Design, synthesis and antibacterial activity evaluation of moxifloxacin-amide-1,2,3-triazole-isatin hybrids

Article abstract of DOI:10.1016/j.bioorg.2019.103162

In this work, a series of novel moxifloxacin-amide-1,2,3-triazole-isatin hybrids 7a-l were designed and synthesized. The in vitro antibacterial activity against a panel of clinically important Gram-positive and Gram-negative bacteria including drug-resistant pathogens was also evaluated. All hybrids showed considerable activity against the tested pathogens with MIC values of ≤0.03 to 128 μg/mL, and some of them such as hybrids 7e, 7g and 7j were comparable to or better than the parent moxifloxacin (MIC: ≤0.03–8 μg/mL). Moreover, hybrids 7e, 7g and 7j also demonstrated low cytotoxicity towards CHO cells. However, the in vivo pharmacokinetic profiles of these three hybrids were generally far inferior to the parent moxifloxacin. The structure-activity relationship and structure-cytotoxicity relationship were also studied and discussed which may help with the identification of new chemical entities as potent antibacterial agents.

Full text of DOI:10.1016/j.bioorg.2019.103162

Journal Pre-Proof
Design, synthesis and antibacterial activity evaluation of moxifloxacin-
amide-1,2,3-triazole-isatin hybrids
Feng Gao, Lei Ye, Fangong Kong, Gang Huang, Jiaqi Xiao
PII:
S0045-2068(19)30965-4
DOI:
https://doi.org/10.1016/j.bioorg.2019.103162
YBIOO 103162
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Bioorganic Chemistry
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24 July 2019
27 July 2019
Please cite this article as: F. Gao, L. Ye, F. Kong, G. Huang, J. Xiao, Design, synthesis and antibacterial activity
evaluation of moxifloxacin-amide-1,2,3-triazole-isatin hybrids, Bioorganic Chemistry (2019), doi: https://doi.org/
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JOURNAL PRE-PROOF
Design, synthesis and antibacterial activity evaluation of
moxifloxacin-amide-1,2,3-triazole-isatin hybrids
Feng Gao a, b, Lei Ye , Fangong Kong , Gang Huang , Jiaqi Xiao
a
a
b*
a, b*
aState Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of
Technology (Shandong Academy of Sciences), Jinan, P. R. China
bShanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health
Sciences, Shanghai, P. R. China
Abstract: In this work, a series of novel moxifloxacin-amide-1,2,3-triazole-isatin
hybrids 7a-l were designed and synthesized. The in vitro antibacterial activity against
a panel of clinically important Gram-positive and Gram-negative bacteria including
drug-resistant pathogens was also evaluated. All hybrids showed considerable activity
against the tested pathogens with MIC values of ≤0.03 to 128 μg/mL, and some of
them such as hybrids 7g, 7m and 7n were comparable to or better than the parent
moxifloxacin (MIC: ≤0.03-8 μg/mL). Moreover, hybrids 7g, 7m and 7n also
demonstrated low cytotoxicity towards CHO cells. However, the in vivo
pharmacokinetic profiles of these three hybrids were generally far inferior to the
parent moxifloxacin. The structure-activity relationship and structure-cytotoxicity
relationship were also studied and discussed which may help with the identification of
new chemical entities as potent antibacterial agents.
Keywords: moxifloxacin; amide; isatin; 1,2,3-triazole; antibacterial; drug-resistant
pathogen; structure-activity relationship
1
. Introduction
Bacterial infections are very common both in hospital and in community settings, and
they are responsible for a main cause of morbidity and mortality throughout the world
[3,4]. Antibiotics can either kill or inhibit the growth of pathogens and they represent
*Corresponding author: huanggang@sumhs.edu.cn (G. Huang); jiaqixiao@qlu.edu.cn (J. Xiao)
1

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effective weapons for fighting bacterial infections [5,6]. Unfortunately, bacteria have
already developed resistance to almost all antibiotics due to the long-term use even
abuse of antibiotics [7,8]. Roughly 700,000 drug-resistant bacterial infection related
deaths occur every year, and the number may increase to 10 million in 2050 if there
are no effective solutions [9,10]. Novel antibacterial agents might be a useful tool to
control the bacterial infection.
Moxifloxacin, the fourth generation of quinolone antibiotics, can act with bacteria by
binding DNA gyrase and topoisomerase IV [11]. Moxifloxacin possesses broad-
spectrum antimicrobial activity and has been used widely to treat various bacterial
infections such as pneumonia, conjunctivitis, endocarditis, tuberculosis, and sinusitis
in clinics [12,13]. However, bacteria also developed resistance to moxifloxacin.
Moreover, serious adverse effects like irreversible peripheral neuropathy [14],
hepatitis [15], Stevens-Johnson syndrome [16] and phototoxicity reactions [17] may
occur as a result of moxifloxacin therapy. To overcome the drug-resistance and
reduce the adverse effects, modification and optimization of moxifloxacin is
necessary.
Isatin and 1,2,3-triazole possess diverse pharmacological properties such as anticancer
[18,19], antitubercular [20,21], antiviral [22,23], and antibacterial [24,25] activities
because these heterocycles can serve as useful tool to manipulate lipophilicity,
polarity, and hydrogen bonding capacity of molecules, consequently improving
pharmacological, pharmacokinetic, toxicological, and physicochemical properties of
drug candidates and ultimately drugs [26]. Obviously, isatin and 1,2,3-triazole
derivatives occupy an important position in the development of new drugs.
R1
Methylene linker
O
O
N
F
COOH
N
R2
N
n
H
N
N
N
N
OMe
H
1
Figure 1 Chemical structures of alkyl tethered moxifloxacin-1,2,3-triazole-isatin
hybrids 1
2

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Fluoroquinolone-1,2,3-triazole-isatin hybrids including moxifloxacin-1,2,3-triazole-
isatin 1 (Figure 1) tethered by various alkyl linkers demonstrated considerable
antimicrobial activity [27-35]. The structure-activity relationship (SAR) and structure-
cytotoxicity relationship demonstrated that the linker between the fluoroquinolone
and 1,2,3-triazole fragments as well as substituents on the isatin moiety influenced the
activity significantly for fluoroquinolone-1,2,3-triazole-isatin hybrids [27-30].
Substituents at C-3 position of isatin motif could control the lipophilicity of the
hybrids, while substituents at the phenyl ring demonstrated the electronic effect which
were closely correlated with the biological activity [31-35]. Introduction of amide into
the C-7 position of fluoroquinolone framework could boost up the biological activity
when compared with the parent, so amide may be excellent linker between the
fluoroquinolone and 1,2,3-triazole moieties [36-38].
Isatin moiety with potential anti-bacterial activity
Moxifloxacin with borad antibacterial activity
amide linker
N
O
N
N
N
Electronic effect
R1
F
COOH
N
O
N
O
H
R2
N
OMe
H
Control the lipophilicity
,2,3-triazole motif with diverse non-covalent interactions
1
Figure 2 Design strategy for moxifloxacin-amide-1,2,3-triazole-isatin hybrids
In this work, a series of novel moxifloxacin-amide-1,2,3-triazole-isatin hybrids were
designed, synthesized and evaluated for their in vitro antibacterial activity against a
panel of Gram-positive and Gram-negative bacteria including drug-resistant
pathogens. The design strategy was depicted in Figure 2.
2
Results and discussion
3

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All moxifloxacin-amide-1,2,3-triazole-isatin hybrids 7a-l were synthesized by the
route depicted in Scheme 1. Treatment of 2-bromoacetic acid 1 with sodium azide
yielded 2-azidoacetic acid 2, which was then reacted with dicyclohexylcarbodiimide
(DCC) and N-hydroxysuccinimide (NHS), giving succinimidyl ester 3 [39].
Condensation of moxifloxacin with succinimidyl ester 3 with triethylamine (TEA) as
base generated 2-azidoacetyl moxifloxacin 4. Alkylation of isatin/5-fluoroisatin/5-
methylisatin/7-fluoroisatin 5a-d with propargyl bromide provided N-propargyl isatin
intermediates 6a-d [30,31]. Cyclization of 2-azidoacetyl moxifloxacin 4 and N-
propargyl isatin intermediates 6a-d in presence of Cu(OAc) provided the desired
2
acetyl tethered moxifloxacin-amide-1,2,3-triazole-isatin hybrids 7a-d [40]. Finally,
condensations of 7a-d with methoxylamine hydrochloride or ethoxylamine
hydrochloride with sodium bicarbonate as base gave acetyl tethered moxifloxacin-
amide-1,2,3-triazole-isatin-oxime hybrids 7e-l.
O
F
COOH
O
N3
O
N
N
N
O
NaN3
O
Moxifloxacin
DMF, TEA
H
DCC, NHS
THF
N3
N
N
N
Br
N3
O
HO
2
H O
HO
OMe
H
1
2
3
4
Cu(OAc)2
DMF
O
O
Br
R1
O
R1
O
N
N
H
K2CO3, DMF
5a-d
6a-d
R1 = H, 5-F, 5-Me, 7-F.
N
N
N
O
N
N
N
N
O
N
N
R1
F
COOH
R1
F
COOH
O
N
O
N
RONH2, NaHCO3
THF, H O
O
H
O
H
R2
N
O
N
N
2
OMe
OMe
H
H
7e-p
7a-d
7
7
7
7
e: R1 = H, R2 = NOMe; 7f: R1 = 5-F, R2 = NOMe;
g: R1 = 5-Me, R2 = NOMe; 7h: R1 = 7-F, R2 = NOMe;
i: R1 = H, R2 = NOEt; 7j: R1 = 5-F, R2 = NOEt;
k: R1 = 5-Me, R2 = NOEt; 7l: R1 = 7-F, R2 = NOEt.
7
a: R1 = H; 7b: R1 = 5-F;
7c: R1 = 5-Me; 7d: R1 = 7-F.
Scheme 1 Synthesis of moxifloxacin-amide-1,2,3-triazole-isatin hybrids 7a-l
The chemical structures and yields of the synthesized moxifloxacin-amide-1,2,3-
triazole-isatin hybrids 7a-l were listed in Table 1. The yields were in a range of 19%
to 66%, and hybrids with carbonyl and methyloxime groups at C-3 position of isatin
4

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moiety showed higher yields than the corresponding ethyloxime analogs which may
be attributed to the steric effect.
Table 1. Chemical structures and yields of moxifloxacin-amide-1,2,3-triazole-isatin
hybrids 7a-l
N
O
N
N
N
R1
F
COOH
N
O
N
O
H
R2
N
OMe
H
7a-l
Compound
R1
H
R2
Yield (%)
7
a
O
44%
52%
39%
34%
57%
43%
66%
31%
35%
27%
7
b
5-F
O
7
c
5-Me
7-F
H
O
7
d
O
7
e
NOMe
NOMe
NOMe
NOMe
NOEt
NOEt
7
f
5-F
5-Me
7-F
H
7
g
7
h
7
i
7
j
5-F
5

JOURNAL PRE-PROOF
7
k
5-Me
7-F
NOEt
NOEt
38%
19%
7
l
The antibacterial activity of the synthesized moxifloxacin-amide-1,2,3-triazole-isatin
hybrids 7a-l against Gram-positive and Gram-negative bacteria was investigated, and
the minimum inhibitory concentration (MIC) values were listed in Table 2 and 3,
respectively.
Table 2. In vitro antibacterial activity of acetyl tethered moxifloxacin-amide-1,2,3-
triazole-isatin hybrids 7a-l against Gram-positive strains.
MIC (μg/mL)
Compd.
MSSE
MRSE
MSSA
MRSA
E.fa.
8
E.fm.
16
7
a
0
.5
4
8
1
1
2
7
b
1
2
1
16
4
16
7
c
0
.25
2
8
2
32
7
d
8
2
8
32
8
128
8
7
e
0
.125
2
0.5
0.125
0.125
2
16
2
7
f
0.125
0.06
0.5
4
8
16
7
g
1
1
4
16
7
h
4
32
8
16
32
32
7
i
0.5
16
2
64
6

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7
j
1
16
8
2
1
2
2
32
8
32
32
16
8
7
k
1
4
7
l
32
2
4
16
8
16
0.5
1
moxifloxacin
vancomycin
0.125
1
0.06
0.5
0.5
1
16
Abbreviations: MSSE, methicillin-sensitive Staphylococcus epidermidis; MRSE, methicillin-resistant
Staphylococcus epidermidis; MSSA, methicillin-sensitive Staphylococcus aureus; MRSA, methicillin-
resistant Staphylococcus aureus; E.fa., Enterococcus faecalis; E.fm., Enterococcus faecium.
All hybrids 7a-l (MIC: 0.06-128 μg/mL) showed considerable antibacterial activity
against the tested six Gram-positive organisms including drug-resistant MRSE and
MRSA strains, and the activities of some hybrids among 7a-l were comparable to or
more potent than those of the parent moxifloxacin (MIC: 0.06-8 μg/mL) and the
reference vancomycin (MIC: 0.5-16 μg/mL) against certain strains. The SAR
indicated the substituents at R position have great influence on the activity, and
1
electron-donating methyl was more favorable than electron-withdrawing fluoro. The
position of substituents on the phenyl ring also had a profound effect on the
antibacterial activity, and hybrids with substituents at C-5 positions were more potent
than the corresponding C-7 position substituted analogs. Compared with unsubstituted
analogs, introduction of methyloxime (R position) at C-3 position of isatin moiety
2
could enhance the activity to some extent, while ethyloxime was harmful to the
activity generally. The most active hybrid 7g (MIC: 0.06-16 μg/mL) was no inferior
to the parent moxifloxacin (MIC: 0.06-8 μg/mL) against all tested Gram-positive
pathogens and it was 2-16 times more potent than moxifloxacin and vancomycin
against MSSE, 2- and 8-fold more active than moxifloxacin against drug-resistant
MRSE and MRSA strains.
Table 3. In vitro antibacterial activity of moxifloxacin-amide-1,2,3-triazole-isatin
hybrids 7a-l against Gram-negative strains.
7

JOURNAL PRE-PROOF
Compd.
MIC (μg/mL)
E.co.1
≤0.03
≤0.03
0.03
E.co.2
≤0.03
≤0.03
0.06
K.p.1
≤0.03
≤0.03
0.06
K.p.2
0.25
1
P.a.
1
A.c.
1
E.c.
≤0.03
0.12
0.5
E.a.
0.12
0.12
0.25
1
P.r.
P.v.
7
a
≤0.03
≤0.03
≤0.03
≤0.03
≤0.03
≤0.03
≤0.03
0.12
≤0.03
≤0.03
≤0.03
≤0.03
≤0.03
≤0.03
≤0.03
0.06
7
b
2
1
7
c
1
2
1
7
d
0.12
0.5
0.12
8
8
2
4
7
e
≤0.03
≤0.03
0.06
≤0.03
≤0.03
0.12
≤0.03
0.03
0.5
1
1
0.5
0.5
1
≤0.03
0.12
0.25
8
0.06
0.25
0.12
1
7
f
4
7
g
0.06
2
4
7
h
0.12
0.25
0.12
8
16
0.5
1
1
7
i
≤0.03
≤0.03
≤0.03
0.06
≤0.03
≤0.03
≤0.03
0.06
≤0.03
≤0.03
0.03
0.5
0.5
1
1
≤0.03
0.12
0.25
4
0.12
0.12
0.5
≤0.03
≤0.03
0.03
≤0.03
≤0.03
0.06
7
j
0.5
1
7
k
1
7
l
012
4
4
2
0.5
≤0.03
≤0.03
>128
≤0.03
≤0.03
>128
moxifloxacin ≤0.03
≤0.03
>128
≤0.03
>128
0.5
>128
0.25
>128
0.125 ≤0.03
0.06
>128
vancomycin
>
128
>128
>128
Abbreviations: E.co.1, Escherichia coli ESBLs(-); E.co.2, Escherichia coli ESBLs(+); K.p.1, Klebsiella
pneumoniae ESBLs(+); K.p.2, Klebsiella pneumonia ESBLs(-); P.a., Pseudomonas aeruginosa; A.c.,
Acinetobactercal coacetious; E.c., Enterobacter cloacae; E.a., Enterobacter aerogenes; P.r., Providentia rettgeri;
P.v., Proteus vulgaris; ESBLs(+): Extended spectrum beta-lactamases (ESBLs).
8

JOURNAL PRE-PROOF
From Table 3, it can be seen that the majority of hybrids 7a-l exhibited excellent
activity against E. coli ESBLs(-), E. coli ESBLs(+), K. pneumoniae ESBLs(+), K.
pneumonia ESBLs(-), E. cloacae, E. aerogenes, P. rettgeri, and Proteus vulgaris with
MIC <1 μg/mL, and moderate activity against P. aeruginosa and A. coacetious with
MIC of 0.5-16 μg/mL. All of them were more potent than vancomycin (MIC: >128
μg/mL), and five of them 7e, 7i, 7j, 7m and 7n with MIC ≤ 1 μg/mL were comparable
to or superior to the parent moxifloxacin (MIC: ≤0.03-0.5 μg/mL) against all tested
Gram-negative strains. In general, incorporation of oximes onto the C-3 position of
isatin fragment increased the activity, and ethyloxime > methyloxime ≈ ketone.
Electron-withdrawing fluoro at C-5 position of isatin could boost up the activity,
while methyl reduced the activity when compared to the unsubstituted analogs.
Movement of fluoro to C-7 position led to great loss of activity, suggesting the
position also influenced the activity remarkedly.
In general, isatin structural scaffold could act as potent DNA gyrase and FtsZ
inhibitors, while moxifloxacin could bind DNA gyrase and topoisomerase IV [41,42].
Thus, this kind of hybrids have the potential to exert multiply action mechanisms, and
were active against drug-resistant strains. The action mechanisms of the hybrids are
being under investigated, and the results will be reported soon.
Table 4 In vitro cytotoxicity of moxifloxacin-amide-1,2,3-triazole-isatin hybrids 7a-l
towards CHO cells
Compound
CC50 (μg/mL)
6
1
3
4
6
2
7
a
7
b
7
c
8
7
d
6
4
7
e
9

JOURNAL PRE-PROOF
6
3
1
1
4
2
6
6
7
f
7
g
7
h
7
i
8
7
j
3
1
2
6
7
k
7
l
>
128
moxifloxacin
All hybrids also displayed acceptable toxicological profiles with CC ranging from 8
5
0
to 64 μg/mL against CHO cells, but they were more toxic than the parent
moxifloxacin (CC : >128 μg/mL). The structure-cytotoxicity relationship study
5
0
revealed that introduction of either electron-donating or electron-withdrawing groups
at C-5 or C-7 position could increase the cytotoxicity, and installation of ethyloxime
and methyloxime at C-3 position of isatin moiety could not improve toxicological
profile when compared with unsubstituted analogs.
Three hybrids 7g, 7m and 7n with promising activity against Gram-positive or Gram-
negative pathogens and low cytotoxicity towards CHO cells were selected for further
investigation on in vivo pharmacokinetics in mice (100 mg/kg, subcutaneous
injection/s.c. administration), and the results were presented in Table 5.
Table 5 The in vivo pharmacokinetic values of hybrids 7g, 7m, 7n and moxifloxacin
in mice
Compd.
Pharmacokinetics (s.c.)
1
0

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Cmax
t1/2 (h)
Tmax (min)
AUC0-inf (ng•h/mL)
(
ng/mL)
7
g
798
3.8
3.1
4.3
2.6
48
39
52
27
2,138
6,435
3,269
19,243
7
m
3,247
1,398
7
n
moxifloxacin
10,783
Cmax: the peak concentration; t : half-life;
1/2
Tmax: the time to reach peak concentration; AUC: the area under the curve.
From Table 5, the in vivo pharmacokinetic profiles of the selected hybrids 7g, 7m and
n were worse than those of the parent moxifloxacin in terms of the peak
7
concentration (Cmax), the time to reach peak concentration (Tmax) and
the area under the curve (AUC0-inf), and this may be attributed to the existence of
1
,2,3-triazole and amide functional groups led to poor solubility and bioavailability.
However, the half-life (t ) of the hybrids was longer than moxifloxacin.
1
/2
3
Conclusions
In summary, twelve moxifloxacin-amide-1,2,3-triazole-isatin hybrids 7a-l, were
prepared and their in vitro antibacterial activity against clinically important Gram-
positive and Gram-negative pathogens including drug-resistant strains was assessed in
this work. The majority of the synthesized hybrids showed considerable in vitro
activity against both drug-sensitive and drug-resistant strains, and acceptable
cytotoxicity towards CHO cells. In particular, three hybrids 7g, 7m and 7n, which
were comparable to or better than the parent moxifloxacin against Gram-positive or
Gram-negative pathogens, also demonstrated low cytotoxicity towards CHO cells.
However, the in vivo pharmacokinetic profiles of these three hybrids were generally
no superior to moxifloxacin.
1
1

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N
O
N
Substituents at C-5 position were
more favorable than C-7 position;
N
N
R1
F
COOH
N
O
N
-F > -H > -Me. Introduction of
O
H
substituents at either C-5 or C-7
position increased the cytotoxicity.
R2
N
OMe
H
-NOMe > -O > -NOEt against Gram-positive pathogens;
-NOEt > -NONe and -O against Gram-negative pathogens.
-NOMe and -NOEt couldn't improve toxicological profile.
Figure 3 The antibacterial SAR and structure-cytotoxicity relationship of
moxifloxacin-amide-1,2,3-triazole-isatin hybrids
The SAR and structure-cytotoxicity relationship were summarized in Figure 3, the
enriched SAR and structure-cytotoxicity relationship may help global efforts for
identification of new chemical entities as potent antibacterial agents with low toxicity.
Acknowledgements
This study was supported by research grants from National Natural Science
Foundation of China (Grant No. 81830052, 81530053),Shanghai Key Laboratory of
Molecular Imaging, China (18DZ2260400) and Natural Science Foundation of
Shandong Province, China (Grant No. ZR2019BA015).
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Graphical Abstract
Design, synthesis and antibacterial activity evaluation of
moxifloxacin-amide-1,2,3-triazole-isatin hybrids
Feng Gao a, b, Lei Ye , Fangong Kong , Gang Huang , Jiaqi Xiao
a
a
b*
a, b*
aState Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu
University of Technology (Shandong Academy of Sciences), Jinan, P. R. China
bShanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine
and Health Sciences, Shanghai, P. R. China
N
O
N
Substituents at C-5 position were
more favorable than C-7 position;
N
N
R1
F
COOH
N
O
N
-F > -H > -Me. Introduction of
O
H
substituents at either C-5 or C-7
position increased the cytotoxicity.
R2
N
OMe
H
-NOMe > -O > -NOEt against Gram-positive pathogens;
-NOEt > -NONe and -O against Gram-negative pathogens.
-NOMe and -NOEt couldn't improve toxicological profile.
Twelve moxifloxacin-amide-1,2,3-triazole-isatin hybrids 7a-l, were prepared and their
in vitro antibacterial activity against clinically important Gram-positive and Gram-
negative pathogens including drug-resistant strains was assessed in this work. The
majority of the synthesized hybrids showed considerable in vitro activity against both
drug-sensitive and drug-resistant strains, and acceptable cytotoxicity towards CHO
cells. In particular, three hybrids 7g, 7m and 7n, which were comparable to or better
than the parent moxifloxacin against Gram-positive or Gram-negative pathogens, also
demonstrated low cytotoxicity towards CHO cells.
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1
2
3
. Moxifloxacin-amide-1,2,3-triazole-isatin hybrids showed considerable
antibacterial activity;
. hybrids 7g, 7m and 7n were no inferior to the parent moxifloxacin against
Gram-positive or Gram-negative pathogens;
. The SAR and structure-cytotoxicity relationship were discussed.
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