Discovery of 6-substituted 4-anilinoquinazolines with dioxygenated rings as novel EGFR tyrosine kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.07.079

It had been reported that some dioxygenated rings fusing with the quinazoline scaffold could lead to new EGFR inhibitors. Based on this, several kinds of oxygenated alkane quinazoline derivatives were synthetized and evaluated as EGFR inhibitors. Their antiproliferative activities were tested against four cancer cell lines: A431, MCF-7, A549, and B16-F10. Most derivatives could counteract EGF-induced EGFR phosphorylation, and their potency was comparable to the reference compound Erlotinib. The size of the fused dioxygenated ring was crucial for the biological activity and the heptatomic ring derivative 19 showed potent in vitro inhibitory activity in the enzymatic assay as well as in the cellular assay.

Full text of DOI:10.1016/j.bmcl.2012.07.079

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5870–5875
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of 6-substituted 4-anilinoquinazolines with dioxygenated rings
as novel EGFR tyrosine kinase inhibitors
Dong-Dong Li a, , Fei Fang a, , Jing-Ran Li a, Qian-Ru Du a, Jian Sun a, Hai-Bin Gong b, , Hai-Liang Zhu a,
⇑
⇑
a State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China
b Xuzhou Central Hospital, Xuzhou 221009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 April 2012
Revised 9 July 2012
Accepted 24 July 2012
Available online 31 July 2012
It had been reported that some dioxygenated rings fusing with the quinazoline scaffold could lead to new
EGFR inhibitors. Based on this, several kinds of oxygenated alkane quinazoline derivatives were synthe-
tized and evaluated as EGFR inhibitors. Their antiproliferative activities were tested against four cancer
cell lines: A431, MCF-7, A549, and B16-F10. Most derivatives could counteract EGF-induced EGFR phos-
phorylation, and their potency was comparable to the reference compound Erlotinib. The size of the fused
dioxygenated ring was crucial for the biological activity and the heptatomic ring derivative 19 showed
potent in vitro inhibitory activity in the enzymatic assay as well as in the cellular assay.
Keywords:
EGFR
Kinase inhibitor
4-Aminoquinazolines
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Receptor tyrosine kinases (RTK) play vital roles in the processes
controlling cellular proliferation, differentiation and evasion from
apoptosis. Among the known RTKs, the ErbB family, particularly
EGFR and HER2 have been extensively focused and clinically vali-
dated as rational targets for cancer therapies.1 The ErbB family in-
cludes four receptors: epidermal growth factor receptor (EGFR/
erbB-1/HER1), erbB-2 (HER2), erbB-3 (HER3), and erbB-4 (HER4).
Each one can be activated through homo or heterodimerization
with other receptors leading to phosphorylation events and down-
stream signaling that could cause excessive growth by inducing
cell proliferation and inhibiting apoptotic pathways.2 Overexpres-
sion and/or coexpression of EGFR and HER2 have been found in
numerous tumor types, including colon, breast, ovarian, head and
neck, and non-small cell lung cancers3 and is associated with poor
prognosis of the patients.4 As to current therapies, small molecule
EGFR inhibitors have been shown to be promising strategies to in-
hibit EGFR and HER2 kinase activities.5 To date, three reversible
anilinnoquinazoline EGFR inhibitors (Gefitinib,6 Erlotinib,7 and
Lapatinib8) (Fig. 1) have been approved by FDA into clinical use.
As shown in Figure 1, they possess the common structure char-
acter: 4-anilino quinazoline moiety, which plays a crucial role and
has been extensively studied in the past ten years. This sort of
inhibitors generally exhibit high potency in vitro, inhibiting EGFR
at nanomolar concentration. However, a major problem is that
these compounds show their poor in vivo activity, and many deriv-
atives from PD153035,9 a most potent inhibitor on isolated EGFR
(IC50 = 25 pM), have been modified by adding solubilizing groups
to address this issue.10 Among a huge of relative studies, one from
Adriana Chilin et al. in Italy arouses our interests.11 They have
modified the molecular structure of PD153035 in two main sites:
one is 6,7-position by incorporating both the 6- and 7-methoxy
groups into rings of various size (dioxolane, dioxane, and dioxepine
rings), and the other is 4-aniline moiety by substituting the bro-
mine atom with other functional groups of different lipophilicity
and/or steric hindrance. In terms of the structure–activity relation-
ships (SARs) of this template, it is widely acceptable that adding an
electron-donating substituent on the 6 or 7-position could enhance
the binding potency of N1 and N3 belonged to the quinazoline
ring.12 The 4-aniline head is involved in the interaction with a
hydrophobic pocket of EGFR and the aniline alteration would dis-
turb the selectivity of small molecules. Therefore, it is a rational
tactic for optimizing EGFR inhibitors. Four small molecules (6b,
7b, 8b, and 10b) (Fig. 2) have been screened among these desired
fifteen EGFR inhibitors (according to this paper, 6,7-position: three
kinds of possibilities; 4-aniline position: five kinds of possibilities;
totally 3 ꢀ 5). Obviously, all the four molecules are sharing the
same sketeton of dioxane and the bromine atom is responsible
for selectivity of EGFR tyrosine kinase (overexpressing EGFR cancer
cells A431: IC50 = 0.75 lM; NIH3T3: >10 l
M),11 compared to other
molecules with three different substituents (CH3, CF3, and 20-F-40-
Br).
Assuming that 30-Br atom of 4-aniline moiety plays a crucial
role in the interaction with a hydrophobic pocket of EGFR and
EGFR inhibitory activity is considered to be dependent on the size
of the fused dioxygenated ring, here we have devised and synthe-
sized a series of novel 4-aminoquinazolines derivatives. The
⇑
Corresponding authors. Tel.: +86 25 83592572; fax: +86 25 83592672.
E-mail address: zhuhl@nju.edu.cn (H.-L. Zhu).
These authors contributed equally to this work.
0960-894X/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.07.079

D.-D. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5870–5875
5871
HN
N
HN
Br
O
O
O
O
O
N
N
O
N
Erlotinib
PD153035
O
S
O
F
F
O
NH
O
HN
N
Cl
N
O
O
O
HN
N
Cl
N
N
Lapatinib
Gefitinib
Figure 1. Some EGFR inhibitors approved by the FDA.
HN
CH3
HN
N
Br
O
O
O
N
N
O
N
R
7b
6b
HN
A431: 0.75
M
O
µ
A431: 0.67 µM
N
NIH3T3: >10 µM
NIH3T3: 5.80
M
M
µ
n
Br
O
N
Template
HN
N
HN
CF3
O
O
F
O
N
N
O
N
8b
A431: 0.77 µM
10b
A431: 6.28 µM
NIH3T3: 5.40
NIH3T3: 7.1
M
µ
µ
O
n
O
HN
N
R
H
N
N
n:1,2,3,4;
R: Br or Cl.
New EGFR Inhibitors
Figure 2. The rational design of these novel EGFR inhibitors.
strategy is illustrated in Figure 2, indicating that either the bro-
mine atom or the chlorine atom is inserted at the meta-position
of 4-aniline ring. The alternations at the 6,7-position also contain
dioxygenated rings with different size. One difference is an obvious
linkage added between dioxygenated ring and quinazoline ring,
which could be formed by an amide bond or carbon-nitrogen sin-
gle bond. As planed, a dozen of novel small molecules (11–22) have
been obtained and evaluated for in vitro EGFR inhibitory activity,
leading to identification of a novel 4-aminoquinazoline compound
19 that exhibited significant antitumor potency.
control and these kinds of analysis include molecular docking (pro-
tein receptor from the RCSB Protein Data Bank database, ID:
1M17), similarity computation over positive control, CDOCKER
interaction energy comparison, and their comparison of molecular
properties. Obviously, the obtained results listed in Figure 3 reveal
that some molecules could perform better than positive control
and the design for these small molecules (11–22) is, to some ex-
tent, reasonable. As shown in this illustration, (a) all the novel
compounds (11–22, 6b, 7b, 8b, and 10b) could be easily inserted
into the inactive EGFR kinase domain;13 (b) they possess high sim-
ilarities (>0.45) over PD153035 as a template, although compounds
(6b–10b) have exceeded the similarity of 0.6; (c) four molecular
properties (molecular_fractional polar surface area, ALogP, and
molecular_weight) have been selected to predict the feasibility of
To investigate the feasibility of compound design before synthe-
sis, some virtual evaluations have been calculated using discovery
studio 3.1 software. The results are summarized in Figure 3. Based
on PD153035, 6b, 7b, 8b, and 10b have been selected as positive

5872
D.-D. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5870–5875
Figure 3. Some feasibility analysis in virtue of the CDOCKER program (Discovery Studio 3.1, Accelrys, Co. Ltd). (a) EGFR inhibitors (11–22, 6b, 7b, 8b, and 10b) are superposed
inside the ATP cleft (receptor, PDB code: 1M17). (b) EGFR inhibitors mentioned above would be superposed over PD153035 as a template. Making the four inhibitors (6b, 7b,
8b, and 10b) as a training set, some small molecular properties have been selected and compared. The results are described as follows: (c) Three kinds of molecular properties
are illustrated clearly. X axis: compound name (11–22, 6b, 7b, 8b, to 10b); Y axis: molecular_fractional polar surface area; Z axis: ALogP; the color bar represents
molecular_weight. (d) CDOCKER results. X axis: compound (11–10b); Y axis: -CDOCKER_interaction energy. (e) Their similarities superimposed on the basis of the structure
PD153035. Molecular similarity described above was performed by the Discovery Studio 3.1 suite. The main procedure was like that: all the prepared molecules were drawn
using the ChemBioDraw Ultra 11.0 software, and then were optimized under the MMFF94 Force Field in the ChemBio3D Ultra 11.0 software. Saved in the MOL format, these
molecules were imported into the Discovery Studio 3.1 software for the docking study and those better docking conformations obtained from the docking process were
superposed for aligning to the reference molecule PD153935 to calculate molecular similarity according to the parameter (50% steric field and 50% electrostatic field) by
clicking the molecular overlay option.
designed compounds; (d) the CDOCKER_interaction energies of
these compounds are negative values, and the higher the bar of
compounds are, the better the docking results are. Clearly, com-
pounds 11, 14, 15, 19–21 precede the four positive molecules.
A general synthetic approach was developed to allow for the ra-
pid generation of C4 aniline quinazoline (5 and 6) with amino
group at the 6-position of the quinazoline ring (Scheme 1). 2-Cya-
no-4-nitro-aniline was reacted with N0N-dimethylformamide di-
methyl acetal to afford compound 2. Cyclization of the
intermediate 2 followed by 3-bromaniline or 3-chloraniline in ace-
tic acid and gave compound 3 or 4, respectively. Reduction of 3 or 4
under the same condition composed of Fe/EtOH/AcOH provided 5
or 6, respectively.
The synthetic route to quinazoline analogues (11–14) was
shown in Scheme 2. The starting reactant (S)-1,4-benzodioxane-
2-carboxylic acid or 1,4-benzodioxan-5-carboxylic acid was pre-
pared under thionyl chloride as solvent to give the corresponding
acyl chloride. After chlorination, that adding the 4-aminoquinoline

D.-D. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5870–5875
5873
O2N
CN
N
O2N
CN
HN
X
i
ii
O2N
CH3
N
N
NH2
CH3
3
4
X=Br
X=Cl
N
1
2
iii
HN
N
X
H2N
N
5
6
X=Br
X=Cl
Scheme 1. Synthesis of amides 1–6. Reagents and conditions: (i) Dimethylformamide dimethyl acetal/70–75 °C; (ii) ArNH2/AcOH/70–75 °C; (iii) Fe/AcOH/EtOH/H2O/70–
80 °C.
O
X
O
O
HN
N
O
OH
O
HN
N
X
i/ii
HN
N
O
O
H2N
O
O
or
OH
N
+
11 X=Br
12 X=Cl
5 X=Br
6
X=Cl
O
X
NH
H
N
N
O
O
N
13 X=Br
14 X=Cl
Scheme 2. Synthesis of 4-anilinoquinazolines 11–14. Reagents and conditions: (i) SOCl2/70–80 °C/reflux/4 h; (ii) EtOAC/K2CO3/ice-bath/overnight.
5 or 6 into a solution of acyl chloride and potassium carbonate dis-
solved in ethyl acetate could provide amide analogues 11, 12, 13 or
14 in 50–70% yield. In order to reduce the rigidity of acid amide
bond in the series and increase the diversity of molecule skeleton,
we prepared the molecules (15–22) that displayed in Scheme 3.
The formation of dioxygenated rings started with protocatechual-
dehyde using different sizes of dibromo alkane, and these relative
intermediates could react with above-mentioned 5 or 6 to produce
the target compounds in good yields.
The compounds listed in Table 1 were evaluated for their anti-
proliferative effects in cellular assays using cancer cell lines such as
A431 and MCF-7 that are known to be relative with epidermal
HN
N
X
O
HO
HO
CHO
HN
N
X
CHO
H2N
O
H
N
ii/iii
n
i
N
+
n
O
N
O
7
n=1
n=2
n=3
CMPD
15
X
n
1
1
2
2
3
3
4
4
5 X=Br
8
9
6
X=Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
10 n=4
16
17
18
19
20
21
22
Scheme 3. Synthesis of 4-anilinoquinazolines 15–22. Reagents and conditions: (i) Protocatechualdehyde/(dibromomethane/DMF: 7, 1,2-dibromomethane/acetone: 8, 1,3-
dibromopropane/acetone: 9, 1,4-dibromobutane/acetone: 10)/K2CO3/reflux/70–80 °C/overnight; (ii) 5 or 6/EtOH/40–60 °C/3–4 h; (iii) EtOH/NaBH4/rt/2–3 h.

5874
D.-D. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5870–5875
Table 1
Table 2
Growth inhibition of selected cell lines
EGFR tyrosine kinase inhibition data for 4-anilinoquinazolines
a
Compound
IC50
(
lg/mL)
Compound
EGFR inhibition (IC50 /
a lM)
A431c
A549d
84.05
>100b
MCF-7e
F10f
11
12
13
14
15
16
17
18
19
20
21
22
1.63
1.29
3.68
2.75
0.63
0.57
1.02
0.79
11
12
13
14
15
16
17
18
19
20
21
22
20.33
46.56
42.89
19.87
6.82
59.47
>100b
9.86
50.13
>100b
>100b
73.84
61.23
68.72
16.43
58.32
71.06
15.51
31.04
>100b
52.18
14.47
7.36
10.69
23.15
5.02
3.62
2.07
3.41
12.55
27.98
2.77
11.98
16.33
1.99
0.098
0.216
1.14
2.59
4.28
2.14
0.92
15.04
13.34
2.26
>100
32.06
21.34
3.21
20.62
17.48
1.74
PD153035b
Erlotinibc
Gefitinibc
0.000025
0.0203
0.021
44.81
8.13
9.48
PD153035
Erlotinib
1.87
4.03
0.94
a
IC50 concentration of drug (lM) to inhibit the phosphorylation of a random
a
IC50 concentrations needed to inhibit cell growth by 50% as determined from
the dose–response curve. Determined by three separate experiments and each was
performed in triplicate.
IC50 not determined because less than 50% inhibition was observed at the
highest tested concentration (10 lg/mL). Higher concentrations were not used to
tyrosine/glutamic acid copolymer by EGFR (prepared from human A431 carcinoma
cell vesicles by immunoaffinity chromatography). See experimental section for
details. Values are the averages from at least two independent dose–response
curves; variation was generally 15%.
b
b
Ref. 14.
Ref. 15.
avoid precipitation of the compounds in the culture medium.
c
c
Epidermoid carcinoma cells.
Adenocarcinomic human alveolar basal epithelial cells.
Breast cancer cells.
d
e
f
Melanoma cells.
heptatomic ring derivatives). Compared to three known EGFR
inhibitors (PD153035, Erlotinib and Gefitinib), although the IC50
value of compound 19 against EGFR tyrosine kinase was lower
than the three former, it was still regarded as a promising small
molecule with EGFR inhibition.
Similarly, on the basis of the inhibitory effect on A431 cell pro-
liferation and EGFR tyrosine kinase inhibition, one less active com-
pound 13 and two more active compounds 19 and 20 were
selected for further studies. These three compounds have separate
growth factor family. Meanwhile, to control for non-specific cyto-
toxicity, compounds were evaluated against A549 lung adenocarci-
noma cells (K-Ras dependent) and B16-F10 mouse melanoma cells.
As expected, many compounds were effective against two EGFR-
related cancer cells A431 and MCF-7 while moderate to A549 cells.
Surprisingly, the murine F10 cells were also good targets that be-
long to these quinazoline derivatives. Replacement of the amido
link of the quinazoline nucleus (compounds 11–14) with the rotat-
able bond (–CH2–NH–) in a series of compounds (15–22) did offer
remarkable superiority in terms of cytotoxic effects on the tumor
cell lines tested, although the m-bromoaniline or chloroaniline still
retained at the 4-amino position. The rigid construction of acyla-
mide attaching dioxygenated ring to the quinazoline ring would
form a huge conjugate surface and this may be a main reason for
the loss of cellular activity. Obviously, the remaining compounds
with the rotatable chemical bond (15–22) possessed a certain level
of antiproliferative activities. Focusing on the size of dioxygenated
ring of these novel molecules that could be divided into four clas-
ses: five-membered ring (15 and 16), hexatomic ring (17 and 18),
heptatomic ring (19 and 20), octatomic ring (21 and 22), their bio-
activities were dependent on corresponding oxygen rings. The or-
der of activity could be concluded as follows: heptatomic
ring > five-membered ring > octatomic ring > hexatomic ring. In
accordance with predictions above that compounds 19 and 20
had lower CDOCKER_interaction energy, the experimental data re-
vealed that compound 19 showed potent against A431 and MCF-7
IC50 values of 3.68, 0.098, and 0.216 lM, respectively, for inhibiting
EGFR tyrosine kinase. As expected, after continuous incubation of
A431 cells with drug at a 100 nM concentration and 10 nM concen-
tration followed by EGF stimulation, compound 19 completely
inhibited autophosphorylation of EGFR in A431 cells at 100 nM
concentration, as shown by Western blot analysis (see Fig. 4). As
to 13 and 20, they were just modest to EGFR autophosphorylation,
even if the concentration could increase to 100 nM.
In order to identify the selection inhibition for EGFR tyrosine ki-
nase, compounds 16, 19, and 22 were tested as potential inhibitors
of other two protein kinases relevant to cancer: HER2 and VEGFR2
(see Supplementary data). As expected, the results in Table 3
showed that all the selected compounds (16, 19, and 22) lowered
at least one order of magnitude in the inhibition for HER2 and VEG-
FR2, when compared to EGFR.
A docking study was performed on the most active compound
19 of these compounds to validate the structure–activity relation-
ship (SAR) of similar compounds. As seen in Figure 5, the structures
of 19 had been docked in the crystal structure of inactive EGFR
cells (2.59 and 4.28 lg/mL, respectively), comparable to PD153035
and Erlotinib that had been approved for several years by FDA.
However, Adriana Chilin et al. reported that the dioxane deriva-
tives were more cytotoxic than the corresponding dioxolane and
dioxepine derivatives.11
To assess whether the antiproliferative activity of all the de-
signed compounds could be only due to inhibition of EGFR, the
ability of the compounds to inhibit EGFR phosphorylation was
evaluated using a cell-based ELISA experiment. As shown in
Table 2, almost all the compounds, including compounds 11–14,
showed a visible but not negligible inhibition of EGFR tyrosine ki-
nase, indicating that EGFR should be considered as a main drug tar-
get that belonged to these compounds (particularly in the case of
Figure 4. Inhibition of EGFR autophosphorylation in intact A431 cells. Cells were
incubated with 13, 20, or 19 at two concentrations (100 and 10 nM) and then
stimulated with EGF. Whole cell lysates were Western blotted using antiphosp-
hotyrosine antibody. Compounds 13 and 20 both inhibited EGFR autophosphory-
lation modestly at 100 nM, while compound 19, showed a potent inhibition of the
ability to autophosphorylate EGFR.

D.-D. Li et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5870–5875
5875
Table 3
In summary, the syntheses and biological evaluation of two
classes of fused dioxygenated quinazolines as EGFR inhibitors have
been described. The cytotoxic activities of all the compounds were
assessed against four cancer cell lines. Most derivatives were able
to suppress EGF-induced EGFR phosphorylation and showed com-
parable potency with respect to PD153035 and Erlotinib as positive
control compounds. The size of the fused dioxygenated ring was
crucial for the cytotoxic activity and for the biological profile. In
particular, the heptatomic ring derivative 19 showed an interesting
profile due to its preferential binding to the inactive form of EGFR,
which could be optimized as a potential EGFR inhibitor in the fur-
ther study. Moreover, further studies on other kinases inhibition
ability of this compound are in progress to investigate its potential
dual behavior.
a
Selected kinase inhibition activities IC50 (lM) for compounds 16, 19, and 22
Compound
HER2
VEGFR2
16
19
22
6.5
4.8
>10
>10
>10
>10
a
Values are the averages from at least two independent dose–response curves;
variation was generally 15%.
Acknowledgments
This work was supported by ‘‘PCSIRT’’ (IRT1020) and the Funda-
mental Research Fund for the Central Universities (No.
1092020803).
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.bmcl.2012.07.079.
References and notes
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1995, 19, 183.
4. Kersemaekers, A.-M. F.; Fleuren, G. J.; Kenter, G. G.; Van den Broek, L. J. C. M.;
Uljee, S. M.; Hermans, J.; Van de Vijver, M. J. Clin. Cancer Res. 1999, 5, 577.
5. Mastalerz, H.; Chang, M.; Chen, P.; Fink, B. E.; Gavai, A.; Han, W.-C.; Johnson,
W.; Langley, D.; Lee, F. Y.; Leavitt, K.; Marathe, P.; Norris, D.; Oppenheimer, S.;
Sleczka, B.; Tarrant, J.; Tokarski, J. S.; Vite, G. D.; Vyas, D. M.; Wong, H.; Wong, T.
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Figure 5. The docking results of compound 19 by the CDOCKER algorithm
(Discovery Studio 3.1, Accelrys, Co. Ltd) exhibit: (a) the optimal pose interacts
with the binding site atoms from protein receptor (PDB code: 1M17). Compound 19
could overlap better on the skeleton of the substrate molecule Erlotinib (green) and
three apparent interactions have been displayed: one Pi–cation interaction formed
by residue Lys721 (yellow) and two hydrogen bonds formed by residue Met769
(yellow) and Cys773 (yellow) around compound 19 (their distances are 5.1, 2.3 and
2.5, respectively). (b) The 2D diagram shows clearly the interactions between three
key residues and ligand 19 and other residues in the binding pocket are also
displayed.
9. Bridges, A. J.; Zhou, H.; Cody, D. R.; Rewcastle, G. W.; McMichael, A.; Showalter,
H. D. H.; Fry, D. W.; Kraker, A. J.; Denny, W. A. J. Med. Chem. 1996, 39, 267.
10. Liu, G.; Hu, D.-Y.; Jin, L.-H.; Song, B.-A.; Yang, S.; Liu, P.-S.; Bhadury, P. S.; Ma, Y.;
Luo, H.; Zhou, X. Bioorg. Med. Chem. Lett. 2007, 15, 6608.
11. Chilin, A.; Conconi, M. T.; Marzaro, G.; Guiotto, A.; Urbani, L.; Tonus, F.;
Parnigotto, P. J. Med. Chem. 2010, 53, 1862.
form (PDB ID: 1M17). In this structure, three residues Lys721,
Met769, and Cys773 located in the binding pocket played a vital
role in the conformation of 19, which had been stabilized by one
Pi–cation interaction and two hydrogen bonds (their distances
were 5.1, 2.3 and 2.5 Å, respectively). Besides, the lead compound
was described to stretch up in the binding site to reduce the inter-
action energy.
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