Design, synthesis and preliminary bioactivity evaluations of substituted quinoline hydroxamic acid derivatives as novel histone deacetylase (HDAC) inhibitors

Article abstract of DOI:10.1016/j.bmc.2015.06.024

Inhibition of HDACs activity has become a promising therapeutic strategy in clinical practice to reverse the abnormal epigenetic states of cancer and other diseases. Therefore, HDAC inhibitors become a relatively new class of anti-cancer agent. In the present study, we reported the design and synthesis of a series of novel HDAC inhibitors using various substituted quinoline rings as the cap group. In vitro studies showed that some compounds have good inhibitory activities against HDACs and potent antiproliferative activities in some tumor cell lines. Especially, compound 9w (IC₅₀ = 85 nM), exhibited better inhibitory effect compared with SAHA (IC₅₀ = 161 nM).

Full text of DOI:10.1016/j.bmc.2015.06.024

Accepted Manuscript
Design, synthesis and preliminary bioactivity evaluations of substituted quino-
line hydroxamic acid derivatives as novel histone deacetylase (HDAC) inhibi-
tors
Lei Wang, Xuben Hou, Huansheng Fu, Xiaole Pan, Wenfang Xu, Weiping Tang,
Hao Fang
PII:
S0968-0896(15)00518-0
DOI:
http://dx.doi.org/10.1016/j.bmc.2015.06.024
BMC 12380
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 April 2015
9 June 2015
10 June 2015
Please cite this article as: Wang, L., Hou, X., Fu, H., Pan, X., Xu, W., Tang, W., Fang, H., Design, synthesis and
preliminary bioactivity evaluations of substituted quinoline hydroxamic acid derivatives as novel histone
deacetylase (HDAC) inhibitors, Bioorganic & Medicinal Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.
2015.06.024
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Design, synthesis and preliminary bioactivity evaluations of substituted quinoline
hydroxamic acid derivatives as novel histone deacetylase (HDAC) inhibitors
Lei Wang a, Xuben Houa, Huansheng Fua, Xiaole Pana, Wenfang Xua, Weiping Tang b, Hao Fang a*
a
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of
Pharmacy, Shandong University, Ji’nan, Shandong, 250012, P.R. China
b
School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison 53705, USA
Abstract：
Inhibition of HDACs activity has become a promising therapeutic strategy in
clinical practice to reverse the abnormal epigenetic states of cancer and other diseases.
Therefore, HDAC inhibitors become a relatively new class of anti-cancer agent. In the
present study, we reported the design and synthesis of a series of novel HDAC
inhibitors using various substituted quinoline rings as the cap group. In vitro studies
showed that some compounds have good inhibitory activities against HDACs and
potent antiproliferative activities in some tumor cell lines. Especially, compound 9w
(IC50 = 85 nM), exhibited better inhibitory effect compared with SAHA (IC50 = 161
nM).
Keywords: quinoline; hydroxamic acid; HDAC; inhibitor; anti-proliferative
1. Introduction
The histone acetylation status plays an essential role in initiation and progression
of tumor among the complex epigenetic regulations.[1, 2] The imbalance between
histone acetylation and deacetylation in cells will lead to changes in cell cycle and
metabolism profile, which in turn trigger the formation of tumors.[3] Histone
deacetylases (HDACs) are important enzymes regulating the balance of acetylation
and deacetylation of histones and non-histone proteins, by catalyzing hydrolysis of
ε-amide bond of lysine residues. The overexpression of HDACs suppresses gene
transcription and leads to silencing of tumor suppressor genes.[4] Thus, HDAC
inhibitors (HDACi) have been recognized as a new class of anticancer agents. HDAC
inhibitors have exhibited outstanding anti-tumor activity by enhancing the level of
histone acetylation and inducing cell cycle arrest, differentiation and apoptosis.[5]
To date, three HDAC inhibitors (Vorinostat, Romidepsin and Belinostat) have
approved for the clinical therapy of cutaneous T-cell lymphoma (CTCL) or peripheral
T-cell lymphoma (PTCL) by FDA. Meanwhile, more than 20 promising HDAC
inhibitors are in clinical or pre-clinical studies for the treatment of various cancers.[6]
Generally, the HDAC inhibitors have a common pharmacophore model including a
zinc ion binding group (ZBG), linker and a cap group (Figure 1). The ZBG chelates
zinc ion at the bottom of HDACs active site. The cap group enhances the affinity with
the surface of HDACs and linker connects the ZBG and the cap group.
*
Corresponding author. Phone: +86-531-88382731. Fax: +86-531-88382548. E-mail: haofangcn@sdu.edu.cn.
1

R2
R1
H
H
n
N
N
N
OH
O
O
Cap group
Linker
ZBG
Figure 1 HDAC inhibitor pharmacophore model and the quinoline-based hydroxamic
acid derivative in current study.
Previously, we have used different heterocycles as the surface recognition cap
group in the design of novel HDAC inhibitors, such as tetrahydroisoquinoline[7, 8]
,
1,3,4-thiadiazole[9, 10], 2-dihydrobenzo[d]isothiazol-3-one-1,1-dioxide[11], indole[12, 13]
and purine[14]. In particular, the tetrahydroisoquinoline-bearing hydroxamic acid
analogues showed potent HDAC inhibitory activity in in-vitro biological evaluations
and intriguing growth inhibition in multiple tumor cell lines. Structurally similar to
tetrahydroisoquinoline, heterocycle quinolone could be used as surface recognition
cap and recently Moffat[15] reported one compound containing 6-fluoro quinolone
(CHR-3996) possessed potent HDAC inhibitory activity and antiproliferative
activities. In order to study the further structure-activity relationship, we designed a
series of novel HDAC inhibitors bearing various substituents in the quinoline ring
(Figure 1), and evaluated their inhibitory activities against HDACs.
2. Chemical synthesis
The synthetic route of our novel HDACi is described in Schemes 1-2. Carboxylic
acids 1a-b were coupled with various amines to obtain intermediates 2a-f. The methyl
group of intermediates 2a-f and 3a-e were oxidized to afford 2-formylquinoline
analogs 4a-k. Reduction of 4a-k yielded substituted 2-hydroxymethylquinolines,
which were then reacted with PBr3 to form alkyl bromides 5a-k. Sequential treatment
of 5a-k with NaN3 in DMF and Staudinger reaction gave 6a-k. Compounds 6a-k were
coupled with various acids to obtain intermediates 8a-y, which were converted to
hydroxamic acids 9a-y by treating with hydroxylamine.
To gain more structure diversity, compounds 10a-b were prepared by Suzuki
cross-coupling reaction. Compounds 10a-b were then converted to hydroxamic acids
11a-b by the same method described above.
2

Scheme 1. Reagents and conditions: (a) EDCI, HOBT, Et3N, CH2Cl2, substituted aniline, 0 °C to
rt, overnight; (b) SeO2, 1,4-dixoane, reflux, 1 h; (c) (i) NaBH4, MeOH, rt, 15 min; (ii) PBr3,
CH2Cl2, rt, overnight; (d) (i) NaN3, DMF, rt, overnight; (ii) PPh3, THF, rt, 5 h; (e) EDCI, HOBT,
Et3N, CH2Cl2, 0 °C to RT, overnight; or SOCl2, Et3N, THF, 0 °C to RT, overnight; (f) NH2OH·HCl,
KOH, MeOH, rt, 1 h.
Scheme 2. Reagents and conditions: (g) Pd(OAc)2, PPh3, phenylboronic acid, Na2CO3, toluene,
reflux, overnight; (f) NH2OH·HCl, KOH, MeOH, rt, 1 h.
3. Results and discussion
HDAC enzymatic inhibitory activities of these quinoline hydroxamic acid
derivatives were evaluated using the Color de Lys™ assay (BML-AK501, Enzo® Life
Sciences) including HDAC 1 & 2. The results were calculated and tabulated as IC50
values in Table 1.
According to the data in Table 1, we found that both the linker and the
substituents in quinoline ring played a significant role in the inhibitory activities
against HDACs. For example, the compounds with shorter linker (n = 3-4, e.g. 9a-9b,
9q-9r) or longer linker (n = 6-7, e.g. 9d-9e, 9m-9n) showed poor inhibition on
HDACs. Compounds with the five methylene units linker showed similar or better
enzyme inhibitory activity compared with SAHA, such as, 9c, 9f, 9v, 9w etc. This
3

results may be explained by the fact that suitable length of the linker (n = 5) is helpful
for the ZBG to chelate with the Zn2+ ion located at the bottom of active site of
HDACs.
In addition, the substituents on the C4 and C6-position of quinoline ring also
significantly impact the inhibitory activity. According to the data in Table 1,
substituents on the C4-position of quinoline ring decreased the enzyme inhibitory
activity. For example, compounds 9c, 9f, 9h and 9j (IC50 = 399, 301, 444, 642 nM,
respectively) showed poorer inhibitory activity against HDAC than compound 9s
(IC50 = 266 nM) without C4-substituent. Moreover, the inhibitory activities of
compounds 9l, 9o and 9w also confirmed this conclusion. Interestingly, introducing
different substituent groups to the C6-position of quinoline ring enhanced the
enzymatic inhibitory activity. For instance, compounds 9l and 9o (IC50 = 343 and 196
nM, respectively) showed better inhibitory activities compared with the corresponding
compounds 9c and 9f (IC50 = 399 and 301 nM, respectively) without C6-substituent.
The inhibitory activities of compounds 9s and 9w also proved this conclusion. This
result demonstrated that the C6-substituent was also crucial to binding affinities. On
the other hand, replacement of halogen substituents with a phenyl group (such as 9w
and 11b) resulted in the decrease of enzymatic inhibitory activity, suggesting a
preference for small group on the C6-position as a surface recognition cap group.
Notably, we could find the fact that only suitable length of the linker (n = 5) is
favor, which is helpful for the ZBG to chelate with the Zn2+ ion located at the bottom
of active site of HDACs. Substituents on the C4-position of quinoline ring decreased
the enzyme inhibitory activity obviously. Interestingly, introducing different
substituent groups to the C6-position of quinoline ring enhanced the enzymatic
inhibitory activity, except the bulky substituents. Therefore, we got a potent target
compound 9w (IC50 = 85 nM) which showed better activity than FDA approved drug
SAHA (IC50 = 161 nM) (Figure 2).
Figure 2 Compounds SARs analysis
4

Table1 The chemical structures and HDACs inhibitory activities of quinoline
hydroxamate derivatives
R2
R1
H
H
n
N
N
N
OH
O
O
IC50a of HDACs
(nM)
Compd
R1
R2
n
H
H
-CONHBn
-CONHBn
-CONHBn
-CONHBn
-CONHBn
-CONHPh
-CONHPh
3
4
5
6
7
5
6
5
6
5
6
5
6
7
5
6
3
4
5
6
5
5
5
6
5
5
5
> 1000
> 1000
9a
9b
9c
H
399 26
780 285
> 1000
H
9d
9e
H
H
301 166
562 177
444 40
> 1000
9f
H
9g
H
-CONHBu-n
9h
9i
H
-CONHBu-n
H
-CONHMe
642 237
> 1000
9j
H
-CONHMe
9k
9l
Br
Br
Br
Br
Br
H
-CONHBn
343 86
> 1000
-CONHBn
9m
9n
9o
-CONHBn
> 1000
-CONHPh
196 43
> 1000
-CONHPh
9p
9q
9r
H
> 1000
H
H
> 1000
H
H
266 110
678 332
155 58
120 15
85 32
9s
H
H
9t
F
H
9u
9v
Cl
Br
Br
I
H
H
9w
9x
H
146 31
132 29
341 46
152 43
161 51
H
-CONHBn
H
9y
Ph
Ph
11a
11b
SAHA
a Values are the mean of three independent determinations and expressed with standard deviations.
5

For a better understanding of the interaction between these quinoline based
derivatives and HDAC, the most active compound 9w was docked to the active site of
HDAC2 (PDB code: 4LXZ) using Surflex-dock[16, 17]. The result in Figure 3
suggested that compound 9w could bind to the active site of HDAC2 and there was a
similar binding mode for compound 9w compared with co-crystallized SAHA, which
all chelated Zn2+ ion by hydroxamic acid group. In addition, the amide bond of
compound 9w and SAHA could form hydrogen bond with ASP104 in the active site
of HDAC2.
Figure 3 The molecular binding mode of compound 9w (yellow) and SAHA (green)
in the active site of HDAC2 using Surflex-dock[16, 17]
.
Structurally speaking, suitable length linker (n = 5) is vital for compound 9w to
chelate the Zn2+ at the active site and the cap group of the compound 9w chould
interact with catalytic pocket comfortably. It is reported that the active site is highly
conserved, the rim of the catalytic pocket differ greatly among different HDAC
isozymes. Significantly, variation of amino acid residues region produces a
significantly narrower catalytic pocket in the homology model of HDAC1.
Compounds with a large and rigid cap group could not occupy catalytic region of
HDAC1. [18, 19]Hence, compound 9w exhibited the most potent inhibitory effect.
To further ascertain the activities of these quinoline-based HDAC inhibitors at the
cellular level, three compounds 9v, 9w and 9y were selected to evaluate their
antiproliferative activities in vitro using cancer cell lines of MDA-MB-231 (breast
cancer cell), PC3 (prostatic cancer cell), K562 (chronic myelogenous leukemia cell)
and A549 (lung cancer cell) by MTT assay. The IC50 values were summarized in
Table 2. According to the inhibition data, all tested compounds showed obvious
anti-proliferative activities compared with SAHA. Moreover, MDA-MB-231 was the
most sensitive cell line to our quinoline-based HDAC inhibitors and 9w showed the
better anti-proliferative activity than SAHA. In addition, 9y exhibited most potent
anti-proliferative activities in PC-3, K562 and A549 cell lines.
6

Table 2 Anti-proliferative activities against MDA-MB231, PC3, K562 and A549 cell
lines.
IC50(µM)a
Compd.
MDA-MB-231
1.84 0.11
0.90 0.25
1.41 0.37
2.02 0.30
PC-3
K562
A549
9.13 1.91
9.26 0.50
8.48 1.29
7.30 0.20
3.39 0.38
4.86 1.38
2.45 0.59
3.94 0.39
2.71 0.34
3.89 0.72
2.58 0.31
5.32 1.64
9v
9w
9y
SAHA
a Values are the mean of three independent determinations and expressed with standard deviations.
4. Conclusions
In summary, we designed and synthesized a series of novel HDAC inhibitors with
different length linkers and substituents in quinoline ring as the cap group. Among
them, 9v, 9w and 9y exhibited similar or higher inhibitory activities in both enzymatic
inhibitory activity and cellular anti-proliferative activity assay compared with SAHA.
These results suggest that compound 9w could be used as new lead compound to
develop more potent HDAC inhibitors in the future.
5. Experimental section
5.1. Chemistry: general procedures
Unless mentioned, all start materials, reagents and solvents are analytical reagents
without further purification. All reactions were monitored by thin-layer
chromatography on 0.25 mm silica gel plates (60GF-254) and visualized with UV
light, chloride ferric or iodine vapor. Melting points were determined by the RY-1
electrothermal melting point apparatus without correction. ESI-MS was determined
on an Aglient-1100 series LC/MSD trap spectrometer. 1H-NMR and 13C-NMR spectra
were obtained on a Brucker DRX spectrometer (300 MHz, 400 MHz). The chemical
shifts are defined as δ values (parts per million) relative to TMS as internal standard.
1
Significant H-NMR data are reported in the following order: multiplicity (s, singlet;
d, doublet; t, triplet; m, multiplet) number of protons. HRMS spectrums were
conducted on an Agilent 6510 Quadrupole Time-of-Flight LC/MS deliver.
5.1.1. N-benzyl-2-methylquinoline-4-carboxamide (2a)
To a solution of 1a (0.94 g, 5 mmol) and Et3N (1.3 mL, 10 mmol) in the
anhydrous THF (150 mL) was added isobutyl chloroformate (0.76 mL, 6 mmol)
slowly under the ice baths. After 1 h, benzylamine (0.82 mL, 7.5 mmol) was added.
The mixture was stirred vigorously overnight at room temperature. The resultant
solution was filtered. The filtrate was concentrated, dissolved in dichloromethane
(150 mL), and washed with 10% citric acid (3 × 50 mL), saturated NaHCO3 (3 × 50
mL) and brine (3 × 50 mL), dried over with MgSO4, and the solution was evaporated
under vacuum. The crude product was purified by column chromatography to afford
1
compound 2a (0.86 g, 62%) as a white solid. Mp: 184-186 ºC. H NMR (300 MHz,
DMSO-d6) δ 9.30 (t, J = 5.85 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.1 Hz,
7

1H), 7.75 (t, J = 8.4 Hz, 1H), 7.57 (t, J = 8.25 Hz, 1H), 7.50 (s, 1H), 7.42-7.35 (m,
4H), 7.31-7.27 (m, 1H), 4.56 (d, J = 6 Hz, 2H), 2.69 (s, 3H). ESI-MS m/z: 277.3
[M+H]+.
Compounds 2b-2d were synthesized by the same method described above.
5.1.2. N-phenyl-2-methylquinoline-4-carboxamide (2b)
Yield: 57%, mp: 177-179 ºC. 1H NMR (300 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.09 (d,
J = 7.8 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.80-7.75 (m, 3H), 7.63-7.58 (m, 2H), 7.40
(t, J = 7.95 Hz, 2H), 7.16 (t, J = 7.35 Hz, 1H), 2.73 (s, 3H). ESI-MS m/z: 263.3
[M+H]+.
5.1.3. N-butyl-2-methylquinoline-4-carboxamide (2c)
1
Yield: 71%, mp: 106-108 ºC. H-NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 5.4 Hz,
1H), 8.07 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.74 (t, J = 8.3 Hz, 1H), 7.57
(t, J = 8.2 Hz, 1H), 7.42 (s, 1H), 3.36-3.33 (m, 2H), 2.68 (s, 3H), 1.58-1.52 (m, 2H),
1.43-1.36 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). ESI-MS m/z: 243.5 [M+H]+.
5.1.4. N,2-dimethylquinoline-4-carboxamide (2d)
1
Yield: 66%, mp: 140-142 ºC. H-NMR (300 MHz, DMSO-d6) δ 8.65-8.61 (m, 1H),
8.10 (dd, J1 = 8.1 Hz, J2 = 0.9 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 9 Hz,
1H), 7.56 (t, J = 8.3 Hz, 1H), 7.44 (s, 1H), 2.87 (d, J = 4.5 Hz, 3H), 2.68 (s, 3H).
ESI-MS m/z: 201.4 [M+H]+.
5.1.5. N-benzyl-6-bromo-2-methylquinoline-4-carboxamide (2e)
To a solution of 1b (2.66 g, 10 mmol) and Et3N (2.6 mL, 20 mmol) in the
anhydrous CH2Cl2 (150 mL) under the ice baths was added slowly HOBT (1.62 g, 12
mmol), followed by EDCI (2.30 g, 12 mmol). After 1 h, benzylamine (2.18 mL, 20
mmol) was added. After the night, the solution of CH2Cl2 was washed with 10% citric
acid (3 × 50 mL), saturated NaHCO3 (3 × 50 mL) and brine (3 × 50 mL), dried over
with MgSO4, and the solvent was evaporated under vacuum. The crude product was
purified by column chromatography to afford compound 2e (2.1 g, 59%) as a white
solid. Mp: 198-200 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 9.37 (t, J = 6 Hz, 1H), 8.29
(d, J = 2.1 Hz, 1H), 7.95-7.86 (m, 2H), 7.59 (s, 1H), 7.45-7.36 (m, 4H), 7.32-7.26 (m,
1H), 4.56 (d, J = 6 Hz, 2H), 2.68 (s, 3H). ESI-MS m/z: 356.4 [M+H] +.
Compound 2f was synthesized by the same method described above.
5.1.6. N-phenyl-6-bromo-2-methylquinoline-4-carboxamide (2f)
Yield: 60%, mp: 210-212 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.30 (d,
J = 4 Hz, 1H), 7.99 (d, J = 9 Hz, 1H), 7.93 (m, 1H), 7.80 (d, J = 8 Hz, 2H), 7.74 (s,
1H), 7.41 (t, J = 8 Hz, 2H), 7.17 (t, J = 8 Hz, 1H), 2.73 (s, 3H). ESI-MS m/z: 341.4
[M+H] +.
5.1.7. N-benzyl-2-formylquinoline-4-carboxamide (4a)
The compound 2a (0.55 g, 2 mmol) was dissolved in 1,4-dioxane (50 mL), then
8

SeO2 (0.27 g, 2.4 mmol) was added. The mixed solution was refluxed for 1 h.
Solvent was concentrated and dissolved in the CH2Cl2 (150 mL). The organic layer
was washed with saturated Na2CO3 and brine, dried over anhydrous MgSO4, and the
solution was evaporated under vacuum. The residue was purified by chromatography
on silica gel to give 4a (0.44 g, 76%) as a white solid. Mp: 169-171 ºC. 1H NMR (300
MHz, DMSO-d6) δ 10.16 (s, 1H), 9.50 (t, J = 6 Hz, 1H), 8.29 (t, J = 8.85 Hz, 2H),
8.00-7.95 (m, 2H), 7.86 (t, J = 8.4 Hz, 1H), 7.44-7.37 (m, 4H), 7.35-7.27 (m, 1H),
4.60 (d, J = 6 Hz, 2H). ESI-MS m/z: 291.3 [M+H] +.
Compounds 4b-4k were synthesized by the same method described above.
5.1.8. N-phenyl-2-formylquinoline-4-carboxamide (4b)
1
Yield: 72%, mp: 216-218 ºC, H NMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.20
(s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 8.00 (t, J = 8.4
Hz, 1H), 7.89 (t, J = 8.25 Hz, 1H), 7.81 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 7.95 Hz, 2H),
7.18 (t, J = 7.5 Hz, 1H). ESI-MS m/z: 277.3 [M+H] +.
5.1.9. N-butyl-2-formylquinoline-4-carboxamide (4c)
Yield: 49%, mp: 146-147 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.89 (t,
J = 5.2 Hz, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.95 (t, J = 7.6 Hz,
1H), 7.93 (s, 1H), 7.85 (t, J = 7.6 Hz, 1H), 3.37 (m, 2H), 1.62-1.54 (m, 2H), 1.44-1.35
(m, 2H), 0.94 (t, J = 7.3 Hz, 3H). ESI-MS m/z: 257.4 [M+H] +.
5.1.10. N-methyl-2-formylquinoline-4-carboxamide (4d)
Yield: 69%, mp: 170-172 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.87 (d,
J = 4.5 Hz, 1H), 8.30 (d, J = 7.8 Hz, 2H), 8.00-7.94 (m, 2H), 7.85 (t, J = 8.3 Hz, 1H),
2.90 (d, J = 4.5 Hz, 3H). ESI-MS m/z: 215.5 [M+H] +.
5.1.11. N-benzyl-6-bromo-2-formylquinoline-4-carboxamide (4e)
Yield: 76%, mp: 188-190 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.56 (s,
1H), 8.50 (d, J = 1.8 Hz, 1H), 8.26 (d, J = 9 Hz, 1H), 8.12-8.07 (m, 2H), 7.42-7.30 (m,
5H), 4.59 (d, J = 6 Hz, 2H). ESI-MS m/z: 370.3 [M+H] +.
5.1.12. N-phenyl-6-bromo-2-formylquinoline-4-carboxamide (4f)
1
Yield: 53%, mp: > 250 ºC, H-NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 10.19 (s,
1H), 8.50 (d, J = 2 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.21 (s, 1H), 8.15 (dd, J1 = 8.8
Hz, J2 = 2.2 Hz, 1H), 7.81 (d, J = 8 Hz, 2H), 7.42 (t, J = 8 Hz, 2H), 7.19 (t, J = 8 Hz,
1H). ESI-MS m/z: 356.3 [M+H] +.
5.1.13. Quinoline-2-carbaldehyde (4g)
Yield: 72%, mp: 72-74 ºC. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.64 (d, J
= 8.4 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 8.4 Hz,
1H), 7.93 (t, J = 7.6 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H). ESI-MS m/z: 158.1 [M+H]+.
5.1.14. 6-fluoroquinoline-2-carbaldehyde (4h)
9

Yield: 64%, mp: 122-124 ºC. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.61 (d,
J = 8.8 Hz, 1H), 8.34-8.30 (m, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.99 (dd, J1 = 9.2 Hz, J2
= 2.8 Hz, 1H), 7.88 (td, J1 = 10.4 Hz, J2 = 2.8 Hz, 1H). ESI-MS m/z: 176.2 [M+H]+.
5.1.15. 6-chloroquinoline-2-carbaldehyde (4i)
Yield: 77%, mp: 146-148 ºC. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.60 (d,
J = 8.4 Hz, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 8.4
Hz, 1H), 7.95 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H). ESI-MS m/z: 192.6 [M+H]+.
5.1.16. 6-bromoquinoline-2-carbaldehyde (4j)
Yield: 80%, mp: 162-164 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.61 (d,
J = 8.4 Hz, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.19 (d, J = 9 Hz, 1H), 8.06-8.02 (m, 2H).
ESI-MS m/z: 237.1 [M+H]+.
5.1.17. 6-iodoquinoline-2-carbaldehyde (4k)
Yield: 75%, mp: 180-182 ºC. 1H-NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 8.32 (s,
1H), 8.20 (d, J = 8.5 Hz, 1H), 8.05 (t, J = 9.1 Hz, 2H), 7.96 (d, J = 8.9 Hz, 1H);
ESI-MS m/z: 284.1 [M+H]+.
5.1.18. N-benzyl-2-(bromomethyl)quinoline-4-carboxamide (5a)
NaBH4 (0.1 g, 2.5 mmol) was added partially to a solution of 4a (1.45 g, 5 mmol)
in MeOH (25 mL) at 0 ºC. Then the mixture was stirred at room temperature for 15
min. Then MeOH was evaporated under vacuum to give the crude product
N-benzyl-2-(hydroxymethyl)quinoline-4-carboxamide.
PBr3 (0.24 mL, 2.5 mmol) was added slowly dropwise to a solution of
N-benzyl-2-(hydroxymethyl)quinoline-4-carboxamide (0.73 g, 2.5 mmol) and Et3N
(0.3 mL, 2.5 mmol) in CH2Cl2 (150 mL) under ice-bath. Then the resulting mixture
was stirred overnight at room temperature. The resulting reaction was washed with
brine (50 mL), dried over anhydrous MgSO4, and the solution was evaporated under
1
vacuum to afford 5a as a white solid. Yield: 40%, mp: 196-198 ºC, H-NMR (400
MHz, DMSO-d6) δ 9.38 (t, J = 5.9 Hz, 1H), 8.09-8.05 (m, 2H), 7.83 (t, J = 8.4 Hz,
1H), 7.73 (s, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.43-7.32 (m, 4H), 7.31-7.29 (m, 1H), 4.89
(s, 2H), 4.57 (d, J = 6 Hz, 2H). ESI-MS m/z: 356.2 [M+H]+.
Compounds 5b-5k were synthesized by the same method described above.
5.1.19. N-phenyl-2-(bromomethyl)quinoline-4-carboxamide (5b)
Yield: 51%, mp: 212-214 ºC, 1H-NMR (300 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.11 (d,
J = 8.4 Hz, 2H), 7.89-7.84 (m, 2H), 7.80 (d, J = 7.5 Hz, 2H), 7.74-7.68 (m, 1H), 7.41
(t, J = 7.8 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 4.92 (s, 2H). ESI-MS m/z: 342.2
[M+H]+.
5.1.20. N-butyl-2-(bromomethyl)quinoline-4-carboxamide (5c)
1
Yield: 25%, mp: 139-141 ºC. H-NMR (300 MHz, DMSO-d6) δ 8.80 (t, J = 4.7 Hz,
1H), 8.09-8.04 (m, 2H), 7.86-7.80 (m, 1H), 7.71-7.67 (m, 1H), 7.66 (s, 1H), 4.98 (s,
10

2H), 3.38-3.32 (m, 2H), 1.62-1.52 (m, 2H), 1.47-1.34 (m, 2H), 0.94 (t, J = 7.5 Hz,
3H). ESI-MS m/z: 322.2 [M+H]+.
5.1.21. N-methyl-2-(bromomethyl)quinoline-4-carboxamide (5d)
1
Yield: 60%, mp: 182-184 ºC. H-NMR (300 MHz, DMSO-d6) δ 8.76 (q, J = 4.2 Hz,
1H), 8.11-8.04 (m, 2H), 7.83 (t, J = 8.4 Hz, 1H), 7.70-7.64 (m, 2H), 4.88 (s, 2H), 2.88
(d, J = 4.8 Hz, 3H). ESI-MS m/z: 280.2 [M+H]+.
5.1.22. N-benzyl-6-bromo-2-(bromomethyl)quinoline-4-carboxamide (5e)
1
Yield: 67%, mp: 197-199 ºC. H-NMR (300 MHz, DMSO-d6) δ 9.46 (t, J = 5.7 Hz,
1H), 8.29 (d, J = 2.1 Hz, 1H), 8.04-7.94 (m, 2H), 7.81 (s, 1H), 7.44-7.28 (m, 5H),
4.88 (s, 2H), 4.57 (d, J = 6 Hz, 2H). ESI-MS m/z: 435.1 [M+H]+.
5.1.23. N-phenyl-6-bromo-2-(bromomethyl)quinoline-4-carboxamide (5f)
Yield: 70%, mp: 196-198 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.32 (d,
J = 2 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.02 (dd, J1 = 8.8 Hz, J2 = 2.2 Hz, 1H), 7.96
(s, 1H), 7.80 (d, J = 8 Hz, 2H), 7.42 (t, J = 8 Hz, 2H), 7.18 (t, J = 8 Hz, 1H), 5.02 (s,
2H). ESI-MS m/z: 421.1 [M+H]+.
5.1.24. 2-(bromomethyl)quinoline (5g)
Yield: 45%, mp: 56-58 ºC. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.4 Hz, 1H),
8.07 (d, J = 8.4 Hz, 1H), 7.80 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 7.74-7.70 (m, 1H),
7.57-7.52 (m, 2H), 4.71 (s, 2H); ESI-MS m/z: 223.1 [M+H]+.
5.1.25. 2-(bromomethyl)-6-fluoroquinoline (5h)
Yield: 43%, mp: 75-77 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 8.8 Hz, 1H),
8.04 (dd, J1 = 9.2 Hz, J2 = 5.6 Hz, 1H), 7.80 (dd, J1 = 9.2 Hz, J2 = 2.8 Hz, 1H),
7.74-7.68 (m, 1H), 7.66 (d, J = 2.8 Hz, 1H), 4.74 (s, 2H); ESI-MS m/z: 241.1
[M+H]+.
5.1.26. 2-(bromomethyl)-6-chloroquinoline (5i)
Yield: 60%, mp: 110-112 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.4 Hz,
1H), 8.15 (d, J = 2.4 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H),
7.77-7.72 (m, 1H), 4.87 (s, 2H). ESI-MS m/z: 257.5 [M+H]+.
5.1.27. 6-bromo-2-(bromomethyl)quinoline (5j)
1
Yield: 48%, mp: 144-146 ºC. H-NMR (300 MHz, DMSO-d6) δ 8.42 (d, J = 8.7 Hz,
1H), 8.31 (d, J = 1.8 Hz, 1H), 7.96-7.91 (m, 2H), 7.75 (d, J = 8.7 Hz, 1H), 4.85 (s,
2H). ESI-MS m/z: 302.0 [M+H]+.
5.1.28. 2-(bromomethyl)-6-iodoquinoline (5k)
1
Yield: 50%, mp: 156-158 ºC. H-NMR (300 MHz, DMSO-d6) δ 8.42 (d, J = 8.7 Hz,
1H), 8.31 (d, J = 1.8 Hz, 1H), 7.96-7.91 (m, 2H), 7.75 (d, J = 8.7 Hz, 1H), 4.85 (s,
2H). ESI-MS m/z: 349.0 [M+H]+.
11

5.1.29. 2-(aminomethyl)-N-benzylquinoline-4-carboxamide (6a)
NaN3 (0.65 g, 10 mmol) was added carefully to a solution of 5a (1.78 g, 5 mmol)
in DMF (10 mL). The reaction was stirred overnight at room temperature. The
reaction mixture was extracted with EtOAc/H2O. Then the organic layer was washed
with brine, dried over anhydrous MgSO4, and the solution was evaporated under
vacuum to give the crude product 2-(azidomethyl)-N-benzylquinoline-4-
carboxamide.
PPh3 (1.57 g, 6 mmol) was added to a solution of 2-(azidomethyl)-N-
benzylquinoline-4-carboxamide in TFH/H2O (20 mL, 9:1). Five hours later, the
solution was concentrated under vacuum and the residue was added to 1MHCl (20
mL). The mixture was stirred for 30 min, then the mixture was filtered to get aqueous
phase. The aqueous phase was basified to pH 10 by the NaHCO3, and extracted with
CH2Cl2 (3 × 50 mL). The combined organic layer was washed with brine, dried over
anhydrous MgSO4, and the solution was evaporated under vacuum to give target
compound 6a without purification for next procedure.
Compounds 6b-6k were synthesized by the same method described above.
The general synthesis method for 8a-8y:
Method A:
To a solution of 7a (0.73 g, 5 mmol) and Et3N (1.3 mL, 10 mmol) in the anhydrous
CH2Cl2 (150 mL) was added HOBT (0.81 g, 6 mmol), followed by EDCI (1.15 g, 6
mmol) at 0 ºC. After 1 h, compound 6a (2.19 g, 7.5 mmol) was added, and the
mixture was stirred vigorously overnight at room temperature. The mixture was
washed with 10% citric acid (3 × 80 mL), saturated NaHCO3 (3 × 80 mL) and brine
(3 × 80 mL), dried over with MgSO4, and the solution was evaporated under vacuum
to give the crude product. The crude product was depurated by column
chromatography to afford compound 8a as a white solid.
Method B:
A solution of 7a (0.73 g, 5 mmol) in SOCl2 (4 mL) was refluxed for 1.5 h. The
removal of SOCl2 under reduced pressure yielded orange oil, which was dissolved in
THF (15 mL). The resulting solution was added dropwise to a solution of 6a (2.19 g,
7.5 mmol) and Et3N (1.3 mL, 10 mmol) in THF (100 mL) at 0 °C. The resulting
reaction mixture was stirred overnight at room temperature. The resultant solution
was filtered. The filtrate was concentrated, dissolved in CH2Cl2 (150 mL), and
washed with 10% citric acid (3 × 50 mL), saturated NaHCO3 (3 × 50 mL) and brine
(3 × 50 mL), dried over with MgSO4, and the solution was evaporated under vacuum.
The crude product was purified by column chromatography to afford compound 8a as
a white solid.
5.1.30.
Methyl
5-(((4-(benzylcarbamoyl)quinolin-2-yl)methyl)amino)-5-oxo
pentanoate (8a)
Yield: 62%, mp: 152-154 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 9.31 (t, J = 6 Hz, 1H),
12

8.55 (t, J = 6 Hz, 1H), 8.07 (d, J = 8 Hz, 1H), 8.03 (d, J = 8 Hz, 1H), 7.79 (t, J = 8.2
Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.48 (s, 1H), 7.42-7.29 (m, 5H), 4.57-4.55 (m, 4H),
3.59 (s, 3H), 2.38 (t, J = 7.4 Hz, 2H), 2.26 (t, J = 7.5 Hz, 2H), 1.83-1.80 (m, 2H).
ESI-MS m/z: 420.5 [M+H]+.
5.1.31. Methyl 6-(((4-(benzylcarbamoyl)quinolin-2-yl)methyl)amino)-6-oxo
hexanoate (8b)
Yield: 49%, mp: 122-124 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 9.31 (t, J = 6 Hz, 1H),
8.54 (t, J = 6 Hz, 1H), 8.07 (d, J = 8 Hz, 1H), 8.02 (d, J = 8 Hz, 1H), 7.79 (t, J = 8.2
Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.39-7.36 (m, 4H), 7.31-7.27 (m, 1H),
4.56 (d, J = 6 Hz, 4H), 3.58 (s, 3H), 2.29 (t, J = 7.4 Hz, 2H), 2.22 (t, J = 7.5 Hz, 2H),
1.58-1.52 (m, 4H). ESI-MS m/z: 434.6 [M+H]+.
5.1.32. Methyl 7-(((4-(benzylcarbamoyl)quinolin-2-yl)methyl)amino)-7-oxo
heptanoate (8c)
Yield: 37%, mp: 119-120 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 9.32 (t, J = 6 Hz, 1H),
8.53 (t, J = 6 Hz, 1H), 8.07 (d, J = 8 Hz, 1H), 8.02 (d, J = 8 Hz, 1H), 7.79 (t, J = 8.2
Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.41-7.36 (m, 4H), 7.31-7.27 (m, 1H),
4.56 (d, J = 6 Hz, 4H), 3.58 (s, 3H), 2.29 (t, J = 7.4 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H),
1.58-1.49 (m, 4H), 1.32-1.30 (m, 2H). ESI-MS m/z: 448.5 [M+H]+.
5.1.33. Methyl 8-(((4-(benzylcarbamoyl)quinolin-2-yl)methyl)amino)-8-oxo
octanoate (8d)
Yield: 63%, mp: 150-152 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 9.34 (t, J = 6 Hz, 1H),
8.54 (t, J = 6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.79 (t, J =
8.2 Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.41-7.32 (m, 4H), 7.30-7.26 (m,
1H), 4.55 (d, J = 6 Hz, 4H), 3.57 (s, 3H), 2.28 (t, J = 7.4 Hz, 2H), 2.20 (t, J = 7.5 Hz,
2H), 1.57-1.46 (m, 4H), 1.28-1.26 (m, 4H). ESI-MS m/z: 462.5 [M+H]+.
5.1.34. Methyl 9-(((4-(benzylcarbamoyl)quinolin-2-yl)methyl)amino)-9-oxo
nonanoate (8e)
Yield: 56%, mp: 136-137 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 9.34 (t, J = 6 Hz, 1H),
8.55 (t, J = 6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8 Hz, 1H), 7.79 (t, J =
8.4 Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.48 (s, 1H), 7.42-7.29 (m, 5H), 4.57-4.55 (m,
4H), 3.57 (s, 3H), 2.28 (t, J = 7.4 Hz, 2H), 2.20 (t, J = 7.4 Hz, 2H), 1.56-1.48 (m, 4H),
1.26 (m, 6H). ESI-MS m/z: 476.6 [M+H]+.
5.1.35. Methyl 7-oxo-7-(((4-(phenylcarbamoyl)quinolin-2-yl)methyl)amino)
heptanoate (8f)
Yield: 83%, mp: 120-122 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.57 (t,
J = 6 Hz, 1H), 8.08-8.04 (m, 2H), 7.85-7.76 (m, 3H), 7.65 (t, J = 8.3 Hz, 1H), 7.58 (s,
1H), 7.39 (t, J = 8 Hz, 2H), 7.16 (t, J = 7.5 Hz, 1H), 4.61 (d, J = 6 Hz, 2H), 3.55 (s,
3H), 2.28-2.19 (m, 4H), 1.60-1.47 (m, 4H), 1.33-1.24 (m, 2H). ESI-MS m/z: 434.6
[M+H]+.
13

5.1.36. Methyl 8-oxo-8-(((4-(phenylcarbamoyl)quinolin-2-yl)methyl)amino)
octanoate (8g)
Yield: 35%, mp: 128-130 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.57 (t,
J = 6 Hz, 1H), 8.08-8.04 (m, 2H), 7.85-7.76 (m, 3H), 7.65 (t, J = 8.3 Hz, 1H), 7.58 (s,
1H), 7.39 (t, J = 7.1 Hz, 2H), 7.16 (t, J = 7.5 Hz, 1H), 4.61 (d, J = 6 Hz, 2H), 3.57 (s,
3H), 2.31-2.16 (m, 4H), 1.57-1.43 (m, 4H), 1.27-1.25 (m, 4H). ESI-MS m/z: 448.5
[M+H]+.
5.1.37. Methyl 7-(((4-(butylcarbamoyl)quinolin-2-yl)methyl)amino)-7-oxo
heptanoate (8h)
1
Yield: 40%, mp: 120-122 ºC. H-NMR (300 MHz, DMSO-d6) δ 8.74 (t, J = 5.4 Hz,
1H), 8.54 (t, J = 6 Hz, 1H), 8.02 (t, J = 7.8 Hz, 2H), 7.78 (t, J = 8.4 Hz, 1H), 7.61 (t,
J = 8.3 Hz, 1H), 7.39 (s, 1H), 4.56 (d, J = 6 Hz, 2H), 3.58 (s, 3H), 3.36-3.30 (m, 2H),
2.29 (t, J = 7.4 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H), 1.61-1.53 (m, 6H), 1.51-1.32 (m,
2H), 1.29-1.21 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). ESI-MS m/z: 414.5 [M+H]+.
5.1.38. Methyl 8-(((4-(butylcarbamoyl)quinolin-2-yl)methyl)amino)-8-oxo
octanoate (8i)
1
Yield: 22%, mp: 116-118 ºC. H-NMR (300 MHz, DMSO-d6) δ 8.73 (t, J = 5.6 Hz,
1H), 8.52 (t, J = 5.9 Hz, 1H), 8.02 (t, J = 9 Hz, 2H), 7.78 (t, J = 8.4 Hz, 1H), 7.61 (t,
J = 8.3 Hz, 1H), 7.39 (s, 1H), 4.56 (d, J = 5.7 Hz, 2H), 3.58 (s, 3H), 3.36-3.30 (m,
2H), 2.28 (t, J = 7.4 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H), 1.60-1.44 (m, 6H), 1.42-1.32
(m, 2H), 1.29-1.26 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H). ESI-MS m/z: 428.6 [M+H]+.
5.1.39. Methyl 7-(((4-(methylcarbamoyl)quinolin-2-yl)methyl)amino)-7-oxo
heptanoate (8j)
1
Yield: 58%, mp: 156-158 ºC. H-NMR (300 MHz, DMSO-d6) δ 8.70 (q, J = 4.8 Hz,
1H), 8.53 (t, J = 6 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.78 (t,
J = 7.2 Hz, 1H), 7.61 (t, J = 8.3 Hz, 1H), 7.42 (s, 1H), 4.56 (d, J = 6 Hz, 2H), 3.58 (s,
3H), 2.87 (d, J = 4.5 Hz, 3H), 2.29 (t, J = 7.5 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H),
1.61-1.48 (m, 4H), 1.34-1.24 (m, 2H). ESI-MS m/z: 372.4 [M+H]+.
5.1.40. Methyl 8-(((4-(methylcarbamoyl)quinolin-2-yl)methyl)amino)-8-oxo
octanoate (8k)
1
Yield: 47%, mp: 136-138 ºC. H-NMR (300 MHz, DMSO-d6) δ 8.70 (q, J = 4.8 Hz,
1H), 8.53 (t, J = 6 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.78 (t,
J = 7.2 Hz, 1H), 7.61 (t, J = 8.3 Hz, 1H), 7.41 (s, 1H), 4.56 (d, J = 6 Hz, 2H), 3.58 (s,
3H), 2.86 (d, J = 4.8 Hz, 3H), 2.28 (t, J = 7.5 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H),
1.57-1.47 (m, 4H), 1.33-1.25 (m, 4H). ESI-MS m/z: 386.6 [M+H]+.
5.1.41. Methyl 7-(((4- (benzylcarbamoyl)-6-bromoquinolin-2-yl)methyl)amino)-7-
oxoheptanoate (8l)
Yield: 75%, mp: 150-152 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 9.44 (t, J = 6 Hz, 1H),
14

8.55 (t, J = 6 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 7.99-7.89 (m, 2H), 7.55 (s, 1H),
7.42-7.31 (m, 4H), 7.30-7.27 (m, 1H), 4.57 (d, J = 5.7 Hz, 4H), 3.58 (s, 3H), 2.28 (t, J
= 7.5 Hz, 2H), 2.21 (t, J = 7.5 Hz, 2H), 1.61-1.48 (m, 4H), 1.34-1.23 (m, 2H).
ESI-MS m/z: 527.4 [M+H]+.
5.1.42. Methyl 8-(((4- (benzylcarbamoyl)-6-bromoquinolin-2-yl)methyl)amino)-8-
oxooctanoate (8m)
1
Yield: 43%, mp: 146-148 ºC. H-NMR (400 MHz, DMSO-d6) δ 9.43 (t, J = 5.6 Hz,
1H), 8.55 (t, J = 5.4 Hz, 1H), 8.26 (s, 1H), 7.98-7.92 (m, 2H), 7.55 (s, 1H), 7.40-7.30
(m, 5H), 4.57 (d, J = 5.6 Hz, 4H), 3.58 (s, 3H), 2.28 (t, J = 7.5 Hz, 2H), 2.21 (t, J =
7.5 Hz, 2H), 1.55-1.49 (m, 4H), 1.28 (m, 4H). ESI-MS m/z: 541.5 [M+H]+.
5.1.43. Methyl 9-(((4- (benzylcarbamoyl)-6-bromoquinolin-2-yl)methyl)amino)-9-
oxononanoate (8n)
Yield: 65%, mp: 156-158 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 9.43 (t, J = 6 Hz, 1H),
8.55 (t, J = 5.8 Hz, 1H), 8.25 (d, J = 2 Hz, 1H), 7.98-7.91 (m, 2H), 7.55 (s, 1H),
7.41-7.30 (m, 5H), 4.56 (d, J = 6 Hz, 4H), 3.57 (s, 3H), 2.28 (t, J = 7.4 Hz, 2H), 2.20
(t, J = 7.4 Hz, 2H), 1.56-1.46 (m, 4H), 1.26 (m, 6H). ESI-MS m/z: 555.5 [M+H]+.
5.1.44. Methyl 7-(((6-bromo-4- (phenylcarbamoyl)quinolin-2-yl)methyl)amino)-7-
oxoheptanoate (8o)
Yield: 80%, mp: 162-164 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.58 (t,
J = 6 Hz, 1H), 8.27 (d, J = 2 Hz, 1H), 8.02-7.95 (m, 2H), 7.78 (d, J = 7.6 Hz, 2H),
7.67 (s, 1H), 7.41 (t, J = 8 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 4.60 (d, J = 6 Hz, 2H),
3.57 (s, 3H), 2.28-2.20 (m, 4H), 1.59-1.48 (m, 4H), 1.32-1.24 (m, 2H). ESI-MS m/z:
513.4 [M+H]+.
5.1.45. Methyl 8-(((6-bromo-4- (phenylcarbamoyl)quinolin-2-yl)methyl)amino)-8-
oxooctanoate (8p)
Yield: 67%, mp: 168-170 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.58 (t,
J = 6 Hz, 1H), 8.27 (d, J = 2 Hz, 1H), 8.02-7.95 (m, 2H), 7.78 (d, J = 7.6 Hz, 2H),
7.66 (s, 1H), 7.40 (t, J = 8 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 4.60 (d, J = 6 Hz, 2H),
3.56 (s, 3H), 2.25-2.19 (m, 4H), 1.58-1.44 (m, 4H), 1.27-1.24 (m, 4H). ESI-MS m/z:
527.4 [M+H]+.
5.1.46. Methyl 5-oxo-5- ((quinolin-2-ylmethyl) amino)pentanoate (8q)
1
Yield: 45%, mp: 101-102 ºC. H NMR (300 MHz, DMSO-d6) δ 8.56 (t, J = 5.9 Hz,
1H), 8.35 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.75 (t, J = 7.5 Hz, 1H), 7.57
(t, J = 7.5 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 4.54 (d, J = 6 Hz, 2H), 3.60 (s, 3H), 2.37
(t, J = 7.5 Hz, 2H), 2.25 (t, J = 7.4 Hz, 2H), 1.81 (m, 2H). ESI-MS m/z: 287.3
[M+H]+.
5.1.47. Methyl 6-oxo-6- ((quinolin-2-ylmethyl) amino) hexanoate (8r)
Yield: 15%, mp: 88-90 ºC. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (t, J = 5.9 Hz, 1H),
15

8.34 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.78-7.72 (m, 1H), 7.60-7.55 (m,
1H), 7.45 (d, J = 8.4 Hz, 1H), 4.54 (d, J = 6 Hz, 2H), 3.58 (s, 3H), 2.33 (t, J = 6.9 Hz,
2H), 2.22 (t, J = 6.8 Hz, 2H), 1.56 (m, 4H). ESI-MS m/z: 301.5 [M+H]+.
5.1.48. Methyl 7-oxo-7- ((quinolin-2-ylmethyl) amino) heptanoate (8s)
Yield: 26%, mp: 88-89 ºC. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (t, J = 5.7 Hz, 1H),
8.34 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.78-7.71 (m, 1H), 7.60-7.55 (m,
1H), 7.45 (d, J = 8.4 Hz, 1H), 4.54 (d, J = 6 Hz, 2H), 3.58 (s, 3H), 2.29 (t, J = 7.4 Hz,
2H), 2.20 (t, J = 7.5 Hz, 2H), 1.61-1.49 (m, 4H), 1.34-1.23 (m, 2H). ESI-MS m/z:
315.3 [M+H]+.
5.1.49. Methyl 8-oxo-8- ((quinolin-2-ylmethyl) amino) octanoate (8t)
1
Yield: 61%, mp: 86-88 ºC. H NMR (300 MHz, DMSO-d6) δ 8.53 (t, J = 6 Hz, 1H),
8.34 (d, J = 8.4 Hz, 1H), 7.97-7.94 (m, 2H), 7.78-7.72 (m, 1H), 7.60-7.55 (m, 1H),
7.45 (d, J = 8.4 Hz, 1H), 4.54 (d, J = 6 Hz, 2H), 3.58 (s, 3H), 2.28 (t, J = 7.35 Hz,
2H), 2.20 (t, J = 7.35 Hz, 2H), 1.54-1.49 (m, 4H), 1.30-1.25 (m, 4H). ESI-MS m/z:
329.5 [M+H]+.
5.1.50. Methyl 7- (((6-fluoroquinolin-2-yl)methyl)amino)-7-oxoheptanoate (8u)
1
Yield: 71%, mp: 72-74 ºC. H-NMR (400 MHz, DMSO-d6) δ 8.54 (t, J = 6 Hz, 1H),
8.34 (d, J = 8.8 Hz, 1H), 8.04-8.00 (m, 1H), 7.79 (dd, J1 = 9.6 Hz, J2 = 3.2 Hz, 1H),
7.69 (td, J1 = 8.1 Hz, J2 = 2.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 4.53 (d, J = 6 Hz,
2H), 3.58 (s, 3H), 2.29 (t, J = 7.2 Hz, 2H), 2.20 (t, J = 7.2 Hz, 2H), 1.59-1.50 (m, 4H),
1.32-1.29 (m, 2H). ESI-MS m/z: 333.4 [M+H]+.
5.1.51. Methyl 7- (((6-chloroquinolin-2-yl)methyl)amino)-7-oxoheptanoate (8v)
1
Yield: 92%, mp: 88-90 ºC. H-NMR (300 MHz, DMSO-d6) δ 8.52 (t, J = 6 Hz, 1H),
8.33 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 9 Hz, 1H), 7.77-7.73
(m, 2H), 7.50 (d, J = 8.4 Hz, 1H), 4.53 (d, J = 6 Hz, 2H), 3.58 (s, 3H), 2.29 (t, J = 7.2
Hz, 2H), 2.20 (t, J = 7.2 Hz, 2H), 1.60-1.49 (m, 4H), 1.33-1.17 (m, 2H). ESI-MS m/z:
349.9 [M+H]+.
5.1.52. Methyl 7- (((6-bromoquinolin-2-yl)methyl)amino)-7-oxoheptanoate (8w)
Yield: 50%, mp: 92-94 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 8.52 (t, J = 5.9 Hz, 1H),
8.33 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 1.8 Hz, 1H), 7.92-7.84 (m, 2H), 7.49 (d, J = 8.7
Hz, 1H), 4.52 (d, J = 5.7 Hz, 2H), 3.58 (s, 3H), 2.29 (t, J = 7.5 Hz, 2H), 2.20 (t, J =
7.5 Hz, 2H), 1.60-1.49 (m, 4H), 1.33-1.24 (m, 2H). ESI-MS m/z: 394.3 [M+H]+.
5.1.53. Methyl 8- (((6-bromoquinolin-2-yl)methyl)amino)-8-oxooctanoate (8x)
1
Yield: 43%, mp: 104-106 ºC. H-NMR (300 MHz, DMSO-d6) δ 8.53 (t, J = 5.9 Hz,
1H), 8.33 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 1.8 Hz, 1H), 7.92-7.84 (m, 2H), 7.50 (d, J
= 8.7 Hz, 1H), 4.53 (d, J = 6 Hz, 2H), 3.58 (s, 3H), 2.28 (t, J = 7.5 Hz, 2H), 2.20 (t, J
= 7.5 Hz, 2H), 1.54-1.49 (m, 4H), 1.30-1.26 (m, 4H). ESI-MS m/z: 408.3 [M+H]+.
16

5.1.54. Methyl 7- (((6-iodoquinolin-2-yl)methyl)amino)-7-oxoheptanoate (8y)
1
Yield: 86%, mp: 79-80 ºC. H-NMR (300 MHz, DMSO-d6) δ 8.53 (t, J = 6 Hz, 1H),
8.43 (d, J = 1.8 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.00 (dd, J1 = 9 Hz, J2 = 1.8 Hz,
1H), 7.75 (d, J = 9 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 4.52 (d, J = 6 Hz, 2H), 3.58 (s,
3H), 2.29 (t, J = 7.2 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H), 1.60-1.47 (m, 4H), 1.33-1.23
(m, 2H). ESI-MS m/z: 441.4 [M+H]+.
5.1.55. N1-((4-(benzylcarbamoyl)quinolin-2-yl)methyl)-N5-hydroxyglutaramide
(9a)
Preparation of hydroxylamine in methanol:
To a solution of hydroxylamine hydrochloride (4.67 g, 67 mmol) in methanol (24
mL) at 0 °C was added slowly dropwise potassium hydroxide (6.60 g, 100 mmol) in
methanol (14 mL). The reaction mixture was stirred at 0 °C for 0.5 h and filtered to
give a solution of hydroxylamine in methanol.
Compound 8a (0.32 g, 0.77 mmol) was dissolved in the solution of
hydroxylamine in methanol (8 mL), and then the reaction mixture was stirred at room
temperature for 1 h. The mixture was acidified with 2M HCl to pH 7. The mixture
was filtrated to give a residue and purified by chromatography on silica gel to give 9a
1
(0.15 g, 47%) as a white solid. Mp: 174-175 ºC. H-NMR (300 MHz, DMSO-d6) δ
10.34 (s, 1H), 9.33 (t, J = 6 Hz, 1H), 8.69 (s, 1H), 8.53 (t, J = 6 Hz, 1H), 8.07-8.00
(m, 2H), 7.80 (t, J = 8.2 Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.48 (s, 1H), 7.42-7.32 (m,
4H), 7.30-7.26 (m, 1H), 4.57 (d, J = 6 Hz, 4H), 2.24 (t, J = 7.5 Hz, 2H), 2.00 (t, J =
7.5 Hz, 2H), 1.83-1.73 (m, 2H); 13C-NMR (100 MHz, DMSO-d6) δ 172.1, 168.8,
166.7, 159.2, 147.2, 142.8, 139.1, 129.9, 128.8, 128.4, 127.3, 127.0, 126.8, 125.2,
123.2, 117.3, 44.7, 42.6, 34.7, 31.8, 21.4; HRMS (AP-ESI) m/z calcd for C23H24N4O4
[M+H]+ 421.1870, found: 421.1867.
Compounds 9b-9y and 11a-11b were synthesized by the same method described
above.
5.1.56. N1-((4-(benzylcarbamoyl)quinolin-2-yl)methyl)-N6-hydroxyadipamide(9b)
1
Yield: 73%, mp: 178-180 ºC. H-NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H),
9.32 (t, J = 5.7 Hz, 1H), 8.65 (s, 1H), 8.53 (t, J = 6 Hz, 1H), 8.04 (t, J = 9 Hz, 2H),
7.80 (t, J = 8.2 Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.48 (s, 1H), 7.42-7.32 (m, 4H),
7.30-7.26 (m, 1H), 4.57 (d, J = 6 Hz, 4H), 2.21 (t, J = 7.5 Hz, 2H), 1.96 (t, J = 7.5 Hz,
2H), 1.60-1.45 (m, 4H); 13C-NMR (100 MHz, DMSO-d6) δ 172.4, 169.0, 166.8, 159.2,
147.2, 142.8, 139.1, 129.9, 128.9, 128.4, 127.3, 126.9, 126.8, 125.2, 123.2, 117.3,
44.7, 42.6, 35.1, 32.1, 24.9, 24.8; HRMS (AP-ESI) m/z calcd for C24H26N4O4 [M+H]+
435.2027, found: 435.2024.
5.1.57. N1-((4- (benzylcarbamoyl)quinolin-2-yl)methyl)-N7-hydroxy
heptanediamide (9c)
Yield: 83%, mp: 162-164 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.33 (t,
J = 6 Hz, 1H), 8.64 (s, 1H), 8.53 (t, J = 6 Hz, 1H), 8.07-8.00 (m, 2H), 7.80 (t, J = 8.2
Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.41-7.32 (m, 4H), 7.30-7.26 (m, 1H),
17

4.57 (d, J = 6 Hz, 4H), 2.20 (t, J = 7.5 Hz, 2H), 1.93 (t, J = 7.5 Hz, 2H), 1.60-1.45 (m,
4H), 1.31-1.21 (m, 2H); 13C-NMR (100 MHz, DMSO-d6) δ 172.5, 169.1, 166.7, 159.3,
147.2, 142.8, 139.1, 129.9, 128.8, 128.4, 127.3, 126.9, 126.8, 125.2, 123.2, 117.3,
44.7, 42.6, 35.2, 32.1, 28.3, 24.9, 24.9; HRMS (AP-ESI) m/z calcd for C25H28N4O4
[M+H]+ 449.2183, found: 449.2190.
5.1.58. N1-((4-(benzylcarbamoyl)quinolin-2-yl)methyl)-N8-hydroxy
octanediamide (9d)
Yield: 67%, mp: 150-152 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.33 (t,
J = 6 Hz, 1H), 8.53 (t, J = 6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 7.8 Hz,
1H), 7.79 (t, J = 8.2 Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.41-7.32 (m, 4H),
7.30-7.26 (m, 1H), 4.57 (d, J = 5.7 Hz, 4H), 2.20 (t, J = 7.5 Hz, 2H), 1.93 (t, J = 7.5
Hz, 2H), 1.57-1.45 (m, 4H), 1.27-1.26 (m, 4H); 13C-NMR (100 MHz, DMSO-d6) δ
172.5, 169.1, 166.7, 159.3, 147.1, 142.9, 139.1, 129.9, 128.8, 128.4, 127.3, 126.9,
126.8, 125.2, 123.2, 117.3, 44.6, 42.6, 35.3, 32.2, 28.4, 28.4, 25.2, 25.0; HRMS
(AP-ESI) m/z calcd for C26H30N4O4 [M+H]+ 463.2340, found: 463.2344.
5.1.59. N1-((4-(benzylcarbamoyl)quinolin-2-yl)methyl)-N9-hydroxy
nonanediamide (9e)
Yield: 73%, mp: 136-137 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.34 (t,
J = 6 Hz, 1H), 8.65 (s, 1H), 8.54 (t, J = 6 Hz, 1H), 8.06-8.00 (m, 2H), 7.79 (t, J = 6.8
Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.47 (s, 1H), 7.41-7.31 (m, 5H), 4.56 (d, J = 5.6 Hz,
4H), 2.20 (t, J = 7.2 Hz, 2H), 1.93 (t, J = 7.2 Hz, 2H), 1.56-1.43 (m, 4H), 1.29-1.22
(m, 6H); 13C-NMR (100 MHz, DMSO-d6) δ 172.6, 169.1, 166.8, 159.3, 147.2, 142.8,
139.1, 129.9, 128.8, 128.4, 127.3, 126.9, 126.8, 125.2, 123.2, 117.3, 44.7, 42.6, 35.3,
32.2, 28.6, 28.5, 28.5, 25.2, 25.1; HRMS (AP-ESI) m/z calcd for C27H32N4O4
[M+H]+ 477.2496, found: 477.2502.
5.1.60. N1-hydroxy-N7-((4-(phenylcarbamoyl)quinolin-2-yl)methyl)
heptanediamide (9f)
1
Yield: 49%, mp: 164-166 ºC. H-NMR (300 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.32
(s, 1H), 8.57 (s, 1H), 8.09-8.04 (m, 2H), 7.85-7.78 (m, 3H), 7.67-7.59 (m, 2H), 7.39 (t,
J = 7.8 Hz, 2H), 7.16 (t, J = 7.5 Hz, 1H), 4.61 (d, J = 6 Hz, 2H), 2.22 (t, J = 7.5 Hz,
13
2H), 1.94 (t, J = 7.5 Hz, 2H), 1.57-1.47 (m, 4H), 1.27 (m, 2H); C-NMR (100 MHz,
DMSO-d6) δ 172.6, 169.1, 165.4, 159.4, 147.3, 142.8, 138.7, 130.1, 128.9, 128.9,
127.1, 125.1, 124.2, 123.0, 119.9, 117.4, 44.7, 35.2, 32.2, 28.3, 24.9, 24.9; HRMS
(AP-ESI) m/z calcd for C24H26N4O4 [M+H]+ 435.2027, found: 435.2036.
5.1.61.N1-hydroxy-N8-((4- (phenylcarbamoyl)quinolin-2-yl)methyl)octanediamide
(9g)
Yield: 40%, mp: 176-178 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.30
(s, 1H), 8.63 (s, 1H), 8.55 (t, J = 6 Hz, 1H), 8.08-8.04 (m, 2H), 7.85-7.76 (m, 3H),
7.67 (t, J = 8.3 Hz, 1H), 7.58 (s, 1H), 7.40 (t, J = 8.0 Hz, 2H), 7.16 (t, J = 7.5 Hz,
1H), 4.61 (d, J = 6 Hz, 2H), 2.21 (t, J = 7.5 Hz, 2H), 1.90 (t, J = 7.5 Hz, 2H),
18

1.57-1.41 (m, 4H), 1.25-1.24 (m, 4H); 13C-NMR (100 MHz, DMSO-d6) δ 172.6,
169.1, 165.4, 159.4, 147.2, 142.8, 138.7, 130.1, 128.9, 128.8, 127.1, 125.0, 124.1,
123.0, 119.9, 117.3, 44.7, 35.3, 32.2, 28.4, 28.4, 25.2, 24.9; HRMS (AP-ESI) m/z
calcd for C25H28N4O4 [M+H]+ 449.2183, found: 449.2189.
5.1.62.N1-((4- (butylcarbamoyl)quinolin-2-yl)methyl)-N7-hydroxyheptanediamide
(9h)
Yield: 88%, mp: 170-172 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.75 (t,
J = 5.6 Hz, 1H), 8.64 (s, 1H), 8.53 (t, J = 6 Hz, 1H), 8.04 (t, J = 8.4 Hz, 2H), 7.79 (t,
J = 8.2 Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.39 (s, 1H), 4.56 (d, J = 5.7 Hz, 2H),
3.37-3.31 (m, 2H), 2.20 (t, J = 7.5 Hz, 2H), 1.94 (t, J = 7.5 Hz, 2H), 1.60-1.50 (m,
6H), 1.40-1.32 (m, 2H), 1.27-1.26 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H). 13C-NMR (100
MHz, DMSO-d6) δ 172.5, 169.0, 166.6, 159.3, 147.2, 143.4, 129.9, 128.8, 126.7,
125.2, 123.2, 117.1, 44.7, 38.7, 35.2, 32.1, 31.0, 28.3, 24.9, 24.9, 19.6, 13.7; HRMS
(AP-ESI) m/z calcd for C22H30N4O4 [M+H]+ 415.2340, found: 415.2334.
5.1.63. N1-((4-(butylcarbamoyl)quinolin-2-yl)methyl)-N8-hydroxyoctanediamide
(9i)
Yield: 56%, mp: 158-160 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.75 (t,
J = 5.7 Hz, 1H), 8.65 (s, 1H), 8.54 (t, J = 6 Hz, 1H), 8.02 (d, J = 7.7 Hz, 2H), 7.79 (t,
J = 8.2 Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.39 (s, 1H), 4.56 (d, J = 6 Hz, 2H),
3.36-3.31 (m, 2H), 2.20 (t, J = 7.5 Hz, 2H), 1.93 (t, J = 7.5 Hz, 2H), 1.60-1.50 (m,
6H), 1.40-1.32 (m, 2H), 1.27-1.26 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H); 13C-NMR (100
MHz, DMSO-d6) δ 172.5, 169.1, 166.6, 159.3, 147.2, 143.3, 129.9, 128.8, 126.7,
125.2, 123.2, 117.1, 44.7, 38.7, 35.3, 32.2, 31.0, 28.4, 25.2, 24.9, 19.6, 13.7; HRMS
(AP-ESI) m/z calcd for C23H32N4O4 [M+H]+ 429.2496, found: 429.2487.
5.1.64. N1-hydroxy-N7-((4- (methylcarbamoyl)quinolin-2-yl)methyl)
heptanediamide (9j)
Yield: 57%, mp: 154-156 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.71 (q,
J = 4.2 Hz, 1H), 8.54 (t, J = 5.7 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 8.02 (d, J = 8.4 Hz,
1H), 7.78 (t, J = 8.4 Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.42 (s, 1H), 4.56 (d, J = 6 Hz,
2H), 2.87 (d, J = 4.5 Hz, 3H), 2.20 (t, J = 7.5 Hz, 2H), 1.94 (t, J = 7.5 Hz, 2H),
1.57-1.45 (m, 4H), 1.37-1.24 (m, 2H); 13C-NMR (100 MHz, DMSO-d6) δ 172.5,
169.1, 167.1, 159.2, 147.2, 143.1, 129.9, 128.8, 126.7, 125.3, 123.2, 117.2, 44.7, 35.2,
32.2, 28.3, 26.0, 24.9, 24.9; HRMS (AP-ESI) m/z calcd for C19H24N4O4 [M+H]+
373.1870, found: 373.1867.
5.1.65. N1-hydroxy-N8-((4-(methylcarbamoyl)quinolin-2-yl)methyl)
octanediamide (9k)
Yield: 50%, mp: 160-162 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.70 (q,
J = 4.5 Hz, 1H), 8.64 (s, 1H), 8.52 (t, J = 6 Hz, 1H), 8.08 (d, J = 7.2 Hz, 1H), 8.02 (d,
J = 8.1 Hz, 1H), 7.78 (t, J = 8.4 Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.42 (s, 1H), 4.56
(d, J = 6 Hz, 2H), 2.87 (d, J = 4.5 Hz, 3H), 2.20 (t, J = 7.5 Hz, 2H), 1.93 (t, J = 7.5
19

Hz, 2H), 1.57-1.43 (m, 4H), 1.27-1.25 (m, 4H); 13C-NMR (100 MHz, DMSO-d6) δ
172.5, 169.1, 167.1, 159.3, 147.2, 143.1, 129.9, 128.8, 126.7, 125.3, 123.2, 117.2,
44.7, 35.3, 32.2, 28.4, 26.0, 25.1, 25.0; HRMS (AP-ESI) m/z calcd for C20H26N4O4
[M+H]+ 387.2027, found: 387.2033.
5.1.66. N1-((4-(benzylcarbamoyl)-6-bromoquinolin-2-yl)methyl)-N7-hydroxy
heptanediamide (9l)
Yield: 37%, mp: 174-176 ºC. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.47 (t,
J = 6 Hz, 1H), 8.59 (t, J = 6 Hz, 1H), 8.26 (d, J = 2 Hz, 1H), 7.99-7.91 (m, 2H), 7.56
(s, 1H), 7.43-7.29 (m, 5H), 4.57 (d, J = 5.6 Hz, 4H), 2.21 (t, J = 7.2 Hz, 2H), 1.94 (t,
J = 7.2 Hz, 2H), 1.57-1.46 (m, 4H), 1.30-1.24 (m, 2H); 13C-NMR (100 MHz,
DMSO-d6) δ 172.6, 169.1, 166.2, 160.1, 145.9, 141.5, 138.9, 133.0, 131.1, 128.5,
127.4, 127.3, 127.1, 124.5, 120.0, 118.5, 44.7, 42.7, 35.2, 32.2, 28.3, 24.9, 24.9;
HRMS (AP-ESI) m/z calcd for C25H27BrN4O4 [M+H]+ 527.1288, found: 527.1296.
5.1.67. N1-((4-(benzylcarbamoyl)-6-bromoquinolin-2-yl)methyl)-N8-hydroxy
octanediamide (9m)
Yield: 70%, mp: 136-138 ºC. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.54 (t,
J = 6 Hz, 1H), 8.66 (t, J = 5.6 Hz, 1H), 8.27 (d, J = 2 Hz, 1H), 8.00-7.93 (m, 2H),
7.60 (s, 1H), 7.42-7.29 (m, 5H), 4.57-4.55 (m, 4H), 2.22 (t, J = 7.2 Hz, 2H), 1.95 (t, J
= 7.2 Hz, 2H), 1.56-1.46 (m, 4H), 1.29-1.22 (m, 4H); 13C-NMR (100 MHz, DMSO-d6)
δ 172.7, 169.1, 166.1, 160.1, 145.6, 141.5, 138.9, 133.1, 130.8, 128.4, 127.4, 127.2,
127.0, 124.5, 120.0, 118.5, 44.5, 42.6, 35.2, 32.2, 28.4, 28.3, 25.1, 24.9; HRMS
(AP-ESI) m/z calcd for C26H29BrN4O4 [M+H]+ 541.1445, found: 541.1435.
5.1.68. N1-((4-(benzylcarbamoyl)-6-bromoquinolin-2-yl)methyl)-N9-hydroxy
nonanediamide (9n)
Yield: 91%, mp: 162-164 ºC. 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.44 (t,
J = 6 Hz, 1H), 8.66 (s, 1H), 8.55 (t, J = 5.6 Hz, 1H), 8.25 (d, J = 2 Hz, 1H), 7.98-7.92
(m, 2H), 7.54 (s, 1H), 7.41-7.31 (m, 5H), 4.56-4.55 (m, 4H), 2.20 (t, J = 7.2 Hz, 2H),
1.93 (t, J = 7.2 Hz, 2H), 1.56-1.45 (m, 4H), 1.29-1.22 (m, 6H); 13C-NMR (100 MHz,
DMSO-d6) δ 172.6, 169.1, 166.1, 160.1, 145.9, 141.5, 138.9, 132.9, 131.1, 128.4,
127.4, 127.2, 127.0, 124.5, 119.9, 118.4, 44.6, 42.7, 35.3, 32.3, 28.6, 28.5, 28.5, 25.2,
25.1; HRMS (AP-ESI) m/z calcd for C27H31BrN4O4 [M+H]+ 555.1601, found:
555.1608.
5.1.69. N1-((6-bromo-4-(phenylcarbamoyl)quinolin-2-yl)methyl)-N7-hydroxy
heptanediamide (9o)
Yield: 92%, mp: 174-176 ºC. 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.35
(s, 1H), 8.67 (s, 1H), 8.62 (t, J = 5.6 Hz, 1H), 8.29 (d, J = 2 Hz, 1H), 8.03-7.95 (m,
2H), 7.80 (d, J = 7.6 Hz, 2H), 7.70 (s, 1H), 7.41 (t, J = 8 Hz, 2H), 7.18 (t, J = 7.6 Hz,
1H), 4.60 (d, J = 6 Hz, 2H), 2.22 (t, J = 7.2 Hz, 2H), 1.93 (t, J = 7.2 Hz, 2H),
1.58-1.45 (m, 4H), 1.30-1.22 (m, 2H); 13C-NMR (100 MHz, DMSO-d6) δ 172.7,
169.1, 164.8, 160.2, 145.9, 141.3, 138.6, 133.1, 131.2, 128.8, 127.1, 124.3, 120.2,
20

120.1, 118.8, 44.7, 35.2, 32.2, 28.3, 24.9, 24.9; HRMS (AP-ESI) m/z calcd for
C24H25BrN4O4 [M+H]+ 513.1132, found: 513.1132.
5.1.70. N1-((6-bromo-4-(phenylcarbamoyl)quinolin-2-yl)methyl)-N8-hydroxy
octanediamide (9p)
Yield: 93%, mp: 170-172 ºC. 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.36
(s, 1H), 8.62 (t, J = 6 Hz, 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.03-7.95 (m, 2H), 7.80 (d, J
= 7.6 Hz, 2H), 7.69 (s, 1H), 7.41 (t, J = 8 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 4.61 (d, J
= 5.6 Hz, 2H), 2.22 (t, J = 7.2 Hz, 2H), 1.91 (t, J = 7.2 Hz, 2H), 1.56-1.44 (m, 4H),
1.28-1.22 (m, 4H); 13C-NMR (100 MHz, DMSO-d6) δ 172.7, 169.1, 164.7, 160.2,
145.9, 141.4, 138.6, 133.2, 131.2, 128.9, 127.1, 124.3, 120.2, 120.1, 118.7, 44.7, 35.3,
32.2, 28.4, 28.4, 25.1, 24.9; HRMS (AP-ESI) m/z calcd for C25H27BrN4O4 [M+H]+
527.1288, found: 527.1281.
5.1.71. N1-hydroxy-N5-(quinolin-2-ylmethyl)glutaramide (9q)
Yield: 85%, mp: 178-180 ºC. 1H NMR (300 MHz, DMSO-d6) δ 10.40 (d, J = 1.2 Hz,
1H), 8.71 (d, J = 1.5 Hz, 1H), 8.56 (t, J = 5.85 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H),
7.98-7.94 (m, 2H), 7.78-7.72 (m, 1H), 7.60-7.55 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H),
4.54 (d, J = 6 Hz, 2H), 2.21 (t, J = 7.35 Hz, 2H), 2.00 (t, J = 7.5 Hz, 2H), 1.82-1.72
(m, 2H); 13C-NMR (100 MHz, DMSO-d6) δ 172.0, 168.8, 159.5, 146.9, 136.7, 129.6,
128.3, 127.8, 126.9, 126.1, 119.6, 44.8, 34.7, 31.8, 21.5; HRMS (AP-ESI) m/z calcd
for C15H17N3O3 [M+H]+ 288.1343, found: 288.1341.
5.1.72. N1-hydroxy-N6-(quinolin-2-ylmethyl)adipamide (9r)
Yield: 44%, mp: 162-164 ºC. 1H NMR (300 MHz, DMSO-d6) δ10.36 (s, 1H), 8.73 (s,
1H), 8.56 (t, J = 5.85 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.98-7.94 (m, 2H), 7.78-7.72
(m, 1H), 7.60-7.55 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 4.54 (d, J = 6 Hz, 2H), 2.20 (t, J
= 7.35 Hz, 2H), 1.96 (t, J = 6.6 Hz, 2H), 1.53-1.51 (m, 4H); 13C-NMR (100 MHz,
DMSO-d6) δ 172.4, 168.9, 159.5, 146.9, 136.6, 129.6, 128.4, 127.8, 126.8, 126.1,
119.6, 44.8, 35.1, 32.1, 24.9, 24.9; HRMS (AP-ESI) m/z calcd for C16H19N3O3
[M+H]+ 302.1499, found: 302.1500.
5.1.73. N1-hydroxy-N7-(quinolin-2-ylmethyl)heptanediamide (9s)
Yield: 64%, mp: 156-158 ºC. 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.69 (d,
J = 1.2 Hz, 1H), 8.55 (t, J = 5.85 Hz, 1H), 8.35 (d, J = 8.7 Hz, 1H), 7.97-7.94 (m,
2H), 7.75 (t, J = 7.5 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 4.53
(d, J = 6 Hz, 2H), 2.20 (t, J = 7.35 Hz, 2H), 1.94 (t, J = 7.2 Hz, 2H), 1.59-1.45 (m,
4H), 1.30-1.20 (m, 2H); 13C-NMR (100 MHz, DMSO-d6) δ 172.5, 169.1, 159.6, 146.7,
136.9, 129.7, 128.2, 127.8, 126.9, 126.1, 119.6, 44.7, 35.2, 32.1, 28.3, 25.0, 24.9;
HRMS (AP-ESI) m/z calcd for C17H21N3O3 [M+H]+ 316.1656, found: 316.1659.
5.1.74. N1-hydroxy-N8-(quinolin-2-ylmethyl)octanediamide (9t)
Yield: 61%, mp: 134-136 ºC. 1H NMR (300 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.67 (s,
1H), 8.54 (t, J = 5.85 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 7.98-7.95 (m, 2H), 7.79 (td,
21

J1 = 8.4 Hz, J2 = 1.5 Hz, 1H), 7.61-7.56 (m, 1H), 7.46 (d, J = 8.4 Hz, 1H), 4.54 (d, J
= 6 Hz, 2H), 2.20 (t, J = 7.35 Hz, 2H), 1.94 (t, J = 7.2 Hz, 2H), 1.57-1.43 (m, 4H),
1.27-1.25 (m, 4H); 13C-NMR (100 MHz, DMSO-d6) δ 172.6, 169.1, 159.5, 145.9,
137.6, 130.1, 127.9, 127.5, 126.9, 126.4, 119.7, 44.4, 35.3, 32.2, 28.4, 28.4, 25.1, 25.0;
HRMS (AP-ESI) m/z calcd for C18H23N3O3 [M+H]+ 330.1812, found: 330.1819.
5.1.75. N1-((6-fluoroquinolin-2-yl)methyl)-N7-hydroxyheptanediamide (9u)
Yield: 86%, mp: 181-182 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.67 (d,
J = 1.5 Hz, 1H), 8.52 (t, J = 6 Hz, 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.05-8.00 (m, 1H),
7.78 (dd, J1 = 9.3 Hz, J2 = 3 Hz, 1H), 7.67 (td, J1 = 10.5 Hz, J2 = 3 Hz, 1H), 7.48 (d, J
= 8.7 Hz, 1H), 4.53 (d, J = 6 Hz, 2H), 2.19 (t, J = 7.2 Hz, 2H), 1.94 (t, J = 7.2 Hz,
2H), 1.59-1.45 (m, 4H), 1.30-1.20 (m, 2H); 13C-NMR (100 MHz, DMSO-d6) δ 172.5,
169.2, 159.4 (d, J = 243.1 Hz), 159.2 (d, J = 26 Hz), 144.1, 136.3, 136.2, 131.1 (d, J
= 9.2 Hz), 127.5 (d, J = 10.3 Hz), 120.4, 119.5 (d, J = 25.6 Hz), 110.9 (d, J = 21.6
Hz), 44.7, 35.2, 32.2, 28.3, 25.0, 24.9; HRMS (AP-ESI) m/z calcd for C17H20FN3O3
[M+H]+ 334.1561, found: 334.1553.
5.1.76. N1-((6-chloroquinolin-2-yl)methyl)-N7-hydroxyheptanediamide (9v)
Yield: 84%, mp: 179-180 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.67 (s,
1H), 8.53 (t, J = 6 Hz, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.99 (d,
J = 9 Hz, 1H), 7.78 (dd, J1 = 9 Hz, J2 = 2.4 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 4.53 (d,
J = 5.7 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H), 1.94 (t, J = 7.5 Hz, 2H), 1.59-1.45 (m, 4H),
1.30-1.21 (m, 2H); 13C-NMR (100 MHz, DMSO-d6) δ 172.6, 169.1, 160.3, 145.4,
136.0, 130.5, 130.4, 130.1, 127.6, 126.5, 120.6, 44.8, 35.2, 32.2, 28.3, 25.0, 24.9;
HRMS (AP-ESI) m/z calcd for C17H20ClN3O3 [M+H]+350.1266, found: 350.1262.
5.1.77. N1-((6-bromoquinolin-2-yl)methyl)-N7-hydroxyheptanediamide (9w)
Yield: 90%, mp: 180-182 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.65 (d,
J = 1.5 Hz, 1H), 8.51 (t, J = 6 Hz, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.25 (d, J = 2.1 Hz,
1H), 7.92-7.84 (m, 2H), 7.49 (d, J = 8.7 Hz, 1H), 4.52 (d, J = 5.7 Hz, 2H), 2.19 (t, J
= 7.5 Hz, 2H), 1.94 (t, J = 7.5 Hz, 2H), 1.59-1.45 (m, 4H), 1.31-1.21 (m, 2H);
13C-NMR (100 MHz, DMSO-d6) δ 172.5, 169.1, 160.3, 145.5, 135.9, 132.6, 130.6,
129.8, 128.2, 120.5, 118.9, 44.8, 35.2, 32.2, 28.3, 25.0, 24.9; HRMS (AP-ESI) m/z
calcd for C17H20BrN3O3 [M+H]+ 394.0761, found: 394.0766.
5.1.78. N1-((6-bromoquinolin-2-yl)methyl)-N8-hydroxyoctanediamide (9x)
Yield: 71%, mp: 158-160 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.51 (t,
J = 5.7 Hz, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.25 (d, J = 1.8 Hz, 1H), 7.92-7.84 (m, 2H),
7.49 (d, J = 8.4 Hz, 1H), 4.52 (d, J = 6 Hz, 2H), 2.19 (t, J = 7.5 Hz, 2H), 1.93 (t, J =
7.5 Hz, 2H), 1.56-1.46 (m, 4H), 1.27-1.24 (m, 4H); 13C-NMR (100 MHz, DMSO-d6) δ
172.6, 169.1, 160.3, 145.3, 136.0, 132.7, 130.4, 129.8, 128.2, 120.5, 118.9, 44.7, 35.3,
32.2, 28.4, 28.4, 25.2, 25.0; HRMS (AP-ESI) m/z calcd for C18H22BrN3O3 [M+H]+
408.0917, found: 408.0936.
22

5.1.79. N1-hydroxy-N7-((6-iodoquinolin-2-yl)methyl)heptanediamide (9y)
Yield: 95%, mp: 160-162 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.66 (d,
J = 1.2 Hz, 1H), 8.51 (t, J = 6 Hz, 1H), 8.42 (d, J = 1.5 Hz, 1H), 8.30 (d, J = 8.4 Hz,
1H), 8.01 (dd, J1 = 9 Hz, J2 = 1.8 Hz, 1H), 7.75 (d, J = 9 Hz, 1H), 7.46 (d, J = 8.1 Hz,
1H), 4.51 (d, J = 5.7 Hz, 2H), 2.19 (t, J = 7.2 Hz, 2H), 1.94 (t, J = 7.2 Hz, 2H),
1.59-1.45 (m, 4H), 1.30-1.23 (m, 2H); 13C-NMR (100 MHz, DMSO-d6) δ 172.5,
169.1, 160.3, 137.9, 136.3, 135.6, 131.5, 131.4, 130.3, 128.8, 128.7, 120.3, 44.8, 35.2,
32.2, 28.3, 25.0, 24.9. HRMS (AP-ESI) m/z calcd for C17H20IN3O3 [M+H]+ 442.0622,
found: 442.0613.
5.1.80. Methyl 7-(((4-(benzylcarbamoyl)-6-phenylquinolin-2-yl)methyl)amino)-7-
oxoheptanoate (10a)
To a nitrogen degassed solution of compound 8l (0.55 g, 1.1 mmol) in toluene (25
mL) were successively added phenylboronic acid (0.16 g, 1.3 mmol), sodium
carbonate (0.35 g, 3.3 mmol), PPh3 (0.05 epuiv) and Pd(OAc)2 (0.05 equiv). The
reaction mixture was refluxed overnight. And water (100 mL) was added. After
extraction with EtOAc (3*50 mL), the combined organic layers were dried over
MgSO4 and the solvent was removed under reduced pressure. The crude material was
purified by column chromatography to afford white solid 10a (0.17 g, 30%). Mp:
1
155-157 ºC. H-NMR (400 MHz, DMSO-d6) δ 9.42 (t, J = 6 Hz, 1H), 8.58 (t, J = 6
Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.14-8.11 (m, 1H), 7.67 (d, J = 8.8 Hz, 2H),
7.54-7.50 (m, 3H), 7.45-7.43 (m, 3H), 7.41-7.40 (m, 3H), 7.35-7.30 (m, 1H),
4.58-4.54 (m, 4H), 3.58 (s, 3H), 2.30 (t, J = 7.4 Hz, 2H), 2.22 (t, J = 7.2 Hz, 2H),
1.60-1.49 (m, 4H), 1.34-1.26 (m, 2H). ESI-MS m/z: 524.8 [M+H]+.
Compound 10b was synthesized by the same method described above.
5.1.81. Methyl 7-oxo-7-(((6-phenylquinolin-2-yl)methyl)amino)heptanoate (10b)
Yield: 60%, mp: 112-114 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 8.53 (t, J = 6 Hz, 1H),
8.41 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.11-8.02 (m, 2H), 7.85-7.82 (m,
2H), 7.55-7.40 (m, 4H), 4.55 (d, J = 6 Hz, 2H), 3.58 (s, 3H), 2.21 (t, J = 7.5 Hz, 2H),
1.95 (t, J = 7.5 Hz, 2H), 1.62-1.49 (m, 4H), 1.35-1.27 (m, 2H). ESI-MS m/z: 391.5
[M+H]+.
5.1.82. N1-((4-(benzylcarbamoyl)-6-phenylquinolin-2-yl)methyl)-N7-hydroxy
heptanediamide (11a)
Yield: 76%, mp: 174-176 ºC. 1H-NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.45 (t,
J = 6 Hz, 1H), 8.68 (s, 1H), 8.59 (t, J = 6 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.12-8.11
(m, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.53-7.46 (m, 3H), 7.41-7.40 (m, 3H), 7.39-7.37 (m,
3H), 7.34-7.31 (m, 1H), 4.59-4.57 (m, 4H), 2.22 (t, J = 7.2 Hz, 2H), 1.95 (t, J = 7.2
Hz, 2H), 1.58-1.49 (m, 4H), 1.31-1.24 (m, 2H); 13C-NMR (100 MHz, DMSO-d6) δ
172.5, 169.1, 166.7, 159.5, 146.6, 143.1, 139.2, 139.2, 138.2, 129.2, 128.5, 128.4,
127.9, 127.5, 127.4, 127.1, 126.9, 123.4, 122.3, 117.7, 44.7, 42.7, 35.2, 32.2, 28.3,
25.0, 24.9; HRMS (AP-ESI) m/z calcd for C31H32N4O4 [M+H]+ 525.2496, found:
525.2502.
23

5.1.83. N1-hydroxy-N7-((6-phenylquinolin-2-yl)methyl)heptanediamide (11b)
Yield: 64%, mp: 158-160 ºC. 1H-NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.65 (s,
1H), 8.52 (t, J = 6 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 1.2 Hz, 1H),
8.11-8.02 (m, 2H), 7.85-7.82 (m, 2H), 7.55-7.40 (m, 4H), 4.55 (d, J = 6 Hz, 2H), 2.21
(t, J = 7.5 Hz, 2H), 1.95 (t, J = 7.5 Hz, 2H), 1.61-1.46 (m, 4H), 1.32-1.27 (m, 2H);
13C-NMR (100 MHz, DMSO-d6) δ 172.4, 169.1, 159.7, 146.3, 139.3, 137.6, 137.0,
129.1, 128.9, 128.7, 127.8, 127.1, 127.0, 125.2, 120.0, 44.5, 35.2, 32.2, 28.3, 25.0,
24.9; HRMS (AP-ESI) m/z calcd for C23H25N3O3 [M+H]+ 392.1969, found: 392.1995.
5.2. In vitro HDAC enzymatic assay
HDAC inhibitory activities of all quinoline hydroxamic acid derivatives were
evaluated by the Color de Lys™ assay (BML-AK501, Enzo® Life Sciences) including
HDAC1&2. Based on the HDAC kit instruction, HDAC1&2 (HeLa cell nucleus
extracts), substrate and tested compounds (including positive control compound) were
diluted to needed concentrations. Firstly, HDAC1&2 (15 µL/well) and tested
compounds (10 µL/well) with different concentrations were incubated at 37 °C for 5
minutes in the 96-well plate. After addition of substrate (25 µL/well), the resulting
mixture kept up incubating at 37 °C for 0.5 h. Nextly, the mixture (50 µL/well) of
Color de Lys Developer and TSA was added. After incubation for 0.5 h, absorbance
values were measured in a microtiter-plate reader at 405 nm. The inhibition rates were
calculated from the ultraviolet absorption values of inhibited wells and positive
control wells. Finally, the IC50 values were gained using a regression analysis method
between the concentration and inhibition rate.
5.3. Molecular docking
Surflex-dock was used for the molecular docking of 9w and all the parameters
were set to the default except mentioned. The HDAC2 active site was gained based on
the co-crystal structure of HDAC2-SAHA (PDB code: 4LXZ). Compound 9w was
optimized using concord method and then assigned with AM1-BCC charges[17]. Other
detail method referred to literature.[16]
5.4. MTT Assay
MDA-MB-231 (breast cancer cell), PC-3 (prostate cancer cell), K562 (chronic
myelogenous leukaemia cell) and A549 (lung cancer cell) were respectively cultured
in RPMI1640 medium (10% FBS) at 37 °C in 5% CO2 humid incubator. Cell
anti-proliferative assay was determined by MTT [(3-[4,5-dimethyl-2-thiazolyl]-2,5-
diphenyl-2H-tetrazolium bromide)] method. Medium (100 µL/well) including cancer
cells (4000 cells/well) was plated in 96-well plates. After incubation for 8 h, different
concentrations of inhibitors (100 µL/well) were added. Followed by 48 h incubation,
0.5% MTT (10 µL/well) was used. After 4 h, DMSO (150 µL) was added and rocked
for 10 min at 37 °C in a shaker. At last, the optical density values were read with a
microtiter-plate reader at 570 nm.
24

Acknowledgments
This work was supported by National Natural Science Foundation China (No.
81373281), Shandong Natural Science Fund for Distinguished Young Scholars (No.
JQ201319), the Program for New Century Excellent Talents in University (No.
NCET-12-0337) and Program for Changjiang Scholars and Innovative Research Team
in University, PCSIRT (No. IRT13028).
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26

R2
R1
H
H
n
N
N
N
OH
O
O
Cap group
Linker
ZBG
Fig.1 HDAC inhibitor pharmacophore model and our substituted quinoline
hydroxamic acid derivative
Scheme 1. Reagents and conditions: (a) EDCI, HOBT, Et3N, CH2Cl2, substituted aniline, 0 °C to
rt, overnight; (b) SeO2, 1,4-dixoane, reflux, 1 h; (c) (i) NaBH4, MeOH, rt, 15 min; (ii) PBr3,
CH2Cl2, rt, overnight; (d) (i) NaN3, DMF, rt, overnight; (ii) PPh3, THF, rt, 5 h; (e) EDCI, HOBT,
Et3N, CH2Cl2, 0 °C to RT, overnight; (f) NH2OH·HCl, KOH, MeOH, rt, 1 h.
Scheme 2. Reagents and conditions: (g) Pd(OAc)2, PPh3, phenylboronic acid, Na2CO3, toluene,
reflux, overnight; (f) NH2OH·HCl, KOH, MeOH, rt, 1 h.
27

Figure 2. Compounds SARs analysis.
Figure 3 The molecular binding mode of compound 9w and SAHA in the active site
of HDAC2 using surflex dock software
28

Tab.1 the structures and HDACs inhibitory activities of quinoline hydroxamate
derivatives
R2
R1
H
H
n
N
N
N
OH
O
O
IC50a of HDACs
(nM)
Compd
R1
R2
n
H
H
-CONHBn
-CONHBn
-CONHBn
-CONHBn
-CONHBn
-CONHPh
-CONHPh
3
4
5
6
7
5
6
5
6
5
6
5
6
7
5
6
3
4
5
6
5
5
5
6
5
5
5
> 1000
> 1000
9a
9b
9c
H
399 26
780 285
> 1000
H
9d
9e
H
H
301 166
562 177
444 40
> 1000
9f
H
9g
H
-CONHBu-n
9h
9i
H
-CONHBu-n
H
-CONHMe
642 237
> 1000
9j
H
-CONHMe
9k
9l
Br
Br
Br
Br
Br
H
-CONHBn
343 86
> 1000
-CONHBn
9m
9n
9o
-CONHBn
> 1000
-CONHPh
196 43
> 1000
-CONHPh
9p
9q
9r
H
> 1000
H
H
> 1000
H
H
266 110
678 332
155 58
120 15
85 32
9s
H
H
9t
F
H
9u
9v
Cl
Br
Br
I
H
H
9w
9x
H
146 31
132 29
341 46
152 43
161 51
H
-CONHBn
H
9y
Ph
Ph
11a
11b
SAHA
a Values are the mean of three independent determinations and expressed with standard deviations.
29