G Model
CCLET-3593; No. of Pages 3
2
J.-K. Liu et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
Scheme 1. Synthetic route of the designed compounds. Reagents and conditions: (a) Trimethylsilylacetylene, PdCl2(PPh3)2, TEA, CuI, THF, <5 8C—r.t., 24 h; (b) (3-
hydroxyphenyl)boronic acid, PdCl2(dppf), K2CO3, 1,4-dioxane, 80 8C, 24 h; (c) 3-bromo chlorobenzene, TBAF, PdCl2(PPh3)2, THF, 80 8C, 8 h; (d) KMnO4, MgSO4, Na2CO3, r.t.,
2 h; (e) 1-methylguanidine hydrochloride, Na2CO3, EtOH/H2O, 90 8C, 2 h; (f) 3-bromopropyne (or ethylmethyl-carbamic chloride or dimethylcarbamoyl chloride) acetone,
K2CO3, r.t., 36 h.
boronic acid in 1,4-dioxane at room temperature and the mixture
was then heated to 80 8C for 24 h to afford 5 (yield 71%). 5 and
TBAF were dissolved in THF and the solution was stirred at room
temperature for 30 min. To the solution 1-bromo-3-chloroben-
zene (take R = –Cl as an example) and PdCl2(PPh3)2 were added.
The resulting mixture was heated to 80 8C for 8 h to give the
diphenylethyne intermediate 6 (yield 40%, R = –Cl). 6 was
dissolved in a mixture solvent of acetone/H2O (v/v = 1.6/1) to
which MgSO4, Na2CO3 and KMnO4 was added. After reacting at
room temperature for 2 h, intermediate 7 was obtained in a yield
of 53%. 7 reacted with 1-methylguanidine hydrochloride in 50%
ethanol at the temperature of 90 8C for 2 h to give cyclic
acylguanidine intermediate 8 (yield 44%). The phenol group of 8
then reacted with 3-bromoprop-1-yne or corresponding carba-
mic chloride in acetone at room temperature to give final product
9a–l.
rings occupy the S1 and S02 pocket, respectively [17]. To obtain
compounds with further improved inhibition efficiency, we have
design and synthesized compounds of formula 9 (Fig. 1). In formula
9 the third phenyl ring was introduced to interact with the
unoccupied S3 pocket through hydrophobic force, the phenol ester
or prop-1-yne group was attached at the meta-position of the third
phenyl ring to fill the S3 sub-pocket formed by a flexible loop
located near the Ser10 loop [18] (Fig. 2). These enhanced
interactions together with the hydrogen bond interactions
between the guanidine and Asp228 and Asp32 [19] are expected
to result in compounds with much improved inhibition efficiency.
Docking results of 9h with BACE1 active binding site showed that
the new compounds retained the essential hydrogen bond
interactions between the guanidine and Asp228 and Asp32. The
third phenyl ring interacted with the S3 pocket while the prop-2-
yn-1-yloxy group nicely filled the S3 sub-pocket as expected. This
is believed to be an important cause of the BACE1 inhibitory
activity improvement.
The structure of the new compounds was characterized by 1H
NMR and MS. Experimental procedures, characterization data and
1H NMR and MS spectra of target compounds, BACE1 inhibition
test methods are available in Supporting information.
Twelve target compounds were synthesized. BACE1 inhibition
test shows that the new compounds exhibited much improved
inhibition efficiency than the compound 2 (Table 1) except for
3. Results and discussion
It has been known that when the lead compound 1 binds to
BACE1 active binding site, the guanidine forms essential hydrogen
bond interactions with Asp228 and Asp32 while the two phenyl
Table 1
Inhibitory activity of the target compounds against BACE1a.
X
O
O
N
NH
N
H
R
Compd.
R
X
Inhibition rate (%)
31.8
IC50 (mmol/L)
O
O
9a
Cl
3.75
N
9b
Cl
25.3
5.84
N
9c
Cl
62.2
44.6
0.182
1.59
9d
OCF3
OCF3
OCF3
O
O
N
N
9e
9f
39.5
87.9
2.51
0.282
Fig. 2. Docking result of compound 9h with BACE1 active binding site (PDB: 4DJV).
Please cite this article in press as: J.-K. Liu, et al., Design and synthesis of 30-(prop-2-yn-1-yloxy)-biphenyl substituted cyclic