; R3 = H; R4 = Me.
R1 = H; R2 = H; R3 = OMe; R4 = OMe.
R1 = H; R2 = I; R3 = H; R4 = I.
N
14b
14c
14d
14e
14f
14g
14h
14i
07
08
06
07
06
06
08
07
92
91
82
87
88
92
91
82
H
H
. TFA
N
H
H
. TFA
5
N
H
H
. TFA
6
N
H
H
. TFA
7
R
1 = H; R2 = Br; R3 = H; R4 = Me.
N
H
H
. TFA
8
R1 = H; R2 = H; R3 = H; R4 = F.
R1 = H; R2 = H; R3 = H; R4 = NO2.
R1 = H; R2 = H; R3 = H; R4 = OMe.
N
H
H
. TFA
9
N
H
H
. TFA
10
N
H
H
. TFA

D. K. Mohapatra et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5241–5245
5243
R1
R1
R2
R3
R2
R3
N3
NH2
1. NaNO2, dil. HCl
0 o
C
2. NaN3, 0 oC-rt
CO2H
CO2H
R4
R4
11
R1
N
12
R1
N
R2
R2
N
N3
H
H
"Click"
EDCI, HOBt
+ 12
10
DIPEA, 0 oC-rt
6 h, 82%
N
R3
N
R3
R4
R4
O
O
14
R1 = H; R2 = H;
R3 = H; R4 = H.
13
Scheme 2. Synthesis of 14.
HO
BnO
BnO
structure of 14 was unambiguously assigned by its single crystal X-
ray diffraction studies (Fig. 3).20 This result encouraged us to verify
other aromatic azido acid derivatives under identical reaction con-
ditions. As exemplified in Table 1, the reaction proceeded smoothly
to completion and the corresponding benzo[e]pyrrolo[1,2-a][1,2,
3]triazolo[5,1-c][1,4]diazepin-8(4H)-one products were obtained
in 6 to 8 h with excellent yields and high purity.
ref. 20
TFA
OH
N
H
N
H
N
CH2Cl2
O
.TFA
Boc
17
16
15
Scheme 3. Synthesis of alkyne 10.
100
90
80
70
60
50
40
30
We extended our studies further to trans-4-hydroxy-L-proline
(15) which was converted into alkyne 17 in 91% yield (Scheme
3).21 In the 1H NMR spectrum, the characteristic acetylinic pro-
ton was observed at d 2.26 ppm. Alkyne 17 was subjected to
Boc-deprotection with TFA in CH2Cl2 at 0 °C. After drying the
reaction mixture, the crude material was coupled with azido
acid 12 by treatment with EDCI, HOBT and DIPEA in DMF to af-
ford azido-alkyne 18 followed by an in situ 1,3-dipolar cycload-
dition to yield 1,2,3-triazole fused tetracyclic 1922 in 8 h with
84% yield over two steps (Scheme 4). The 1H NMR spectrum
showed a singlet resonance at d 7.61 ppm and a multiplet at d
4.36 ppm corresponding to olefinic proton and methine proton
attached to the olefin, respectively. Debenzylation of compound
19 was carried out by using H2/Pd-C in EtOAc to afford 20 in
95% yield.
0
100
200
300
400
500
These results were then extended to other aromatic azido acid
derivatives under identical reaction conditions. As exemplified in
Table 2, the reaction proceeded smoothly to completion and the
corresponding 5-(benzyloxy)-benzo[e]-pyrrolo[1,2-a][1,2,3]-triaz-
olo[5,1c][1,4]diazepine-8(4H)-one products (19a–h) were obtained
in 7–10 h with excellent yields and high purity (Table 2).
These Triazole compounds have been analysed for their efficacy
as enzymatic protease inhibitors like serine protease, cysteine pro-
tease and aspartase protease.23
Inhibitor concentration
B
100
90
80
70
60
50
40
30
20
10
The inhibitors were screened at different level of concentra-
tions. Initially the inhibition at concentration level of 1 lM was
determined. The compounds showing no inhibition or inhibition
less than 50% were not investigated further. Those showing activ-
ities more than 50% were taken and the screening was done at low-
er level of concentration (Fig. 4). Thus, optimum range of
concentration was found where compound showed activity in
the range of 50%. Several assays in a varying range of concentration
at that level were performed to determine the IC50 (the concentra-
tion of inhibitor at which it shows 50% inhibition of enzyme)24 and
later the experiment was repeated with a different concentration
of substrate. The results are summarized in the tabular format.
None of the compound showed aspartic protease inhibition activity
(Table 3).
50
100
150
200
250
300
350
400
concentration
Figure 4. IC50 plot against trypsin for 14h and papain for 14f.

5244
D. K. Mohapatra et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5241–5245
Table 2
One-pot amide coupling and intramolecular 1,3-dipolar cycloaddition reaction under catalyst free condition
S.No.
2
Acid
Amine (17)
Product (19)
Time (h)
07
Yield (%)
84
BnO
R1 = H; R2 = Cl; R3 = H; R4 = H.
19a
N
H
. TFA
H
BnO
BnO
BnO
BnO
BnO
BnO
BnO
3
4
5
6
7
8
9
R1 = H; R2 = H; R3 = NO2; R4 = H.
R1 = H; R2 = H; R3 = Br; R4 = H.
R1 = H; R2 = H; R3 = H; R4 = Me.
R1 = H; R2 = OMe; R3 = OMe; R4 = H.
R1 = I; R2 = H; R3 = I; R4 = H.
19b
19c
19d
19e
19f
10
10
09
08
09
07
09
90
85
83
80
86
89
87
N
H
H
. TFA
N
H
H
. TFA
N
H
H
. TFA
N
H
H
. TFA
N
H
H
. TFA
R1 = Br; R2 = H; R3 = Me; R4 = H.
19g
19h
N
H
H
. TFA
R1 = H; R2 = H; R3 = F; R4 = H.
N
H
H
. TFA
R1
R2
R3
N3
H
1,3-dipolar
cycloaddition
EDCI, HOBt
17 + 12
DIPEA, 0 oC-rt
7 h, 84%
N
OBn
R1
O
R4
18
N
N
R1
N
N
R2
N
H
R2
R3
N
H2/Pd-C
H
EtOAc, rt, 4 h
95%
N
O
R3
N
OBn
OH
R4
R4
O
20
19
Scheme 4. Synthesis of alkyne 19.
In conclusion, we have achieved the first regioselective one-pot
synthesis of several new chiral tetracyclic triazole derivatives by
peptide bond formation and an in situ intramolecular 1,3-dipolar
cycloaddition reaction between easily affordable azides and
alkynes with excellent yield and high purity. The synthesized com-
pounds were evaluated against protease inhibitors and some of
them showed weak to good serine protease inhibition activity.
Even though the inhibition levels are only at lM levels, we believe,
these novel and unprecedented class of molecules are certain to
find applications in biology.

D. K. Mohapatra et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5241–5245
5245
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19d
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SP
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SP
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108.2
naa
290.2
na
535.8
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206.4
na
674.3
na
195.6
na
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ꢀ
= +220.9 (c
;
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1H NMR
(CDCl3, 200 MHz) d 2.14 (quin, 2H, J = 6.8 Hz), 2.51–2.62 (m, 2H), 3.71–3.86 (m,
2H), 4.76 (t, 1H, J = 5.8 Hz), 7.56 (dt, 1H, J = 1.4, 7.7 Hz), 7.64 (s, 1H), 7.69 (dt,
1H, J = 1.6, 7.5 Hz), 8.00 (dd, 1H, J = 1.3, 8.0 Hz), 8.12 (dd, 1H, J = 1.6, 7.7 Hz); 13C
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ꢀ
= +147.5 (c 1.4,
CHCl3); IR (CHCl3) 3436, 2925, 1637, 1471, 1409, 1085 cmꢁ1
;
1H NMR (CDCl3,
200 MHz) d 2.49–2.62 (ddd, 1H, J = 4.6, 8.4, 13.2 Hz), 2.79 (ddt, 1H, J = 2.4, 7.4,
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