Synthesis of novel 1,2,5-oxadiazoles and evaluation of action against Acinetobacter baumannii

Article abstract of DOI:10.1016/j.bmc.2017.08.015

With multidrug resistant bacteria on the rise, novel antibiotics are becoming highly sought after. In 2008, eleven compounds were identified by high throughput screening as inhibitors of BasE, a key enzyme of the non-ribosomal peptide synthetase pathway found in Acinetobacter baumannii. Herein, we describe the preparation of four structurally similar heterocyclic lead compounds from that study, including one 1,2,5-oxadiazole. A further library of 30 analogues containing the oxadiazole moiety was then generated. All compounds were screened against Acinetobacter baumannii and their minimum inhibitory concentration data is reported, with (E)-3-(2-hydroxyphenyl)-N-(4-methyl-1,2,5-oxadiazol-3-yl)acrylamide 32 found to have an MIC of 0.5 mM. This work provides the foundation for further investigation of 1,2,5-oxadizoles as novel inhibitors of A. baumannii.

Full text of DOI:10.1016/j.bmc.2017.08.015

Accepted Manuscript
Synthesis of novel 1,2,5-oxadiazoles and evaluation of action against Acineto-
bacter baumannii
Rebecca M. Christoff, Gerald L. Murray, Xenia P. Kostoulias, Anton Y. Peleg,
Belinda M. Abbott
PII:
S0968-0896(16)31484-5
DOI:
http://dx.doi.org/10.1016/j.bmc.2017.08.015
BMC 13918
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 December 2016
31 July 2017
8 August 2017
Please cite this article as: Christoff, R.M., Murray, G.L., Kostoulias, X.P., Peleg, A.Y., Abbott, B.M., Synthesis of
novel 1,2,5-oxadiazoles and evaluation of action against Acinetobacter baumannii, Bioorganic & Medicinal
Chemistry (2017), doi: http://dx.doi.org/10.1016/j.bmc.2017.08.015
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Synthesis of novel 1,2,5-oxadiazoles and evaluation of action
against Acinetobacter baumannii
Rebecca M. Christoffa, Gerald L. Murrayb,c,d, Xenia P. Kostouliasd, Anton Y. Pelegd,e and
Belinda M. Abbotta*
a Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University,
Melbourne, Victoria 3086, Australia
b Murdoch Childrens Research Institute, Melbourne, Victoria 3052, Australia
c Royal Women's Hospital, Melbourne, Victoria 3052, Australia
d Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of
Microbiology, Monash University, Clayton, Victoria 3168, Australia
e Department of Infectious Diseases, The Alfred Hospital and Monash University, Melbourne, Victoria
3004, Australia
Graphical abstract
Abstract
With multidrug resistant bacteria on the rise, novel antibiotics are becoming highly sought after. In 2008,
eleven compounds were identified by high throughput screening as inhibitors of BasE, a key enzyme of the
non-ribosomal peptide synthetase pathway found in Acinetobacter baumannii. Herein, we describe the
preparation of four structurally similar heterocyclic lead compounds from that study, including one 1,2,5-
oxadiazole. A further library of 30 analogues containing the oxadiazole moiety was then generated. All
compounds were screened against Acinetobacter baumannii and their minimum inhibitory concentration
data is reported, with (E)-3-(2-hydroxyphenyl)-N-(4-methyl-1,2,5-oxadiazol-3-yl)acrylamide 32 found to
have an MIC of 0.5 mM. This work provides the foundation for further investigation of 1,2,5-oxadizoles as
novel inhibitors of A. baumannii.
1

Keywords
1,2,5-Oxadiazoles; Acinetobacter baumannii; BasE inhibitors; Antibiotic resistance
Introduction
The rise of multidrug resistant bacteria is becoming a significant problem worldwide. In 2013, the Centers
for Disease Control and Prevention reported that there are at least two million infections and 23,000 deaths
caused by multidrug resistant pathogens each year in the United States alone.1 Surgical patients, those
undergoing chemotherapy and the critically ill are all in acute need of effective antibiotics and many
commonplace medical treatments would not be practical without ways to combat bacterial infection.2
Resistance can be attributed to a spontaneous or acquired mutation resulting in the drug becoming
ineffective against the target. Bacteria can also enhance their ability to remove compounds by more
effective degradation enzymes or by improving their efflux systems. The evolution of resistance
mechanisms is compounded by the inappropriate use of antimicrobial drugs and inadequate mechanisms to
prevent and control the spread of infection.3,4 Despite the increased need for effective treatments, the
discovery of novel therapeutic antibiotics has lagged far behind, with only one new class of antibiotics
introduced in the past decade.5
Acinetobacter baumannii is a Gram-negative organism known to cause pneumonia, meningitis and
infections of the bloodstream, urinary tract, skin and wounds.6 Commonly found in the hospital
environment, A. baumannii can survive for long periods on inanimate surfaces due to its ability to form
biofilms.7 A. baumannii has a highly plastic genome and readily acquires new resistance mechanisms.8
Alarmingly, there are now pan-resistant isolates of A. baumannii that are untreatable by antibiotic therapy.8
New targets are urgently needed in order to develop novel antibacterial agents to combat rising drug
resistance. One potential pathway of interest is the siderophore mediated iron acquisition pathway.
Bacteria require iron for growth and survival.9, 10 At approximately 10-24 M,11 the free iron concentration in
a typical vertebrate host is too low to support bacterial virulence. In these circumstances, bacteria acquire
iron through another mechanism comprising the release and recovery of siderophores. Siderophores are
small, structurally diverse scavenger molecules that chelate iron(III) with high affinity. Released in iron
deficient conditions, siderophores are essential for bacterial virulence.9, 10
First characterised in 1992 by Yamamoto et al., acinetobactin (Figure 1) is the siderophore produced by A.
baumannii12 and is synthesised via the non-ribosomal peptide synthetase pathway.13 Initially, the aryl acid
adenylating enzyme, BasE, catalyses the formation of 2,3-dihydroxybenzoate-adenosine monophosphate
(DHB-AMP) from 2,3-dihydroxybenzoic acid and adenosine monophosphate. The DHB-AMP conjugate
then undergoes acylation by BasE. This acylated complex forms the aryl cap, a common feature of all
siderophores, and is transported by BasF to BasA, BasB and BasD for further processing. Inhibiting BasE
would halt siderophore production, thus preventing bacteria from acquiring the iron essential for their
2

virulence. Notably, the genes of the BasE system are highly upregulated during A. baumannii infection and
mutagenesis of the acinetobactin cluster has been shown to attenuate bacteria in a murine model of
disease.14 With no known homologues in humans, BasE is an ideal drug target for further study.13
Figure 1. BasE siderophore acinetobactin.
In 2008, a series of compounds were identified as inhibitors of BasE by a high throughput screen (HTS)
conducted by Neres and coworkers.10 One of the compounds (HTS-23 in Figure 2), with a dissociation
constant in the submicromolar range, was further developed and a series of analogues was described in
2013.13 While the analogues of compound HTS-23 displayed potent enzyme inhibition of BasE, they lacked
whole cell activity against A. baumannii.
Figure 2. Selected HTS hit compounds identified against BasE in 2008.10
Interested in the whole cell activity of the remaining high throughput screen hit results, we herein describe
for the first time the synthesis and characterisation of four of the structurally similar heterocyclics identified
by Neres et al. (HTS-27, HTS-28, HTS-30 and HTS-33 in Figure 2). All contain two cyclic rings, mostly
aromatic, linked by a thioether alongside either an amide or carbonyl group. Three of the compounds
contain a methylpyrimidine ring while the fourth has a pyridine instead. Of the four known compounds
3

prepared and tested, HTS-27 exhibited activity against A. baumannii under iron deficient conditions and a
series of analogues of this hit were then synthesised for biological evaluation.
Results and discussion
The preparation of HTS-27, HTS-28, HTS-30 and HTS-33 was achieved as shown in Scheme 1. While all
of these lead compounds are commercially available, their synthesis and characterisation is reported here,
Synthesis of HTS-27
O
N
O
N
O
N
O
O
N
N
N
O
O
c
b
a
d
Br
S
N
N
N
NH2
O
H
H
2
1
(61%)
(27%)
3 (HTS-27) (
28%)
Synthesis of HTS-28
O
O
O
Br
S
N
e
S
S
S
N
4
(35%)
5 (HTS-28)
(58%)
Synthesis of HTS-30
O
O
S
N
Br
e
N
R1
R1
1
6 (HTS-30)
R = Br (52%)
1
7
R = H (71%)
Synthesis of HTS-33
O
O
N
b
Br
e
S
N
NH
N
N
9 (HTS-33)
(74%)
8
(96%)
to the best of our knowledge, for the first time.
Scheme 1. Reaction conditions: (a) One pot reaction over 3 days; 1. NaOH, H2O, 10 ˚C → rt. 2. NaNO2, 20% HClO4, 10 ˚C → rt. 3. NaOH, NH2OH.HCl, 90 ˚C,
urea, reflux. (b) Bromoacetyl bromide, DIPEA, CH2Cl2, -20 ˚C. (c) 2-Mercaptopyridine, Na2CO3, EtOH, H2O. (d) Br2, diethyl ether, 0 ˚C. (e) 2-Mercapto-4-
methylpyrimidine, Na2CO3, EtOH, H2O.
The synthesis of HTS-27 was undertaken over a three step process. Preparation of 4-methyl-1,2,5-
oxadiazole-3-amine 1 was undertaken from ethyl acetoacetate in a one pot reaction over three days as
reported by Sheremetev et al.15 Initially, freshly distilled ethyl acetoacetate was added to sodium hydroxide
in water at 10 ˚C forming an emulsion, which was stirred to homogenization overnight. Sodium nitrite was
added the following day, followed by perchloric acid to form an oxime which undergoes decarboxylation.
On the third day, sodium hydroxide was added, followed by an excess of hydroxyl amine hydrochloride
then a further addition of sodium hydroxide. The mixture was heated to 95 °C for two hours to facilitate the
cyclisation process then urea, a dehydrating agent, was added in one portion to assist cyclisation and the
reaction was refluxed for three hours. The product was extracted from the reaction mixture with multiple
4

washings of dichloromethane yielding 4-methyl-1,2,5-oxadiazol-3-amine 1 in 27% yield. Though the
literature reports a 51% yield for this reaction, this result was unable to be replicated despite increasing the
reaction time and equivalents of reagent. A number of side products were visualised via TLC but not
isolated, thus contributing to a poor yield. The product was also found to be highly water soluble and
required further extraction than the previously reported number of washes to reach the modest yield
reported here.
Acylation of 1 was then undertaken with bromoacetyl bromide and base in dichloromethane at -20˚C, as
adapted from the literature,16 to form the corresponding amide 2 in a 61% yield. Finally, via procedures
described by Loghmani-Khouzani and Hajiheidari,17 the brominated compound 2 was coupled with 2-
mercaptopyridine in aqueous ethanol with sodium carbonate to obtain 3 (HTS-27) in 28% yield after
column chromatography. Unfortunately, a further fraction of product could not be satisfactorily purified.
To prepare HTS-28, 2-acetylthiophene was initially brominated as reported by Sharma et al.18 Coupling of
the 2-(2-bromoacetyl)thiophene (4) with 2-mercapto-4-methylpyrimidine in aqueous ethanol with base
gave 5 (HTS-28), where acidification precipitated the desired product in 58% yield. The same procedure
was applied to commercially available 2,4’-dibromoacetophenone and 2-mercapto-4-methylpyrimidine to
give 6 (HTS-30) in 52% yield. Compound 7, an analogue of HTS-30 without the para-bromo substitution,
was also synthesised in 71% yield when 2-bromoacetophenone was used as the starting material.
Finally, synthesis of HTS-33 involved acylation of 1,2,3,4-tetrahydroisoquinoline with bromoacetyl
bromide as reported in literature16 to produce compound 8, which was then coupled with the corresponding
thiol in aqueous ethanol as previously employed, to give 9 (HTS-33) in 74% yield.
All compounds were subjected to testing for antibiotic activity against A. baumannii American Type
Culture Centre (ATCC) 17978 via a minimum inhibitory concentration (MIC) assay. The iron chelator 2,2’-
dipyridyl was added to the medium to simulate the iron depleted conditions under which siderophores are
required for growth.19,20 Results were obtained in triplicate and the median value identified as the MIC.
Compound HTS-27 displayed antibiotic activity with a MIC of 2 mM, while an MIC of 4 mM was
determined for HTS-28. Neither HTS-30 or HTS-33 had observable activity under the conditions tested,
with an MIC > 4 mM. As a consequence, it was decided to pursue the synthesis of analogues of HTS-27 to
determine whether structural changes could improve potency. The analogues prepared are summarised in
Tables 1 and 2 below.
5

Table 1. Chemical structures, synthetic yields and MIC against A. baumannii for thioether and dimeric analogues of HTS-27.
Compound
R1
Yield
(%)
MICa
2 mM
HTS-27
28
10
11
94
4 mM
4 mM
90
12
13
76
73
2 mM
> 4 mM
14
85
2 mM
15
16
48
12
> 4 mM
> 4 mM
Reaction conditions: (a) Corresponding thiol, Na2CO3, EtOH, H2O.
a Median MIC value for Acinetobacter baumannii (ATCC 17978) from
a minimum of three independent experiments.
6

Table 2. Chemical structures, synthetic yields and MIC against A. baumannii for 2-, 3- and 4-substituted analogues of HTS-27.
Compound
R1
R2
Yield
(%)
MICa
1 mM
Compound
R1
R2
Yield
(%)
MICa
2 mM
18
CH3
5b
31
CH3
33
19
CH3
73
2 mM
32
CH3
95c
0.5 mM
20
21
CH3
CH3
83
66
1 mM
34
35
CH3
CH3
57
4 mM
> 4 mM
45c
> 4 mM
OH
OH
22
23
CH3
CH3
57
59
1 mM
37
38
Ph
Ph
41
26
> 4 mM
> 4 mM
> 4 mM
24
25
CH3
CH3
68
81
1 mM
39
40
Ph
Ph
17
43
> 4 mM
> 4 mM
> 4 mM
26
27
CH3
79
44
1 mM
4 mM
41
Ph
41
> 4 mM
CH3
43
44
Propyl
Propyl
67
81
> 4 mM
1 mM
28
29
CH3
CH3
72
72
1 mM
2 mM
Reaction conditions: (a) Corresponding acid, PCl5, CH2Cl2, reflux.
a Median MIC value for Acinetobacter baumannii (ATCC 17978) from a minimum of three independent experiments.
b Alternative procedure. Reaction conditions: (a) Cinnamic acid, SOCl2. (b) 4-Methyl-1,2,5-oxadiazole-3-amine, THF, NaHCO3.
c Obtained from deprotection of compounds 30 and 32 with methanolic ammonia.
7

Preparation of 2-bromo-N-(4-methyl-1,2,5-oxadiazol-3-yl)acetamide 2, as described previously, followed
by coupling to a variety of thiols resulted in the production of six analogues 10-15 in yields ranging from
48-94%. In addition, aniline was also reacted with compound 2 with the view to expand the scope of
potential analogues. However, column chromatography of the crude material resulted in the isolation of the
dimeric compound 16, which was confirmed by NMR analysis and mass spectrometry.
A further library of analogues was then prepared by acylating 4-methyl-1,2,5-oxadiazole-3-amine 1 with
various acid chlorides. The first acid chlorides were prepared from the corresponding acids with thionyl
chloride followed by coupling to 4-methyl-1,2,5-oxadiazole-3-amine 1 in dry tetrahydrofuran with sodium
bicarbonate overnight, as described by Shin et al.21 Cinnamic acid gave compound 18, isolated by column
chromatography in a 5% yield while compound 19, prepared from phenoxyacetic acid, was isolated in a
25% yield. Due to these low yields, an alternative procedure was explored where the acid chloride was
generated in situ, in order to eliminate the need for isolation.22 Phenoxyacetic acid was refluxed with
phosphorus pentachloride in dichloromethane for 30 minutes followed by the addition of 4-methyl-1,2,5-
oxadiazole-3-amine 1 and further reflux for two hours. This method successfully obtained the product 19,
with an improved yield of 73% in sufficient purity following extraction.
Continuing to use the simplified and higher yielding procedure, a variety of analogues were synthesised
from varying the corresponding acid. To explore the importance of the nitrogen in the pyridine ring,
analogue 20 was prepared from thioacetic acid. Four chlorine substituted analogues of 19, designated 21-
24, were then synthesised to determine the tolerance of electronegative groups around the ring. Three
naphthalene derivatives were produced to give compounds 25-27, two with a shortened linker to the
oxadiazole while the third resulting in a larger aromatic derivative. Analogue 28 explores the effect of no
heteroatom next to the aromatic system with the following compound 29 containing a para substituted
methoxy group.
Compounds 31-32 and 34-35 are cinnamic acid derivatives, related to unsubstituted analogue 18. Initially,
2-hydroxycinnamic acid was refluxed with phosphorus pentachloride without phenolic protection but
purification resulted in recovery of the oxadiazole starting material and identification of two side products,
coumarin and a dimer. NMR shifts were found to correspond to those reported by Kim et al. identifying
formation of these products when 2-hydroxycinnamic acid was stirred with base in various solvents at room
temperature.23 To avoid this outcome, the 2-hydroxycinnamic acid and 3,4-dihydroxycinnamic acid were
stirred in acetic anhydride and sulfuric acid at 0 ˚C to produce the acetylated product which was
subsequently refluxed with phosphorus pentachloride and the oxadiazole, producing compounds 31 and 34.
To attain two further analogues the resulting derivatives were deprotected with methanolic ammonia
solution to afford 32 and 35.
To explore the role of the methyl substituent on the oxadiazole, a small series of analogues were also
prepared with alternative functionality on the heterocyclic ring. 4-Phenyl-1,2,5-oxadiazol-3-amine (36) was
8

synthesised from ethyl benzoylacetate in a one pot reaction as described by Sheremetev et al24 (Scheme 2).
Subsequent coupling of 36 with five different acids, through the use of phosphorus pentachloride, produced
the 4-phenyl compounds 37-41. Additionally, two 4-propyl oxadiazole analogues 43 and 44 were prepared
to see if a longer chain would be tolerated if the 4-phenyl group was not accepted.
Scheme 2. Reaction conditions: (a) One pot reaction over 3 days; 1. NaOH, H2O, 10 ˚C → rt. 2. NaNO2, 20% HClO4, 10 ˚C → rt. 3. NaOH, NH2OH.HCl, 90 ˚C,
urea, reflux.
All analogues were tested against A. baumannii (ATCC 17978) under the same conditions as previously
described, however care must be taken when interpreting results where changes of less than an order of
magnitude are observed. The alternate heterocycles trialled as thioethers 10-15 had undetectable activity,
the exception being the 4,5-dihydrothiazole 12 and benzoimidazole 14 compounds with MIC values of 2
mM. The dimer 16 did not have detectable activity. However, removal of the pyridyl nitrogen from HTS-
27 to give compound 20 did not appear to be detrimental to activity, with MIC values of 2 mM for the lead
and 1 mM for the benzene analogue. Changing the thioether of the lead to an oxygen or carbon bridge
resulting in compounds 19 and 28 was also tolerated. Substitution of the ether 19 with 4-chloro and 3,4-
dichloro functionality on the aromatic ring gave MIC values of 1 mM (analogues 22 and 24 respectively)
but compounds 21 and 23, with 2-chloro and 2,3-dichloro substitution respectively, were not potent. For
compound 28, the 4-methoxy analogue 29 was also acceptable. Naphthyl analogues 25-27 did not appear
promising, though compound 26 had an MIC of 1 mM.
Interestingly, introducing rigidity through the alkene of compounds 18, 31 and 32 gave a new synthetic
direction to pursue. Unfortunately, the 3,4-subsituted analogues 34 and 35 were not active. Compound 32,
(E)-3-(2-hydroxyphenyl)-N-(4-methyl-1,2,5-oxadiazol-3-yl)acrylamide, returned the most promising MIC
value of 0.5 mM, offering potential for further development. Finally, none of the 4-phenyl analogues 37-41
exhibited detectable activity while the influence of the 4-propyl substituent on the activity of analogues 42
and 43 requires further exploration.
These antibacterial results are comparable to those observed in 2013 by Neres and co-workers.13 There are a
number of potential explanations for the modest level of activity of these compounds against A. baumanii
despite the previously demonstrated high affinity for BasE.10 These include: (i) potential low compound
solubility in water, (ii) an unknown ability to cross bacterial membranes, (iii) the possibility of export from
the bacterial cell via broad-specificity multi-drug export systems of A. baumannii, and (iv) the ability of
9

other iron-acquisition systems to compensate for the loss of the acinetobactin cluster function. Solubility
does not appear to be a significant influence on activity. Analogues with an MIC of 1 mM were found to
have cLogP values in the range of 1.71 - 3.07. While compound 32 with an MIC 0.5 mM had a slightly
lower cLogP value of 1.45, a decrease to cLogP of 0.77 was found for HTS-27, which had a higher MIC of
2 mM. While poor affinity cannot be ruled out, as direct testing against BasE has not yet been undertaken,
compound 20 was tested in an environment with a normal iron concentration, and growth was not inhibited.
This indicates that the inhibition is iron-related, and thus most likely siderophore related.
Conclusion
Four heterocyclic compounds previously reported as high throughput screen hits against BasE of A.
baumannii10 have been synthesised, characterised and had their antibiotic activity evaluated. Despite being
promising inhibitors of BasE,10 two of the HTS hits showed little to no antibacterial activity toward A.
baumannii while the other two compounds indicated modest activity. A library of HTS-27 analogues was
then prepared, adapting and improving upon existing synthetic methods. Compound 32 was identified as
the most potent analogue with a MIC of 0.5 mM against A. baumannii (ATCC 17978). These studies
contribute to the exploration of BasE and siderophore biosynthesis as a target for novel antibiotics in A.
baumannii.
Acknowledgments
We are very grateful for the ongoing support and many helpful discussions provided by Dr. Les Deady. We
also thank the La Trobe Institute of Molecular Science for their generous financial support. R. M. C. also
acknowledges the support of La Trobe University and the Australian Government as a recipient of an
Australian Postgraduate Award. A.Y.P acknowledges support from an Australian National Health and
Medical Research Council Practitioner Fellowship (APP1117940).
Supplementary data
Supplementary data associated with this article can be found, in the online version, at XXXX.
References
1.
2.
3.
4.
5.
CDC, Antibiotic Resistance Threats in the United States, USA, 2013.
Worthington, R. J.; Melander, C. Curr. Trends Biotechnol. 2013, 31, 177.
Fishbain, J.; Peleg, A. Y. Clin. Infect. Dis. 2010, 51, 79.
Tanwar, J.; Das, S.; Fatima, Z.; Hameed, S. Interdiscip. Perspect. Infect. Dis. 2014, 2014, 7.
Conly, J.; Johnston, B. Can. J. Infect. Dis. 2005, 16, 159.
10

6.
Michalopoulos, A.; Falagas, M. E. Expert Opin. Pharmacother. 2010, 11, 779.
7.
8.
9.
10.
11.
12.
13.
Tomaras, A. P.; Dorsey, C. W.; Edelmann, R. E.; Actis, L. A. Microbiology 2003, 149, 3473.
Doi, Y.; Murray, G. L.; Peleg, A. Y. Semin. Respir. Crit. Care Med. 2015, 36, 85.
Robbel, L.; Knappe, T. A.; Linne, U.; Xie, X.; Marahiel, M. A. FEBS J. 2010, 277, 663.
Neres, J.; Wilson, D. J.; Celia, L.; Beck, B. J.; Aldrich, C. C. Biochemistry 2008, 47, 11735.
Raymond, K. N.; Dertz, E. A.; Kim, S. S. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 3584.
Yamamoto, S.; Okujo, N.; Sakakibara, Y. Arch. Microbiol. 1994, 162, 249.
Neres, J.; Engelhart, C. A.; Drake, E. J.; Wilson, D. J.; Fu, P.; Boshoff, H. I.; Barry, C. E., 3rd;
Gulick, A. M.; Aldrich, C. C. J. Med. Chem. 2013, 56, 2385.
14. Gaddy, J. A.; Arivett, B. A.; McConnell, M. J.; Lopez-Rojas, R.; Pachon, J.; Actis, L. A. Infect.
Immun. 2012, 80, 1015.
15.
16.
Sheremetev, A. B.; Shamshina, Y. L.; Dmitriev, D. E. Russ. Chem. Bull. 2005, 54, 1032.
An, H.; Cook, P. D.; Fraser, A. S.; Guinosso, C. J.; Kawasaki, A. M. U.S. Patent
WO1999000669A1, 1999.
17.
18.
Loghmani-Khouzani, H.; Hajiheidari, D. J. Fluorine Chem. 2010, 131, 561.
Sharma, V. K.; Hung, D. T.; Lee, K.-C.; Thanigaimalai, P.; Kang, J. S.; Kim, H.-M.; Jung, S.-H.
MedChemComm 2011, 2, 731.
19.
20.
Murray, G. L.; Attridge, S. R.; Morona, R. Microbes and Infection 2005, 7, 1296.
Lo, M.; Murray, G. L.; Khoo, C. A.; Haake, D. A.; Zuerner, R. L.; Adler, B. Infect. Immun. 2010,
78, 4850.
21. Shin, D. S.; Masciocchi, D.; Gelain, A.; Villa, S.; Barlocco, D.; Meneghetti, F.; Pedretti, A.; Han,
Y.-M.; Han, D. C.; Kwon, B.-M.; Legnani, L.; Toma, L. MedChemComm 2010, 1, 156.
22.
Woster, P. M. J. Med. Chem. 2012, 55, 7378.
23. Kim, M.-J.; Kim, J.-J.; Won, J.-E.; Kang, S.-B.; Park, S.-E.; Jung, K.-J.; Lee, S.-G.; Yoon, Y.-J.
Bull. Korean Chem. Soc. 2008, 29, 2247.
24. Sheremetev, A. B. Russ. Chem. Bull. 2005, 54, 1057.
Hazeldine, S.; Pachaiyappan, B.; Steinbergs, N.; Nowotarski, S.; Hanson, A. S.; Casero, R. A., Jr.;
11