A modular approach to the synthesis of 1,4,5-substituted-2-aminoimidazoles

Article abstract of DOI:10.1016/j.tetlet.2011.12.090

Diversified 1,4,5-substituted-2-aminoimidazoles were rapidly assembled via sequential N-H insertion and Grignard addition to α-diazoesters. Lead compounds were identified as antibiotics against Gram-positive bacteria with an MIC value as low as 2 μg/mL.

Full text of DOI:10.1016/j.tetlet.2011.12.090

Tetrahedron Letters 53 (2012) 1204–1206
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A modular approach to the synthesis of 1,4,5-substituted-2-aminoimidazoles
⇑
Zhaoming Su , Lingling Peng , Christian Melander
North Carolina State University, Department of Chemistry, Raleigh, NC 27695-8204, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Diversified 1,4,5-substituted-2-aminoimidazoles were rapidly assembled via sequential N–H insertion
Received 20 November 2011
Revised 19 December 2011
Accepted 20 December 2011
Available online 30 December 2011
and Grignard addition to
positive bacteria with an MIC value as low as 2
a
-diazoesters. Lead compounds were identified as antibiotics against Gram-
l
g/mL.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
N–H insertion
2-Aminoimidazole
Antibiotic
Polysubstitution
Heterocycle
Multidrug resistant bacteria continue to be a growing threat to
the biomedical community.1 For example, it is estimated that 70%
of nosocomial infections in the United States are resistant to at
least one antibiotic.2 The ability of bacteria to develop resistance
to every antibiotic introduced into the clinic3 clearly underpins
the necessity to develop novel antibiotics and approaches to con-
trol pathogenic bacterial behavior.
Recently, Van der Eycken and co-workers have presented an
elegant route to the synthesis of trisubstituted-2-AIs via an intra-
molecular silver catalyzed heterocyclization.8 Parallel to this ap-
proach, we have developed a facile approach to highly diversified
1,4,5-substituted-2-AIs via N–H insertion followed by Grignard
addition to
a-diazoesters. For our purposes, this approach was
preferable due to its modular nature in which we could rapidly
assemble diverse 2-AIs for preliminary biological screening. Using
this approach, we have accessed a pilot library and demonstrated
antibiotic activity against Acinetobacter baumannii (A. baumannii),
Escherichia coli (E. coli), methicillin sensitive Staphylococcus aureus
(MSSA), and methicillin resistant S. aureus (MRSA).
A plethora of small molecules containing a core 2-aminoimidaz-
ole (2-AI) heterocycle have emerged over the past few decades4a–c
with activities ranging from biofilm inhibition to tubulin-binding
agents.4d,e Our own interest in the biological activity of the 2-AI
framework was inspired by bromoageliferin/oroidin and an initial
report that bromoageliferin possessed anti-biofilm activity.5 Given
the paucity of small molecules reported with antibiofilm activity,
our group has explored the structure–activity relationship (SAR)
of a variety of 2-AI and 2-aminobenzimidazole scaffolds in the con-
text of both antibiofilm and antibiotic activity.6 We have noted
that as one transitions from simple 4-substituted-2-aminoimidaz-
oles to 2-aminoimidazole scaffolds that contain higher substitution
patterns, the biological activity typically transitions from non-toxic
modulators of biofilm formation to molecules that become micro-
bicidal (Fig. 1). This was recently highlighted in studying the bio-
logical activity of both 4,5-substituted and 1,5-substituted-2-
aminoimidazoles.7 Given this trend, we posited that transitioning
to 1,4,5-substituted-2-aminoimidazoles would deliver a class of
compounds that had augmented microbicidal activity.
⇑
Corresponding author.
E-mail address: christian_melander@ncsu.edu (C. Melander).
These authors have contributed equally to this work.
Figure 1. Oroidin derived 2-aminoimidazole scaffolds.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.090

Z. Su et al. / Tetrahedron Letters 53 (2012) 1204–1206
1205
Table 1
Antibiotic activity screening of the pilot librarya
Compound
A. baumannii
E. coli
MSSA
MRSAb
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
128
256
256
16
>256
4
>256
>256
32
>256
>256
4
256
8
>256
2
128
>256
4
>256
>256
4
>256
>256
64
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
>256
64
>256
>256
>256
>256
>256
>256
>256
>256
>256
64
Figure 2. Retrosynthesis of 1,4,5-substituted-2-AI.
>256
8
>256
32
>256
4
>256
32
16
>256
8
4
a
MIC values were determined in
ATCC number is BAA 44 for tested MRSA.
l
g/mL.
b
Table 2
Biological screening of lead compounds against different MRSA strainsa
MRSAb
4d
8
4
2
4
4o
8
8
8
8
MRSA
4d
2
8
4
2
4o
BAA 1770
BAA 1556
BAA 811
BAA 1685
BAA 1753
BAA 44
33591
700789
43300
4
8
8
8
4
8
a
MIC values were determined in
MRSA strains were identified by ATCC number.
l
g/mL.
b
for several conditions, [RuCl2(p-cymene)]2 in DCM was determined
to be the most effective conditions. Ethyl diazoarylacetate 1 was
then reacted with a variety of anilines to afford the desired N-
aryl-a-amino ester 2 in 89–99% yield. With 2 in hand, the key
Weinreb intermediate was delivered by treatment with N,O-
dimethylhydroxylamine hydrochloride and isopropylmagnesium
chloride in 79–93% yield. Subsequent addition with various readily
available Grignard reagents allowed installation of diversified sub-
stituents on 3 with yields from 42–92%. Finally, cyclization with
cyanamide at pH 4.3 delivered the target 1,4,5-substituted-2-AIs
4 in 14–87% yield.
With the pilot library in hand, we first screened for its antibiotic
activity against both Gram-positive and Gram-negative bacteria
strains that include MRSA, MSSA, A. baumannii, and E. coli. The mic-
rodilution protocol10 was used to quantify activity and the mini-
mum inhibitory concentration (MIC) values were determined
(summarized in Table 1). We observed from this screen that this
class of small molecules was microbicidal primarily against
Gram-positive strains. Compounds 4d,n, and o were determined
to be our lead compounds with MIC values (lg/mL) of 2, 4, 64,
>256; 32, 32, 64, 64, and 4, 8, 16, >256 against MRSA, MSSA, A. bau-
mannii, and E. coli, respectively.
Given the activity against MRSA, we were interested in evaluat-
ing this library for its antimicrobial activity against various MRSA
Scheme 1. Synthesis of 1,4,5-substituted-2-AIs. Reaction conditions: (a) [Ru(p-
cymene)Cl2]2 (1 mol %), DCM, rt, 2 h; (b) N,O-dimethylhydroxylamine hydrochlo-
ride, i-PrMgCl, THF, À20 °C, 1 h; (c) R3MgBr, THF, À20–0 °C, 1 h; (d) NH2CN, EtOH/
H2O, pH 4.3, 95 °C, 3 h.
From a synthetic standpoint, we envisioned that the desired
1,4,5-substituted-2-aminoimidazole could be assembled from
strains isolated from a nosocomial environment. MRSA has
emerged as a major cause of illness and death in hospitals,11 which
includes lower respiratory tract infections, surgical site infections,
cardiovascular infections, and pneumonia.12 We obtained 9 differ-
ent MRSA strains and screened for activity with lead compounds
4d and 4o. The lead compounds behaved consistently among the
cyclization of an N-substituted
a-amino ketone with cyanamide.
In turn, the corresponding -amino ketone could be readily pre-
a
pared from an N–H insertion between an appropriate diazoester
and a commercially available amine followed by conversion to
the Weinreb amide and Grignard addition (Fig. 2).
Our application of this synthetic approach is outlined in
Scheme 1. We initiated our work by screening of conditions for
the N–H insertion reaction. Ruthenium complexes have been
extensively studied recently for N–H insertion9 and, after tests
different MRSA strains recording MIC values as low as 2
(Table 2). This antimicrobial activity is comparable to vancomycin
(MIC 2 g/mL), which is widely used to treat MRSA infections. Oxa-
cillin, which these MRSA strains are resistant to, record MIC values
of 64
g/mL.13
lg/mL
l
l

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Z. Su et al. / Tetrahedron Letters 53 (2012) 1204–1206
2. Clatworthy, A. E.; Pierson, E.; Hung, D. T. Nat. Chem. Biol. 2007, 3, 541–548.
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3. Palumbi, S. R. Science 2001, 293, 1786–1790.
synthesis of 1,4,5-substituted-2-aminoimidazoles, which allows
rapid assembly and diversity from readily available building
blocks. Lead compounds 4d and 4o were identified as antimicrobial
reagents against Gram-positive bacterial strains. Given the biolog-
ical activity of 1,4,5-substituted-2-aminoimidazoles, it is highly
likely that more functionalized polysubstituted 2-aminoimidazoles
will present enhanced antibiotic activity. These studies are ongoing
in our lab and will be reported in due course.
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Acknowledgments
The authors thank the DOD DMRDP program (W81XWH-11-2-
0115) for support of this work. The DMRDP program is adminis-
tered by the Department of Army; The U.S. Army Medical Research
Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-
5014 is the awarding and administering acuitision office. The con-
tent of this manuscript does not necessarily reflect the position or
the policy of the Government, and no official endorsement should
be inferred.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.090.
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