Synthesis and in vitro antibacterial activity of new aminothiazole-oximepiperidone cephalosporins

Article abstract of DOI:10.1016/j.bmcl.2021.127928

Four new aminothiazole-oximepiperidone cephalosporins (10a-10d) were synthesized, with their in vitro antibacterial activities against hospital isolated Gram-negative bacteria assessed. The results showed that compounds 10a-10d effectively inhibit a varie

Full text of DOI:10.1016/j.bmcl.2021.127928

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Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and in vitro antibacterial activity of new
aminothiazole-oximepiperidone cephalosporins
,b,
Zhengwu Shena *, Wei Xub, Jingfeng Yub, Lixia Chenb, Jinghua Zhanga, Sihan Shenga,
,
Xun Dongc *, Hongzhu Bianc
a School of Medicine, Shanghai Jiao Tong University, 280 South Chongqing Road, Shanghai 200025, PR China
b School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, PR China
c Yunnan Baiyao Group Co., Ltd., 3686 Yunnan Baiyao Street, Kunming 650200, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Four new aminothiazole-oximepiperidone cephalosporins (10a-10d) were synthesized, with their in vitro anti-
bacterial activities against hospital isolated Gram-negative bacteria assessed. The results showed that compounds
10a-10d effectively inhibit a variety of Gram-negative bacteria. Compound 10a was the most potent compound,
with comparable activity as ceftazidime. The combination of compound 10a and Avibactam was very active
against almost all bacteria tested, which including multidrug resistant K. pneumoniae and A. baumannii.
Compared to Avycaz, this combination is more potent against ESBL producing K. pneumoniae. Thus, the com-
bination of 10a and Avibactam is of interest for further studies.
Cephalosporin
Aminothiazole-oximepiperidone
Gram-negative bacteria
β-Lactamase
Multidrug resistance (MDR) bacterial infection, especially MDR
Gram-negative bacterial infection, is one of the biggest threats to global
public health.1 “Superbug” are spreading at an alarming rate all over the
world. These “superbugs” are resistant to almost all available antibi-
otics. The Infectious Diseases Society of America (IDSA) announced that
“ESCAPE” pathogens (vancomycin resistant Enterococcus faecium (VRE);
methicillin resistant Staphylcoccus aureus (MRSA); Escherichia coli and
Klebsiella species; Acinetobacter baumanii; Pseudomonas aeruginosa;
Enterobacterie spp) is one of the largest challenges facing human health in
the 21st century.2,3,4 In China, the threat of bacterial resistance is even
more severe.5,6 Due to the abuse of antibiotics, bacteria have a serious
resistance to the existing antibiotics. According to a survey conducted in
Chinese hospitals in 2009,6 more than 60% of Staphylococcus aureus
were methicillin-resistant (MRSA); more than 60% of Pseudomonas
aeruginosa strains were multi drug resistant, including ceftazidime,
ciprofloxacin, amikacin and imipenem; more than 50% of Acinetobacter
baumannii strain were resistant to meropenem and imipenem, and about
70% of Escherichia coli strains were resistant to fluoroquinolones. Thus,
the development of safe and effective broad-spectrum antibiotics,
especially broad-spectrum antibiotics against Gram-negative bacteria,
has become an urgent global issue.1 In the past two decades, there have
been several new antibiotics approved for the market, including cef-
ceftazidime/avibactam combination (Avycaz),11 meropenem/vabor-
bactam combination,12 etc. However, the development rate of new an-
tibiotics is still far from meeting the needs.13 Fig 1
ß-Lactam antibiotics are widely used due to their good safety profile,
well tolerance, clear antibacterial mechanism and strong antibacterial
activities. However, with increasing numbers of resistant bacteria the
efficacy of ß-lactam antibiotics has been largely affected. Gram-negative
bacteria can produce various ß-lactamases, including ESBLs, AmpC,
KPC, VIM, IMP and metal ß-lactamases (MBL). These enzymes hydrolyze
the ß-lactam, which is the main cause of drug resistance in Gram-
negative bacteria. In extreme cases, some bacteria even produce both
ESBLs and carbapenemase, and are therefore resistant to most ß-lactam
antibiotics.14
The efflux system in Gram-negative bacteria is the second drug
resistance mechanism that pumps antibiotics out of the cells and prevent
them from producing antibacterial effects.15 Therefore, to effectively
inhibit drug-resistant Gram-negative bacteria, antibiotics need to resist
the hydrolysis of ß-lactamase while escaping the efflux system to achieve
the best effect.
KP-736 is an earlier-synthesized aminothiazole oximepiperidone
cephalosporin with the activity against a wide range of Gram-negative
bacteria. It has better activity against Pseudomonas and imipenem
resistant bacteria compared to ceftazidime, cefotaxime and cefepime.16
taroline
fosamil,7
antoloxacin,8
doripenem,9
ceftobiprole,10
* Corresponding authors.
E-mail addresses: Jeff_shen_1999@yahoo.com (Z. Shen), Xundong@qq.com (X. Dong).
https://doi.org/10.1016/j.bmcl.2021.127928
Received 9 December 2020; Received in revised form 17 February 2021; Accepted 25 February 2021
Available online 8 March 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

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Z. Shen et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127928
H2N
NH
NH
O
O
O
O
OH
OH
OH
N
ONa
N
N
OH
O
O
O
O
OH
N
O
O
HN
N
N
N
H
H
O
H
N
H
H
N
S
O
N
N
S
N
S
N
S
H2N
H2N
H2N
N
S
N
N
N
O
OSO3H
N
S
N
O
SO3H
HO3S
O
CO2Na
Syn/PTXC2416
BAL19764
KP-736
BAL29880
BAL30072
Fig. 1. The structures of KP-736, BAL19764, BAL29880 and BAL30072.
Scheme 1. The synthesis of 10a-10d.
KP-736 also has a high affinity to the PBP 3 of both E. coli K-12 and
Pseudomonas aeruginosa NCTC-10490, thus, it has strong bactericidal
activity against these two strains.
The aminothiazole oximepiperidone side chain of Syn/PTXC2416
(BAL19764) allows the molecule to enter the cell of the Gram-negative
bacteria through the ferric ion transfer related non-membrane pore
2

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Z. Shen et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127928
Table 1
In vitro Antibacterial activity of compounds 10a-10d (MIC: mg/L)#
Strain
MIC (mg/L)
10a
10a/Avibactam (w/w
10b
10b/Avibactam (w/w
10c
10d
Ceftazidime
Ceftazidime/Avibactam (w/
= 1/1)
= 1/1)
w = 1/1)
Enterococcus faecalis (ATCC 51299)
Escherichia coli (ATCC 25922)
Escherichia coli (ATCC 35218)
Escherichia coli (NCTC 13353(
Escherichia coli (ECO+ 15–3)
Escherichia coli (ECO+ 15–4)
Escherichia coli (ECO+ 15–5)
Klebsiella pneumonia (ATCC 700603)
Klebsiella pneumoniae (ATCC BAA-1705)
Multidrug resistant Klebsiella pneumoniae
(KR 15-1)
>64
0.5
>64
0.25
0.25
0.5
1
>64
2
>64
0.125
0.125
1
>64
1
>64
2
>64
0.06
0.06
64
>64
0.125
0.06
0.5
0.25
0.5
1
0.5
0.5
1
0.25
>64
>64
>64
>64
64
>64
64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
1
8
>64
>64
64
0.5
0.5
64
1
16
0.5
>64
8
32
32
4
64
2
64
>64
>64
64
4
>64
1
2
>64
>64
2
Multidrug resistant Klebsiella pneumoniae
(KR 15-2)
>64
>64
1
1
>64
>64
1
1
>64
>64
>64
>64
>64
>64
2
2
Multidrug resistant Klebsiella pneumoniae
(KR 15-3)
Acinetobacter baumannii (NCTC 13304)
Multidrug resistant Acinetobacter
baumanni (AR 15-2)
>64
>64
16
16
>64
>64
32
16
>64
>64
>64
>64
64
8
8
>64
Multidrug resistant Acinetobacter
baumanni (AR 15-3)
>64
>64
1
8
8
1
>64
>64
4
8
8
1
>64
>64
16
>64
>64
2
>64
>64
1
16
8
Multidrug resistant Acinetobacter
baumanni (AR 15-4)
Pseudomonas aeruginosa (ATCC 27853)
0.5
#
Notes: “ECO+ ”“ represents Escherichia coli with extended-spectrum β-lactamases (ESBLs).
path.17,18 In addition, this side chain cannot be recognized by the
widespread efflux system in bacteria. The metal ion complexing ability
of the adjacent ketone and hydroxyl group in piperidone also inhibits
metal ß-lactamase and OXA-48 type ß-lactamase. Therefore, the triple
combination of Syn/PTXC2416, clavulanic acid (inhibit class A and D ß-
lactamase) and BAL29880 (inhibit class C ß-lactamase) can greatly
expand the antibacterial spectrum and antibacterial properties.19
BAL30072 also has an aminothiazole oximepiperidone side chain,
Table 2
Antibacterial activity of 10a and its combination with avibactam (MIC: mg/L).
Entry
Organism (no. of isolates)
Strain
10a
1:1 Combination of 10a
Ceftazidime
1:1 Combination of
Meropenem
and Avibactam
Ceftazidime and Avibactam
1
Carbapenem- resistant Acinetobacter
baumannii (10)
ABA 17-2
ABA 17-3
ABA 17-5
ABA 17-6
ABA 17-8
ABA 17-9
ABA 17-10
ABA 17-11
ABA 17-12
ABA 17-13
KR 15-4
＞64
＞64
＞64
＞64
＞64
＞64
＞64
＞64
＞64
＞64
＞64
＞64
16
16
16
16
16
16
16
16
8
＞64
＞64
＞64
＞64
＞64
＞64
32
8
64
2
8
16
3
8
64
4
8
32
5
8
32
6
8
32
7
4
16
8
32
8
32
9
16
2
64
8
16
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
＞64
＞64
＞64
32
2
64
Carbapenem- resistant Klebsiella
pneumoniae (10)
4
2
>64
>64
>64
>64
>64
>64
>64
32
KR 15-5
2
2
KR 15-6
0.5
1
1
KR 15-7
＞64
＞64
＞64
＞64
＞64
＞64
＞64
32
＞64
＞64
64
2
KR 15-8
4
4
KR 15-9
2
2
KR 15-10
KR 15-11
KR 15-12
KR 15-13
PAE 17-1
PAE 17-5
PAE 17-8
KPN+ 17–1
KPN+ 17–2
KPN+ 17–3
KPN+ 17–4
KPN+ 17–5
KPN+ 17–6
KPN+ 17–7
KPN+ 17–8
KPN+ 17–9
KPN+ 17–10
KPN+ 17–11
KPN+ 17–12
1
＞64
＞64
64
2
1
2
4
4
32
2
64
1
64
Carbapenem- resistant Pseudomonas
aeruginosa (3)
16
32
16
0.25
0.125
4
32
8
16
64
64
32
16
1
32
32
32
32
Carbapenem- sensitive Klebsiella
pneumoniae (with ESBLs) (15)
64
64
0.06
<0.03
<0.03
0.06
<0.03
<0.03
0.06
0.125
0.06
<0.03
0.06
<0.03
2
2
0.25
2
＞64
＞64
8
＞64
＞64
1
2
4
1
0.25
0.5
4
0.25
＞64
＞64
64
0.25
2
8
＞64
＞64
64
0.5
0.5
1
2
0.5
0.25
0.25
1
＞64
＞64
1
16
4
8
0.125
4
(continued on next page)
3

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Z. Shen et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127928
Table 2 (continued)
Entry
Organism (no. of isolates)
Strain
10a
1:1 Combination of 10a
Ceftazidime
1:1 Combination of
Meropenem
and Avibactam
Ceftazidime and Avibactam
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
KPN+ 17–13
KPN+ 17–14
KPN+ 17–15
KPNꢀ 15–2
KPNꢀ 17–16
KPNꢀ 17–17
KPNꢀ 17–18
KPNꢀ 17–19
KPNꢀ 17–20
ECO+17–2
ECO+17–3
ECO+17–5
ECO+17–6
ECO+17–8
ECO+17–10
ECO+17–11
ECO+17–12
ECO+17–14
ECO+17–15
ECO+17–17
ECO+17–18
ECO+17–21
ECO+17–22
ECOꢀ 17–1
ECOꢀ 17–4
ECOꢀ 17–7
ECOꢀ 17–9
ECOꢀ 17–16
ECOꢀ 17–19
ECOꢀ 17–20
ECL 17-1
1
≤0.03
0.5
0.125
≤0.03
0.06
0.125
0.06
≤0.03
0.06
0.25
0.125
1
4
0.25
2
<0.03
1
4
2
64
0.06
0.5
0.125
≤0.03
≤0.03
0.06
2
32
1
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
0.06
Carbapenem- sensitive Klebsiella
pneumoniae (without ESBLs) (6)
0.125
2
0.25
0.25
0.125
0.125
0.25
0.125
0.25
0.25
0.25
0.5
0.125
0.125
0.25
0.125
2
Carbapenem-sensitive Escherichia coli
(with ESBLs) (14)
2
2
64
32
16
4
4
0.5
0.5
0.06
4
32
16
0.25
0.5
4
＞64
4
32
0.5
0.25
0.25
0.25
0.5
0.5
0.5
0.5
0.25
0.125
0.5
0.5
0.5
0.5
0.06
1
8
0.25
0.25
0.5
64
＞64
＞64
8
16
64
32
0.5
2
0.5
64
＞64
32
0.25
2
8
0.25
1
＞64
64
Carbapenem-sensitive Escherichia coli.
0.5
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
<0.03
0.125
0.06
(without ESBLs) (7)
0.25
0.125
0.5
0.5
0.25
0.25
0.5
64
0.25
0.125
0.25
0.25
0.25
0.25
0.25
1
0.5
2
1
0.25
1
Enterobacter cloacae (10)
ECL 17-2
＞64
64
1
1
ECL 17-3
2
1
0.25
0.25
1
ECL 17-4
0.5
4
0.5
64
<0.03
0.06
ECL 17-5
32
2
ECL 17-6
1
0.25
＞64
0.125
0.5
1
0.25
2
<0.03
0.25
ECL 17-7
＞64
16
8
2
ECL 17-8
2
0.125
0.25
1
<0.03
<0.03
<0.03
0.125
0.06
ECL 17-9
2
ECL 17-10
EAE 17-1
1
0.5
2
Enterobacter aerogenes (10)
32
64
2
8
1
EAE 17-2
1
16
0.5
EAE 17-3
0.5
1
0.5
8
0.25
0.5
<0.03
0.125
0.125
4
EAE 17-4
8
EAE 17-5
64
＞64
4
2
16
0.5
EAE 15-3
16
＞64
0.25
16
4
EAE 15-4
0.5
1
0.25
0.5
<0.03
0.125
0.06
EAE 15-5
8
EAE 15-6
16
4
0.5
2
8
0.25
1
EAE 15-7
16
0.125
0.06
Carbapenem- sensitive Pseudomonas
aeruginosa (10)
PAE 17-7
0.25
4
0.25
2
0.125
0.25
8
0.125
0.125
0.25
0.5
PAE 17-9
0.25
PAE 17-10
PAE 17-11
PAE 17-21
PAE 17-22
PAE 17-24
PAE 17-26
PAE 17-29
PAE 17-30
Escherichia coli ATCC
25922
2
2
0.25
8
2
0.25
4
2
4
2
1
2
1
1
0.5
2
0.5
1
4
4
2
2
2
1
1
1
1
2
1
1
0.5
1
1
0.25
0.25
0.25
0.125
0.25
0.125
2
Standard strain (5)
0.5
<0.03
97
Escherichia coli NCTC
13353
＞64
＞64
1
0.5
16
1
＞64
＞64
1
0.5
4
<0.03
16
98
A. baumannii NCTC
13304
99
P. aeruginosa ATCC
27853
0.5
2
1
100
K. pneumonia ATCC
BAA-1705
64
2
64
32
Notes: “KPN+” represents Klebsiella pneumoniae with extended-spectrum β-lactamases (ESBLs); “KPNꢀ ” means Klebsiella pneumoniae without extended broad-spectrum
β-lactamases (ESBLs); “ECO+”“ represents Escherichia coli with extended-spectrum β-lactamases (ESBLs); ”ECOꢀ “ represents Escherichia coli without extended-
spectrum β-lactamases (ESBLs).
4