Novel diversely substituted 1-heteroaryl-2-imidazolines for fragment-based drug discovery

Article abstract of DOI:10.1016/j.tetlet.2012.03.122

A palladium-catalyzed Buchwald-Hartwig arylation protocol has been applied to achieve high-yielding N-heteroarylation of a diverse set of privileged 2-imidazolines. The resulting compounds are of interest as a novel type of molecular tool for fragment-bas

Full text of DOI:10.1016/j.tetlet.2012.03.122

Tetrahedron Letters 53 (2012) 2876–2880
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel diversely substituted 1-heteroaryl-2-imidazolines for
fragment-based drug discovery
⇑
Mikhail Krasavin
Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed Buchwald–Hartwig arylation protocol has been applied to achieve high-yielding
N-heteroarylation of a diverse set of privileged 2-imidazolines. The resulting compounds are of interest
as a novel type of molecular tool for fragment-based drug discovery. The potential for combining two
2-imidazoline moieties in a heteroarene-linked dimer via sequential Pd-catalyzed arylation has been
demonstrated.
Received 1 February 2012
Revised 16 March 2012
Accepted 29 March 2012
Available online 4 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Fragment-based drug discovery
2-Imidazolines
Rule of Three
Buchwald–Hartwig reaction
2-Haloazines
Imidazoline dimers
Since its invention at Abbott Laboratories in 1996,1 fragment-
based drug discovery2 continues to evolve into a remarkably effi-
cient alternative to the traditional high-throughput screening
(HTS) technology of lead generation, both in terms of compound
numbers involved and the existing rational approaches for subse-
quent follow-up and optimization of the initial hits.3 In particular,
X-ray crystallography guided optimization of fragments allows one
to achieve significant increase in ligand affinity in strikingly few
iterations. Success stories of such streamlined fragment-based
drug discovery include nanomolar inhibitors of Aurora kinase4 as
well as heat shock protein 90 (Hsp90),5 which have advanced into
clinical trials for cancer.
quinoxaline, etc.) are typically not conducive to high solubility of
the resulting fragments.
In our program aimed at designing novel fragments for protein
affinity screening, attention was devoted to the 2-imidazoline scaf-
fold which has high solubility11 and can be regarded as being priv-
ileged. The latter aspect is clearly evidenced by the wide spectrum
of biological activities reported for 2-imidazoline-based com-
pounds, such as binding to nicotinic acetylcholine receptors,12
inhibition of K+ channels,13 suppression of NF-kB-mediated inflam-
matory response,14 antagonistic modulation of angiotensin II
receptors,15 prominent adrenergic activity,16 and affinity to spe-
cialized imidazoline binding sites (or putative receptors) where
discovery of certain subtype (I1, I2, I3) selective modulators can lead
to many useful therapeutic applications.17
2-Substituted 2-imidazolines 1 are very common and can be ac-
cessed in a variety of ways from readily available precursors, as
recently reviewed by Crouch.18 We designed a series of 1,2-disub-
stututed imidazoline fragments 2 where an additional, preferably
heteroaromatic moiety would contribute to the protein affinity,
while the molecular weight of the resultant compounds would re-
main low (<300 Da). Electron-deficient nitrogen heterocycles are
expected to reduce the basicity (or cationic character19) of the imi-
dazoline core (thereby reducing chances for non-specific protein
binding) and provide opportunities for additional interactions with
a protein (Fig. 1). Retrosynthetically, 2 can be derived from 1 via
heteroarylation of the latter with suitable heteroaromatic halides.
Direct nucleophilic substitution of 2-chloroazines with 2-imidazo-
lines has been reported to require the presence of an additional
Typically, fragments display weaker (lM to mM range) affinity
to a biological target compared to traditional HTS hits. However,
given their much smaller molecular weight, the ligand efficiency
of fragment hits (i.e. binding energy per atom)6 is quite high. In
designing new fragments, one should take into account certain
guidelines restricting molecular weight (<300 Da) as well as other
calculated properties of the future fragments (the so-called ‘Rule of
Three’).7 Moreover, fragment compounds should be sufficiently
soluble to permit their screening at high concentrations and,
ideally, should incorporate privileged8 structures. A large number
of privileged motifs have been identified to date9 and are suggested
as a basis for fragment design.10 However, many of these cores (in
particular, fused aromatic coumarin, benzothiophene, quinolone,
⇑
Tel.: +61 7 3735 6041; fax: +61 7 3735 6001.
E-mail address: m.krasavin@griffith.edu.au
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.122

M. Krasavin / Tetrahedron Letters 53 (2012) 2876–2880
2877
O
'softer' interaction swith
O
H
anionic amino acid residues
R
N
R
N
N
HN
N
2, imidazoline pKa = 4.86a (R = Ph, HetAr = 2-Py)
H
1
O
pKa = 10.9a (R = Ph)
additional H-bonding interactions
Figure 1. 2-Substituted 2-imidazolines 1 and the design of the new 1-heteroaryl 2-imidazoline fragments 2. apKa value was calculated using ACD Labs 6.00 software.
Table 1
2-Substituted 2-imidazolines 1a–k prepared in this work
1)EDA (1.05 equiv.), CH2Cl2, 0 oC, 20 min
R
N
O
R
HN
1a-k
2) NBS (1.05 equiv.), CH2Cl2, 0 oC --> r. t., 16 h
Compound
Structure
Isolated yield (%)
78a
N
Scheme 1. Preparation of 2-substituted 2-imidazolines.
1a
N
H
N
electron-withdrawing (such as nitro20 or carboxamide21) substitu-
ent in the azine coupling partner, thereby limiting the reaction
scope. Transition metal catalyzed N-arylation of amidines (2-imi-
dazolines being a special case of a cyclic amidine) has been studied
quite extensively, as recently reviewed by Maes and co-workers22
However, such methodology has not been developed for 2-imidaz-
olines.23 Herein, we report on the preparation of diversely substi-
tuted, fragment-like N-heteroaryl 2-imidazolines via Pd-catalyzed
Buchwald-Hartwig arylation24 of 2-substituted 2-imidazolines.
A series of 2-substituted 2-imidazolines 1a–k were synthesized
on 10–40 mmol scale from the respective aldehyde precursors via
condensation with ethylenediamine (EDA) and treatment with NBS
(Scheme 1).25 Compounds 1a–k were isolated by simple crystalli-
zation or chromatographically in good to excellent yields (Table 1).
Having prepared a range of the starting materials for the target
N-heteroaryl fragments 2, we proceeded to identify a suitable
N-arylation protocol. From the literature review22 on N-arylation
of amidines, methods employing copper–amine complexes to cat-
alyze this reaction were as commonplace as those where palla-
dium(II) complex catalysts were used. However, our attempts to
N-arylate 1a with 2-chloropyrazine under such conditions as CuI/
1b
1c
94b
89a
O
N
H
N
N
H
OMe
N
1d
1e
67c
63b
N
H
N
N
H
N
1f
89b
N
H
NO2
N
N
1g
1h
1i
96b
63b
68b
N
H
N
DMEDA/K2CO3/DMF, 80 °C, 12 h26 or CuI/
L-proline/Cs2CO3/DMF,
110 °C, 20 h27 led to negligible conversions and the formation of
multiple by-products. In selecting an alternative Pd-catalyzed
protocol for the desired N-arylation, we were motivated by our
prior experience in achieving N-arylation of poorly reactive hetero-
cyclic amidines.28 The same protocol29 was applied to imidazolines
1a–k and a range of 2-haloazines to prepare a diverse set of the tar-
get fragment-like 1,2-disubstituted imidazolines 2a–t (Scheme 2).
The isolated yields after column chromatography were generally
good (Table 2).30 Notably, the molecular weights of compounds
N
H
N
N
N
H
N
Cl
N
1j
48b
56c
MeO
N
H
N
HetArHal (1.1 equiv.)
N
N
N
1k
N
H
R
R
Pd(OAc)2 (2 mol%)
BINAP (4 mol%)
N
H
a
HetAr
Isolated by conversion of the crude product into a hydrochloride salt and
crystallization of the latter from MeOH.
Cs2CO3 (1-3 equiv.)
toluene,100 oC, 16-20 h
b
1a-k
2a-t
Isolated by crystallization of the crude product from ethyl acetate–hexanes.
Isolated by column chromatography on silica gel using CH2Cl2–MeOH-28% aq
c
NH4OH (90:9.5:0.5) as eluent.
Scheme 2. N-heteroarylation of 2-imidazolines 1a–k.

2878
M. Krasavin / Tetrahedron Letters 53 (2012) 2876–2880
Table 2
N-heteroaryl 2-imidazolines 2a–t prepared in this work
Compound
Starting material
Halide
R
HetAr
Isolated yield (%)
85
MW
MS [M+H]+ m/z
*
*
F
N
2a
1a
Cl
298.4
299.3
N
*
*
2b
2c
1i
Br
Br
78
93
242.3
281.2
243.3
282.2
N
N
F
*
1a
*
*
N
F
Br
2d
1d
Cl
66
285.4
286.4
N
*
*
*
2e
2f
1e
1f
Cl
Cl
68
54
263.3
295.3
264.3
296.2
N
Ph
*
*
*
N
N
*
*
NO2
*
N
N
N
2g
2h
1g
1c
Cl
65
91
239.3
280.3
240.3
281.2
N
Br
N
N
OMe
*
*
2i
1e
1a
1a
Cl
Cl
Cl
92
66
78
264.3
280.4
218.3
265.4
281.4
219.3
Ph
N
*
Ph
*
2j
N N
*
*
N
*
2k
N
N
*
2l
1a
1h
Cl
Cl
74
81
204.3
239.3
205.3
240.4
N
N
N
N
*
*
2m
N
*
*
*
2n
2o
2p
1h
1k
1b
Cl
Br
Cl
76
61
62
300.4
268.4
231.2
301.4
269.4
232.3
N
N
Ph
*
*
N
O
*
F
N
*
*
2q
2r
1c
1g
Cl
48
85
280.3
242.3
281.4
243.3
N N
OMe
*
*
N
Br
N
F
O
Ph
*
2s
2t
1b
1j
Cl
63
93
290.3
288.7
291.3
289.3
*
N N
*
Cl
MeO
N
Br
N
*

M. Krasavin / Tetrahedron Letters 53 (2012) 2876–2880
2879
F
RBr (1.1 equiv.)
N
NC
*
, 24%
2u, R =
N
N
Pd(OAc)2 (2mol%)
BINAP (4 mol%)
O
N
H
O
N
*
,19%
R
2v, R =
Cs2CO3 (1-3 equiv.)
1b
N
toluene,100 oC, 16-20 h
Scheme 3. Examples of less reactive haloaromatics.
N
N
O
N
H
R
N
RNHR' (1.0 equiv.)
O
N
N
(1.0 equiv.)
N
N
N
N
R'
N
N
N
Pd(OAc)2 (2 mol%)
BINAP (4 mol%)
N
Pd(OAc)2 (2 mol%)
BINAP (4 mol%)
Cs2CO3 (1-3 equiv.)
Br
Cs2CO3 (1-3 equiv.)
toluene, 100 oC, 6-8 h
4, 79%
toluene, 100 oC, 20 h
2c
3a, RNHR' = morpholine, 78%
3b, RNHR' = hexamethyleneimine, 83%
Scheme 4. Further Buchwald-Hartwig reactions of compound 2c.
3. Murray, C. W.; Rees, D. C. Nat. Chem. 2009, 1, 187–192.
2a–t did not exceed 300 Da thereby making these compounds
excellent substrates for fragment-based drug discovery.31
4. Howard, S.; Berdini, V.; Boulstridge, J. A.; Carr, M. G.; Cross, D. M.; Curry, J.;
Devine, L. A.; Early, T. R.; Fazal, L.; Gill, A. L.; Heathcote, M.; Maman, S.;
Matthews, J. E.; McMenamin, R. L.; Navarro, E. F.; O’Brien, M. A.; O’Reilly, M.;
Rees, D. C.; Reule, M.; Tisi, D.; Williams, G.; Vinkovic, M.; Wyatt, P. G. J. Med.
Chem. 2009, 52, 379–388.
5. Woodhead, A. J.; Angove, H.; Carr, M. G.; Chessari, G.; Congreve, M.; Coyle, J.
E.; Cosme, J.; Graham, B.; Day, P. J.; Downham, R.; Fazal, L.; Feltell, R.;
Figueroa, E.; Frederickson, M.; Lewis, J.; McMenamin, R.; Murray, C. W.;
O’Brien, M. A.; Parra, L.; Patel, S.; Phillips, T.; Rees, D. C.; Rich, S.; Smith, D.-M.;
Trewartha, G.; Vinkovic, M.; Williams, B.; Woolford, A. J.-A. J. Med. Chem.
2010, 53, 5956–5969.
6. Abadzapatero, C.; Metz, J. Drug Discovery Today 2005, 10, 464–469.
7. Congreve, M.; Carr, R.; Murray, C.; Jhoti, H. Drug Discovery Today 2003, 8, 876–
877.
8. Evans, B. E. J. Med. Chem. 1988, 31, 2235–2246.
9. Welsch, M. E.; Shyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14,
347–361.
10. Barelier, S.; Krimm, I. Curr. Opin. Chem. Biol. 2011, 15, 469–474.
11. Remko, M.; Swart, M.; Bickelhaupt, F. M. Bioorg. Med. Chem. 2006, 14, 1715–
1728.
12. Ferretti, G.; Dukat, M.; Giannella, M.; Piergentili, A.; Pigini, M.; Quaglia, W.;
Damaj, M. I.; Matrin, B. R.; Glennon, R. A. J. Med. Chem. 2002, 45, 4724–4731.
13. Favaloro, J. L.; Andrews, K. L.; McPherson, G. A. Arch. Pharmacol. 2003, 367, 397–
405.
14. Kahlon, D. K.; Lansdell, T. A.; Fisk, J. S.; Hupp, C. D.; Friebe, T. L.; Hovde, S.;
Jones, A. D.; Dyer, R. D.; Henry, R. W.; Tepe, J. J. J. Med. Chem. 2009, 52, 1302–
1309.
15. Guo, X.-Z.; Shi, L.; Wang, R.; Liu, X.-X.; Li, B.-G.; Lu, X.-X. Bioorg. Med. Chem.
2008, 16, 10301–10310.
The scope of the Pd-catalyzed32 N-(hetero)arylation protocol ap-
pears to be limited to highly reactive 2-haloazines. When applied to
less reactive 5-bromopyrimidine or 4-cyano-2-fluorophenyl
bromide (which we considered sufficiently electron-deficient to
participate in the Buchwald–Hartwig coupling, based on literature
precedence33,34), the yields of the respective N-arylation products
2u–v were markedly lower (Scheme 3). Simple non-activated aryl
halides (iodobenzene, 4-iodobiphenyl) or even 2-haloazines with
electron-donating substituents (2-chloro-5-hydroxypyridine, 4-
amino-2-chloropyrimidine) failed to undergo the desired reaction.
Finally, we were interested to determine if N-heteroaryl imidaz-
olines containing reactive halogen substituents (such as 2c) could
serve as a starting point for introducing further diversity to the no-
vel N-heteroaryl 2-imidazoline scaffold. Quite satisfyingly, 2c
could indeed be used to N-heteroarylate reactive secondary amines
(such as morpholine or hexamethyleneimine) providing high
yields of the fragment-like products 3a,b. Moreover, under the
same conditions, 2c underwent a facile and high-yielding reaction
with a second 2-imidazoline providing access to a novel type of
heteroarene-linked, non-symmetrical 2-imidazoline dimer,
4
(Scheme 4). Dimeric imidazoline derivatives are of significant
interest as potential anti-infective agents.35
16. Hong, S.-S.; Bavadekar, S. A.; Lee, S.-I.; Patil, P. N.; Lalchandani, S. G.; Feller, D.
R.; Miller, D. D. Bioorg. Med. Chem. Lett. 2005, 15, 4691–4695.
17. Li, J.-X.; Zhang, Y. Eur. J. Pharmacol. 2011, 658, 49–56. and references cited
therein..
In conclusion, we have identified a reliable protocol for N-hetero-
arylation of privileged 2-imidazolines and applied it to the synthesis
of
a
diverse set of novel fragment-like compounds.36 These
18. Crouch, R. D. Tetrahedron 2009, 65, 2387–2397.
19. Choi, Y. W.; Rogers, J. A. Pharm. Res. 1990, 7, 508–512.
20. Ryu, J. M.; Lee, J. S.; Park, W. J.; Yun, H.; Kim, K. Y. PCT Int. Appl. WO
2010007987, 175 pp.; Chem. Abstr. 2010, 153, 62137.
compounds will be screened for their affinity to therapeutically
relevant proteins using Fourier-transform mass spectrometry37
and the results will be reported in due course.
21. Caroff, E.; Fretz, H.; Hilpert, K.; Houille, O.; Hubler, F.; Meyer, E. PCT Int. Appl.
WO 2006114774, 381 pp.; Chem. Abstr. 2006, 145, 471852.
22. Rauws, T. R. M.; Maes, B. U. W. Chem. Soc. Rev. 2012, 41, 2463–2497.
23. (a) Several isolated examples of transition metal catalyzed arylations of azine
scaffolds are available in the recent patent literature: (a) Galemmo, R. A., Jr.;
Artis, D. R.; Ye, X. M.; Aubele, D. L.; Truong, A. P.; Bowers, S.; Hom, R. K.; Zhu, Y.-
L.; Neitz, R. J.; Sealy, J.; Adler, M.; Beroza, P.; Anderson, J. P. PCT Int. Appl. WO
2011079118, 439 pp.; Chem. Abstr. 2011, 155, 152558.; (b) Bamberg, J. T.;
Bartlett, M.; Dubois, D. J.; Elworthy, T. R.; Hendricks, R. T.; Hermann, J. C.;
Kondru, R. K.; Lemoine, R.; Lou, Y.; Owens, T. D.; Park, J.; Smith, D. B.; Soth, M.;
Yang, H.; Yee, C. W. US Patent Appl. US 20090215750, 102 pp.. Chem. Abstr.
2009, 151, 313587.
Acknowledgments
The author acknowledges support from Griffith University
(New Researcher Grant 2012, project 215586). Dr. Hoan Vu of Esk-
itis Institute is thanked for high-resolution mass spectrometry
measurements.
24. Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal. 2006, 348,
23–39.
References and notes
25. Fujioka, H.; Murai, K.; Ohba, Y.; Hiramatsu, A.; Kita, Y. Tetrahedron Lett. 2005,
46, 2197–2199.
26. Yang, X.; Liu, H.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Synlett 2010, 101–106.
27. Huang, C.; Fu, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Commun. 2008, 6333–6335.
1. Shuker, S. B.; Hajduk, P. J.; Meadows, R. P.; Fesik, S. W. Science 1996, 274, 1531–
1534.
2. Congreve, M.; Chessari, G.; Tisi, D.; Woodhead, A. J. J. Med. Chem. 2008, 51,
3661–3680.

2880
M. Krasavin / Tetrahedron Letters 53 (2012) 2876–2880
28. Sandulenko, Y.; Komarov, A.; Rufanov, K.; Krasavin, M. Tetrahedron Lett. 2008,
49, 5990–5993.
29. General procedure (0.5–3.0 mmol scale) for the preparation of compounds 2a–t: A
[M+H]+ calcd for C16H17N4O 281.1397, found 281.1384. Compound 2p: 62%
yield (40?50% acetone in hexane), white solid, mp = 123-125 °C. 1H NMR
(500 MHz, CDCl3) d 8.06 (d, J = 4.6 Hz, 1H), 7.36 (ddd, J = 11.6, 8.1, 1.4 Hz, 1H),
7.27 (d, J = 1.0 Hz, 1H), 7.04 (ddd, J = 8.1, 4.6, 3.4 Hz, 1H), 6.63 (d, J = 3.4 Hz, 1H),
6.35 (dd, J = 3.4, 1.8 Hz, 1H), 4.08 (m, 2H), 4.01 (m, 2H); 13C NMR (125 MHz,
CDCl3) d 153.1, 151.7 (d, JC-F = 257.5 Hz), 145.6, 144.4 (d, JC-F = 11.3 Hz), 143.3
(d, JC-F = 5.0 Hz), 143.2, 123.9 (d, JC-F = 17.5 Hz), 120.8 (d, JC-F = 2.5 Hz), 112.4,
111.1, 54.2, 51.6 (d, JC-F = 1.3 Hz); HRMS m/z [M+Na]+ calcd for C12H10FN3ONa
254.0700, found 254.0692.
thick-glass, screw-capped pressure tube (50 mL) was charged with
a
suspension of the starting imidazoline (1.0 equiv), heteroaryl halide (1.1
equiv) and Cs2CO3 (1.0–3.0 equiv, an additional equivalent per salt component
of the reactants) in toluene (3 mL/mmol). Pd(OAc)2 (0.02 equiv) and BINAP
(0.4 equiv) were weighed out into a vial, suspended in toluene (2 mL/mmol)
and shaken in a 100 °C oil bath for 2 min. The resulting clear, purple catalyst
solution was added in one portion to the vigorously stirred reaction mixture.
The tube was filled with argon, capped, and stirred at 100 °C for 16–20 h. The
mixture was cooled, and partitioned between EtOAc and H2O. The organic layer
was separated, dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. The resulting crude material was purified by column chromatography
on silica gel using an appropriate gradient of acetone in hexane (or MeOH in
CH2Cl2) as eluent to provide the target product 2.
31. Although we did not perform quantitative solubility measurements for
compounds 2a–t, all were remarkably soluble in polar organic solvents
(CH2Cl2, CHCl3, MeOH, EtOAc). In order to test for solubility in aqueous
medium, we prepared a 100 mM solution of a representative compound 2t in
methanol and added 10
l
L
of this solution to
a
50Â volume of pH 7.2
phosphate buffer solution. There was no observable precipitation.
32. In a control experiment, reaction of 1k with 2-bromopyrimidine under the
general procedure conditions, but in the absence of Pd(OAc)2, did not produce
any of the arylation product 2o.
30. Characterization data for representative compounds: Compound 2a: 85% yield
(30% acetone in hexane), clear oil. 1H NMR (500 MHz, CDCl3)
d 8.52 (d,
J = 5.0 Hz, 1H), 7.76-7.81 (m, 2H), 7.45 (m, 1H), 7.16-7.21 (m, 2H), 4.11 (t,
J = 8.5 Hz, 2H), 3.87 (t, J = 8.5 Hz, 2H), 3.00 (d, J = 7.0 Hz, 2H), 2.16 (sept,
J = 7.0 Hz, 1H), 1.01 (d, J = 6.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) d 163.2 (d, JC-
F = 245.0 Hz), 163.1 (d, JC-F = 2.5 Hz), 161.5, 158.5, 158.1, 139.4 (d, JC-F = 7.5 Hz),
122.6 (d, JC-F = 2.5 Hz), 117.7 (d, JC-F = 21.3 Hz), 114.0 (d, JC-F = 23.8 Hz), 108.7,
51.6, 48.7, 40.8, 26.1, 22.6; HRMS m/z [M+H]+ calcd for C17H20FN4 299.1667,
found 299.1654. 2h – 91% yield (30% acetone in hexane), waxy solid. 1H NMR
(500 MHz, CDCl3) d 8.49 (d, J = 4.8 Hz, 2H), 7.94 (s, 2H), 7.60 (dd, J = 7.7, 1.5 Hz,
1H), 7.28 (td, Jt = 7.7 Hz, Jd = 1.5 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.89 (d,
J = 8.2 Hz, 1H), 6.77 (t, J = 4.8 Hz, 1H), 4.11 (t, J = 9.1 Hz, 2H), 3.98 (t, J = 9.1 Hz,
2H), 3.86 (s, 3H); 13C NMR (125 MHz, CDCl3) d 158.7, 158.2, 157.8, 157.6, 132.2,
129.9, 127.9, 125.6, 120.5, 119.7, 113.2, 111.0, 55.4, 52.0, 48.8; HRMS m/z
33. Kim, G. S.; Cho, Y. J.; Kwon, H. J.; Kim, B. O.; Kim, S. M.; Yoon, S. S. Eur. Pat. Appl.
EP 2096108, 356 pp.; Chem. Abstr. 2009, 151, 300937.
34. Wood, H. B.; Adams, A. D.; Freeman, S.; Szewczyk, J. W.; Santini, C.; Huang, Y.
PCT Int. Appl. WO 2008085316, 152 pp.; Chem Abstr. 2008, 149, 176187.
35. Jacobs, M. R.; Bajaksouziana, S.; Good, C. E.; Butler, M. M.; Williams, J. D.; Peet,
N. P.; Bowlin, T. L.; Endimiani, A.; Bonomo, R. A. Diagnostic Microbiol. Infect. Dis.
2011, 69, 114–116.
36. All of the compounds synthesized in this work have been deposited with the
Queensland Compound Library (Griffith University) and are available for
collaborative discovery projects.
37. Vu, H.; Pham, N. B.; Quinn, R. J. J. Biomol. Screen. 2008, 13, 265–275.