Discovery and Development of 8-Substituted Cycloberberine Derivatives as Novel Antibacterial Agents against MRSA

Article abstract of DOI:10.1021/acsmedchemlett.8b00094

8-Acetoxycycloberberine (2) with a unique skeleton was first identified to display a potent activity profile against Gram-positive bacteria, especially methicillin-resistant S. aureus (MRSA) with minimum inhibitory concentration (MIC) values of 1-8 μg/mL, suggesting a possible novel mechanism of action against bacteria. Taking 2 as the lead, 23 new 8-substituted cycloberberine (CBBR) derivatives including ether, amine, and amide were synthesized and evaluated for their antibacterial effect. The structure-activity relationship revealed that the introduction of a suitable substituent at the 8-position could greatly enhance the potency against MRSA. Among them, compounds 5d and 9e demonstrated equally effective anti-MRSA potency as lead 2, with an advantage of having a more stable pharmacokinetics feature. A preliminary mechanism study indicated that compound 9e acted upon bacteria partly through catalyzing the cleavage of bacterial DNA. Therefore, we consider that 8-substituted CBBR derivatives constitute a promising class of antibacterial agents in the treatment of MRSA infections.

Full text of DOI:10.1021/acsmedchemlett.8b00094

Letter
Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Discovery and Development of 8‑Substituted Cycloberberine
Derivatives as Novel Antibacterial Agents against MRSA
Tianyun Fan,† Xinxin Hu,† Sheng Tang, Xiaojia Liu, Yanxiang Wang, Hongbin Deng, Xuefu You,
Jiandong Jiang, Yinghong Li,* and Danqing Song*
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences &
Peking Union Medical College, Beijing 100050, China
S
* Supporting Information
ABSTRACT: 8-Acetoxycycloberberine (2) with a unique skeleton was first identified to display a potent activity profile against
Gram-positive bacteria, especially methicillin-resistant S. aureus (MRSA) with minimum inhibitory concentration (MIC) values
of 1−8 μg/mL, suggesting a possible novel mechanism of action against bacteria. Taking 2 as the lead, 23 new 8-substituted
cycloberberine (CBBR) derivatives including ether, amine, and amide were synthesized and evaluated for their antibacterial
effect. The structure−activity relationship revealed that the introduction of a suitable substituent at the 8-position could greatly
enhance the potency against MRSA. Among them, compounds 5d and 9e demonstrated equally effective anti-MRSA potency as
lead 2, with an advantage of having a more stable pharmacokinetics feature. A preliminary mechanism study indicated that
compound 9e acted upon bacteria partly through catalyzing the cleavage of bacterial DNA. Therefore, we consider that 8-
substituted CBBR derivatives constitute a promising class of antibacterial agents in the treatment of MRSA infections.
KEYWORDS: Cycloberberine, berberine, structure−activity relationship, antibacterial, MRSA
ntimicrobial resistance is a major global health concern,
Aand of the Gram-positive bacteria, drug-resistant Staph-
ylococcus aureus (S. aureus) is a serious threat.1 Over a period of
decades, S. aureus isolated from patients has developed
increasing resistance to several classes of clinical antibacterials,
such as β-lactam, fluoroquinolone, macrolide, glycopeptide, and
oxazolidinone.2,3 Especially, the challenge of treating methi-
Figure 1. Structures and antibacterial activities of 1, CBBR, and 2, as
well as the modification strategy.
cillin-resistant S. aureus (MRSA) was highlighted in a recent
report published by the U.S. Centers for Disease Control and
Prevention (CDC).4 Vancomycin, as one of the last resort
therapies for MRSA infection, has issues that restrict its utility
including slow bactericidal activity, low tissue penetration, and
increasing reports of vancomycin-intermediate S. aureus
(VISA).5−7 Although daptomycin remains as one of the main
treatment options for MRSA, resistance cases in patients
treated with daptomycin are a growing concern.8,9 This
situation has resulted in a very pressing need for the discovery
of novel antibacterial candidates for the treatment of infections
arising from MRSA.
To explore and discover new chemical entity (NCE) against
MRSA, a library of berberine (1, Figure 1) derivatives
constructed in our lab was screened for their antibacterial
activity using phenotype screening assay.10 Surprisingly,
cycloberberine (CBBR, Figure 1) derivatives,11 such as 8-
acetoxycyclo-berberine (2, Figure 1), were first identified to
display satisfactory activity profile against both methicillin-
susceptible S. aureus (MSSA) and MRSA strains with minimum
inhibitory concentration (MIC) values ranging from of 1−8
μg/mL (Table 1), suggesting a possible novel mechanism of
action against bacteria. The unique chemical scaffold and
antibacterial activity profile of compound 2 against MRSA
organisms, high-level resistant pathogens across the world,
spurred us to further carry out structural modifications and
optimization so as to develop them into a novel family of
antimicrobial agents against MRSA.
Received: February 23, 2018
Accepted: April 16, 2018
Published: April 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.8b00094
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
Table 1. Antimicrobial Activities of the Target Compounds against Drug-Susceptible Gram-Positive Strains
a
b
c
MIC (μg/mL), minimum inhibitory concentration. The American Type Culture Collection (ATCC). Strains isolated from patients in Chinese
hospitals.
However, as shown in Figure 1, it is well-known that the
compound 2 as the lead, we describe 23 new 8-substituted
CBBR analogues for their synthesis, in vitro effects against
MSSA and MRSA, structure−activity relationship (SAR)
analysis, and stability in blood as well as primary mechanism
of action of the representative compound.
ester bond at the 8-position of compound 2 could be easily
hydrolyzed by esterases resulting in a poor in vivo
pharmacokinetic (PK) profile. Therefore, a series of new 8-
substituted CBBR ether, amine, and amide derivatives was then
constructed and synthesized, aiming at overcoming PK
instability of compound 2. In the present study, taking
The synthetic route used for the preparation of the CBBR
analogues is described in Scheme 1 with commercially available
B
DOI: 10.1021/acsmedchemlett.8b00094
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
a
CBBR was obtained with a combined yield of 67%, much
higher than our previous report (38%).12 Then, CBBR was
heated at 195−210 °C under vacuum (20−30 mmHg) and
acidified in concentrated HCl/ethanol (5:95 by vol.) to get the
key intermediate 4 in 92% yield using the previous
procedures.11,12 Compound 4 was etherified to provide the
final products 5a−l in 23−42% yield.
Scheme 1. Synthesis of All the Target Compounds
Compounds 6a−c were prepared using the corresponding
amines in 27−45% yield. Similarly, intermediate 7 was prepared
with 2,4-dimethoxybenzylamine as the nucleophilic reagent as
well as the solvent. Free amine was then obtained by the
removal of 2,4-dimethoxybenzyl using HCl/CH3OH in 81%
yield. The desired products 9a−f were obtained by amidation
with corresponding acyl chloride using pyridine as the base with
17−43% yield. All the final products were purified with flash
column chromatography on silica gel using CH2Cl2 and MeOH
as eluent.
All of the newly synthesized compounds were initially
examined for their activities using standard techniques13 against
drug-susceptible Gram-positive strains including MSSA,
methicillin-susceptible S. epidermidis (MSSE), S. saprophyticus
(S. s), and S. hominis (S. h) taking levofloxacin (Lev) as a
reference drug. Structures of the 23 CBBR analogues and their
MIC values against Gram-positive bacteria are summarized in
Table 1.
a
Reagents and conditions: (a) NaBH4, 5% NaOH/K2CO3, CH3OH,
rt, 3 h; (b) (1) 40% glyoxal, HOAc/CH3CN, reflux, 6 h; (2)
methanol/HCl (2:1 by vol.), rt, 24 h; (c) 2,4-dimethoxybenzylamine/
R2NH2, 100−116 °C, 4−32 h; (d) 20−30 mmHg, 195−210 °C, 40
min; (e) R1COCH2Br, KOH, DMF, 68−75 °C, 4−24 h; (f) 1:1 HCl/
CH3OH, rt, 24 h; (g) R3COCl, pyridine, CH3CN, 40−91 °C, 3−72 h.
1 as the starting material. Compound 1 was selectively reduced
to the dihydroberberine (3) using NaBH4 as a reductive agent
in the presence of 5% NaOH/K2CO3 in 81% yield. Glyoxal
(40%) was added to the mixture of 3 and HOAc/CH3CN to
give 13-acetaldehyde berberine, which was used for the next
step without purification.11 A cyclization reaction took place on
the addition of methanol/HCl (2:1 by vol.), and the desired
The SAR study was mainly focused on the influence of the
substituent at the 8-position, and then a series of 8-substituted
CBBR derivatives was obtained. First, 8-acetoxy in compound 2
was respectively replaced with several ether groups, by which
Table 2. Antibacterial Activities of the Target Compounds against Drug-Resistant Gram-Positive Strains
a
MIC (μg/mL)
MRSA
VISA
ATCC 700698
16
0.5
b
Code
ATCC 33591
13−18
13−23
12−3
12−8
12−13
12−16
ATCC-BAA-1708
ATCC 700699
2
4
0.25
>64
32
>64
2
1
0.25
>64
32
>64
4
2
0.25
>64
32
>64
2
4
0.25
>64
32
>64
4
8
0.5
>64
64
>64
4
4
1
2
0.5
>64
32
>64
2
8
0.5
>64
32
>64
4
32
0.25
>64
>64
>64
8
4
5a
5b
5c
5d
5e
5f
>64
32
>64
4
>64
>64
>64
8
16
8
32
16
>64
8
16
8
16
8
16
8
32
8
32
16
>64
4
32
64
>64
32
64
16
64
8
>64
>64
>64
>64
>64
>64
>64
>64
32
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
8
5g
5h
5i
>64
8
>64
8
>64
16
16
4
>64
8
>64
4
16
4
16
8
16
4
8
32
4
16
8
5j
8
5k
5l
4
4
16
4
16
4
16
8
8
8
4
4
4
4
6a
6b
6c
7
64
32
64
8
64
32
64
8
64
32
64
8
64
32
32
8
64
32
64
8
64
32
32
8
64
32
64
8
64
64
>64
16
4
16
>64
4
8
4
8
8
8
4
4
4
64
4
9a
9b
9c
9d
9e
9f
>64
8
>64
8
>64
8
>64
8
>64
8
>64
16
>64
16
4
>64
8
>64
4
>64
64
>64
4
>64
64
2
>64
32
2
>64
8
>64
32
2
>64
32
2
>64
16
2
>64
16
2
>64
>64
16
>64
4
2
8
>64
0.125
>64
32
>64
32
>64
32
>64
32
>64
32
>64
32
>64
16
>64
32
>64
2
Lev
a
b
MIC (μg/mL), minimum inhibitory concentration. mupA positive (isolates with mupirocin resistance).
C
DOI: 10.1021/acsmedchemlett.8b00094
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
CBBR ether analogues 5a−l were then generated and tested.
Compounds 5a−c with small aliphatic chains or rings lost their
antimicrobial activities completely; while compound 5d with
large adamantyl14 exhibited activities with MICs ranging from 2
to 4 μg/mL, similar to that of lead 2. The results suggested that
large volume at position 8 might be helpful for maintaining
good activities. Based on the results, various benzenes with
electron-withdrawing or electron-donating groups were re-
spectively attached, and then new compounds 5e−l were
created and tested. Compound 5g is much weaker than other
analogs with similar phenyl substitutions, while compounds 5f,
5h, and 5i−l exhibited comparable antimicrobial activities with
MICs values of 2−32 μg/mL, regardless of electron-with-
drawing or electron-donating groups on the benzene ring.
Then, we moved our SAR investigation onto the amine or
amide moiety at the 8-position. With an introduction of a free
amine group, 2-furanmethanamine, and substituted benzyl-
amines at position 8, respectively, five new CBBR amine
analogues (6a−c, 7, and 8) were generated and measured.
However, as described in Table 1, all of them abolished the
activity completely or partially, suggesting that introduction of
an amine substituent at the 8-position might not be helpful for
potency. The potencies of compounds 7 and 8 reduced slightly,
and the MIC values ranged from 4 to 8 μg/mL compared with
the lead 2. Introduction of amide resulted in compounds 9a−f
that were tested for activity. The activity of compound 9a with
adamantyl was abolished, while the potencies of compounds
9b−d and 9f with cyclic or heterocyclic dropped obviously.
Both compound 9a and 5d contain 1-adamantyl moiety, while
the activity is quite different. Surprisingly, compound 9e with
1,2,3-thiadiazole15,16 attached exhibited comparable activity to
the lead 2 (MICs = 1−8 μg/mL), suggesting that a thiadiazole
group might be beneficial for antibacterial activity. The results
illustrated that introducing a suitable substituent at the 8-
position might be helpful for potency.
All of the target compounds were measured for their
antibacterial activity using standard methods13 against ten drug-
resistant S. aureus strains (MRSA/VISA) with Lev as a
reference drug as summarized in Table 2. Their potencies
against MRSA/VISA were basically consistent with that of
drug-susceptible strains, suggesting a different mechanism of
action from the current antibacterial drugs. Among them, most
of compounds showed potential anti-MRSA effect on not only
ATCC strains but also isolated ones from Chinese patients,
with MIC values between 2 and 64 μg/mL. More importantly,
compounds 5d, 7, 8, 9b, and 9e displayed promising effects
against both MRSA and VISA strains with MICs values ranging
from 2−64 μg/mL, similar to reference drug Lev. Especially,
compounds 5d and 9e with different structures displayed
excellent potencies with MIC of 2−4 μg/mL, and thus, both of
them were selected as representative compounds for the next
investigation. In addition, the key intermediate 4 was also
tested for the activity, and results showed that it displayed a
promising effect against both MRSA and VISA.
Figure 2. Structure of enalapril and metabolic stability of key
compounds in whole blood.
ratios of the compounds 5d and 9e in blood were still 58.0 and
57.2%, respectively, much higher than that of lead 2 and
enalapril, as described in Figure 2. The results suggested that
compounds 5d and 9e possessed much more stable in vitro
blood stability than lead 2.
To evaluate the safety of this kind of compounds, the
cytotoxic effects of the representative compounds 2, 5d, and 9e
on A549 cells were carried out using MTT assay.19 As displayed
in Figure 3, lead 2 had no cytotoxic activity in A549 cells with
Figure 3. Cytotoxic effects of compounds 2, 5d, and 9e on A549 cells.
Following pretreatment with compounds 2, 5d, and 9e at the indicated
concentrations for 24 h, the cell viability of A549 cells were
determined by MTT assay. Control cells were treated with 0.4% (v/
v) DMSO.
CC50 value over 33.6 μg/mL, while compound 9e demon-
strated the moderate cytotoxicity with a CC50 of 16.1 μg/mL,
much lower than that of compound 5d of 2.0 μg/mL. The
quaternary ammonium structure at the 6-position in compound
9e made itself not easy to traverse the cellular membrane;20
therefore, compound 9e showed a moderate selectivity toward
bacteria versus cells with the MIC values of 2−4 μg/mL.
In order to further understand the mechanism of action of
this kind of compounds, the preliminary mechanism of action
of the representative compound 9e was carried out. Based on
its plane rigid structure, we speculated that this kind of
compounds might act upon microorganisms by intercalating
into DNA of bacteria.21 Therefore, the activity of compound 9e
toward supercoiled pET-32a (bacterial expression vector) DNA
was conducted under physiological conditions (4 h, 37 °C)
using agarose gel electrophoresis (GE). As shown in Figure 4, a
strong dependence on the concentration (lanes 2−5),
converting pET-32a DNA from CCC form (Form I) into
open circular form (OC, Form II), could be detected on their
cleaving activity. This result indicated that compound 9e acted
upon bacteria partly through catalyzing the cleavage of bacterial
DNA. Furthermore, compound 9e exerted the potent
Thus, compound 4 could be selected as a parent structure to
make prodrugs for potential antibacterial agents against MRSA.
As displayed in Figure 2, CBBR ether 5d and amine 9e were
chosen to further explore the in vitro stability in whole blood
taking enalapril containing an ester bond (Figure 2) as the
control.17,18 Compounds 2, 5d, and 9e and enalapril were
incubated with blood isolated from the Sprague-Dawly (SD)
rats, and samples were taken out at 0, 30, 60, 120, 240, and 420
min, respectively. As expected, after 420 min, the remaining
D
DOI: 10.1021/acsmedchemlett.8b00094
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
REFERENCES
■
(1) Brown, E. D.; Wright, G. D. Antibacterial drug discovery in the
resistance era. Nature 2016, 529, 336−343.
(2) Liu, C.; Bayer, A.; Cosgrove, S. E.; Daum, R. S.; Fridkin, S. K.;
Gorwitz, R. J.; Kaplan, S. L.; Karchmer, A. W.; Levine, D. P.; Murray,
B. E.; Rybak, J. M.; Talan, D. A.; Chambers, H. F. Clinical practice
guidelines by the Infectious Diseases Society of America for the
treatment of methicillin-resistant Staphylococcus aureus infections in
adults and children: executive summary. Clin. Infect. Dis. 2011, 52,
285−292.
Figure 4. Agarose GE patterns for the cleavage of pET-32a DNA by
compound 9e of increasing concentrations at 37 °C (4 h).
(3) Drebes, J.; Kunz, M.; Pereira, C. A.; Betzel, C.; Wrenger, C.
̈
MRSA infections: from classical treatment to suicide drugs. Curr. Med.
Chem. 2014, 21, 1809−1819.
antibacterial activity with MIC values of 2−4 μg/mL, possibly
due to other antibacterial mechanisms of this kind of
compounds.22−24
(4) Centers for Disease Control and Prevention. Antibiotic resistance
threats in the United States, 2013. https://www.cdc.gov/
drugresistance/threat-report-2013/.
Twenty-three new 8-substituted CBBR derivatives with a
unique chemical scaffold were synthesized and examined for
their activity against Gram-positive bacteria including MRSA
and VISA. SAR revealed that a suitable substituent at the 8-
position could greatly enhance the antibacterial potency.
Among them, compounds 5d and 9e exhibited potent activities
against all tested drug-susceptible and drug-resistant strains
with MICs ranging from 2 to 4 μg/mL, suggesting a possible
novel mechanism of action against bacteria. Moreover,
compound 9e showed much better stability in whole blood
than that of lead 2. A preliminary mechanism study indicated
that compound 9e acted upon bacteria partly through
catalyzing the cleavage of bacterial DNA. Therefore, we
consider 8-substituted CBBR derivatives to be a promising
class of anti-MRSA agents, and compound 9e has been chosen
for the further investigation.
(5) Mohammad, H.; Mayhoub, A. S.; Ghafoor, A.; Soofi, M.;
Alajlouni, R. A.; Cushman, M.; Seleem, M. N. Discovery and
characterization of potent thiazoles versus methicillin-and vancomy-
cin-resistant Staphylococcus aureus. J. Med. Chem. 2014, 57, 1609−
1615.
(6) Rybak, M.; Lomaestro, B.; Rotschafer, J. C.; Moellering, R.; Craig,
W., Jr; Billeter, M.; Dalovisio, J. R.; Levine, D. P. Therapeutic
monitoring of vancomycin in adult patients: a consensus review of the
American Society of Health-System Pharmacists, the Infectious
Diseases Society of America, and the Society of Infectious Diseases
Pharmacists. Am. J. Health-Syst. Pharm. 2009, 66, 82−98.
(7) Han, J. H.; Edelstein, P. H.; Lautenbach, E. Reduced vancomycin
susceptibility and staphylococcal cassette chromosome mec (SCCmec)
type distribution in methicillin-resistant Staphylococcus aureus bacter-
aemia. J. Antimicrob. Chemother. 2012, 67, 2346−2349.
(8) Kullar, R.; Casapao, A. M.; Davis, S. L.; Levine, D. P.; Zhao, J. J.;
Crank, C. W.; Segreti, J.; Sakoulas, G.; Cosgrove, S. E.; Rybak, M. J. A
multicentre evaluation of the effectiveness and safety of high-dose
daptomycin for the treatment of infective endocarditis. J. Antimicrob.
Chemother. 2013, 68, 2921−2926.
(9) Sharma, M.; Riederer, K.; Chase, P.; Khatib, R. High rate of
decreasing daptomycin susceptibility during the treatment of persistent
Staphylococcus aureus bacteremia. Eur. J. Clin. Microbiol. Infect. Dis.
2008, 27, 433−437.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.8b00094.
(10) Wang, Y. X.; Fu, H. G.; Li, Y. H.; Jiang, J. D.; Song, D. Q.
Synthesis and biological evaluation of 8-substituted berberine
derivatives as novel anti-mycobacterial agents. Acta Pharm. Sin. B
2012, 2, 581−587.
(11) Li, Y. B.; Zhao, W. L.; Wang, Y. X.; Zhang, C. X.; Jiang, J. D.; Bi,
C. W.; Tang, S.; Chen, R. X.; Shao, R. G.; Song, D. Q. Discovery,
synthesis and biological evaluation of cycloprotoberberine derivatives
as potential antitumor agents. Eur. J. Med. Chem. 2013, 68, 463−472.
(12) Bi, C. W.; Zhang, C. X.; Li, Y. B.; Zhao, W. L.; Shao, R. G.; Mei,
L.; Song, D. Q. Synthesis and structure-activity relationship of
cycloberberine as anti-cancer agent. Acta Pharmacol. Sin. 2013, 48,
1800−1806.
(13) MICs were determined as described by the NCCLS; see
National Committee for Clinical Laboratory Standards. Performance
Standards for Antimicrobial Susceptibility Testing: 11th Informational
Supplement; National Committee for Clinical Laboratory Standards:
Wayne, PA, 2001; Vol. 21, p M100-S11.
(14) Liu, J.; Obando, D.; Liao, V.; Lifa, T.; Codd, R. The many faces
of the adamantyl group in drug design. Eur. J. Med. Chem. 2011, 46,
1949−1963.
(15) Sashidhara, K. V.; Rao, K. B.; Kushwaha, P.; Modukuri, R. K.;
Singh, P.; Soni, I.; Shukla, P. K.; Chopra, S.; Pasupuleti, M. Novel
chalcone-thiazole hybrids as potent inhibitors of drug resistant
Staphylococcus aureus. ACS Med. Chem. Lett. 2015, 6, 809−813.
(16) Mohammad, H.; Reddy, P. V. N.; Monteleone, D.; Mayhoub, A.
S.; Cushman, M.; Seleem, M. N. Synthesis and antibacterial evaluation
of a novel series of synthetic phenylthiazole compounds against
methicillin-resistant Staphylococcus aureus (MRSA). Eur. J. Med. Chem.
2015, 94, 306−316.
Synthetic procedures, analytical data, and antibacterial
and cytotoxic assays (PDF)
AUTHOR INFORMATION
Corresponding Authors
*Tel: +86 10 63033012. Fax: +86 10 63165268. E-mail:
liyinghong@imb.pumc.edu.cn.
*Tel: +86 10 63165268. Fax: +86 10 63165268. E-mail:
songdanqing@imb.pumc.edu.cn.
ORCID
■
Danqing Song: 0000-0002-2557-5009
Author Contributions
†T.F. and X.H. contributed equally.
Funding
This work was supported by the National Natural Science
Foundation of China (81361138020 and 81621064), Beijing
Natural Science Foundation (7172136), and the CAMS
initiative for innovative medicine (2017-12M-1-012).
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
MRSA, methicillin-resistant S. aureus; VISA, vancomycin-
intermediate S. aureus; MSSE, methicillin-susceptible S.
epidermidis
E
DOI: 10.1021/acsmedchemlett.8b00094
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
(17) Magiera, S.; Kusa, J. Evaluation of a rapid method for the
therapeutic drug monitoring of aliskiren, enalapril and its active
metabolite in plasma and urine by UHPLC-MS/MS. J. Chromatogr. B:
Anal. Technol. Biomed. Life Sci. 2015, 980, 79−87.
(18) Ferron, G. M.; Jusko, W. J. Species differences in sirolimus
stability in humans, rabbits, and rats. Drug Metab. Dispos. 1998, 26,
83−84.
(19) Wang, Y. X.; Pang, W. Q.; Zeng, Q. X.; Deng, Z. S.; Fan, T. Y.;
Jiang, J. D.; Deng, H. B.; Song, D. Q. Synthesis and biological
evaluation of new berberine derivatives as cancer immunotherapy
agents through targeting IDO1. Eur. J. Med. Chem. 2018, 143, 1858−
1868.
(20) Richter, M. F.; Drown, B. S.; Riley, A. P.; Garcia, A.; Shirai, T.;
Svec, R. L.; Hergenrother, P. J. Predictive compound accumulation
rules yield a broad-spectrum antibiotic. Nature 2017, 545, 299−304.
(21) Jeyakkumar, P.; Zhang, L.; Avula, S. R.; Zhou, C. H. Design,
synthesis and biological evaluation of berberine-benzimidazole hybrids
as new type of potentially DNA-targeting antimicrobial agents. Eur. J.
Med. Chem. 2016, 122, 205−215.
(22) Chu, M.; Zhang, M. B.; Liu, Y. C.; Kang, J. R.; Chu, Z. Y.; Yin,
K. L.; Ding, L. Y.; Ding, R.; Xiao, R. X.; Yin, Y. N.; Liu, X. Y.; Wang, Y.
D. Role of berberine in the treatment of methicillin-resistant
Staphylococcus aureus infections. Sci. Rep. 2016, 6, 24748.
(23) Sun, N.; Du, R. L.; Zheng, Y. Y.; Huang, B. H.; Guo, Q.; Zhang,
R. F.; Wong, K. Y.; Lu, Y. J. Antibacterial activity of N-methyl
benzofuro[3,2-b]quinoline and N-methylbenzoindolo[3,2-b]-quino
line derivatives and study of their mode of action. Eur. J. Med.
Chem. 2017, 135, 1−11.
(24) Kelley, C.; Zhang, Y.; Parhi, A.; Kaul, M.; Pilch, D. S.; LaVoie, E.
J. 3-Phenyl substituted 6,7-dimethoxyisoquinoline derivatives as FtsZ-
targeting antibacterial agents. Bioorg. Med. Chem. 2012, 20, 7012−
7029.
F
DOI: 10.1021/acsmedchemlett.8b00094
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX