Design, synthesis and biological evaluation of novel triaryldimethylaminobutan-2-ol derivatives against Mycobacterium tuberculosis

Article abstract of DOI:10.1016/j.bioorg.2020.104054

Bedaquiline (TMC207), a typical diarylquinoline anti-tuberculosis drug, has been approved by FDA to specifically treat MDR-TB. Herein we describe design, synthesis, and in vitro biological evaluation against Mycobacterium tuberculosis of a series of triaryldimethylaminobutan-2-ol derivatives obtaining from the structural modification of TMC207. Compounds 23, 25, 28, 32, 39 and 43 provided superior anti-mycobacterial activity than positive control PC01 which shows the same configuration and contains TMC207. Compounds 16, 20, 29, 34, 37, 45 and 47 exhibited the similar activity to positive control PC01. Most importantly, the series of compounds showed excellent activity against XDR-Mtb. The result of acute toxicity suggested that this class of triaryldimethylaminobutan-2-ol derivatives should be graded as low. Further SAR analysis indicates that a large steric bulk of triaryl and 7-Br, 3-OCH₃ on 1-naphthyl are critical.

Full text of DOI:10.1016/j.bioorg.2020.104054

BioorganicChemistry102(2020)104054
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Design, synthesis and biological evaluation of novel
triaryldimethylaminobutan-2-ol derivatives against Mycobacterium
tuberculosis
⁎
Ping Liua,1, Shiyong Fana,1, Bin Wangb, Ruiyuan Caoa, Xiaokui Wanga, Song Lia, Yu Lub,
,
⁎
Wu Zhonga,
a National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Taiping Road 27, Beijing 100850, PR China
b Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Bedaquiline (TMC207), a typical diarylquinoline anti-tuberculosis drug, has been approved by FDA to speci-
fically treat MDR-TB. Herein we describe design, synthesis, and in vitro biological evaluation against
Mycobacterium tuberculosis of a series of triaryldimethylaminobutan-2-ol derivatives obtaining from the struc-
tural modification of TMC207. Compounds 23, 25, 28, 32, 39 and 43 provided superior anti-mycobacterial
activity than positive control PC01 which shows the same configuration and contains TMC207. Compounds 16,
20, 29, 34, 37, 45 and 47 exhibited the similar activity to positive control PC01. Most importantly, the series of
compounds showed excellent activity against XDR-Mtb. The result of acute toxicity suggested that this class of
triaryldimethylaminobutan-2-ol derivatives should be graded as low. Further SAR analysis indicates that a large
steric bulk of triaryl and 7-Br, 3-OCH3 on 1-naphthyl are critical.
ATP synthase
Diarylquinoline
Triaryldimethylaminobutan-2-ol
Anti-tuberculosis drugs
1. Introduction
Mtb strains at a range of minimum inhibitory concentration (MIC) of
0.01–0.12 μg/mL [8]. Combinations of TMC207 with current drugs [8–10]
Tuberculosis (TB) is a communicable disease that is a major cause of ill
health, one of the top 10 causes of death worldwide and the leading cause
of death from a single infectious agent (ranking above HIV/AIDS). It is
caused by the bacillus Mycobacterium tuberculosis, which is spread when
people who are sick with TB expel bacteria into the air; for example, by
coughing [1]. It is much more serious accompanying with the increasing of
individuals that infect the human immunodeficiency virus (HIV). HIV can
markedly enhance the rate of both new Mtb infection and activation of
latent infection [2]. HIV-positive patients are more susceptible to Mtb with
a 50-fold risk of incidence increase over HIV-negative patients [3].
Otherwise, the emergence of multidrug-resistant TB (MDR-TB) and recently
developed extensive drug-resistant TB (XDR-TB) provide new challenges to
current first-line TB drug regimens which were just developed more than
40 years ago [4–6]. All these alarming situations intensify the need to find
novel, inexpensive, more efficient and lower toxicity anti-TB drugs.
Bedaquiline (TMC207), a diarylquinoline, improved cure rates when
added to a multidrug-resistant tuberculosis (MDR-TB) treatment regimen in
a previous placebo-controlled, phase 2 trial (NCT00449644) [7]. It exhibits
a promising in vitro activity against both drug-sensitive and drug-resistive
especially Pyrazinamide (PZA) [11] exerting a synergistic effect are more
active and shorter regimens than those recommended by WHO. TMC207
shows higher selectivity against mycobacteria than any other Organisms
and almost innoxious in clinical study [8,12]. The fact TMC207 retains
activity against MDR-TB and XDR-TB [13] suggests that it exhibit marked
effect through a different cellular target. The genomes of Mtb strains resist
TMC207 have been sequenced [14,15]. The point mutations identified as
Asp28 → Val (D28V), Ala63 → Pro (A63P), Ile66 → Met (I66M), Asp28
→
Pro (D28P) or Glu61 → Asp (E61D) in different TMC207-resistive strains
are all located at adenosine triphosphate (ATP) synthase c subunit which is
encoded by gene atpE. Accordingly, TMC207 exerts its high anti-TB activity
with a unique mechanism of action targeting the membrane-spanning
domain c subunit acting as a proton pump of ATP synthase.
There already had been some structural modifications of TMC207
due to its high activity and new target [16–20]. Studies on structure
activity relationship (SAR) of the diarylquinoline compounds were re-
ported. Docking research of TMC207 and its another three stereo-
isomers suggested that the hydroxyl and N,N-dimethylamino moieties
play a capital role in binding to the target protein [21]. It was also
⁎ Corresponding authors.
E-mail addresses: zhongwu@bmi.ac.cn (W. Zhong), luyu4876@hotmail.com (Y. Lu).
1 Ping Liu and Shiyong Fan contributed equally to this article.
https://doi.org/10.1016/j.bioorg.2020.104054
Received 30 March 2020; Received in revised form 8 June 2020; Accepted 26 June 2020
Availableonline30June2020
0045-2068/©2020ElsevierInc.Allrightsreserved.

P. Liu, et al.
BioorganicChemistry102(2020)104054
Fig. 1. Design of TMC207 derivatives. R1: Br, H; R2: Br, H; R3: para, meta, ortho-CH3, para, meta-Cl; R4: CH3, H; R5: 1-naphthyl, phenyl, para, meta, ortho-bromo-
phenyl, 2,4-difluorophenyl.
demonstrated by Ram et al. [16] the importance of the naphthalene
moiety which presumably acts as a binding motif with its lipophilic
nature. A large steric bulk of triaryl of TMC207 is critical for its se-
lectivity against Mycobacterium tuberculosis [21].
Hydrochloride 49 using the synthetic sequence illustrated in Scheme 1
[23–25]. The synthesis was started with the reaction of 3-hydroxy-2-
naphthoic acid (1) with bromine in AcOH to obtain 4, 7-Dibromo-3-
hydroxy-2-naphthoic Acid (2) in good yield (90%). Treatment of
compound 2 with powdery tin in AcOH provided 7-Bromo-3-hydroxy-2-
naphthoic Acid (3) in yield 96.5%. Methylation of compound 3 with
(CH3)2SO4 in acetone could afford Methyl 7-bromo-3-methoxy-2-
naphthoate (4a) in yield 86%. In the same way, compounds Methyl 4,7-
dibromo-3-methoxy-2-naphthoate (4b) and Methyl 3-methoxy-2-
naphthoate (4c) were prepared respectively from compound 2 in 75%
yield and compound 1 in 81% yield. Esters 4a-4b were reduced to al-
cohols 5a-5b with LiAlH4 in ether in yields 85–98%. Compounds 5a-5b
were converted to aldehydes 6a-6b respectively in the presence of ac-
tive MnO2 in acetone in yields 84–87%. Nucleophilic addition of al-
dehyde 6a with different Grignard reagents prepared by substituted
bromobenzene afforded compounds 7a-7f in yields 90–95%. According
to the same method, 7g (94%) and 7h (92%) were prepared from 6b,
and 7i (89%) was from 6c. The compounds 7a-7h can be reduced to 8a-
8h (75–88%) in the presence of NaBH4 and AlCl3 in THF. Otherwise, 7i
was converted into two compounds 8i (41%) and 8j (36%) by the same
method. Mannich bases (10a-10f) were prepared from the commer-
cially available substituted-ethanones (9a-9f) with dimethylamine hy-
drochloride and paraformaldehyde in 95% ethanol in a range of
59–67% yields. Finally, 8a-8j were allowed to react with 10a-10f in the
presence of LDA in THF to provide target compounds 11–48. Hydro-
chloride 49 was prepared from compound 18 with HCl-Et2O in acetone.
All the synthesized compounds were fully characterized by 1H NMR and
MS. The configurations of Compounds 11 and 17 were confirmed by
single crystal x-ray diffraction [26,27].
How can we get more hopeful anti-TB derivatives from the structure
of TMC207 keeping the demonstrated considerable moieties? We used
computer aided drug design (CADD) software to design a series of novel
anti-TB compounds (Fig. 1). 100 new compounds were generated
through the functional module Combinatorial Transform of Med Chem
Studio (Simulations Plus, Inc., USA, http://www.simulations-plus.com)
[22] with setting up the parameter of one point derivatization (see
Table S1 in the supplemental material). A preferable compound retains
the active parts and changes quinoline ring into naphthalene. As there
is no evidence to show effect on activity of quinoline’s nitrogen nor
binding between quinoline’s nitrogen and the target protein in docking
studies [21], the exchange may retain perfect properties TMC207 has.
Besides, the compound exhibits better predictive value in ADMET
through another kind of software ADMET Predictor version 5.5 (Si-
mulations Plus, Inc., USA, http://www.simulations-plus.com). The
prediction of TMC207′s ADMET risk is scored as 10 while the preferable
compound is 8 ((see Table S2 in the supplemental material)).
After R-group and SAR analysis of TMC207 and its analogs in patent
using software Medchem Studio, we presented
a series of triar-
yldimethylaminobutan-2-ol derivatives. At 1-position, we used phenyl
substituted by electron withdrawing group (Cl) at para, meta position and
electron donating group (CH3) at para, meta, ortho position to investigate
their influence of activity. At 2-position, we reasonably reduced the bulk
of the molecule using halogen substituted phenyl in order to enhancing
the membrane penetration which may lead to an improved fit into the
binding site. We hope that these modifications of TMC207 can provide
satisfactory results for finding some new potential anti-TB drugs.
2.2. Antimycobacterial activity
2. Results
All the compounds 11–49 were evaluated for their minimum in-
hibitory concentration (MIC) against the Mtb strain H37Rv in a mi-
croplate Alamar Blue assay (MABA) [28]. Several compounds were
found to effectively inhibit the growth of replicating Mtb in with low
MICs (Table 2). We synthesized two compounds PC01 and PC02 fol-
lowing the synthetic route in patent [25] as positive control. It was
2.1. Synthetic studies
We have so far prepared
a
series of different triar-
yldimethylaminobutan-2-ol derivatives 11–48 (Table 1) and
a
2

P. Liu, et al.
BioorganicChemistry102(2020)104054
Table 1
Table 1 (continued)
The structure of target compounds triaryldimethylaminobutan-2-ol derivatives.
Compd. No.
R1
Br
R2
H
R3
R4
R5
Config.
Compd. No.
R1
Br
R2
H
R3
R4
R5
Config.
25
H
CH3
1R,2S/1S,2R
11
H
CH3
1R,2R/1S,2S
26
Br
H
H
CH3
1R,2R/1S,2S
12
13
14
15
16
17
18
19
Br
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
1R,2S/1S,2R
1R,2S/1S,2R
1R,2R/1S,2S
1R,2R/1S,2S
1R,2S/1S,2R
1R,2R/1S,2S
1R,2S/1S,2R
1R,2R/1S,2S
27
28
29
30
31
32
33
34
35
Br
Br
Br
Br
Br
Br
Br
Br
H
H
H
H
H
H
H
H
H
H
p-Cl
p-Cl
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
1R,2R/1S,2S
1R,2S/1S,2R
1R,2S/1S,2R
1R,2R/1S,2S
1R,2R/1S,2S
1R,2S/1S,2R
1R,2R/1S,2S
1R,2S/1S,2R
1R,2R/1S,2S
H
H
H
Br
Br
H
p-Cl
p-Cl
p-Cl
p-Cl
p-Cl
H
p-Cl
p-Cl
H
H
Br
H
20
21
Br
Br
H
H
p-Cl
p-Cl
CH3
CH3
1R,2S/1S,2R
1R,2R/1S,2S
p-Cl
36
H
H
p-Cl
CH3
1R,2S/1S,2R
22
23
24
Br
Br
Br
H
H
H
p-Cl
H
CH3
CH3
CH3
1R,2S/1S,2R
1R,2S/1S,2R
1R,2R/1S,2S
37
38
39
Br
Br
Br
H
p-CH3
p-CH3
H
CH3
CH3
CH3
1R,2S/1S,2R
1R,2R/1S,2S
1R,2S/1S,2R
H
H
Br
(continued on next page)
3

P. Liu, et al.
BioorganicChemistry102(2020)104054
Table 1 (continued)
changes were observed in tissues of mice dissected at the 7th day.
3. Discussion
Based on our strategy of modifying TMC207, we have presented a
new class of anti-TB compounds. Table 2 reveals that triaryl-based
compounds show good anti-TB activity. Comparing target compounds
with the positive control compounds, we can find out that some target
compounds replacing the quinoline rings of TMC207 and its derivates
with naphthalene rings show satisfactory anti-TB activity. Thereby it
can confirm that quinoline’s nitrogen atom of TMC207 is not the
binding site attaching to ATP synthase and not contributed to its high
activity.
Compd. No.
R1
Br
R2
Br
R3
R4
R5
Config.
40
H
CH3
1R,2R/1S,2S
The MICs against M. tuberculosis H37Rv of TMC207, PC01 and
PC02 are 0.025, 0.189 and > 32 μg/mL respectively. TMC207 shows
the strongest anti-TB activity due to its most stable connection to amino
acid residues of ATP synthase. Like TMC207 and its stereoisomers,
racemate of target compounds which contain (1R, 2S) compounds
summarized in Table 2 display superior anti-TB activity than those
racemate which contain another configuration.
41
42
43
44
45
46
47
48
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
H
H
H
H
H
H
H
OH
1R,2S/1S,2R
1R,2R/1S,2S
1R,2S/1S,2R
1R,2R/1S,2S
1R,2S/1S,2R
1R,2R/1S,2S
1R,2S/1S,2R
1R,2R/1S,2S
H
OH
From the structures we can observe that compound 12 has a Br atom
at 7-position of 1-naphthyl but compound 13 has not. This small dif-
ference has led to various activities. MIC of compound 12 is 0.594 μg/
mL while 13 is 2.047 μg/mL. The same phenomenon can be observed
between compounds 16 and 18. It implicates that 7-Br attaching to 1-
naphthyl plays an important role in keeping compound’s anti-TB ac-
tivity.
m-Cl
m-Cl
m-CH3
m-CH3
o-CH3
o-CH3
CH3
CH3
CH3
CH3
CH3
CH3
Compounds 39 bearing a hydrogen bond acceptor (OCH3) at 3-po-
sition of 1-naphthyl has shown very high activity (MIC is 0.124 μg/mL).
Replacement of hydrogen bond receptor (OCH3) with hydrogen bond
donor (OH) in compound 41 resulted in poor activity profile (MIC is
1.000 μg/mL). It might suggest that the docking site of ATP synthase
with 1-naphthyl’s 3-position of target compound provide a hydrogen
bond donor.
Compounds 16, 37, 43, 45 and 47 whose 1-phenyl were linked with
an electron-withdrawing group (Cl) or an electron-donating group
(CH3) at ortho, meta or para positions exhibited comparable activity
profile to positive control PC01. In addition, compounds 20, 23, 25, 28,
29, 32 and 34 whose 2-naphthyl were replaced with ortho, meta or para
bromo-substituted phenyl also showed comparable activity profile to
positive control PC01. From the information mentioned above we
consider that substituent type and its position attaching to 1-phenyl and
2-phenyl of target compounds are unimportant.
found that racemate whose configuration was 1R,2S/1S,2R possess
superior antituberculosis activity than racemate whose configuration
was 1R,2R/1S,2S. Compounds 23, 25, 28, 32, 39 and 43 provided
superior anti-mycobacterial activity than positive control PC01 which
shows the same configuration and contains TMC207. Compounds 16,
20, 29, 34, 37, 45 and 47 exhibited the similar activity to positive
control PC01.
Comparing compound 18 and its hydrochloride 49, we saw that the
MIC of 18 is 1.454 μg/mL while 49 is 0.962 μg/mL. It might indicate
that salification can enhance the compound’s activity profile.
In Table 3, we can see that MICs of compound 39 against XDR-Mtb
strains 040 and 004 are 0.085 μg/mL and 0.182 μg/mL separately while
their MICs against H37Rv are0.074 μg/mL. The comparable activity
tells us the series of compounds can perfectly inhibit drug-resistant Mtb
even XDR-Mtb and illustrate their promising future.
In addition, compounds 23, 25, 28, 32, 39, 43 and 45 who showed
high activity against drug-sensitive strains H37Rv were evaluated
especially their MICs against two clinical-isolated Mtb strains 040 and
004 in MABA (Table 3). 040 is a kind of strains resistant to Isoniazid
(INH), Rifampin (RMP), Protionamid (Pto), Rifapeatine (RPT), Oflox-
acin (OFX), Levofloxcin (LVFX) and 004 is resistant to Streptomycin
(SM), RMP, RPT, Kanamycin KM, OFX. They are all sort of XDR-Mtb
strains. The results showed that the compounds 28 and 39 exhibited
exciting activity against XDR-Mtb strains and illustrated the promise of
this series of compounds.
From the results of acute toxicity listed in Table 4, we can find out
that IC50s of compounds 12, 16, 20, 23, 25, 28, 32, 39 and 43 are all
greater than 500 mg/kg. Also, no obvious pathological changes were
observed in tissues of mice. Therefore, the toxicity of this series of
compounds we synthesized could be graded as low.
4. Conclusion
In summary, we synthesized a series of compounds modified from
TMC207. All target compounds were evaluated for their MICs against
M. tuberculosis strain H37Rv in MABA. Compounds 16, 20, 23, 25, 28,
29, 32, 34, 37, 39, 43, 45 and 47 showed comparable activity profile to
positive control PC01. Especially importantly, they also showed ex-
cellent activity against XDR-Mtb. From SAR analysis of this series of
compounds, it was demonstrated that quinoline’s nitrogen atom of
2.3. Acute toxicity
Preliminary assessment of acute toxicity of compounds 12, 16, 20,
23, 25, 28, 32, 39 and 43 in mice is shown in Table 4. During the
7 days there was no mice dead after the intragastric administration in a
single dose of 500 mg/kg in test groups. And no obvious pathological
4

P. Liu, et al.
BioorganicChemistry102(2020)104054
Scheme 1. Reagents and conditions: (i) bromine
(2.5 equiv), AcOH, reflux, 10 h, 90%; (ii) powdery
tin (1.2 equiv), 12 N HCl (1.5 equiv), AcOH, re-
flux, 12 h, 96%; (iii) (CH3)2SO4 (2.5 equiv), K2CO3
(5 equiv), acetone, reflux, 10 h, 75–86%; (iv)
LiAlH4 (1.1 equiv), diethyl ether, reflux,
5 h,
85–98%; (v) MnO2 (15 equiv), acetone, r.t., 48 h,
84–87%; (vi) substituted bromobenzene (1.2
equiv), Mg turnings (1.2 equiv), I2 (catalytic
amount), THF, reflux, 3 h, 89–95%; (vii) NaBH4 (5
equiv), AlCl3 (3 equiv), THF, reflux, 20 h, 81–86%;
(viii) (a) dimethylamine hydrochloride (1.3
equiv), paraformaldehyde (1.3 equiv), 12 N HCl
(0.02 equiv), 95% ethanol, reflux, 2 h, 69–85%;
(b) NaHCO3, alkalization, 90–95%; (ix) 8a-8j (1
equiv), 10a-10f (1.5 equiv), 2.5 M n-BuLi (1.1
equiv), Diisopropyl amine (1.1 equiv), THF,
−78 °C, 10 h; (x) HCl-Et2O, acetone, r.t., 88%.
TMC207 is not necessary for its activity. We also found out that 7-Br
and 3-position hydrogen bond acceptor (OCH3) play a key role in anti-
TB activity. In addition, a large steric bulk of triaryl is necessary for
high selectivity against mycobacterium. The experiment of acute toxi-
city in mice provided the point that the toxicity of
triaryldimethylaminobutan-2-ol derivatives we synthesized could be
graded as low. Accordingly, this class of triaryldimethylaminobutan-2-
ol derivatives has shown a great potential to develop novel, high ef-
fective and hypotoxic anti-TB agents.
5

P. Liu, et al.
BioorganicChemistry102(2020)104054
Table 2
Table 4
MICs of compounds against M. tuberculosis H37Rv.
Acute toxicity of compounds in mice (IC50).
Compd. No. Config.
MIC (μg/
Compd. No. Config.
MIC (μg/
mL)
Compd. No.
IC50 (mg/kg)
mL)
12
16
20
23
25
28
32
39
43
> 500
> 500
> 500
> 500
> 500
> 500
> 500
> 500
> 500
PC01a
12
1R,2S/
1S,2R
0.189
0.594
2.047
0.244
1.454
0.184
0.956
0.118
0.103
0.109
0.206
0.111
0.224
0.754
0.222
0.124
1.000
0.114
0.180
0.258
0.962
0.025
0.047
0.040
PC02b
11
14
15
17
19
21
24
26
27
30
31
33
35
38
40
42
44
46
48
1R,2R/
1S,2S
> 32
1.977
3.178
2.883
3.052
2.166
1.000
2.000
1.000
2.000
2.000
2.000
> 32
1.000
1.000
1.000
4.000
3.773
8.000
1.999
13
16
18
20
22
23
25
28
29
32
accurate mass detection (Agilent, Santa Clara, CA, USA).
34
4,7-Dibromo-3-hydroxy-2-naphthoic Acid (2). In
1 L three-
36
necked bottle, 3-hydroxy-2-naphthoic acid (1, 50 g, 0.27 mol) was
suspended in glacial acetic acid (600 mL). To this mechanically stirred
mixture was added dropwise a solution of bromine (34 mL, 0.67 mol) in
glacial acetic acid (100 mL) maintaining the reaction temperature in
the range of 20–30 °C, Following the addition, the reaction mixture was
refluxed for 10 h, then cooled to room temperature and filtered.
Washed the filter cake with water (3 × 100 mL), ether (100 mL) and
dried to obtain yellow product (82.8 g, 90%). 1H NMR (400 MHz,
DMSO‑d6): δ 7.83 (dd, J = 2.0, 9.2 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H),
8.40 (d, J = 2.0 Hz, 1H), 8.63 (s, 1H). FAB MS (m/z): [M]+ = 344.8.
7-Bromo-3-hydroxy-2- naphthoic Acid (3). In 1 L three-necked
bottle, 4,7-dibromo-3-hydroxy-2-naphthoic acid (2, 40 g, 0.116 mol)
was suspended in glacial acetic acid (500 mL) then 12 N HCl (130 mL)
and powdery tin (18 g, 0.153 mol) was added. The reaction mixture was
refluxed for 12 h, then cooled to room temperature and filtered.
Washed the filter cake with water (3 × 100 mL) and dried to obtain
yellow product (29.9 g, 96.5%). 1H NMR (400 MHz, DMSO‑d6): δ 7.36
(s, 1H), 7.64 (dd, J = 2.0, 8.8 Hz, 1H), 7.75 (d, J = 9.2 Hz, 1H), 8.28
(d, J = 1.6 Hz, 1H), 8.54 (s, 1H), 11.21 (br s, 1H).
37
39
41
43
45
47
49
TMC207
INH
RFP
a
PC01 means one compound which was consist of TMC207 and its en-
antiomer for positive control.
b
PC02 means one compound which was consist of another two diastereomer
of TMC207 for positive control.
Table 3
MICs of compounds against clinical-isolated M. tuberculosis strains 040 and 004.
Compd. No.
MICs against Mtb strains (μg/mL)
040
004
Methyl 7-bromo-3-methoxy-2-naphthoate (4a). In 2 L three-
necked bottle, 7-bromo-3-hydroxy-2- naphthoic acid (3, 112 g,
0.42 mol) was suspended in acetone (1 L). To this mechanically stirred
mixture was added anhydrous potassium carbonate (288 g, 2.08 mol)
and dimethyl sulfate (99 mL, 1.05 mol). The reaction was refluxed for
about 10 h, then cooled to room temperature and water (50 mL) was
added stirred for 2 h to destroy any remaining dimethyl sulfate. The
inorganic material was filtered and the acetone was removed under
reduced pressure. The residue was taken up in methylene chloride,
washed several times with water, dried over anhydrous magnesium
sulfate, filtered, concentrated and recrystallized in ethyl acetate and
petroleum ether to afford white product (105.6 g, 86%). 1H NMR
(400 MHz, CDCl3): δ 3.96 (s, 3H), 4.00 (s, 3H), 7.18 (s, 1H), 7.58 (dd,
J = 2.0, 8.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 8.19 (s,
1H). GC MS (m/z): [M]+ = 294.0.
43
0.125
0.125
0.152
0.084
0.091
0.096
0.085
0.019
0.5
45
0.5
23
0.331
0.298
0.307
0.348
0.182
0.118
25
28
32
39
TMC207
040 is the clinical M. tuberculosis resistant to INH RMP Pto RPT OFX LVFX
004 is the clinical M. tuberculosis resistant to SM RMP RPT KM OFX
(INH = isoniazid, RMP = rifampin, SM = streptomycin RPT = rifapeatine
OFX = ofloxacin , Pto = protionamid LVFX = levofloxcin, KM = kanamycin)
5. Experimental section
5.1. Chemistry-general methods
Methyl 4,7-dibromo-3-methoxy-2-naphthoate (4b). 4b was pre-
pared from compound 2 according to the method of compound 4a in
75% yield. 1H NMR (400 MHz, CDCl3): δ 3.98 (s, 3H), 4.03 (s, 3H), 7.80
(s, 1H), 8.07 (dd, J = 1.6, 9.2 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.49
(s, 1H). GC MS (m/z): [M]+ = 371.9.
All chemicals and reagents used were of analytical reagent.
Purification and drying of reagents and solvents was carried out ac-
cording to literature procedure. Melting points were determined using a
RY-1 apparatus. Thin-layer chromatography (TLC) was carried out on
silica gel (Yantai dexin Bio-Technology Co., Ltd., Yantai, China) GF/UV
254 and the column chromatography were performed on silica gel
(10–40 μm) (200–300 mesh; Yantai Chemical Industry Research
Institute, Yantai, China) visualized under UV light at 254 and 365 nm.
1H NMR spectra was recorded at 400 MHz on JNM-ECA-400 instrument
(JEOL Ltd., Tokyo, Japan) in the solvent indicated below. The values of
chemical shifts (δ) are expressed in ppm and the coupling constants (J)
in hertz (Hz). Mass spectra were recorded on Micromass ZabSpec high-
resolution magnetic-sector mass spectrometer (FAB MS) (Waters,
Milford, MA, USA) and the Agilent G6230A mass spectrometer for
Methyl 3-methoxy-2-naphthoate (4c). 4c was prepared from
compound 1 according to the method of compound 4a in 81% yield. 1H
NMR (400 MHz, CDCl3): δ 3.89 (s, 3H), 3.89 (s, 3H), 7.42 (s, 1H),
7.53–7.57 (m, 1H), 7.61–7.65 (m, 1H), 7.89–7.95 (m, 3H). GC MS (m/
z): [M]+ = 216.1.
(7-Bromo-3-methoxynaphthalen-2-yl)methanol (5a). In
2 L
three-necked bottle, lithium aluminum hydride (16 g, 0.42 mol) was
suspended in dry ether (200 mL) under the nitrogen. To the stirred
mixture was added dropwise a solution of Methyl 7-bromo-3-methoxy-
2-naphthoate (4a, 116.2 g, 0.39 mol) dissolved in dry ether (1 L)
keeping the solution boiling. Then the reaction was refluxed for about
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BioorganicChemistry102(2020)104054
5 h and cooled to room temperature. Water (100 mL) was added
dropwise carefully. The inorganic material was filtered, and the ether
was removed under reduced pressure. The residue was taken up in ethyl
acetate, washed several times with water, dried over anhydrous mag-
nesium sulfate, filtered and concentrated to get white crude product
which was pure enough for next step (102.5 g, 98%): 1H NMR
(400 MHz, CDCl3): δ 3.98 (s, 3H), 4.83 (s, 2H), 7.10 (s, 1H), 7.51 (dd,
J = 1.6, 8.8 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.66 (s, 1H), 7.92 (s,
1H). GC MS (m/z): [M]+ = 266.0.
bromobenzenes in a range of 89–95% yields.
3-Benzyl-6-bromo-2-methoxynaphthalene (8a). In 500 mL three-
necked bottle, (7-bromo-3-methoxynaphthalen-2-yl) (phenyl)methanol
(7a, 30.4 g, 0.09 mol) was dissolved in anhydrous tetrahydrofuran
(200 mL) and sodium borohydride (17 g, 0.45 mol) was suspended in it
under nitrogen gas. The mixture was stirred and cooled in ice water
about 30 min and then anhydrous aluminum trichloride (35.6 g,
0.27 mol) was added in batch maintaining the reactive temperature
under 20 °C. The mixture was refluxed for about 20 h and cooled to
room temperature. Water (100 mL) was added slowly and the mixture
was extracted with ethyl acetate (3 × 100 mL) and dried over anhy-
drous magnesium sulfate, then filtered and concentrated to get white
crude product. The crude product was purified by column chromato-
graphy over silica gel (10–40 μm), eluent: petroleum ether to afford 8a
(25.5 g, 88%). 1H NMR (400 MHz, CDCl3): δ 3.91 (s, 3H), 4.09 (s, 2H),
7.05 (s, 1H), 7.31–7.21 (m, 5H), 7.34 (s, 1H), 7.44 (dd, J = 2.0, 8.8 Hz,
1H), 7.57 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H). GC MS (m/z):
[M]+ = 326.0.
(4,7-Dibromo-3-methoxynaphthalen-2-yl) methanol (5b). 5b
was prepared from compound 4b according to the method of compound
5a in 85% yield. 1H NMR (400 MHz, CDCl3): δ 4.02 (s, 3H), 4.85 (s,
2H), 7.43 (s, 1H), 7.61 (dd, J = 1.6, 8.8 Hz, 1H), 7.78 (d, J = 9.2 Hz,
1H), 8.03 (d, J = 9.2 Hz, 1H). GC MS (m/z): [M]+ = 343.9.
(3-Methoxynaphthalen-2-yl) methanol (5c). 5c was prepared
from compound 4c according to the method of compound 5a in 92%
yield. 1H NMR (400 MHz, CDCl3): δ 3.97 (s, 3H), 4.82 (s, 2H), 7.13 (s,
1H), 7.33–7.37 (m, 1H), 7.42–7.46 (m, 1H), 7.72–7.77 (m, 3H). GC MS
(m/z): [M]+ = 188.1.
6-Bromo-2-methoxy-3-(4-methylbenzyl) naphthalene (8b). 8b
was prepared from compound 7b according to the method of compound
8a in75 % yield. 1H NMR (400 MHz, CDCl3): δ 2.33 (s, 3H), 3.91 (s,
3H), 4.05 (s, 2H), 7.05 (s, 1H), 7.11 (dd, J = 8.4, 12.0 Hz, 4H), 7.34 (s,
1H), 7.43 (dd, J = 2.0, 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.81 (d,
J = 1.6 Hz, 1H). GC MS (m/z): [M]+ = 340.1.
7-Bromo-3-methoxy-2-naphthaldehyde (6a). In 500 mL three-
necked bottle, (7-bromo-3-methoxynaphthalen-2-yl) methanol (5a,
34.1 g, 0.128 mol) was dissolved in acetone (350 mL), then manganese
dioxide (167 g, 1.92 mol) was added. The mixture was stirred me-
chanically at room temperature for 48 h. Filtered and the filter cake was
washed with acetone (4 × 200 mL). The filtrate was concentrated then
recrystallized in methanol to get yellow solid (29.3 g, 87%). 1H NMR
(400 MHz, DMSO‑d6): δ 4.01 (s, 3H), 7.59 (s, 1H), 7.72 (dd, J = 2.0,
8.8 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 8.35 (s, 1H), 10.47 (s, 1H). GC
MS (m/z): [M]+ = 264.0.
6-Bromo-2-methoxy-3-(3-methylbenzyl) naphthalene (8c). 8c
was prepared from compound 7c according to the method of compound
8a in 81% yield. 1H NMR (400 MHz, CDCl3): δ 2.31 (s, 3H), 3.92 (s,
3H), 4.05 (s, 2H), 7.06–7.02 (m, 4H), 7.19 (t, J = 8.8 Hz, 1H), 7.34 (s,
1H), 7.44 (dd, J = 2.0, 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.81 (d,
J = 1.6 Hz, 1H). GC MS (m/z): [M]+ = 340.1.
4,7-Dibromo-3-methoxy-2-naphthaldehyde (6b). 6b was pre-
pared from compound 5b according to the method of compound 6a in
84% yield. 1H NMR (400 MHz, DMSO‑d6): δ 4.04 (s, 3H), 7.80 (dd,
J = 2.0, 9.2 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H),
8.64 (s, 1H), 10.47 (s, 1H). GC MS (m/z): [M]+ = 341.9.
6-Bromo-2-methoxy-3-(2-methylbenzyl) naphthalene (8d). 8d
was prepared from compound 7d according to the method of compound
8a in 76% yield. 1H NMR (400 MHz, CDCl3): δ 2.25 (s, 3H), 3.95 (s,
3H), 4.06 (s, 2H), 7.08–7.06 (m, 3H), 7.21–7.14 (m, 3H), 7.44 (dd,
J = 2.0, 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H).
GC MS (m/z): [M]+ = 340.1.
3-Methoxy-2-naphthaldehyde (6c). 6c was prepared from com-
pound 5c according to the method of compound 6a in 87% yield. 1H
NMR (400 MHz, DMSO‑d6): δ 4.02 (s, 3H), 7.41–7.45 (m, 1H), 7.53 (s,
1H), 7.59–7.63 (m, 1H), 7.90 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.0 Hz,
1H), 8.36 (s, 1H), 10.48 (s, 1H). GC MS (m/z): [M]+ = 186.1.
(7-Bromo-3-methoxynaphthalen-2-yl) (phenyl)methanol (7a).
In 500 mL three-necked bottle, a mixture of magnesium turnings (6 g,
0.25 mol), anhydrous tetrahydrofuran (50 mL) and a grain of iodine
3-(4-Chlorobenzyl)-6-bromo-2-methoxynaphthalene (8e). 8e
was prepared from compound 7e according to the method of compound
8a in 82% yield. 1H NMR (400 MHz, CDCl3): δ 3.90 (s, 3H), 4.06 (s,
2H), 7.07 (s, 1H), 7.11 (d, J = 6.8 Hz, 1H), 7.26–7.23 (m, 3H), 7.35 (s,
1H), 7.45 (dd, J = 2.0, 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.83 (d,
J = 2.0 Hz, 1H). GC MS (m/z): [M]+ = 360.0.
(catalytic amount) was unstirred.
A
solution of bromobenzene
3-(3-Chlorobenzyl)-6-bromo-2-methoxynaphthalene (8f). 8f
was prepared from compound 7f according to the method of compound
8a in 81% yield. 1H NMR (400 MHz, CDCl3): δ 3.90 (s, 3H), 4.05 (s,
2H), 7.06 (s, 1H), 7.17–7.14 (m, 2H), 7.23–7.16 (m, 2H), 7.38 (s, 1H),
7.46 (dd, J = 1.6, 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.84 (d,
J = 1.2 Hz, 1H). GC MS (m/z): [M]+ = 360.0.
(26.3 mL, 0.25 mol) in anhydrous tetrahydrofuran (40 mL) was mixed
in dropping funnel and 10 mL of the mixture was added into the three-
necked bottle without stirring. About 10 min later, the color of iodine
was disappeared accompanying the generation of gas bubble. The re-
action mixture was stirred and the rest of solution of bromobenzene was
added dropwise into it. The reaction was refluxed for 3 h and then
cooled to room temperature. A solution of 7-Bromo-3-methoxy-2-
naphthaldehyde (6a, 26.4 g, 0.1 mol) in anhydrous tetrahydrofuran
(150 mL) was added dropwise into the reaction and it was refluxed for
another 1.5 h then cooled. Hydrochloric acid (50 mL, 5%) was added
slowly and the reaction solution was concentrated to remove tetra-
hydrofuran. The mixture was extracted with ethyl acetate and washed
several times with water, dried over anhydrous magnesium sulfate,
filtered and concentrated to get white crude product (36 g) which could
be used for the next step without further purification. The crude pro-
duct could be also purified by column chromatography over silica gel
(10–40 μm), eluent: methylene chloride/petroleum ether (1/2, v/v) to
afford 7a (30.4 g, 89%): 1H NMR (400 MHz, CDCl3): δ 3.90 (s, 3H), 6.15
(s, 1H), 7.09 (s, 1H), 7.30–7.28 (m, 1H), 7.36–7.32 (m, 2H), 7.42–7.40
(m, 2H), 7.49 (dd, J = 2.0, 8.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.63
(s, 1H), 7.90 (d, J = 1.6 Hz, 1H). GC MS (m/z): [M]+ = 342.1.
Compounds 7b-7i were prepared without further purification from 6a-
6c reacted with different commercially available substituted
2-Benzyl-3-methoxynaphthalene (8g). 8g was prepared from
compound 7g according to the method of compound 8a in 80% yield.
1H NMR (400 MHz, CDCl3): δ 3.91 (s, 3H), 4.11 (s, 2H), 7.10 (s, 1H),
7.31–7.19 (m, 6H), 7.40–7.36 (m, 1H), 7.47 (s, 1H), 7.66 (d,
J
= 7.2 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H). GC MS (m/z):
[M]+ = 248.0.
2-(4-Chlorobenzyl)-3-methoxynaphthalene (8h). 8h was pre-
pared from compound 7h according to the method of compound 8a in
82% yield. 1H NMR (400 MHz, CDCl3): δ 3.89 (s, 3H), 4.06 (s, 2H), 7.10
(s, 1H), 7.17–7.15 (m, 2H), 7.24–7.22 (m, 2H), 7.30 (dt, J = 0.8,
7.6 Hz, 1H), 7.39 (dt, J = 1.6, 7.6 Hz, 1H), 7.46 (s, 1H), 7.68 (d,
J
= 8.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H). GC MS (m/z):
[M]+ = 282.1.
3-Benzyl-1,6-dibromo-2-methoxynaphthalene (8i) and 3-
Benzyl-1,6-dibromonaphthalen-2-ol (8j). 8i and 8j were prepared
from compound 7i according to the method of compound 8a in 41%
and 36% yield respectively. 8i 1H NMR (400 MHz, CDCl3): δ 3.82 (s,
3H), 4.19 (s, 2H), 7.25–7.22 (m, 3H), 7.33–7.30 (m, 2H), 7.41 (s, 1H),
7

P. Liu, et al.
BioorganicChemistry102(2020)104054
7.58 (dd, J = 2.0, 9.2 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 8.06 (d,
J = 9.6 Hz, 1H), GC MS (m/z): [M]+ = 404.0. 8j 1H NMR (400 MHz,
CDCl3): δ 4.17 (s, 2H), 6.05 (s,1H), 7.34–7.24 (m, 5H), 7.38 (s, 1H),
7.56 (dd, J = 2.0, 9.2 Hz, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.84 (s, 1H).
ESI MS (m/z): [M-H]+ = 388.9.
(naphthalen-1-yl)-1-phenylbutan-2-ol (13 and 14). 13 and 14 was
prepared from 8g and 10a according to the method of compound 11
and 12. But the purification was changed by column chromatography
over silica gel (10–40 μm) using a different eluent: methylene chloride/
methanol/ammonia water (400/1/0.1, v/v) to afford two fractions. The
first fraction was crystallized in isopropyl ether to obtain compound 13
and the second fraction was crystallized in isopropyl ether to obtain
compound 14.
3-(Dimethylamino)-1-(naphthalen-1-yl) propan-1-one (10a). In
500 mL three-necked bottle, 1-(naphthalen-1-yl) ethanone (9a, 25 g,
0.15 mol), dimethylamine hydrochloride (15.6 g, 0.19 mol) and par-
aformaldehyde (7.2 g, 0.08 mol) were placed in the bottle. After the
addition of 0.3 mL of concentrated hydrochloric acid in 40 mL of 95%
ethanol, the mixture was refluxed for 2 h. Then the acetone (100 mL)
was added while the solution was still hot. Cooled slowly to room
temperature and chilled overnight in the refrigerator. Filtered and
washed with acetone (2 × 20 mL) to afford white solid 3-(dimethyla-
mino)-1-(naphthalen-1-yl)propan-1-one Hydrochloride (26.8 g, 69%).
The solid was dissolved in water, alkalinized with saturated Sodium
hydrogen carbonate aqueous solution and extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate, then
filtered and concentrated to get colorless oleosus product (10a, 20.5 g,
89%) which was easily decomposed but suitable for next step without
further purification. Compounds 10b-10f were prepared without fur-
ther purification from different commercially available substituted-
ethanones in a range of 59–67% yields.
13, yield 2.14%, mp 154.0–154.8 °C. 1H NMR (400 MHz, CDCl3): δ
1.98 (br s, 8H), 2.25–2.28 (m, 1H), 2.45–2.47 (m, 1H), 4.07 (s, 3H),
6.07 (s, 1H), 6.88–6.89 (m, 3H), 7.10 (s, 2H), 7.20 (s, 1H), 7.31–7.38
(m, 2H), 7.43 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.59–7.63
(m, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.88–7.90
(m, 3H), 8.37 (br s, 1H), 8.67 (d, J = 8.0 Hz, 1H), 8.85 (s, 1H). 13C
NMR (100 MHz, CDCl3): δ 157.21, 143.31, 141.26, 135.42, 133.35,
131.42, 130.51, 130.02, 129.14, 128.10, 127.85, 127.44, 127.23,
126.35, 125.63, 125.33, 125.28, 125.18, 124.63, 123.64, 105.15,
82.53, 76.87, 56.48, 56.17, 48.43, 44.67, 32.67. ESI MS (m/z):
[M + H]+ = 476.4. HRMS (ESI) m/z calcd for C33H33NO2 [M + H]+
:
476.2589, found 476.2590.
14, yield 2.86%, mp 185.7–187.7 °C. 1H NMR (400 MHz, CDCl3): δ
1.99 (br s, 8H), 2.34–2.37 (m, 1H), 2.48–2.51 (m, 1H), 3.02 (s, 3H),
5.89 (s, 1H), 6.53 (s, 1H), 7.18–7.24 (m, 5H), 7.35–7.43 (m, 4H), 7.54
(t, J = 7.2 Hz, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H),
7.94 (d, J = 7.6 Hz, 2H), 7.98 (d, J = 6.4 Hz, 1H), 8.19 (br s, 1H), 8.39
(s, 1H), 8.54 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 156.68,
142.73, 141.46, 134.85, 133.27, 131.49, 130.31, 129.88, 129.00,
128.23, 128.07, 127.48, 127.02, 126.30, 125.84, 125.70, 125.48,
125.18, 124.52, 123.53, 104.93, 82.74, 77.45, 56.52, 56.00, 48.97,
44.78, 33.57. ESI MS (m/z): [M + H]+ = 476.3. HRMS (ESI) m/z calcd
for C33H33NO2 [M + H]+: 476.2589, found 476.2590.
1-(7-Bromo-3-ethylnaphthalen-2-yl)-4-(dimethylamino)-2-
(naphthalen-1-yl)-1-phenylbutan-2-ol (11 and 12). In 100 mL three-
necked bottle, n-Butyl Lithium (2.5 M in hexane, 4 mL, 10 mmol) was
added slowly using an injector at −40 °C under nitrogen gas to a so-
lution of diisopropylamine (1.4 mL, 10 mmol) in anhydrous tetra-
hydrofuran (15 mL). The mixture was stirred at −40 °C for 30 min and
cooled to −78 °C.
A solution of 3-benzyl-6-bromo-2-methox-
ynaphthalene (8a, 3.0 g, 9.2 mmol) in anhydrous tetrahydrofuran
(15 mL) was dropped into the reaction. The mixture was stirred at
−78 °C for 40 min. A solution of 3-(dimethylamino)-1-(naphthalen-1-
yl) propan-1-one (10a, 2.9 g, 12.8 mmol) in anhydrous tetrahydrofuran
(15 mL) was added dropwise. The mixture was stirred at −78 °C for
10 h and hydrolyzed with saturated ammonium chloride aqueous so-
lution at −40 °C. The mixture was extracted with ethyl acetate and the
organic layer was dried over anhydrous magnesium sulfate, filtered and
the solvent was evaporated. The residue was purified by column
chromatography over silica gel (10–40 μm), eluent: ethyl acetate/pet-
roleum ether/methanol/ammonia water (1/50/0.05/0.01, v/v) to af-
ford two fractions. The first fraction was crystallized in isopropyl ether
to obtain compound 11 and the second fraction was crystallized in
isopropyl ether to obtain compound 12.
1-(7-Bromo-3-methoxynaphthalen-2-yl)-1-(4-chlorophenyl)-4-
(dimethylamino)-2-(naphthalen-1-yl) butan-2-ol (15 and 16). 15
and 16 was prepared from 8e and 10a according to the method of
compound 11 and 12.
15, yield 31.6%, mp 185.1–185.5 °C. 1H NMR (400 MHz, DMSO‑d6):
δ 1.86–1.91 (m, 8H), 2.01–2.08 (m, 2H), 3.28 (s, 3H), 5.82 (s, 1H), 6.79
(s, 1H), 7.29–7.45 (m, 6H), 7.56–7.60 (m, 2H), 7.79–7.84 (m, 4H), 7.92
(d, J = 1.6 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 8.48 (s, 1H), 8.57 (d,
J = 9.2 Hz, 1H). 13C NMR (100 MHz, DMSO-D6) δ 142.22, 140.81,
134.63, 133.90, 133.62, 129.87, 129.72, 129.47, 129.35, 128.83,
128.69, 128.34, 127.91, 127.43, 126.02, 125.67, 125.11, 116.34,
105.12, 81.45, 56.08, 55.72, 50.01, 44.89, 34.87. ESI MS (m/z):
[M + H]+ = 590.3. HRMS (ESI) m/z calcd for C33H31BrClNO2
[M + H]+: 590.1284 found 590.1279.
11, yield 2.95%, mp 168.1–169.1 °C. 1H NMR (400 MHz, CDCl3): δ
2.00–2.05 (m, 8H), 2.35 (br s, 1H), 2.51 (br s, 1H), 3.01 (s, 3H), 5.87 (s,
1H), 6.48 (s, 1H), 7.21–7.27 (m, 4H), 7.35–7.44 (m, 3H), 7.52–7.57 (m,
2H), 7.78 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.91–7.95 (m, 3H), 8.21 (br
s, 1H), 8.33 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 157.15, 143.17, 133.52, 131.25, 130.98, 129.38, 128.52,
127.47, 126.91, 126.13, 125.98, 125.40, 124.87, 124.27, 123.85,
123.49, 104.62, 88.55, 78.34, 77.52, 77.37, 76.31, 76.08, 56.54, 54.93,
51.32, 43.89, 35.01. ESI MS (m/z): [M + H]+ = 556.5. HRMS (ESI) m/
z calcd for C33H32BrNO2 [M + H]+: 556.1674, found 556.1670.
12, yield 2.36%, mp 200.9–201.6 °C. 1H NMR (400 MHz, CDCl3): δ
1.92 (m, 2H), 1.98 (s, 6H), 2.18 (t, J = 9.6 Hz, 1H), 2.45 (m, 1H), 4.07
(s, 3H), 6.05 (s, 1H), 6.88 (t, J = 3.2 Hz, 3H), 7.11 (s, 2H), 7.16 (s, 1H),
7.32 (t, J = 8.0 Hz, 1H), 7.47–7.51 (m, 2H), 7.60 (t, J = 8.8 Hz, 2H),
7.68 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 8.34 (br
s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.75 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 155.98, 142.41, 133.18, 130.36, 130.01, 129.90, 128.44,
127.95, 127.84, 127.55, 127.36, 126.39, 125.88, 125.01, 124.66,
124.29, 104.08, 81.95, 77.44, 77.33, 77.12, 76.81, 76.73, 56.44, 54.64,
50.56, 44.81, 34.39. ESI MS (m/z): [M + H]+ = 556.5. HRMS (ESI) m/
z calcd for C33H32BrNO2 [M + H]+: 556.1674, found 556.1670.
4-(Dimethylamino)-1-(3-methoxynaphthalen-2-yl)-2-
16, yield 25.3%, mp 149.0–149.9 °C. 1H NMR (400 MHz, CDCl3): δ
1.94–1.99 (m, 8H), 2.17 (br s, 1H), 2.45 (br s, 1H), 4.07 (s, 3H), 6.01 (s,
1H), 6.84 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 7.16 (s, 1H),
7.35 (t, J = 8.0 Hz, 2H), 7.47–7.51 (m, 2H), 7.58–7.63 (m, 2H), 7.69
(d, J = 7.6 Hz, 2H), 7.90 (t, J = 8.0 Hz 2H), 8.02 (s, 1H), 8.39 (br s,
1H), 8.59 (d, J = 8.4 Hz, 1H), 8.67 (s, 1H). 13C NMR (100 MHz, DMSO-
D6) δ 143.12, 141.35, 134.81, 133.93 133.68, 129.98, 129.72, 129.35,
129.10, 127.90, 127.14, 127.04, 126.83, 125.84, 125.02, 124.82,
124.31, 116.29, 103.79, 80.86, 57.23, 54.31, 50.42, 43.93, 35.15. ESI
MS (m/z): [M
+
H]+
= 590.3. HRMS (ESI) m/z calcd for
C
33H31BrClNO2 [M + H]+: 590.1284 found 590.1280.
1-(4-Chlorophenyl)-4-(dimethylamino)-1-(3-methox-
ynaphthalen-2-yl)-2-(naphthalen-1-yl) butan-2-ol (17 and 18). 17
and 18 was prepared from 8h and 10a according to the method of
compound 11 and 12.
17, yield 30.1%, mp 215.4–215.9 °C. 1H NMR (400 MHz, CDCl3): δ
2.00 (br s, 8H), 2.27 (t, J = 12.4 Hz, 1H), 2.48 (d, J = 12.8 Hz, 1H),
3.09 (s, 3H), 5.85 (s, 1H), 6.54 (s, 1H), 7.17–7.24 (m, 3H), 7.32 (d,
J = 8.0 Hz, 2H), 7.38–7.42 (m, 2H), 7.51–7.55 (m, 2H), 7.69 (d,
J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H),
8.02 (d, J = 6.8 Hz, 1H), 8.24 (br s, 1H), 8.37 (s, 1H), 8.48 (d,
8

P. Liu, et al.
BioorganicChemistry102(2020)104054
J = 8.8 Hz, 1H). 13C NMR (100 MHz, CDCl3):δ 155.37, 141.15, 134.47,
133.90, 130.98, 130.53, 130.27, 130.05, 129.84, 129.16, 128.81,
128.15, 127.62, 127.41, 126.63, 125.35, 124.72, 124.38, 124.27,
123.81, 123.14, 104.31, 57.31, 56.43, 47.15, 43.26, 35.72. ESI MS (m/
z): [M + H]+ = 510.4. HRMS (ESI) m/z calcd for C33H32ClNO2
[M + H]+: 510.2200 found 510.2194.
618.0227.
1-(7-Bromo-3-methoxynaphthalen-2-yl)-2-(4-bromophenyl)-4-
(dimethylamino)-1-phenylbutan-2-ol (23 and 24). 23 and 24 was
prepared from 8a and 10e according to the method of compound 13
and 14.
23, yield 3.17%, mp 189.8–190.7 °C. 1H NMR (400 MHz, CDCl3): δ
1.70 (br s, 1H), 2.04–2.21 (m, 9H), 3.95 (s, 3H), 5.00 (s, 1H), 6.96–7.02
(m, 3H), 7.08 (s, 1H), 7.23 (d, J = 7.2 Hz, 2H), 7.34 (dd, J = 8.8,
12.0 Hz, 4H), 7.45 (dd, J = 2.0, 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H),
7.96 (d, J = 1.6 Hz, 1H), 8.15 (br s, 1H), 8.67 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ155.17, 134.02, 131.73, 131.38, 130.97, 130.27,
129.31, 128.92, 128.28, 128.05, 127.51, 120.05, 117.38, 105.18,
80.29, 78.02, 77.21, 77.15, 76.21, 54.93, 55.21, 52.72, 45.17, 35.29.
ESI MS (m/z): [M + H]+ = 584.2. HRMS (ESI) m/z calcd for
18, yield 24.8%, mp 180.5–181.2 °C. 1H NMR (400 MHz, CDCl3): δ
1.98 (br s, 8H), 2.24 (br s, 1H), 2.43 (br s, 1H), 4.07 (s, 3H), 6.03 (s,
1H), 6.83 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 7.6 Hz, 2H), 7.20 (s, 1H),
7.33–7.38 (m, 2H), 7.43 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H),
7.60 (t, J = 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.4 Hz,
1H), 7.86–7.91 (m, 3H), 8.41 (br s, 1H), 8.62 (d, J = 8.0 Hz, 1H), 8.76
(s, 1H). 13C NMR (100 MHz, CDCl3):δ 156.48, 140.16, 134.87, 133.30,
131.91, 131.60, 131.34, 131.21, 130.07, 129.96, 128.94, 128.24,
128.19, 127.51, 127.16, 126.33, 125.99, 125.48, 125.27, 124.60,
123.67, 105.01, 56.48, 56.00, 48.37, 44.76, 33.41. ESI MS (m/z):
C
29H29Br2NO2 [M + H]+: 584.0623 found 584.0619.
24, yield 4.34%, mp 228.2–229.9 °C. 1H NMR (400 MHz, CDCl3): δ
[M
+
H]+
=
510.4. HRMS (ESI) m/z calcd for C33H32ClNO2
1.62 (br s, 1H), 2.03–2.17 (m, 9H), 3.69 (s, 3H), 4.94 (s, 1H), 6.74 (s,
1H), 7.19–7.40 (m, 9H), 7.71 (d, J = 6.8 Hz, 2H), 7.86 (d, J = 1.6 Hz,
1H), 8.08 (br s, 1H), 8.38 (s, 1H). 13C NMR (100 MHz, CDCl3): δ155.80,
133.42, 131.34, 131.10, 130.58, 130.01, 129.21, 128.64, 128.03,
127.78, 126.32, 119.77, 116.50, 104.41, 81.03, 77.40, 77.31, 77.07,
76.77, 55.87, 55.46, 52.08, 44.79, 36.07. ESI MS (m/z):
[M + H]+ = 584.2. HRMS (ESI) m/z calcd for C29H29Br2NO2
[M + H]+: 584.0623 found 584.0617.
[M + H]+: 510.2200 found 510.2194.
1-(7-Bromo-3-methoxynaphthalen-2-yl)-2-(3-bromophenyl)-1-
(4-chlorophenyl)-4-(dimethylamino) butan-2-ol (19 and 20). 19
and 20 was prepared from 8e and 10d according to the method of
compound 11 and 12.
19, yield 35.3%, mp 177.1–177.6 °C. 1H NMR (400 MHz, CDCl3): δ
1.62 (br s, 1H), 2.06 (br s, 8H), 2.22–2.24 (m, 1H), 3.73 (s, 3H), 4.93 (s,
1H), 6.75 (s, 1H), 6.98 (t, J = 8.0 Hz, 1H), 7.14 (dd, J = 0.8 Hz, 8.0 Hz,
1H), 7.26 (d, J = 8.8 Hz, 2H), 7.32–7.39 (m, 3H), 7.63 (s, 1H), 7.69 (d,
J = 8.4 Hz, 2H), 7.85 (d, J = 1.6 Hz, 2H), 8.23 (br s, 1H), 8.31 (s, 1H).
13C NMR (100 MHz, CDCl3): δ 155.59, 149.93, 140.30, 132.96, 132.38,
132.18, 130.00, 129.23, 129.12, 129.06, 128.80, 127.95, 124.97,
122.03, 104.50, 81.01, 77.45, 55.91, 55.59, 51.26, 44.85, 36.03. ESI
1-(7-Bromo-3-methoxynaphthalen-2-yl)-2-(3-bromophenyl)-4-
(dimethylamino)-1-phenylbutan-2-ol (25 and 26). 25 and 26was
prepared from 8a and 10d according to the method of compound 13
and 14.
25, yield 2.96%, mp 212.3–212.8 °C. 1H NMR (400 MHz, CDCl3): δ
1.70 (d, J = 10.8 Hz, 1H), 2.04–2.25 (m, 9H), 3.96 (s, 3H), 4.99 (s, 1H),
6.94–7.12 (m, 5H), 7.24 (d, J = 7.6 Hz, 3H), 7.39 (d, J = 7.6 Hz, 1H),
7.45 (dd, J = 1.6, 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.600 (s, 1H),
7.97 (d, J = 1.6 Hz, 1H), 8.20 (br s, 1H), 8.67 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ156.58, 140.86, 133.74, 131.63, 130.36, 130.04,
129.62, 129.45, 129.34, 129.16, 129.05, 127.94, 127.37, 125.74,
125.14, 122.26, 116.93, 104.81, 81.68, 77.40, 77.08, 56.10, 55.83,
51.76, 44.87, 34.73. ESI MS (m/z): [M + H]+ = 584.3. HRMS (ESI) m/
z calcd for C29H29Br2NO2 [M + H]+: 584.0623 found 584.0618.
26, yield 4.17%, mp 200.2–200.6 °C. 1H NMR (400 MHz, CDCl3): δ
1.61 (br s, 1H), 2.05–2.24 (m, 9H), 3.73 (s, 3H), 4.98 (s, 1H), 6.74 (s,
1H), 6.98 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.19–7.42 (m,
6H), 7.64 (s, 1H), 7.75 (s, 2H), 7.86 (d, J = 1.6 Hz, 1H), 8.15 (br s, 1H),
8.34 (s, 1H). 13C NMR (100 MHz, CDCl3): δ155.72, 141.07, 134.05,
131.21, 130.72, 130.40, 129.93, 129.55, 129.01, 128.87, 128.52,
127.31, 127.01, 125.25, 125.11, 123.06, 117.13, 103.92, 82.02, 77.41,
77.04, 55.83, 55.65, 51.26, 44.72, 35.73. ESI MS (m/z):
[M + H]+ = 584.2. HRMS (ESI) m/z calcd for C29H29Br2NO2
[M + H]+: 584.0623 found 584.0616.
MS (m/z): [M
+
H]+
= 618.1. HRMS (ESI) m/z calcd for
C29H28Br2ClNO2 [M + H]+: 618.0233 found 618.0229.
20, yield 27.2%, mp 183.9–184.9 °C. 1H NMR (400 MHz, CDCl3): δ
1.67 (d, J = 11.2 Hz, 1H), 2.05–2.23 (m, 9H), 3.96 (s, 3H), 4.95 (s, 1H),
6.97 (d, J = 8.4 Hz, 2H), 7.08 (s, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.19 (d,
J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H),
7.46 (dd, J = 2.0, 8.4 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H),
7.96 (d, J = 1.6 Hz, 1H), 8.27 (s, 1H), 8.62 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 156.39, 150.12, 139.64, 133.33, 131.68, 131.52, 130.02,
129.95, 129.52, 129.35, 129.23, 128.00, 127.54, 125.10, 122.40,
117.08, 104.91, 81.56, 77.46, 56.08, 55.85, 51.10, 44.88, 34.64. ESI
MS (m/z): [M
+
H]+
= 618.2. HRMS (ESI) m/z calcd for
C
29H28Br2ClNO2 [M + H]+: 618.0233 found 618.0228.
1-(7-Bromo-3-methoxynaphthalen-2-yl)-2-(4-bromophenyl)-1-
(4-chlorophenyl)-4-(dimethylamino)butan-2-ol (21 and 22). 21
and 22 was prepared from 8e and 10e according to the method of
compound 11 and 12.
21, yield 34.7%, mp 219.5–220.4 °C. 1H NMR (400 MHz, CDCl3): δ
1.60 (br s, 1H), 2.05–2.24 (m, 9H), 3.70 (s, 3H), 4.90 (s, 1H), 6.75 (s,
1H), 724–7.28 (m, 4H), 7.33–7.40 (m, 4H), 7.65 (d, J = 8.4 Hz, 2H),
7.84 (d, J = 1.6 Hz, 1H), 8.16 (br s, 1H), 8.35 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 155.65, 146.47, 140.19, 133.07, 132.12, 131.40,
130.71, 130.00, 129.75, 129.03, 128.81, 127.95, 127.92, 127.02,
120.15, 116.42, 104.12, 81.73, 77.05, 55.92, 55.76, 50.97, 45.29,
33.57. ESI MS (m/z): [M + H]+ = 618.3. HRMS (ESI) m/z calcd for
1-(7-Bromo-3-methoxynaphthalen-2-yl)-1-(4-chlorophenyl)-4-
(dimethylamino)-2-phenylbutan-2-ol (27 and 28). 27 and 28 was
prepared from 8e and 10b according to the method of compound 11
and 12.
27, yield 30.2%, mp 196.8–197.3 °C. 1H NMR (400 MHz, CDCl3): δ
1.62 (br s, 1H), 2.05–2.26 (m, 9H), 3.69 (s, 3H), 4.96 (s, 1H), 6.73 (s,
1H), 7.01 (t, J = 7.2 Hz, 1H), 7.15 (t, J = 7.6 Hz, 2H), 7.24 (s, 1H),
7.26 (s, 1H), 7.32 (dd, J = 2.0, 8.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H),
7.49 (d, J = 6.8 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 1.6 Hz,
1H), 8.06 (br s, 1H), 8.38 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 155.85,
147.13, 140.47, 132.58, 131.96, 128.62, 127.75, 127.64, 125.98,
125.90, 116.50, 81.09, 55.94, 51.74, 44.85, 36.41. ESI MS (m/z):
[M + H]+ = 540.2. HRMS (ESI) m/z calcd for C29H29BrClNO2
[M + H]+: 540.1128 found 540.1119.
C
29H28Br2ClNO2 [M + H]+: 618.0233 found 618.0228.
22, yield 25.3%, mp 213.5–214.2 °C. 1H NMR (400 MHz, CDCl3): δ
1.68 (d, J = 11.2 Hz, 1H), 2.04–2.20 (m, 9H), 3.94 (s, 3H), 4.95 (s, 1H),
6.96 (d, J = 8.4 Hz, 2H), 7.08 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.32 (d,
J = 8.8 Hz, 2H), 7.37 (d, J = 9.2 Hz, 2H), 7.46 (dd, J = 2.0, 8.4 Hz,
1H), 7.57 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 1.2 Hz, 1H), 8.20 (br s, 1H),
8.62 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 155.17, 146.81, 141.02,
133.41, 132.80, 130.74, 130.02, 129.74, 129.55, 128.97, 128.65,
128.31, 127.90, 127.78, 119.91, 116.66, 104.52, 80.97, 77.07, 55.85,
55.47, 51.49, 44.83, 36.08. ESI MS (m/z): [M + H]+ = 618.3. HRMS
(ESI) m/z calcd for C29H28Br2ClNO2 [M + H]+: 618.0233 found
28, yield 25.7%, mp 182.2–182.8 °C. 1H NMR (400 MHz, CDCl3): δ
1.72 (d, J = 10.0 Hz, 1H), 2.04–2.22 (m, 9H), 3.95 (s, 3H), 5.02 (s, 1H),
6.93 (d, J = 8.4 Hz, 2H), 7.08 (s, 1H), 7.13–7.17 (m, 3H), 7.24–7.27
(m, 2H), 7.43–7.47 (m, 3H), 7.58 (d, J = 8.4 Hz, 1H), 7.97 (d,
9

P. Liu, et al.
BioorganicChemistry102(2020)104054
J = 1.6 Hz, 1H), 8.14 (br s, 1H), 8.68 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 156.35, 147.63, 141.02, 133.18, 132.64, 129.12, 127.25,
126.92, 125.08, 124.91, 116.02, 82.39, 54.03, 51.47, 44.21, 35.41. ESI
34, yield 3.46%, mp 200.2–200.7 °C. 1H NMR (400 MHz, CDCl3): δ
2.03–2.17 (m, 9H), 2.75 (br s, 1H), 3.97 (s, 3H), 6.09 (s, 1H), 6.92–7.01
(m, 4H), 7.08 (s, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.33–7.35 (m, 2H), 7.45
(dd, J = 2.0, 8.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.8 Hz,
1H), 7.81 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 8.29 (br s, 1H),
8.70 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 157.00, 145.08, 140.23,
134.96, 133.22, 131.44, 130.13, 130.04, 129.91, 129.10, 128.44,
127.95, 127.41, 127.13, 119.61, 116.91, 104.89, 82.76, 56.51, 55.90,
45.77, 44.77, 30.81. ESI MS (m/z): [M + H]+ = 584.0. HRMS (ESI) m/
MS (m/z): [M
+
H]+
= 540.2. HRMS (ESI) m/z calcd for
C
29H29BrClNO2 [M + H]+: 540.1128 found 540.1120.
1-(7-Bromo-3-methoxynaphthalen-2-yl)-4-(dimethylamino)-
1,2-diphenylbutan-2-ol (29 and 30). 29 and 30 was prepared from
8a and 10b according to the method of compound 13 and 14.
29, yield 2.73%, mp 170.9–171.6 °C. 1H NMR (400 MHz, CDCl3): δ
1.73 (d, J = 10.8 Hz, 1H), 1.98–2.25 (m, 9H), 3.95 (s, 3H), 5.06 (s, 1H),
6.93–7.00 (m, 3H), 7.05 (s, H), 7.11 (t, J = 7.2 Hz, 1H), 7.21–7.24 (m,
3H), 7.44–7.46 (m, 3H), 7.57 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 2.0 Hz,
1H), 8.08 (s, 1H), 8.73 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 155.65,
148.52, 142.74, 133.53, 131.56, 130.52, 129.17, 128.78, 128.00,
127.02, 126.54, 125.32, 104.78, 80.73, 77.43, 75.93, 55.21, 51.34,
44.72, 35.87. ESI MS (m/z): [M + H]+ = 506.4. HRMS (ESI) m/z calcd
for C29H30BrNO2 [M + H]+: 506.1517 found 506.1515.
z calcd for C29H29Br2NO2 [M + H]+ +
: : 584.0623 found 584.0617.
1-(4-Chlorophenyl)-2-(2,4-difluorophenyl)-4-(dimethylamino)-
1-(3-methoxynaphthalen-2-yl)butan-2-ol (35 and 36). 35 and 36
was prepared from 8gand 10f according to the method of compound 11
and 12.
35, yield 9.57%, oil. 1H NMR (400 MHz, CDCl3): δ 2.04–2.34 (m,
10H), 3.68 (s, 3H), 5.24 (s, 1H), 6.58–6.64 (m, 2H), 6.78 (s, 1H),
7.21–7.30 (m, 4H), 7.52 (d, J = 8.0 Hz, 2H), 7.61–7.72 (m, 4H), 8.30
(s, 1H). 13C NMR (100 MHz, CDCl3): δ141.21, 132.25, 131.27, 131.28,
128.53, 128.02, 126.86, 126.35, 123.92, 111.03, 105.39, 104.17,
103.82, 81.38, 77.35, 58.64, 56.17, 47.23, 45.21, 33.62. ESI MS (m/z):
[M + H]+ = 496.0. HRMS (ESI) m/z calcd for C29H28ClF2NO2
[M + H]+: 496.1855 found 496.1849.
30, yield 3.51%, mp 201.9–203.7 °C. 1H NMR (400 MHz, CDCl3): δ
1.65 (br s, 1H), 2.02–2.29 (m, 9H), 3.68 (s, 3H), 5.00 (s, 1H), 6.72 (s,
1H), 7.00 (t, J = 7.2 Hz, 1H), 7.12–7.21 (m, 3H), 7.26–7.37 (m, 4H),
7.50 (d, J = 8 Hz, 2H), 7.73 (d, J = 7.2 Hz, 2H), 7.86 (d, J = 1.6 Hz,
1H), 8.00 (br s, 1H), 8.42 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 156.02,
147.45, 141.91, 133.88, 131.23, 130.04, 129.26, 128.46, 127.66,
126.17, 126.06, 125.76, 104.32, 81.16, 77.39, 76.75, 55.97, 52.31,
44.82, 36.40. ESI MS (m/z): [M + H]+ = 506.4. HRMS (ESI) m/z calcd
for C29H30BrNO2 [M + H]+: 506.1517 found 506.1517.
36, yield 5.31%, mp 190.6–192.4 °C. 1H NMR (400 MHz, CDCl3): δ
2.05–2.23 (m, 10H), 3.94 (s, 3H), 5.29 (s, 1H), 6.70–6.77 (m, 2H), 6.96
(d, J = 8.4 Hz, 2H), 7.12 (s, 1H), 7.23–7.28 (m, 2H), 7.33 (dt, J = 1.2,
6.8 Hz, 1H), 7.40 (dt, J = 1.2, 6.8 Hz, 1H), 7.48–7.54 (m, 1H), 7.70 (d,
J = 8.4 Hz, 1H), 7.82 (d, J = 7.6 Hz, 2H), 8.43 (br s, 1H), 8.76 (s, 1H).
13C NMR (100 MHz, CDCl3): δ140.27, 131.95, 131.42, 130.41, 128.12,
127.42, 126.26, 125.94, 123.55, 110.81, 104.99, 103.85, 103.60,
80.99, 77.34, 56.61, 55.81, 48.37, 44.71, 32.44. ESI MS (m/z):
[M + H]+ = 496.3. HRMS (ESI) m/z calcd for C29H28ClF2NO2
[M + H]+: 496.1855 found 496.1848.
1-(7-Bromo-3-methoxynaphthalen-2-yl)-2-(2-bromophenyl)-1-
(4-chlorophenyl)-4-(dimethylamino)butan-2-ol (31 and 32). 31
and 32 was prepared from 8e and 10c according to the method of
compound 11 and 12.
31, yield 29.3%, mp 219.1–219.8 °C. 1H NMR (400 MHz, CDCl3): δ
2.02–2.18 (m, 9H), 2.77 (br s, 1H), 3.66 (s, 3H), 5.89 (s, 1H), 6.73 (s,
1H), 6.89 (dt, J = 1.6, 6.8 Hz, 1H), 7.10 (dt, J = 1.2, 8.0 Hz, 1H),
7.25–7.28 (m, 2H), 7.39–7.41 (m, 3H), 7.68 (d, J = 8.4 Hz, 2H), 7.84
(s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 8.30 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 156.57, 144.88, 140.54, 135.26, 131.92, 130.94, 130.03,
129.98, 129.01, 128.82, 128.24, 127.21, 127.01, 126.53, 119.25,
117.31, 104.72, 82.16, 77.39, 77.05, 76.82, 55.31, 54.73, 45.57, 44.83,
32.17. ESI MS (m/z): [M + H]+ = 618.3. HRMS (ESI) m/z calcd for
1-(7-Bromo-3-methoxynaphthalen-2-yl)-4-(dimethylamino)-2-
(naphthalen-1-yl)-1-p-tolylbutan-2-ol (37 and 38). 37 and 38 was
prepared from 8b and 10a according to the method of compound 13
and 14.
37, yield 1.75%, oil. 1H NMR (400 MHz, CDCl3): δ 1.90–2.19 (m,
12H), 2.55 (d, J = 12.4 Hz, 1H), 4.06 (s, 3H), 6.02 (s, 1H), 6.69 (d,
J = 7.6 Hz, 2H), 7.01 (d, J = 6.8 Hz, 2H), 7.14 (s, 1H), 7.32–7.37 (m,
1H), 7.45–7.50 (m, 2H), 7.59 (d, J = 7.6 Hz, 2H), 7.68 (d, J = 7.6 Hz,
1H), 7.88 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 6.8 Hz, 1H), 8.01 (s, 1H),
7.63 (s, 1H), 8.65 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 156.79,
135.04, 134.82, 131.71, 130.55, 130.08, 130.01, 129.92, 129.06,
128.17, 127.99, 127.46, 125.29, 125.21, 124.60, 116.99, 104.97,
56.22, 56.05, 48.67, 44.57, 33.67, 20.94. ESI MS (m/z):
C
29H28Br2ClNO2 [M + H]+: 618.0233 found 618.0226.
32, yield 25.2%, mp 180.8–181.6 °C. 1H NMR (400 MHz, CDCl3): δ
2.02–2.17 (m, 9H), 2.74 (br s, 1H), 3.97 (s, 3H), 6.08 (s, 1H), 6.95 (d,
J = 8.4 Hz, 2H), 7.00 (t, J = 7.6 Hz, 1H), 7.09 (s, 1H), 7.16 (t,
J = 7.6 Hz, 1H), 7.29 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 8.4 Hz, 1H),
7.53–7.59 (m, 2H), 7.83 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H), 8.36 (br s,
1H), 8.63 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 157.00, 145.08,
140.23, 134.96, 133.22, 131.44, 130.13, 130.04, 129.91, 129.10,
128.44, 127.95, 127.41, 127.13, 119.61, 116.91, 104.89, 82.76, 77.44,
77.12, 76.80, 56.51, 55.90, 45.77, 44.77, 30.81. ESI MS (m/z):
[M + H]+ = 618.5. HRMS (ESI) m/z calcd for C29H28Br2ClNO2
[M + H]+: 618.0233 found 618.0227.
[M
+
H]+
= 569.9. HRMS (ESI) m/z calcd for C34H34BrNO2
[M + H]+: 570.1830 found 570.1831.
38, yield 3.03%, mp 189.5–190.8 °C. 1H NMR (400 MHz, DMSO‑d6):
δ 1.86–1.91 (m, 8H), 2.09–2.11 (m, 2H), 2.28 (s, 3H), 3.20 (s, 3H), 5.77
(s, 1H), 6.75 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.27–7.36 (m, 2H),
7.42–7.46 (m, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 7.6 Hz, 2H),
7.80 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 8.04 (d, J = 7.2 Hz, 1H), 8.48 (s,
1H), 8.57 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 155.36,
135.57, 134.68, 132.41, 131.58, 130.37, 130.29, 129.29, 128.83,
128.07, 127.21, 128.79, 125.37, 125.02, 124.17, 117.03, 104.21,
57.17, 56.72, 47.1, 45.37, 35.67, 22.31. ESI MS (m/z):
1-(7-Bromo-3-methoxynaphthalen-2-yl)-2-(2-bromophenyl)-4-
(dimethylamino)-1-phenylbutan-2-ol (33 and 34). 33 and 34 was
prepared from 8a and 10c according to the method of compound 13
and 14.
33, yield 2.95%, mp 210.8–212.1 °C. 1H NMR (400 MHz, CDCl3): δ
2.02–2.18 (m, 9H), 2.82 (br s, 1H), 3.64 (s, 3H), 5.90 (s, 1H), 6,71 (s,
1H), 6.88 (dt, J = 1.6, 7.6 Hz, 1H), 7.07 (dt, J = 1.2, 8.0 Hz, 1H), 7.21
(d, J = 7.2 Hz, 1H), 7.28–7.38 (m, 5H), 7.43 (dd, J = 1.6, 8.0 Hz, 1H),
7.77 (d, J = 7.6 Hz, 2H), 7.85 (d, J = 1.2 Hz, 1H), 7.91 (d, J = 7.2 Hz,
1H), 8.15 (br s, 1H), 8.32 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 155.85,
145.21, 141.31, 135.32, 133.51, 131.72, 130.57, 129.82, 129.71,
129.27, 128.76, 127.47, 127.32, 126.84, 119.15, 116.03, 103.98,
81.83, 55.97, 55.15, 46.32, 45.07, 31.27. ESI MS (m/z):
[M + H]+ = 584.3. HRMS (ESI) m/z calcd for C29H29Br2NO2
[M + H]+: 584.0623 found 584.0616.
[M
+
H]+
= 570.1. HRMS (ESI) m/z calcd for C34H34BrNO2
[M + H]+: 570.1830 found 570.1830.
1-(4,7-Dibromo-3-methoxynaphthalen-2-yl)-4-(dimethyla-
mino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol (39 and 40). 39 and
40 was prepared from 8i and 10a according to the method of com-
pound 13 and 14.
39, yield 20.5%, mp 181.2–181.5 °C. 1H NMR (400 MHz, CDCl3): δ
1.94–2.08 (m, 9H), 2.48 (br s, 1H), 3.85 (s, 3H), 5.91 (s, 1H), 6.89–6.91
(m, 3H), 7.02–7.04 (m, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.52 (t,
J = 7.6 Hz, 1H), 7.61–7.71 (m, 3H), 7.81 (d, J = 7.2 Hz, 1H), 7.92 (d,
10

P. Liu, et al.
BioorganicChemistry102(2020)104054
J = 8.4 Hz, 1H), 8.11 (d, J = 9.2 Hz, 2H), 8.45 (br s, 1H), 8.64 (d,
J = 8.8 Hz, 1H), 8.96 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 140.33,
137.63, 134.83, 132.65, 130.57, 130.44, 130.19, 128.51, 127.50,
127.26, 126.00, 125.56, 125.22, 124.70, 82.69, 61.66, 56.41, 50.90,
44.77, 33.61. ESI MS (m/z): [M + H]+ = 634.6. HRMS (ESI) m/z calcd
for C33H31Br2NO2 [M + H]+: 634.0779 found 634.0773.
for C33H31BrClNO2 [M + H]+: 590.1284 found 590.1281.
1-(7-Bromo-3-methoxynaphthalen-2-yl)-4-(dimethylamino)-2-
(naphthalen-1-yl)-1-m-tolylbutan-2-ol (45 and 46). 45 and 46 was
prepared from 8c and 10a according to the method of compound 13
and 14.
45, yield 2.35%, mp 190.7–192.3 °C. 1H NMR (400 MHz, CDCl3): δ
1.87–1.99 (m, 8H), 2.01 (s, 3H), 2.09–2.16 (m, 1H), 2.46 (d,
J = 14.4 Hz, 1H), 4.07 (s, 3H), 6.00 (s, 1H), 6.68 (d, J = 7.2 Hz, 1H),
7.77 (t, J = 7.6 Hz, 1H), 6.89 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 7.15 (s,
1H), 7.34 (t, J = 7.6 Hz, 1H), 7.46–7.49 (m, 2H), 7.57–7.62 (m, 2H),
7.67 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.2 Hz,
1H), 8.02 (s, 1H), 8.24 (br s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 8.69 (s, 1H).
13C NMR (100 MHz, CDCl3): δ156.92, 142.58, 141.24, 136.36, 134.86,
133.76, 131.70, 131.04, 130.79, 130.13, 129.88, 129.01, 128.09,
127.60, 127.32, 126.95, 126.40, 125.60, 125.18, 124.51, 116.93,
104.82, 82.69, 56.51, 56.04, 48.93, 44.84, 33.66, 21.49. ESI MS (m/z):
40, yield 24.4%, mp 189.9–190.5 °C. 1H NMR (400 MHz, CDCl3): δ
1.97–2.03 (m, 8H), 2.22 (t, J = 13.2 Hz, 1H), 2.49 (t, J = 14.4 Hz, 1H),
3.23 (s, 3H), 5.71 (s, 1H), 7.22–7.25 (m, 1H), 7.32–7.43 (m, 5H),
7.53–7.57 (m, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.73–7.80 (m, 4H), 7.93
(d, J = 1.6 Hz, 1H), 8.31 (d, J = 7.2 Hz, 1H), 8.37 (br s, 1H), 8.51 (d,
J = 8.8 Hz, 1H), 8.81 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 141.52,
138.07, 134.23, 133.54, 130.57, 130.57, 130.02, 128.37, 127.16,
126.76, 126.25, 125.81, 124.87, 123.81, 81.62, 60.57, 56.58, 51.26,
44.38, 34.15. ESI MS (m/z): [M + H]+ = 634.5. HRMS (ESI) m/z calcd
for C33H31Br2NO2 [M + H]+: 634.0779 found 634.0774.
1,6-Dibromo-3-(4-(dimethylamino)-2-hydroxy-2-(naphthalen-
1-yl)-1-phenylbutyl)naphthalen-2-ol (41 and 42). 41 and 42 was
prepared from 8j and 10a according to the method of compound 13 and
14.
[M
+
H]+
= 570.7. HRMS (ESI) m/z calcd for C34H34BrNO2
[M + H]+: 570.1830, found 570.1829.
46, yield 3.14%, mp 185.6–186.9 °C. 1H NMR (400 MHz, CDCl3): δ
1.95–2.00 (m, 8H), 2.36–2.51 (m, 5H), 2.92 (s, 3H), 5.82 (s, 1H), 6.46
(s, 1H), 7.07 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.26–7.29
(m, 3H), 7.42 (t, J = 7.2 Hz, 1H), 7.53–7.56 (m, 2H), 7.70 (s, 1H),
7.78–7.83 (m, 2H), 7.88–7.89 (m, 2H), 8.17 (br s, 1H), 8.30 (s, 1H),
8.52 (d, J = 8.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ155.81, 143.97,
141.72, 137.16, 135.36, 133.80, 131.20, 130.81 130.61, 130.23,
129.61, 129.51, 128.59, 127.16, 127.22, 126.71, 126.10, 125.81,
125.23, 123.96, 116.42, 103.97, 83.01, 55.21, 56.81, 49.17, 45.04,
31.82, 22.62. ESI MS (m/z): [M + H] + = 570.5. HRMS (ESI) m/z calcd
for C34H34BrNO2 [M + H]+: 570.1830, found 570.1830.
41, yield 23.3%, mp 186.7–187.2 °C. 1H NMR (400 MHz, CDCl3): δ
2.14 (br s, 8H), 2.30–2.38 (m, 1H), 2.60 (d, J = 12.8 Hz, 1H), 5.45 (s,
1H), 6.81–6.97 (m, 5H), 7.38 (t, J = 8.0 Hz, 1H), 7.55–7.59 (m, 2H),
7.68 (t, J = 7.6 Hz, 2H), 7.77–7.82 (m, 2H), 7.93 (s, 1H), 7.99 (d,
J = 8.0 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 8.36 (d, J = 7.2 Hz, 1H),
12.11 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ151.53, 141.07, 139.26,
134.39, 132.18, 131.16, 131.01, 129.71, 129.51, 129.00, 128.92,
128.48, 127.50, 127.37, 126.01, 125.72, 125.56, 125.15, 124.72,
116.19, 56.82, 45.10, 33.07. ESI MS (m/z): [M + H]+ = 620.3. HRMS
(ESI) m/z calcd for
C32H29Br2NO2 [M
+
H]+
:
620.0623 found
1-(7-bromo-3-methoxynaphthalen-2-yl)-4-(dimethylamino)-2-
(naphthalen-1-yl)-1-o-tolylbutan-2-ol (47 and 48). 47 and 48 was
prepared from 8d and 10a according to the method of compound 13
and 14.
620.0617.
42, yield 26.1%, mp 185.8–186.4 °C. 1H NMR (400 MHz, CDCl3): δ
2.08–2.19 (m, 8H), 2.38 (br s, 1H), 2.55 (br s, 1H), 5.40 (s, 1H),
7.27–7.38 (m, 6H), 7.48 (t, J = 7.6 Hz, 1H), 7.60–7.66 (m, 2H), 7.74
(d, J = 8.8 Hz, 1H), 7.80–7.85 (m, 3H), 8.16 (d, J = 7.2 Hz, 1H), 8.45
(d, J = 8.8 Hz, 1H), 12.29 (br s, 1H). 13C NMR (100 MHz, CDCl3):
δ150.97, 140.28, 139.74, 134.93, 131.93, 130.67, 130.34, 129.88,
129.66, 129.32, 129.15, 128.58, 127.30, 127.17, 126.14, 125.88,
125.36, 125.01, 124.20, 116.63, 56.20, 44.21, 32.54. ESI MS (m/z):
[M + H]+ = 620.3. HRMS (ESI) m/z calcd for C32H29Br2NO2
[M + H]+: 620.0623 found 620.0619.
47, yield 2.16%, mp 198.6–199.8 °C. 1H NMR (400 MHz, CDCl3): δ
1.79 (s, 3H), 1.89–2.00 (m, 9H), 2.62 (d, J = 9.6 Hz, 1H), 4.20 (s, 3H),
6.18 (s, 1H), 6.61 (d, J = 7.2 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 6.99 (t,
J = 7.2 Hz, 1H), 7.19 (s, 1H), 7.37–7.45 (m, 3H), 7.54 (dt, J = 1.6,
7.2 Hz, 1H), 7.61 (t, J = 8.0 Hz, 2H), 7.81 (d, J = 7.2 Hz, 1H), 7.93 (d,
J = 1.6 Hz, 1H), 8.12 (s, 1H), 8.20 (br s, 1H), 8.22 (d, J = 6.4 Hz, 1H),
8.47 (d, J = 7.6 Hz, 1H), 8.74 (d, J = 9.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 157.02, 141.98, 141.03, 137.82, 134.51, 133.03, 131.53,
131.07, 130.92, 130.19, 130.08, 129.69, 129.12, 128.18, 128.00,
127.91, 127.05, 126.02, 125.00, 124.83, 124.10, 124.00, 116.08,
102.77, 81.45, 55.05, 53.02, 47.01, 44.29, 31.92, 22.10. ESI MS (m/z):
1-(7-Bromo-3-methoxynaphthalen-2-yl)-1-(3-chlorophenyl)-4-
(dimethylamino)-2-(naphthalen-1-yl)butan-2-ol (43 and 44). 43
and 44 was prepared from 8f and 10a according to the method of
compound 13 and 14.
[M
+
H]+
= 570.7. HRMS (ESI) m/z calcd for C34H34BrNO2
43, yield 26.3%, mp 176.8–177.3 °C. 1H NMR (400 MHz, CDCl3): δ
1.88–2.16 (m, 9H), 2.46 (d, J = 14.4 Hz, 1H), 4.08 (s, 3H), 6.00 (s, 1H),
6.78 (t, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 7.6 Hz,
1H), 7.17 (s, 1H), 7.24 (s, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.47–7.5 (m,
2H), 7.58 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.69 (d,
J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H),
8.03 (d, J = 1.2 Hz, 1H), 8.33 (br s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.63
(s, 1H). 13C NMR (100 MHz, CDCl3): δ 144.22, 135.20, 133.07, 131.02,
130.23, 129.53, 129.01, 128.17, 127.83, 127.05, 125.18, 124.19,
124.00, 123.01, 115.13, 105.14, 83.57, 57.52, 56.18, 49.62, 41.21,
33.91. ESI MS (m/z): [M + H]+ = 590.6. HRMS (ESI) m/z calcd for
[M + H]+: 570.1830, found 570.1829.
48, yield 2.85%, mp 207.8–208.1 °C. 1H NMR (400 MHz, CDCl3): δ
2.01–2.05 (m, 8H), 2.40–2.59 (m, 5H), 2.88 (s, 3H), 6.10 (s, 1H), 6.46
(s, 1H), 7.13–7.23 (m, 3H), 7.28–7.29 (m, 3H), 7.43 (t, J = 7.6 Hz, 1H),
7.52–7.59 (m, 2H), 7.82 (d, J = 7.2 Hz, 1H), 7.86–7.89 (m, 2H), 8.20
(br s, 1H), 8.24 (s, 1H), 8.49–8.54 (m, 2H). 13C NMR (100 MHz, CDCl3):
δ 156.25, 142.58, 140.82, 137.51, 134.63, 132.80, 131.69, 131.20,
130.78, 130.16, 130.03, 129.57, 129.49, 128.46, 127.85, 127.51,
127.39, 126.12, 125.59, 125.01, 124.64, 124.28, 116.20, 103.74,
82.22, 56.43, 54.32, 45.06, 44.79, 33.74, 21.10. ESI MS (m/z):
[M
+
H]+
= 570.6. HRMS (ESI) m/z calcd for C34H34BrNO2
C
33H31BrClNO2 [M + H]+: 590.1284 found 590.1281.
[M + H]+: 570.1830, found 570.1831.
44, yield 29.7%, mp 194.7–195.1 °C. 1H NMR (400 MHz, CDCl3): δ
1-(4-Chlorophenyl)-4-(dimethylamino)-1-(3-methox-
2.02 (br s, 8H), 2.25–2.31 (m, 1H), 2.49 (d, J = 14.0 Hz, 1H), 3.03 (s,
3H), 5.826 (s, 1H), 6.49 (s, 1H), 7.25–7.31 (m, 6H), 7.41 (d, J = 7.6 Hz,
1H), 7.52–7.56 (m, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.6 Hz,
1H), 7.87 (s, 1H), 7.95 (d, J = 7.6 Hz, 2H), 8.31 (s, 2H), 8.46 (d,
J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 143.68, 134.89, 132.82,
130.68, 130.00, 129.24, 128.44, 128.31, 128.03, 127.65, 125.81,
125.33, 125.20, 124.62, 117.12, 104.91, 82.44, 56.43, 56.07, 48.75,
44.81, 33.41. ESI MS (m/z): [M + H]+ = 590.5. HRMS (ESI) m/z calcd
ynaphthalen-2-yl)-2-(naphthalen-1-yl)butan-2-ol
hydrochloride
(49). In 50 mL three-necked bottle, compound (18, 100 mg,
0.196 mmol) was dissolved in acetone (5 mL). To the mixture was
added dropwise saturated Hydrogen Chloride-ether solution (20 mL).
The reaction solution was stirred for 12 h at room temperature, then
filtered and washed with ether to obtain off-white solid 49 (68 mg,
yield 63.6%): mp > 255 °C. 1H NMR (400 MHz, DMSO‑d6): δ 2.04 (br
s, 2H), 2.39 (s, 3H), 2.44 (s, 3H), 2.97–3.10 (m, 2H), 4.16 (s, 3H), 5.87
11

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BioorganicChemistry102(2020)104054
(s, 1H), 5.94 (s, 1H), 6.96 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 7.6 Hz, 2H),
7.33–7.39 (m, 2H), 7.44–7.47 (m, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.75
(d, J = 8.0 Hz, 2H), 7.83–7.87 (m, 3H), 7.95 (d, J = 8.4 Hz, 1H), 8.25
(s, 1H), 8.66 (d, J = 8.0 Hz, 1H), 9.53 (s, 1H). 13C NMR (100 MHz,
DMSO‑d6):δ 156.27, 140.35, 134.92, 133.39, 130.72, 130.04, 129.74,
129.29, 129.01, 128.75, 128.21, 128.00, 127.93, 127.01, 126.07,
125.71, 125.09, 124.78, 124.17, 123.79, 123.27, 104.83, 56.92, 56.03,
48.38, 44.19, 33.01.
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5.2. Biological analysis
The test compound MICs against Mtb strains were assessed by the
MABA using TMC207, RMP, INH, PC01 and PC02 as positive controls.
Compound stock solutions were prepared in DMSO at a concentration
of 5 mg/mL. Two-fold dilutions of compounds were prepared in
Middlebrook 7H9 broth medium in a volume of 100 μL in 96-well
plastic microtiter plates (Falcon3072, Becton Dickinson, Lincoln Park,
N. J.) and the final test concentrations ranged from 12.5 to 0.0125 μg/
ml. Mtb (100 μL inoculum of 2 × 106 CFU/mL) was added, yielding a
final testing volume of 200 μL. The plates were incubated at 37 °C. On
the 7th day of incubation 50 μL of 5% Tween 80 and 20 μL of Alamar
Blue (Setotec, England) were added to the test plate. After incubation at
37 °C for 24 h, the fluorescence was read in a computer-controlled
fluorometer (spectramax Gemini EM, Molecular Devices) at an excita-
tion wavelength of 530 nm and an emission wavelength of 590 nm. The
MICs were defined as the lowest concentration effecting a reduction in
fluorescence of ≥90% relative to the mean of replicate bacteria-only
controls. Reported MICs are an average of three individual measure-
ments.
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Suspensions of test compounds were prepared in 0.5% carbox-
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model, Antimicrob. Agents Chemother. 52 (2008) 3568–3572.
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Funding sources
[13] E. Huitric, P. Verhasselt, K. Andries, S.E. Hoffner, In vitro antimycobacterial spec-
trum of a diarylquinoline ATP synthase inhibitor, Antimicrob. Agents Chemother.
51 (2007) 4202–4204.
This work was funded by the National Science and Technology
Major Projects for “Major New Drugs Innovation and Development”
(2018ZX09711003) of China.
[14] E. Huitric, P. Verhasselt, A. Koul, K. Andries, S. Hoffner, D.I. Andersson, Rates and
mechanisms of resistance development in Mycobacterium tuberculosis to a novel
diarylquinoline ATP synthase inhibitor, Antimicrob. Agents Chemother. 54 (2010)
1022–1028.
Declaration of Competing Interest
[15] S. Petrella, E. Cambau, A. Chauffour, K. Andries, V. Jarlier, W. Sougakoff, Genetic
basis for natural and acquired resistance to the diarylquinoline R207910 in my-
cobacteria, Antimicrob. Agents Chemother. 50 (2006) 2853–2856.
[16] R.S. Upadhayaya, J.K. Vandavasi, N.R. Vasireddy, V. Sharma, S.S. Dixit,
J. Chattopadhyaya, Design, synthesis, biological evaluation and molecular model-
ling studies of novel quinoline derivatives against Mycobacterium tuberculosis,
Bioorg. Med. Chem. 17 (2009) 2830–2841.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Appendix A. Supplementary material
[17] R.S. Upadhayaya, J.K. Vandavasi, R.A. Kardile, S.V. Lahore, S.S. Dixit, H.S. Deokar,
P.D. Shinde, M.P. Sarmah, J. Chattopadhyaya, Novel quinoline and naphthalene
derivatives as potent antimycobacterial agents, Eur. J. Med. Chem. 45 (2010)
1854–1867.
Combinatorial Transform from TMC207 and ADMET prediction of
TMC207 and preferable compound could be found in supplementary
data. Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bioorg.2020.104054.
[18] R.S. Upadhayaya, G.M. Kulkarni, N.R. Vasireddy, J.K. Vandavasi, S.S. Dixit,
V. Sharma, J. Chattopadhyaya, Design, synthesis and biological evaluation of novel
triazole, urea and thiourea derivatives of quinoline against Mycobacterium tu-
berculosis, Bioorg. Med. Chem. 17 (2009) 4681–4692.
[19] R.S. Upadhayaya, S.V. Lahore, A.Y. Sayyed, S.S. Dixit, P.D. Shinde,
J. Chattopadhyaya, Conformationally-constrained indeno[2,1-c]quinolines–a new
class of anti-mycobacterial agents, Org. Biomed. Chem. 8 (2010) 2180–2197.
[20] A. Lilienkampf, J. Mao, B. Wan, Y. Wang, S.G. Franzblau, A.P. Kozikowski,
Structure-activity relationships for a series of quinoline-based compounds active
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