Antibacterial activities of Groebke-Blackburn-Bienayme-derived imidazo[1,2-a]pyridin-3-amines

Article abstract of DOI:10.1016/j.bmc.2012.07.052

We sought to explore the imidazo[1,2-a]pyridin-3-amines for TLR7 (or 8)-modulatory activities. This chemotype, readily accessed via the Groebke-Blackburn-Bienayme multi-component reaction, resulted in compounds that were TLR7/8-inactive, but exhibited bacteriostatic activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). To investigate the mechanism of antibacterial activity of this new chemotype, a resistant strain of S. aureus was generated by serially passaging the organism in escalating doses of the most active analogue. A comparison of minimum inhibitory concentrations (MICs) of known bacteriostatic agents in wild-type and resistant strains indicates a novel mechanism of action. Structure-activity relationship studies have led to the identification of positions on the scaffold for additional structural modifications that should allow for the introduction of probes designed to examine cognate binding partners and molecular targets, while not significantly compromising antibacterial potency.

Full text of DOI:10.1016/j.bmc.2012.07.052

Bioorganic & Medicinal Chemistry 20 (2012) 5850–5863
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Antibacterial activities of Groebke–Blackburn–Bienaymé-derived
imidazo[1,2-a]pyridin-3-amines
⇑
Nikunj M. Shukla, Deepak B. Salunke, Euna Yoo, Cole A. Mutz, Rajalakshmi Balakrishna, Sunil A. David
Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence, KS 66047, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We sought to explore the imidazo[1,2-a]pyridin-3-amines for TLR7 (or 8)-modulatory activities. This
chemotype, readily accessed via the Groebke–Blackburn–Bienaymé multi-component reaction, resulted
in compounds that were TLR7/8-inactive, but exhibited bacteriostatic activity against Gram-positive
bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). To investigate the mechanism of
antibacterial activity of this new chemotype, a resistant strain of S. aureus was generated by serially
passaging the organism in escalating doses of the most active analogue. A comparison of minimum inhib-
itory concentrations (MICs) of known bacteriostatic agents in wild-type and resistant strains indicates a
novel mechanism of action. Structure–activity relationship studies have led to the identification of
positions on the scaffold for additional structural modifications that should allow for the introduction
of probes designed to examine cognate binding partners and molecular targets, while not significantly
compromising antibacterial potency.
Received 22 June 2012
Revised 26 July 2012
Accepted 31 July 2012
Available online 8 August 2012
Keywords:
Antibacterials
Imidazopyridines
Antibiotics
MRSA
Bacteriostatic
Multicomponent reaction
Groebke reaction
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The introduction of antibiotics into the therapeutic armamen-
tarium in the early 20th century revolutionized the management
of microbial infections. Once considered ‘wonder drugs’, antibiotics
have perhaps become victims of their own success, and resistance
to these drugs have almost invariably followed on the heels of their
widespread use (and misuse). The incidence of methicillin-resis-
tant Staphylococcus aureus (MRSA) infections continues to increase
alarmingly not only in hospital-associated settings (nosocomial
infections), but in recent times, also in community settings in the
United States, and throughout the globe. The increase in morbidity
and mortality due to S. aureus infections1 is a reflection of
increased invasive procedures, indwelling devices, older age, and
comorbidities, as well as the acquisition of resistance to com-
monly-used antimicrobial agents. Of particular concern is the
emergence of multidrug-resistant strains of Gram-positive
bacteria, with the loss of susceptibility to a wide range of
reserve antibiotics such as vancomycin.2 The need for the develop-
ment of effective antibiotics is urgent, especially in the face of a
diminishing pipeline of drugs for antimicrobial chemotherapy.
Our work in the recent past has focused on the discovery and
development of vaccine adjuvants. Of particular interest to us are
small molecule agonists of toll-like receptor-7 (TLR7). Given that
the known small molecule agonistic chemotypes are limited to
imidazoquinolines3–5 and oxoadenines,6–10 we are actively explor-
ing related structures. We have recently noted that 1H-imi-
dazo[4,5-c]pyridin-4-amines are TLR7-agonistic (Yoo, E. et al.,
manuscript submitted, Fig. 1). We therefore asked whether the
structurally-related imidazo[1,2-a]pyridin-3-amines (Fig. 1) would
possess TLR7-modulatory properties. This chemotype is readily
amenable to a rapid elaboration of combinatorial libraries using
the one-pot multi-component Groebke–Blackburn–Bienaymé
reaction.11–13 An initial test-library of 24 compounds proved to
be neither agonistic nor antagonistic at TLR7. However, some of
the initial compounds were found to have antibacterial activity
against S. aureus with a clear indication of possible structure–activ-
ity relationships. Subsequent focused libraries of compounds were
synthesized. These latter compounds, too, were not active in TLR7
screens, but displayed prominent bacteriostatic activity against
several Gram-positive bacteria, including methicillin-resistant S.
aureus (MRSA). To investigate the mechanism of antibacterial
activity of this new chemotype, a resistant strain of S. aureus was
generated by serially passaging the organism in escalating doses
of the most active analogue. A comparison of minimum inhibitory
Abbreviations: ATCC, American Type Culture Collection; DavePhos, 2-dicyclo-
hexylphosphino-20-(N,N-dimethylamino)biphenyl; E. fecalis, Enterococcus fecalis;
ESI-TOF, electrospray ionization-time of flight; HIV, human immunodeficiency
virus; MBC, minimum bactericidal concentration; MIC, minimum inhibitory con-
centration; MRSA, methicillin-resistant S. aureus; MW, microwave; NF-
jB, nuclear
factor- B; Pd2(dba)3, tris(dibenzylideneacetone)dipalladium(0); SAR, structure–
j
activity relationship; ssRNA, single-stranded RNA; S. pneumoniae, Streptococcus
pneumoniae; S. pyogenes, Streptococcus pyogenes; TLR, toll like receptor.
⇑
Tel.: +1 785 864 1610; fax: +1 785 864 1961.
E-mail address: sdavid@ku.edu (S.A. David).
0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2012.07.052

N. M. Shukla et al. / Bioorg. Med. Chem. 20 (2012) 5850–5863
5851
R3
and 2-aminopyrazine), three isonitriles (2-isocyano-2-methylpro-
pane, isocyanocyclohexane, (isocyanomethyl)benzene), and four
aldehydes (benzaldehyde, 2-phenylacetaldehyde, 1-naphthalde-
hyde, anthracene-9-carbaldehyde). The syntheses of 1a–3h
(Scheme 1) proceeded smoothly. All compounds were tested in
TLR7 agonism and antagonism assays using specific reporter
gene-based cellular assays as described earlier14–16; to our disap-
pointment, none of the compounds displayed any activity in these
N
R3
N
N
N
N
R1
N
H
R1
R2
R2
imidazo[4,5-c]pyridines
imidazo[1,2-a]pyridines
Figure 1. Structures of 1H-imidazo[4,5-c]pyridine and 1H-imidazo[1,2-a]pyridine
scaffolds.
assays up to concentrations of 250 lM (data not shown). The assay
plates were stored in the autoclave room at room temperature
prior to disposal, and, quite by accident, we observed a dose-
dependent inhibition of a bacterial contaminant in such plates.
We therefore decided to examine the antibacterial activities of
these compounds in antibacterial screens (E. coli ATCC 9637 and
S. aureus ATCC 13709) routinely employed in our laboratory.17,18
Four compounds were identified to be inhibitory to S. aureus ATCC
13709 but not E. coli ATCC 9637. Maximal antibacterial activity re-
sided in compounds derived from 2-aminopyridine, bearing either
a bulky N-tert-butyl or cyclohexyl groups at C3, and a large aro-
matic pendant group (naphthyl or anthracenyl) at C2 (1e, 1g, 2e,
concentrations (MICs) of known bacteriostatic agents in wild-type
and resistant strains indicate a novel mechanism of action. These
findings served as a point of departure for further exploration of
SAR and mechanisms of bacteriostatic activity in this chemotype.
2. Results and discussion
Our initial test-library comprising of twenty-four compounds
was synthesized (Scheme 1) using two amidines (2-aminopyridine
X
NC
NC
NC
N
NH2
X=CH, 2-aminopyridine
2-isocyano-2-methylpropane
X
isocyanocyclohexane
X
(isocyanomethyl)benzene
X
X=N, 2-aminopyrazine
N
N
N
N
N
N
O
Bn
N
H
N
H
N
H
benzaldehyde
1a
2a
3a
, X=CH
, X=CH
, X=CH
1b, X=N
2b, X=N
3b, X=N
X
X
X
N
N
N
N
N
N
O
Bn
N
N
N
2-phenyl
H
H
H
acetaldehyde
1c
2c
3c
, X=CH
, X=CH
, X=CH
1d, X=N
2d, X=N
3d, X=N
X
X
X
N
O
N
N
N
N
N
Bn
N
N
N
H
H
H
1-naphthaldehyde
1e
2e
3e
, X=CH
, X=CH
, X=CH
1f, X=N
2f, X=N
3f, X=N
X
X
X
N
N
N
N
N
N
Bn
N
N
N
H
H
H
O
anthracene-9-
carbaldehyde
1g
2g
2h
3g
3h
, X=CH
, X=N
, X=CH
, X=N
, X=CH
, X=N
1h
Scheme 1. Synthesis of a library of compounds using Groebke multicomponent reaction using 2 different amidines, 3 different isonitriles and 4 different aldehydes. Reagents
and conditions: (i) MW, 400 W, 110 °C, 20 min, HCl/dioxane, CH3CN.

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N. M. Shukla et al. / Bioorg. Med. Chem. 20 (2012) 5850–5863
Table 1
Table 1 (continued)
Minimum inhibitory concentration values (l
g/mL) of compoundsa
Structure
Compound
number
MIC (
l
g/mL)
MRSA
Structure
Compound
number
MIC (
S.
l
g/mL)
S.
MRSA
aureus
aureus
N
N
2c
ND
NT
NT
N
N
1a
1b
ND
NT
NT
N
N
H
H
N
N
N
N
N
2d
ND
N
N
N
N
ND
H
N
H
N
2e
2f
7.81
15.62
N
H
N
1c
ND
ND
NT
NT
N
H
N
N
N
N
N
ND
NT
N
N
N
1d
N
H
N
H
N
N
2g
3.91
3.91
1e
1f
62.5
31.25
N
H
N
H
N
N
N
N
N
N
N
ND
NT
2h
7.81
NT
N
N
H
H
N
N
1g
3.91
3.91
N
N
N
H
3a
3b
ND
ND
NT
NT
Bn
Bn
N
H
N
N
N
N
N
1h
ND
NT
N
N
H
H
N
N
N
3c
ND
ND
NT
NT
N
N
N
2a
2b
ND
ND
NT
NT
Bn
Bn
N
H
N
N
H
N
N
3d
N
N
H
N
H

N. M. Shukla et al. / Bioorg. Med. Chem. 20 (2012) 5850–5863
5853
Table 1 (continued)
Table 1 (continued)
Structure
Compound
number
MIC (
l
g/mL)
Structure
Compound
number
MIC (
S.
lg/mL)
S.
MRSA
MRSA
aureus
aureus
N
N
N
N
N
3e
3f
15.62
NT
NT
5c
5d
5e
5f
5g
5h
5i
15.62
15.62
Bn
N
N
H
H
N
N
N
N
ND
ND
N
Bn
Bn
N
H
7.81
3.91
15.62
15.62
ND
3.91
3.91
NT
N
H
N
3g
3h
4a
4b
NT
NT
NT
NT
N
N
N
H
N
H
N
N
N
ND
N
N
Bn
N
H
N
Si
H
N
N
N
N
15.62
N
N
H
NT
N
H
NH2
N
N
N
N
15.62
N
H
O
NT
N
H
N
Cl
N
N
N
N
4c
ND
NT
N
ND
NT
N
H
H
Cl
N
N
N
N
5a
3.91
3.91
7.81
7.81
N
6
ND
NT
H2N
H
N
N
N
N
5b
N
H
7a
7.81
NT
N
H
(continued on next page)

5854
N. M. Shukla et al. / Bioorg. Med. Chem. 20 (2012) 5850–5863
Table 1 (continued)
Table 1 (continued)
Structure
Compound
number
MIC (
S.
l
g/mL)
Structure
Compound
number
MIC (
l
g/mL)
MRSA
MRSA
S.
aureus
aureus
Br
N
N
N
N
11
12
13
15.62
NT
NT
NT
7b
31.25
NT
N
N
H
N
N
N
7c
62.5
NT
F3COC
N
HN
H
3.91
N
N
N
H
N
N
NH
8a
ND
NT
N
N
7.81
N
H
N
N
N
Cl
N
8b
7.81
NT
NH
N
N
H
14
7.81
15.62
N
NH
8c
15.62
NT
NH
H2N
Br
N
N
N
N
9
7.81
NT
15
15.62
NT
N
H
N
H
Cl
NH2
HN
N
N
N
N
H
N
16
3.91
7.81
N
H
10
3.91
NT
NH
N
a
ND denotes no activity detected at 100 lg/mL and NT denotes not tested.
tive leads (1e, 1g and 2g) against a variety of other Gram-positive
organisms (Enterococcus fecalis (E. fecalis) clinical isolates of Strep-
tococcus pneumoniae (S. pneumoniae) and Streptococcus pyogenes (S.
pyogenes)); significant MICs (<10 lg/mL) were observed in all of
the leads only against S. pyogenes, indicating a narrow spectrum
2g, Scheme 1, Table 1). The MICs of both 1g and 2g for S. aureus
ATCC 13709 and MRSA ATCC 33591 were 3.91 g/mL, (Table 1),
and 7.81 g/mL for coagulase-negative S. epidermidis ATCC 35983
(Supplementary data). We examined the MIC values of representa-
l
l
of activity (data not shown).

N. M. Shukla et al. / Bioorg. Med. Chem. 20 (2012) 5850–5863
5855
The active compounds listed above were all determined to be
bacteriostatic rather than bactericidal by conventional microplate
MBC assays (Fig. 2).19 The outer membrane of Gram-negative bac-
teria serves as a permeability barrier for hydrophobic antimicrobi-
als20,21, and we wondered if the lack of activity of these compounds
against Gram-negative bacteria could be attributable to its bulky,
nonpolar nature. We therefore performed additional assays using
polymyxin B nonapeptide,22–24 which is commonly used to per-
meabilize the outer-membranes of Gram-negative bacteria, ren-
dering the organisms susceptible to otherwise impermeable
antimicrobials17; however, the imidazopyridines did not exert
any significant antibacterial effect even at high concentrations of
polymyxin B nonapeptide (Fig. 2), confirming that the antibacterial
spectrum of these compounds is specific to Gram-positive
organisms.
hyde as the invariant components, and varied the amidine
component; we chose 2-aminopyrimidine, 2,3-diaminopyridine,
and 2-amino-3-chloropyrazine (Scheme 2). The 2-amino-3-chloro-
pyrazine-derived compound 4c was inactive, while 4a and 4b
exhibited lower activities than 1g (Table 1). Next, we varied the
isonitrile component. We explored nine different isonitriles
(Scheme 3) chosen to include linear aliphatic (as in 5a and 5b),
branched aliphatic (5c–5e), silyl-containing (5f), adamantyl (5g),
and aromatic substituents (5h, 5i). We observed that the N-2,4,4-
trimethylpentan-2-yl group of 5e, could be dealkylated under
strongly acidic conditions as has been reported recently,25 afford-
ing the possibility of introducing alkyl or acyl substituents (repre-
sented by 7a–7c, Scheme 4) that were not accessible through
commercially available isonitriles. Optimal activity profiles ap-
peared to correspond to compounds with branched-chain substit-
uents (5d, 5e), while compounds with aromatic substituents (5h,
5i) were bereft of antibacterial activity (Table 1).
Given that 1g and 2g demonstrated identical potencies, we arbi-
trarily selected isocyanocyclohexane and anthracene-9-carbalde-
Noting that bulky, aldehyde-derived aromatic substituents
at C2 corresponded to maximal activity (exemplified by the
anthracenyl group in 1g, 2g, 5a–5g), it was of interest to explore
other similar functional groups. Compounds with biphenyl (8a),
phenanthrenyl (8b), and pyrenyl (8c) substituents were therefore
synthesized and evaluated (Scheme 5). Compounds 8b and 8c
exhibited lower activity than the anthracenyl-bearing compound,
while the biphenyl compound 8a was inactive, pointing to the
necessity of a large polycyclic, aromatic group at C2; the higher
activity of 5e with its bulky anthracenyl group would appear to
suggest that the polycyclic group of a particular topology is a
determinant of activity.
The compound that showed maximal activity thus far was the
very lipophilic 5e, and it was desirable to explore more polar
analogues for future evaluation in in vivo models. We therefore
attempted to introduce N,N-dimethylaminopropylamino groups
on both the amidine- and aldehyde-derived portions of 5e. This
was achieved in a straightforward manner using appropriate
halo-substituted components, followed by Buchwald–Hartwig
coupling as depicted in Scheme 6. The antibacterial activities of
10 and 12 were found to be identical to that of 5e (Table 1).
Although the lead compounds of this chemotype exhibit nar-
row-spectrum bacteriostatic activity against Gram-positive organ-
isms, the substantial potency against MRSA warranted an attempt
at understanding the mechanism of action. Our preliminary studies
have been to examine the antibiograms of wild-type and 5e-resis-
tant S. aureus organisms, comparing a variety of antimicrobials
with known mechanisms of action. 5e-resistant S. aureus organ-
isms were generated by exposing the bacterium to escalating doses
of the compound. Within about 10 serial passages, organisms that
0.8
1g MIC
1g MBC
0.4
0.0
5e MIC
5e MBC
Amoxicillin MIC
Amoxicillin MBC
Ciprofloxacin MIC
Ciprofloxacin MBC
Neg. Ctrl.
10-10
10-9
10-8
10-7
10-6
10-5
10-4
10-3
Compound Concentration (g/mL)
1.2
0.9
0.6
0.3
withstood 5e up to concentrations of 100 lg/mL emerged. The
1g + 6.66 µg/mL of PMBN
1g + 0.832 µg/mL of PMBN
1g + 0.104 µg/mL of PMBN
1g + 0.013 µg/mL of PMBN
1g + 0.001 µg/mL of PMBN
1g
MICs of various classes of bacteriostatic and bactericidal antibiotics
were found to be identical within experimental error for both the
wild-type and 5e-resistant S. aureus, suggesting that the molecular
target of 5e and related compounds were distinct and unique
(Fig. 3).
PMBN = Polymyxin B nonapeptide
We noticed, however, that upon prolonged storage
(ꢀ2 weeks), aqueous solutions of hydrochloride salts of both 10
and 12 were degrading gradually, giving rise to N-dealkylated
products as was discussed earlier (LC–MS data in Supplementary
data, Page S136). Furthermore, we were desirous of introducing a
functional group that would permit facile coupling of probes
such as fluorophores or biotin in order to identify the possible
molecular target(s) of 5e. We elected to replace the N-2,4,4-trim-
ethylpentan-2-yl group with the more stable tert-butyl group,
and the N,N-dimethylaminopropylamino group with a 1,8-diami-
nooctane, using the Buchwald-Hartwig coupling strategy em-
ployed earlier (Scheme 7). The introduction of the primary
amine-bearing 1,8-diaminooctanyl group on either the anthrace-
10-7
10-6
10-5
Concentration of compound 1g (g/mL)
Figure 2. Top: Minimum inhibitory concentration (MIC) and minimum bactericidal
concentration (MBC) data of active 1H-imidazo[1,2-a]pyridine compounds. MICs
were determined using MRSA (ATCC strain 33591) by broth microdilution method
in Mueller–Hinton broth (MHB). Ciprofloxacin and amoxicillin were used as
positive and negative controls, respectively. For MBC determinations, 0.5
each of the 384 wells in the parent MIC plate was diluted into 80 L of fresh MHB.
lL of
l
Bottom: Lack of sensitization in E. coli (ATCC strain 9637) by polymyxin
nonapeptide to 1g.
B

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N. M. Shukla et al. / Bioorg. Med. Chem. 20 (2012) 5850–5863
NH2
N
N
N
N
N
or
N
N
N
Cl
N
NH2
NH2
N
H
H
or
NH2
or
O
N
NH2
N
i
4a
4b
N
N
Cl
N
NC
or
N
H
4c
Scheme 2. Groebke reaction using different amidines. Reagents and conditions: (i) MW, 400 W, 110 °C, 30 min, HCl/dioxane, CH3CN.
NC
R
R
O
N
N
i
O
i
N
N
R
N
H
N
R
8a-8c
N
NH2
NC
N
NH2
H
5a-5i
5a
5b
5c
5d
O
5e
5f
R=
5h
5i
8a
8b
8c
R =
Si
Scheme 5. Groebke reaction using various aldehydes. Reagents and conditions: (i)
MW, 400 W, 110 °C, 20 min, HCl/dioxane, CH3CN.
5g
Cl
Scheme 3. Groebke reaction using various isonitriles. Reagents and conditions: (i)
MW, 400 W, 110 °C, 20 min, HCl/dioxane, CH3CN.
methicillin-resistant S. aureus (MRSA). We note that antibacterial
activities of the imidazo[1,2-a]pyridines have been reported
earlier; the compounds reported herein show narrow-spectrum
selectivity, only against Gram-positive organisms.26,27 Our preli-
minary results suggest that the mechanism of action may be dis-
tinct from known bacteriostatics. Structure–activity relationship
studies have led to the identification of positions on the scaffold
for additional structural modifications that should allow for the
introduction of probes designed to examine cognate binding part-
ners and molecular targets, while not significantly compromising
antibacterial potency.
nyl or pyridinyl portions of the molecule do not result in signif-
icant attenuation of antibacterial activity relative to 1g (Table 1),
allowing the possibility of exploring the binding partners for
these compounds.
In conclusion, our attempts at exploring imidazo[1,2-a]pyridin-
3-amines for TLR7 (or 8)-modulatory activities have unexpectedly
led to the identification of a novel chemotype with substantial
bacteriostatic activity against Gram-positive bacteria, including
N
N
N
N
N
N
ii or iii
i
N
R2
N
H
H2N
R1
6
5e
7a
: R1 = C8H17; R2 = H
7b: R1 = R2 = C8H17
7c
: R1 = COCF3; R2 = H
Scheme 4. Derivatization of the C3-amine. Reagents and conditions: (i) HCl/dioxane. For compounds 7a and 7b; (ii) C7H15CHO, CH3COOH, NaCNBH3, MeOH. For compound
7c; (iii) (CF3CO)2O, CH2Cl2.

N. M. Shukla et al. / Bioorg. Med. Chem. 20 (2012) 5850–5863
5857
N
NH2
N
N
N
N
ii
O
i
N
H
N
NC
H
Cl
NH
N
9
10
Cl
N
Br
Br
HN
N
NH2
N
N
i
ii
N
N
O
NC
N
N
H
H
11
12
Scheme 6. Syntheses of polar derivatives of 5e. Reagents and conditions: (i) MW, 400 W, 110 °C, 30 min, HCl/dioxane, CH3CN; (ii) K(O-tBu), Pd2(dba)3, DavePhos, NH2–
(CH2)3–NH(CH3)2, dioxane, 80 °C.
under reduced pressure using standard rotary evaporators. Flash
column chromatography was carried out using RediSep Rf ‘Gold’
high performance silica columns on CombiFlash Rf instrument
Hatched bars: Wild-type S. aureus
Solid bars: 5e-resistant S. aureus
unless otherwise mentioned, while thin-layer chromatography
was carried out on silica gel CCM pre-coated aluminum sheets.
Microwave reactions were done in Synthos 3000 instrument (An-
ton Paar). IR spectra were recorded on Shimadzu 8400 series FTIR
instrument and values are reported in cmꢁ1. Purity for all final
compounds was confirmed to be greater than 95% by LC–MS using
100
10
1
a Zorbax Eclipse Plus 4.6 ꢂ 150 mm, 5
lm analytical reverse phase
18 column with H2O–isopropanol or H2O–CH3CN gradients and an
C
Agilent ESI-TOF mass spectrometer (mass accuracy of 3 ppm) oper-
ating in the positive ion acquisition mode. Unless otherwise men-
tioned, the compounds synthesized were obtained as yellow solids.
3.1.1. Synthesis of compound 1a: N-(tert-butyl)-2-
phenylimidazo[1,2-a]pyridin-3-amine
To the solution of 2-aminopyridine (24 mg, 0.25 mmol) in anhy-
drous acetonitrile, were added benzaldehyde (28
catalytic amount of 4 N HCl/dioxane (10 L) and tert-butyl isoni-
trile (27 L, 0.24 mmol). The reaction mixture was then heated
lL, 0.28 mmol), a
l
l
under microwave conditions (400 W, 110 °C, 20 min). After the
reaction mixture was cooled to room temperature, solvent was re-
moved and the residue was purified using column chromatography
to obtain the compound 1a as white solid (44 mg, 69%). 1H NMR
(400 MHz, CDCl3) d 8.23 (dt, J = 6.9, 1.2 Hz, 1H), 7.90 (dt, J = 8.1,
1.6 Hz, 2H), 7.55 (dt, J = 9.0, 1.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H),
7.31 (t, J = 7.4 Hz, 1H), 7.13 (ddd, J = 9.0, 6.6, 1.3 Hz, 1H), 6.77 (td,
J = 6.8, 1.1 Hz, 1H), 3.12 (s, 1H), 1.04 (s, 9H). 13C NMR (101 MHz,
CDCl3) d 135.42, 128.43, 128.32, 127.52, 124.17, 123.64, 117.48,
111.46, 101.91, 56.59, 30.43. MS (ESI) calcd for C17H19N3, m/z
265.16, found 266.17 (M+H)+.
Figure 3. Comparison of antimicrobial susceptibility of wild-type S. aureus ATCC
13709 (hatched bars) and 5e-resistant organism (solid bars) to
a range of
bacteriostatic antibiotics with known mechanisms of action, and 5e. Bacteriostatics
include trimethoprim and sulfamethoxazole (dihydrofolate reductase pathway),
doxycycline and amikacin (30S ribosomal subunit), chloramphenicol (23S ribo-
somal subunit), erythromycin and tylosin (50S ribosomal subunit), nisin (lipid II),
nitrofurantoin (bacterial DNA); also included were the bactericidal controls,
ciprofloxacin, amoxicillin, and cefotaxime.
3. Experimental section
3.1. Chemistry
Compounds 1b–1f, 2a–2f and 3a–3f were synthesized similarly
as compound 1a.
3.1.2. Compound 1b: N-(tert-butyl)-2-phenylimidazo
[1,2-a]pyrazin-3-amine (45 mg, 62%)
All of the solvents and reagents used were obtained commer-
cially and used as such unless noted otherwise. Moisture- or air-
sensitive reactions were conducted under nitrogen atmosphere in
oven-dried (120 °C) glass apparatus. The solvents were removed
1H NMR (400 MHz, CDCl3) d 9.00 (d, J = 1.4 Hz, 1H), 8.14 (dd,
J = 4.6, 1.5 Hz, 1H), 7.91 (dd, J = 8.3, 1.3 Hz, 2H), 7.86 (d,
J = 4.6 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 3.19

5858
N. M. Shukla et al. / Bioorg. Med. Chem. 20 (2012) 5850–5863
N
NH2
N
N
N
N
i
ii
O
N
N
H
NC
H
Cl
NH
13
14
Cl
H2N
NH2
Br
Br
HN
N
NH2
N
N
i
ii
N
N
O
N
NC
H
N
H
15
16
Scheme 7. Syntheses of 1g derivatives bearing terminal primary amines. Reagents and conditions: (i) MW, 400 W, 110 °C, 30 min, HCl/dioxane, CH3CN; (ii) (a) K(O-tBu),
Pd2(dba)3, DavePhos, NH2–(CH2)8–NHBoc, dioxane, 80 °C; (b) 4 M HCl/dioxane.
(s, 1H), 1.05 (s, 9H). 13C NMR (101 MHz, CDCl3) d 143.54, 142.40,
137.43, 134.38, 129.04, 128.66, 128.38, 128.33, 125.17, 116.49,
100.13, 57.11, 30.45. MS (ESI) calcd for C16H18N4, m/z 266.15, found
267.16 (M+H)+.
126.02, 125.31, 125.19, 116.54, 105.36, 98.21, 56.51, 29.81. MS
(ESI) calcd for C20H20N4, m/z 316.17, found 317.17 (M+H)+.
3.1.7. Compound 1g: 2-(anthracen-9-yl)-N-(tert-butyl)
imidazo[1,2-a]pyridin-3-amine (55 mg, 63%)
3.1.3. Compound 1c: 2-benzyl-N-(tert-butyl)imidazo
[1,2-a]pyridin-3-amine (41 mg, 61%)
IR (CHCl3) mmax (cmꢁ1): 2970, 1500, 1473, 1342, 1311. 1H NMR
(400 MHz, CDCl3) d 8.52 (s, 1H), 8.40 (dt, J = 6.9, 1.2 Hz, 1H), 8.09–
8.02 (m, 2H), 7.93–7.86 (m, 2H), 7.66 (dt, J = 9.0, 1.1 Hz, 1H), 7.51–
7.38 (m, 4H), 7.29–7.20 (m, 1H), 6.89 (td, J = 6.8, 1.1 Hz, 1H), 2.69
(s, 1H), 0.64 (s, 9H). 13C NMR (101 MHz, CDCl3) d 142.71, 131.45,
130.94, 128.75, 127.60, 126.80, 126.34, 126.19, 125.06, 124.00,
123.62, 117.57, 111.40, 101.78, 97.01, 55.59, 29.72. MS (ESI) calcd
for C25H23N3, m/z 365.19, found 366.20 (M+H)+.
1H NMR (400 MHz, CDCl3) d 8.16 (dt, J = 6.9, 1.1 Hz, 1H), 7.47
(dt, J = 9.0, 1.0 Hz, 1H), 7.28–7.23 (m, 4H), 7.21–7.14 (m, 1H),
7.08 (ddd, J = 9.0, 6.7, 1.3 Hz, 1H), 6.72 (td, J = 6.8, 1.1 Hz, 1H),
4.20 (s, 2H), 2.57 (s, 1H), 1.18 (s, 9H). 13C NMR (101 MHz, CDCl3)
d 139.83, 139.62, 128.68, 128.48, 126.06, 123.41, 123.35, 117.06,
110.93, 101.78, 98.20, 55.71, 34.36, 30.45. MS (ESI) calcd for
C
18H21N3, m/z 279.17, found 280.19 (M+H)+.
3.1.8. Compound 1h: 2-(anthracen-9-yl)-N-(tert-butyl)
imidazo[1,2-a]pyrazin-3-amine (50 mg, 57%)
3.1.4. Compound 1d: 2-benzyl-N-(tert-butyl)imidazo
[1,2-a]pyrazin-3-amine (31 mg, 43%)
1H NMR (400 MHz, CDCl3) d 9.14 (d, J = 1.5 Hz, 1H), 8.57 (s, 1H),
8.31 (dd, J = 4.6, 1.5 Hz, 1H), 8.12–8.05 (m, 2H), 7.98 (d, J = 4.6 Hz,
1H), 7.83–7.75 (m, 2H), 7.53–7.42 (m, 4H), 2.75 (s, 1H), 0.65 (s,
9H). 13C NMR (101 MHz, CDCl3) d 143.65, 139.88, 138.08, 131.37,
130.86, 129.05, 128.96, 128.35, 127.48, 126.81, 125.52, 125.24,
116.55, 101.78, 56.14, 29.77. MS (ESI) calcd for C24H22N4, m/z
366.18, found 367.19 (M+H)+ and 389.18 (M+Na)+.
1H NMR (400 MHz, CDCl3) d 8.92 (d, J = 1.4 Hz, 1H), 8.06 (dd,
J = 4.6, 1.5 Hz, 1H), 7.81 (d, J = 4.6 Hz, 1H), 7.32–7.27 (m, 2H),
7.25–7.18 (m, 3H), 4.24 (s, 2H), 2.62 (s, 1H), 1.20 (s, 9H). 13C
NMR (101 MHz, CDCl3) d 142.95, 142.78, 138.88, 137.32, 128.72,
128.67, 126.45, 116.28, 56.29, 34.39, 30.48. MS (ESI) calcd for
C
17H20N4, m/z 280.17, found 281.18 (M+H)+.
3.1.5. Compound 1e: N-(tert-butyl)-2-(naphthalen-1-yl)
imidazo[1,2-a]pyridin-3-amine (56 mg, 74%)
3.1.9. Compound 2a: N-cyclohexyl-2-phenylimidazo
[1,2-a]pyridin-3-amine white solid (51 mg, 73%)
1H NMR (400 MHz, CDCl3) d 8.34 (dt, J = 6.9, 1.1 Hz, 1H), 8.02–
7.85 (m, 3H), 7.68–7.44 (m, 5H), 7.19 (ddd, J = 9.0, 6.7, 1.3 Hz,
1H), 6.83 (td, J = 6.8, 1.1 Hz, 1H), 3.00 (s, 1H), 0.78 (s, 9H). 13C
NMR (101 MHz, CDCl3) d 133.83, 132.94, 131.98, 128.48, 128.25,
128.15, 126.57, 125.73, 125.70, 125.34, 123.97, 123.64, 117.45,
111.37, 101.79, 100.00, 55.95, 29.76. MS (ESI) calcd for C21H21N3,
m/z 315.17, found 316.19 (M+H)+.
1H NMR (500 MHz, CDCl3) d 8.16 (d, J = 6.8 Hz, 1H), 8.05 (dd,
J = 8.3, 1.2 Hz, 2H), 7.62 (d, J = 9.0 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H),
7.32 (t, J = 7.4 Hz, 1H), 7.17 (ddd, J = 8.9, 6.7, 1.2 Hz, 1H), 6.82 (td,
J = 6.8, 0.9 Hz, 1H), 3.32 (s, 1H), 3.07–2.85 (m, 1H), 1.81 (d,
J = 13.1 Hz, 2H), 1.68 (dd, J = 9.1, 3.6 Hz, 2H), 1.60–1.54 (m, 1H),
1.28–1.12 (m, 5H). 13C NMR (126 MHz, CDCl3) d 141.02, 135.43,
133.45, 128.74, 127.74, 127.20, 125.17, 125.04, 123.07, 116.94,
112.30, 57.02, 34.27, 25.81, 24.94. MS (ESI) calcd for C19H21N3,
m/z 291.17, found 292.18 (M+H)+.
3.1.6. Compound 1f: N-(tert-butyl)-2-(naphthalen-1-yl)imidazo
[1,2-a]pyrazin-3-amine (29 mg, 38%)
1H NMR (400 MHz, CDCl3) d 9.07 (d, J = 1.4 Hz, 1H), 8.24 (dd,
J = 4.6, 1.5 Hz, 1H), 7.97–7.87 (m, 4H), 7.67–7.42 (m, 4H), 3.08 (s,
1H), 0.80 (s, 9H). 13C NMR (101 MHz, CDCl3) d 143.57, 141.83,
133.85, 131.76, 131.71, 128.98, 128.95, 128.67, 128.27, 126.94,
3.1.10. Compound 2b: N-cyclohexyl-2-phenylimidazo[1,2-a]
pyrazin-3-amine (25 mg, 36%)
1H NMR (500 MHz, CDCl3) d 8.99 (d, J = 1.4 Hz, 1H), 8.01 (ddd,
J = 4.6, 3.2, 1.8 Hz, 3H), 7.85 (d, J = 4.6 Hz, 1H), 7.48 (t, J = 7.7 Hz,

N. M. Shukla et al. / Bioorg. Med. Chem. 20 (2012) 5850–5863
5859
2H), 7.38 (t, J = 7.4 Hz, 1H), 3.26 (s, 1H), 3.00 (s, 1H), 1.82 (dd,
J = 6.6, 5.4 Hz, 2H), 1.70 (dd, J = 9.3, 3.3 Hz, 2H), 1.62–1.55 (m,
1H), 1.34–1.07 (m, 5H). 13C NMR (126 MHz, CDCl3) d 143.37,
139.08, 136.82, 133.62, 129.01, 128.90, 128.30, 127.42, 126.70,
115.73, 57.02, 34.41, 25.69, 24.91. MS (ESI) calcd for C18H20N4,
m/z 292.17, found 293.18 (M+H)+.
3.1.16. Compound 2h: 2-(anthracen-9-yl)-N-cyclohexylimidazo
[1,2-a]pyrazin-3-amine (17 mg, 18%)
1H NMR (500 MHz, CDCl3) d 9.12 (d, J = 1.4 Hz, 1H), 8.59 (s, 1H),
8.13–8.06 (m, 3H), 7.97 (d, J = 4.6 Hz, 1H), 7.72 (dd, J = 8.7, 0.6 Hz,
2H), 7.46 (dddd, J = 10.0, 7.8, 6.5, 1.1 Hz, 4H), 2.91 (d, J = 6.2 Hz,
1H), 2.62 (s, 1H), 1.48 (d, J = 12.6 Hz, 2H), 1.29 (dd, J = 24.7,
8.3 Hz, 3H), 0.91–0.76 (m, 3H), 0.76–0.63 (m, 2H). 13C NMR
3.1.11. Compound 2c: 2-benzyl-N-cyclohexylimidazo
[1,2-a]pyridin-3-amine (51 mg, 70%)
(126 MHz, CDCl3) d 142.63, 136.28, 135.36, 130.29, 130.12,
128.74, 128.01, 127.76, 127.36, 125.75, 125.54, 124.62, 124.25,
114.68, 54.95, 32.71, 24.20, 23.32. MS (ESI) calcd for C26H24N4,
m/z 392.20, found 393.20 (M+H)+.
1H NMR (500 MHz, CDCl3) d 8.04 (dt, J = 6.8, 1.1 Hz, 1H), 7.52–
7.46 (m, 1H), 7.31–7.26 (m, 4H), 7.19 (qd, J = 5.3, 2.7 Hz, 1H),
7.10 (ddd, J = 9.0, 6.7, 1.3 Hz, 1H), 6.76 (td, J = 6.8, 1.1 Hz, 1H),
4.16 (s, 2H), 2.77 (s, 1H), 2.60 (s, 1H), 1.79–1.67 (m, 4H), 1.59 (s,
1H), 1.32–1.04 (m, 5H). 13C NMR (126 MHz, CDCl3) d 141.11,
139.62, 137.49, 128.68, 128.53, 126.20, 125.44, 123.43, 122.59,
116.93, 111.41, 57.32, 34.17, 34.11, 25.74, 24.85. MS (ESI) calcd
for C20H23N3, m/z 305.19, found 306.20 (M+H)+.
3.1.17. Compound 3a: N-benzyl-2-phenylimidazo[1,2-a]pyridin-
3-amine white solid (62 mg, 86%)
1H NMR (500 MHz, CDCl3) d 7.98 (ddt, J = 3.7, 3.0, 1.6 Hz, 3H),
7.57 (dt, J = 9.0, 1.0 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.39–7.26 (m,
6H), 7.13 (ddd, J = 9.0, 6.7, 1.3 Hz, 1H), 6.74 (td, J = 6.8, 1.1 Hz,
1H), 4.20 (d, J = 6.1 Hz, 2H), 3.52 (t, J = 6.0 Hz, 1H). 13C NMR
3.1.12. Compound 2d: 2-benzyl-N-cyclohexylimidazo
[1,2-a]pyrazin-3-amine (37 mg, 50%)
(126 MHz, CDCl3) d 141.57, 139.06, 136.04, 134.13, 128.84,
128.30, 127.82, 127.65, 127.16, 125.77, 124.32, 122.50, 117.52,
111.94, 52.57. MS (ESI) calcd for C20H17N3, m/z 299.14, found
300.15 (M+H)+.
1H NMR (500 MHz, CDCl3) d 8.92 (d, J = 1.4 Hz, 1H), 7.93 (dd,
J = 4.6, 1.5 Hz, 1H), 7.81 (d, J = 4.6 Hz, 1H), 7.33–7.25 (m, 4H),
7.22 (ddd, J = 6.2, 3.3, 1.6 Hz, 1H), 4.20 (s, 2H), 2.81 (s, 1H), 2.68
(s, 1H), 1.84–1.65 (m, 4H), 1.60 (d, J = 6.1 Hz, 1H), 1.24–0.95 (m,
5H). 13C NMR (126 MHz, CDCl3) d 141.19, 139.22, 137.30, 135.01,
127.27, 127.20, 127.17, 125.71, 125.04, 114.00, 55.65, 32.84,
32.76, 24.09, 23.31. MS (ESI) calcd for C19H22N4, m/z 306.18, found
307.20 (M+H)+.
3.1.18. Compound 3b: N-benzyl-2-phenylimidazo[1,2-a]
pyrazin-3-amine (45 mg, 62%)
1H NMR (500 MHz, CDCl3) d 8.98 (d, J = 1.3 Hz, 1H), 7.94 (dt,
J = 8.1, 1.6 Hz, 2H), 7.82 (dd, J = 4.6, 1.4 Hz, 1H), 7.77 (d,
J = 4.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H),
7.34–7.27 (m, 5H), 4.23 (d, J = 2.4 Hz, 2H), 3.66 (s, 1H). 13C NMR
3.1.13. Compound 2e: N-cyclohexyl-2-(naphthalen-1-yl)
imidazo[1,2-a]pyridin-3-amine (24 mg, 29%)
(126 MHz, CDCl3) d 143.46, 138.76, 138.56, 136.79, 133.34,
129.06, 129.03, 128.99, 128.46, 128.24, 128.08, 127.42, 127.18,
115.38, 52.39. MS (ESI) calcd for C19H16N4, m/z 300.14, found
301.15 (M+H)+.
1H NMR (500 MHz, CDCl3) d 8.20 (d, J = 6.8 Hz, 1H), 7.95–7.88
(m, 3H), 7.72–7.64 (m, 2H), 7.59–7.54 (m, 1H), 7.53–7.45 (m,
2H), 7.25–7.20 (m, 1H), 6.90 (t, J = 6.8 Hz, 1H), 3.15 (s, 1H), 2.63
(t, J = 9.6 Hz, 1H), 1.58 (d, J = 12.6 Hz, 2H), 1.50–1.36 (m, 3H),
1.04–0.77 (m, 5H). 13C NMR (126 MHz, CDCl3) d 141.06, 133.76,
131.95, 128.57, 128.49, 128.15, 126.76, 126.65, 125.86, 125.50,
125.36, 124.30, 122.89, 117.21, 112.14, 56.32, 33.70, 25.47, 24.51.
MS (ESI) calcd for C23H23N3, m/z 341.19, found 342.20 (M+H)+.
3.1.19. Compound 3c: N,2-dibenzylimidazo[1,2-a]
pyridin-3-amine (33 mg, 44%)
1H NMR (500 MHz, CDCl3) d 7.95 (dt, J = 6.8, 1.1 Hz, 1H), 7.49
(dt, J = 9.1, 0.9 Hz, 1H), 7.38–7.15 (m, 10H), 7.09 (ddd, J = 9.0, 6.7,
1.3 Hz, 1H), 6.72 (td, J = 6.7, 1.1 Hz, 1H), 4.01 (s, 2H), 3.94 (d,
J = 5.5 Hz, 2H), 2.99 (s, 1H). 13C NMR (126 MHz, CDCl3) d 141.18,
139.68, 139.24, 137.57, 128.69, 128.62, 128.57, 128.28, 127.59,
126.25, 125.93, 123.36, 122.14, 117.15, 111.44, 52.83, 34.13. MS
(ESI) calcd for C21H19N3, m/z 313.16, found 314.18 (M+H)+.
3.1.14. Compound 2f: N-cyclohexyl-2-(naphthalen-1-yl)
imidazo[1,2-a]pyrazin-3-amine (50 mg, 61%)
1H NMR (500 MHz, CDCl3) d 9.05 (d, J = 1.5 Hz, 1H), 8.05 (dd,
J = 4.6, 1.5 Hz, 1H), 7.96–7.93 (m, 2H), 7.92–7.89 (m, 2H), 7.61
(ddd, J = 15.2, 7.5, 4.2 Hz, 4H), 7.55–7.48 (m, 1H), 3.27 (s, 1H),
2.73 (s, 1H), 1.61 (dd, J = 9.5, 3.2 Hz, 2H), 1.44 (ddd, J = 14.5, 11.6,
4.6 Hz, 3H), 1.07–0.82 (m, 5H). 13C NMR (126 MHz, CDCl3) d
143.40, 138.38, 136.73, 133.80, 131.90, 130.80, 129.03, 128.84,
128.58, 128.53, 128.07, 126.87, 126.08, 125.30, 125.27, 115.67,
56.12, 33.85, 25.35, 24.50. MS (ESI) calcd for C22H22N4, m/z
342.18, found 343.19 (M+H)+ and 365.17 (M + Na)+.
3.1.20. Compound 3d: N,2-dibenzylimidazo[1,2-a]
pyrazin-3-amine (19 mg, 25%)
1H NMR (500 MHz, CDCl3) d 7.83–7.72 (m, 2H), 7.35–7.25 (m,
5H), 7.25–7.18 (m, 4H), 7.16 (dd, J = 7.0, 2.2 Hz, 2H), 4.03 (s, 2H),
3.96 (d, J = 3.9 Hz, 2H), 3.15–3.05 (m, 1H). 13C NMR (126 MHz,
CDCl3) d 141.87, 139.52, 137.76, 137.68, 135.44, 128.01, 127.89,
127.75, 127.71, 127.66, 127.63, 127.59, 127.56, 127.26, 127.19,
126.97, 126.84, 126.75, 125.57, 114.09, 51.49, 51.46, 33.19. MS
(ESI) calcd for C20H18N4, m/z 314.15, found 315.17 (M+H)+.
3.1.15. Compound 2g: 2-(anthracen-9-yl)-N-cyclohexylimidazo
[1,2-a]pyridin-3-amine (83 mg, 88%)
1H NMR (500 MHz, CDCl3) d 8.54 (s, 1H), 8.23 (dt, J = 6.8, 1.2 Hz,
1H), 8.06 (d, J = 8.4 Hz, 2H), 7.83 (dd, J = 8.7, 0.8 Hz, 2H), 7.66 (dt,
J = 9.0, 1.0 Hz, 1H), 7.49–7.44 (m, 2H), 7.40 (ddd, J = 8.6, 6.5,
1.3 Hz, 2H), 7.23 (ddd, J = 9.0, 6.7, 1.3 Hz, 1H), 6.90 (td, J = 6.8,
1.1 Hz, 1H), 2.80 (d, J = 7.4 Hz, 1H), 2.62–2.49 (m, 1H), 1.47 (d,
J = 12.6 Hz, 2H), 1.35–1.24 (m, 3H), 0.89–0.77 (m, 3H), 0.68 (dt,
J = 12.8, 6.6 Hz, 2H). 13C NMR (126 MHz, CDCl3) d 142.02, 134.01,
131.38, 131.20, 128.59, 128.34, 128.10, 127.64, 126.25, 126.12,
125.10, 123.40, 122.81, 117.72, 111.60, 56.18, 33.62, 25.39,
24.38. MS (ESI) calcd for C27H25N3, m/z 391.20, found 392.22
(M+H)+.
3.1.21. Compound 3e: N-benzyl-2-(naphthalen-1-yl)
imidazo[1,2-a]pyridin-3-amine (42 mg, 50%)
1H NMR (500 MHz, CDCl3) d 8.15–8.10 (m, 1H), 8.01 (d,
J = 8.3 Hz, 1H), 7.94–7.86 (m, 2H), 7.61 (d, J = 9.0 Hz, 1H), 7.55–
7.44 (m, 4H), 7.18 (ddd, J = 9.0, 6.7, 1.3 Hz, 1H), 7.15–7.11 (m,
3H), 7.02 (dd, J = 6.5, 3.0 Hz, 2H), 6.83 (td, J = 6.8, 1.0 Hz, 1H),
3.92 (d, J = 4.9 Hz, 2H), 3.53 (s, 1H). 13C NMR (126 MHz, CDCl3) d
141.35, 138.75, 135.57, 133.79, 132.14, 131.50, 128.45, 128.37,
128.33, 127.88, 127.34, 127.31, 126.49, 125.88, 125.82, 125.27,
123.69, 122.50, 117.60, 111.80, 52.42. MS (ESI) calcd for
C
24H19N3, m/z 349.16, found 350.18 (M+H)+.

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N. M. Shukla et al. / Bioorg. Med. Chem. 20 (2012) 5850–5863
3.1.22. Compound 3f: N-benzyl-2-(naphthalen-1-yl)imidazo
[1,2-a]pyrazin-3-amine (12 mg, 14%)
3H), 0.69 (dd, J = 22.4, 11.8 Hz, 2H). 13C NMR (126 MHz, CDCl3) d
143.61, 136.76, 134.02, 131.59, 131.27, 131.26, 128.77, 128.58,
127.43, 126.61, 126.17, 125.63, 125.29, 115.63, 56.13, 33.74,
25.16, 24.33. MS (ESI) calcd for C26H23ClN4, m/z 426.16, found
427.17 (M+H)+.
1H NMR (500 MHz, CDCl3) d 9.01 (d, J = 1.5 Hz, 1H), 7.97–7.89
(m, 4H), 7.83 (d, J = 4.6 Hz, 1H), 7.49 (tddd, J = 10.0, 6.8, 3.6,
1.4 Hz, 4H), 7.17–7.08 (m, 3H), 7.01–6.94 (m, 2H), 3.96 (d,
J = 5.8 Hz, 2H), 3.78 (t, J = 5.8 Hz, 1H). 13C NMR (126 MHz, CDCl3)
d 143.50, 138.21, 137.83, 136.53, 133.78, 131.90, 130.44, 129.08,
128.95, 128.89, 128.49, 128.46, 128.02, 127.77, 127.73, 127.58,
126.78, 126.06, 125.45, 125.21, 115.35, 51.83. MS (ESI) calcd for
Compounds 5a–5i were synthesized similarly as compound 1a.
3.1.28. Compound 5a: 2-(anthracen-9-yl)-N-butylimidazo
[1,2-a]pyridin-3-amine (22 mg, 25%)
C
23H18N4, m/z 350.15, found 351.18 (M+H)+.
1H NMR (500 MHz, CDCl3) d 8.55 (s, 1H), 8.19 (dt, J = 6.8, 1.2 Hz,
1H), 8.06 (d, J = 8.4 Hz, 2H), 7.84 (dd, J = 8.7, 0.8 Hz, 2H), 7.67 (dt,
J = 9.1, 1.0 Hz, 1H), 7.48–7.44 (m, 2H), 7.40 (ddd, J = 8.6, 6.5,
1.3 Hz, 2H), 7.22 (ddd, J = 9.0, 6.7, 1.3 Hz, 1H), 6.90 (td, J = 6.8,
1.1 Hz, 1H), 2.89 (t, J = 6.1 Hz, 1H), 2.64 (q, J = 6.6 Hz, 2H), 1.09–
0.97 (m, 2H), 0.86–0.72 (m, 2H), 0.43 (t, J = 7.4 Hz, 3H). 13C NMR
3.1.23. Compound 3g: 2-(anthracen-9-yl)-N-benzylimidazo
[1,2-a]pyridin-3-amine (47 mg, 49%)
1H NMR (500 MHz, CDCl3) d 8.55 (s, 1H), 8.18 (dt, J = 6.9, 1.2 Hz,
1H), 8.07 (d, J = 8.5 Hz, 2H), 7.82 (dd, J = 8.8, 0.9 Hz, 2H), 7.66 (dt,
J = 9.0, 1.1 Hz, 1H), 7.50–7.43 (m, 2H), 7.39 (ddd, J = 8.7, 6.5,
1.3 Hz, 2H), 7.22 (ddd, J = 9.0, 6.7, 1.3 Hz, 1H), 7.05–6.95 (m, 3H),
6.90–6.82 (m, 3H), 3.74 (d, J = 6.3 Hz, 2H), 3.25 (t, J = 6.3 Hz, 1H).
13C NMR (126 MHz, CDCl3) d 140.88, 137.71, 132.57, 130.36,
130.23, 127.77, 127.54, 127.15, 127.02, 126.76, 126.63, 126.10,
125.31, 125.10, 124.09, 122.54, 121.46, 116.74, 110.71, 51.19. MS
(ESI) calcd for C28H21N3, m/z 399.17, found 400.20 (M+H)+.
(126 MHz, CDCl3)
d 141.97, 133.07, 131.52, 131.47, 129.40,
128.68, 128.39, 127.80, 126.46, 126.21, 125.25, 123.46, 122.61,
117.92, 111.80, 47.92, 32.18, 19.67, 13.53. MS (ESI) calcd for
C
25H23N3, m/z 365.19, found 366.20 (M+H)+.
3.1.29. Compound 5b: 2-(anthracen-9-yl)-N-pentylimidazo
[1,2-a]pyridin-3-amine (35 mg, 38%)
1H NMR (500 MHz, CDCl3) d 8.55 (s, 1H), 8.19 (dt, J = 6.8, 1.2 Hz,
1H), 8.06 (d, J = 8.4 Hz, 2H), 7.84 (dd, J = 8.7, 0.8 Hz, 2H), 7.67 (dt,
J = 9.0, 1.1 Hz, 1H), 7.49–7.44 (m, 2H), 7.40 (ddd, J = 8.6, 6.5,
1.3 Hz, 2H), 7.22 (ddd, J = 9.0, 6.7, 1.3 Hz, 1H), 6.90 (td, J = 6.8,
1.1 Hz, 1H), 2.91 (t, J = 6.4 Hz, 1H), 2.65 (q, J = 6.7 Hz, 2H), 1.02
(dt, J = 14.3, 7.0 Hz, 2H), 0.82–0.65 (m, 4H), 0.52 (t, J = 7.1 Hz,
3H). 13C NMR (126 MHz, CDCl3) d 141.85, 132.95, 131.40, 131.34,
129.24, 128.56, 128.26, 127.67, 126.32, 126.10, 125.13, 123.31,
122.48, 117.81, 111.67, 48.05, 29.68, 28.58, 22.07, 13.70. MS (ESI)
calcd for C26H25N3, m/z 379.20, found 380.22 (M+H)+.
3.1.24. Compound 3h: 2-(anthracen-9-yl)-N-benzylimidazo
[1,2-a]pyrazin-3-amine (8 mg, 8%)
1H NMR (500 MHz, CDCl3) d 9.09 (d, J = 1.4 Hz, 1H), 8.59 (s, 1H),
8.08 (d, J = 8.5 Hz, 2H), 8.01 (dd, J = 4.6, 1.5 Hz, 1H), 7.91 (d,
J = 4.6 Hz, 1H), 7.69 (dd, J = 8.8, 0.7 Hz, 2H), 7.52–7.45 (m, 2H),
7.41 (ddd, J = 8.6, 6.5, 1.2 Hz, 2H), 7.06–6.94 (m, 3H), 6.83–6.77
(m, 2H), 3.78 (d, J = 5.3 Hz, 2H), 3.44 (s, 1H). 13C NMR (126 MHz,
CDCl3) d 143.66, 138.12, 137.10, 135.78, 131.32, 131.19, 130.28,
129.06, 128.75, 128.50, 128.33, 127.55, 127.41, 126.56, 126.53,
125.74, 125.28, 115.37, 51.61. MS (ESI) calcd for C27H20N4, m/z
400.17, found 401.19 (M+H)+.
3.1.30. Compound 5c: 2-(anthracen-9-yl)-N-isopropylimidazo
[1,2-a]pyridin-3-amine (15 mg, 18%)
Compounds 4a–4c were synthesized similarly as compound 1a.
1H NMR (500 MHz, CDCl3) d 8.54 (s, 1H), 8.25 (dt, J = 6.8, 1.2 Hz,
1H), 8.08–8.04 (m, 2H), 7.84 (dd, J = 8.7, 0.9 Hz, 2H), 7.66 (dt,
J = 9.0, 1.1 Hz, 1H), 7.49–7.44 (m, 2H), 7.41 (ddd, J = 8.6, 6.5,
1.3 Hz, 2H), 7.23 (ddd, J = 9.0, 6.7, 1.3 Hz, 1H), 6.90 (td, J = 6.8,
1.1 Hz, 1H), 2.86 (dq, J = 12.5, 6.3 Hz, 1H), 2.71 (d, J = 6.4 Hz, 1H),
0.69 (d, J = 6.3 Hz, 6H). 13C NMR (126 MHz, CDCl3) d 142.10,
134.36, 131.39, 131.13, 128.63, 128.31, 128.29, 127.69, 126.23,
126.17, 125.11, 123.56, 122.78, 117.69, 111.64, 49.20, 23.15. MS
(ESI) calcd for C24H21N3, m/z 351.17, found 352.19 (M+H)+.
3.1.25. Compound 4a: 2-(anthracen-9-yl)-N-cyclohexylimidazo
[1,2-a]pyrimidin-3-amine (40 mg, 43%)
1H NMR (500 MHz, CDCl3) d 8.61 (dd, J = 4.1, 2.1 Hz, 1H), 8.56
(s, 1H), 8.54 (dd, J = 6.8, 2.1 Hz, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.83
(dd, J = 8.7, 0.8 Hz, 2H), 7.49–7.44 (m, 2H), 7.41 (ddd, J = 8.6, 6.5,
1.3 Hz, 2H), 6.97 (dd, J = 6.8, 4.1 Hz, 1H), 2.83 (s, 1H), 2.47 (s, 1H),
1.43 (d, J = 12.9 Hz, 2H), 1.29 (d, J = 7.4 Hz, 3H), 0.82 (t, J = 6.6 Hz,
3H), 0.75–0.62 (m, 2H). 13C NMR (126 MHz, CDCl3) d 148.91,
144.93, 135.89, 131.34, 131.05, 130.37, 128.66, 128.12, 127.26,
126.67, 126.29, 126.07, 125.18, 108.17, 56.46, 33.55, 25.28, 24.28.
MS (ESI) calcd for C26H24N4, m/z 392.20, found 393.22 (M+H)+.
3.1.31. Compund 5d: 2-(anthracen-9-yl)-N-isopropylimidazo
[1,2-a]pyridin-3-amine (37 mg, 41%)
1H NMR (500 MHz, CDCl3) d 8.54 (s, 1H), 8.23 (dd, J = 6.8, 1.0 Hz,
1H), 8.06 (d, J = 8.3 Hz, 2H), 7.89–7.83 (m, 2H), 7.67 (dt, J = 9.0,
1.0 Hz, 1H), 7.50–7.37 (m, 4H), 7.23 (ddd, J = 9.0, 6.7, 1.3 Hz, 1H),
6.90 (td, J = 6.8, 1.1 Hz, 1H), 2.79–2.61 (m, 2H), 1.12–0.95 (m,
2H), 0.92–0.82 (m, 2H), 0.79–0.67 (m, 1H), 0.63 (d, J = 6.2 Hz,
2H), 0.39 (t, J = 7.1 Hz, 2H), 0.29 (t, J = 7.4 Hz, 1H). 13C NMR
3.1.26. Compound 4b: 2-(anthracen-9-yl)-N3-cyclohexylimidazo
[1,2-a]pyridine-3,8-diamine (15 mg, 15%)
1H NMR (500 MHz, CDCl3) d 8.54 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H),
7.86 (dd, J = 8.7, 0.7 Hz, 2H), 7.70 (dd, J = 6.7, 0.9 Hz, 1H), 7.49–7.44
(m, 2H), 7.43–7.37 (m, 2H), 6.74 (t, J = 7.0 Hz, 1H), 6.40 (dd, J = 7.3,
0.9 Hz, 1H), 4.57 (s, 2H), 2.77 (s, 1H), 2.56 (s, 1H), 1.49 (d,
J = 12.4 Hz, 2H), 1.29 (d, J = 5.7 Hz, 3H), 0.94–0.75 (m, 3H), 0.75–
0.61 (m, 2H). 13C NMR (126 MHz, CDCl3) d 135.97, 135.69,
132.06, 131.45, 131.37, 129.03, 128.57, 128.36, 127.62, 126.37,
126.06, 125.12, 113.22, 112.69, 101.65, 56.09, 33.63, 25.41, 24.41.
MS (ESI) calcd for C27H26N4, m/z 406.22, found 407.23 (M+H)+.
(126 MHz, CDCl3)
d 142.03, 134.21, 131.41, 131.39, 131.36,
131.19, 131.13, 128.62, 128.61, 128.59, 128.36, 128.34, 127.64,
127.61, 126.26, 126.15, 126.13, 125.09, 123.45, 123.34, 122.68,
122.60, 117.74, 117.71, 111.62, 59.63, 53.06, 39.14, 26.01, 20.85,
18.53, 13.58, 9.01. MS (ESI) calcd for C26H25N3, m/z 379.20, found
380.22 (M+H)+.
3.1.27. Compound 4c: 2-(anthracen-9-yl)-8-chloro-N-
3.1.32. Compound 5e: 2-(anthracen-9-yl)-N-(2,4,4-trimeth
ylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine (51 mg, 50%)
IR (CHCl3) mmax (cmꢁ1): 2956, 1519, 1481, 1365, 1340. 1H NMR
(500 MHz, CDCl3) d 8.53 (s, 1H), 8.41 (d, J = 6.9 Hz, 1H), 8.05 (d,
J = 7.7 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 9.0 Hz, 1H),
cyclohexylimidazo[1,2-a]pyrazin-3-amine (20 mg, 20%)
1H NMR (500 MHz, CDCl3) d 8.59 (s, 1H), 8.10–8.06 (m, 3H), 7.77
(d, J = 4.5 Hz, 1H), 7.70 (dd, J = 8.7, 0.7 Hz, 2H), 7.52–7.47 (m, 2H),
7.46–7.41 (m, 2H), 2.93 (d, J = 6.8 Hz, 1H), 2.66–2.58 (m, 1H),
1.48 (d, J = 12.4 Hz, 2H), 1.32 (d, J = 6.9 Hz, 3H), 0.92–0.79 (m,

N. M. Shukla et al. / Bioorg. Med. Chem. 20 (2012) 5850–5863
5861
7.50–7.38 (m, 4H), 7.24 (ddd, J = 8.9, 6.7, 1.2 Hz, 1H), 6.88 (td,
J = 6.8, 1.0 Hz, 1H), 2.89 (s, 1H), 0.97 (s, 2H), 0.68 (s, 6H), 0.52 (s,
9H). 13C NMR (126 MHz, CDCl3) d 142.71, 137.08, 131.44, 131.01,
129.27, 128.71, 127.53, 126.78, 126.32, 126.24, 125.05, 123.94,
123.70, 117.51, 111.35, 59.61, 55.82, 31.20, 30.95, 28.61. MS (ESI)
calcd for C29H31N3, m/z 421.25, found 422.27 (M+H)+.
126.32, 125.88, 125.33, 123.00, 122.10, 117.82, 111.89. MS (ESI)
calcd for C21H15N3, m/z 309.13, found 310.14 (M+H)+.
3.1.38. Syntheses of Compounds 7a and 7b
To a solution of compound 6 (20 mg, 0.065 mmol) in anhydrous
methanol, were added octyl aldehyde (15 lL, 0.098 mmol), 4 drops
of acetic acid and sodium cyanoborohydride (6 mg, 0.098 mmol).
The reaction mixture was stirred for 18 h and the solvent was then
removed under vacuum. The residue was purified using column
chromatography to obtain compounds 7a (3% methanol/CH2Cl2)
and 7b (2% methanol/CH2Cl2).
3.1.33. Compound 5f: 2-(anthracen-9-yl)-N-((trimethylsilyl)
methyl)imidazo[1,2-a]pyridin-3-amine (33 mg, 35%)
1H NMR (500 MHz, CDCl3) d 8.55 (s, 1H), 8.15 (dt, J = 6.8, 1.1 Hz,
1H), 8.06 (d, J = 8.4 Hz, 2H), 7.89 (dd, J = 8.7, 0.7 Hz, 2H), 7.69–7.65
(m, 1H), 7.49–7.44 (m, 2H), 7.43–7.38 (m, 2H), 7.22 (ddd, J = 9.0,
6.7, 1.3 Hz, 1H), 6.91 (td, J = 6.8, 1.0 Hz, 1H), 2.60 (s, 1H), 2.15 (s,
2H), -0.31 (s, 9H). 13C NMR (126 MHz, CDCl3) d 141.55, 132.06,
131.73, 131.42, 131.23, 128.58, 128.10, 127.65, 126.45, 126.02,
125.11, 123.20, 122.44, 117.79, 111.61, 38.69, -3.37. MS (ESI) calcd
for C25H25N3Si, m/z 395.18, found 396.20 (M+H)+.
3.1.39. Compound 7a: 2-(anthracen-9-yl)-N-octylimidazo
[1,2-a]pyridin-3-amine (10 mg, 36%)
1H NMR (500 MHz, CDCl3) d 8.54 (s, 1H), 8.20 (dt, J = 6.8, 1.1 Hz,
1H), 8.06 (d, J = 8.4 Hz, 2H), 7.84 (dd, J = 8.7, 0.7 Hz, 2H), 7.67 (d,
J = 9.0 Hz, 1H), 7.50–7.43 (m, 2H), 7.42–7.37 (m, 2H), 7.23 (ddd,
J = 9.0, 6.7, 1.3 Hz, 1H), 6.91 (td, J = 6.8, 1.1 Hz, 1H), 2.92 (s, 1H),
2.70–2.61 (m, 2H), 1.21–1.11 (m, 2H), 0.99 (ddd, J = 15.6, 8.8,
7.1 Hz, 4H), 0.90–0.84 (m, 2H), 0.82 (t, J = 7.3 Hz, 3H), 0.73–0.66
(m, 4H). 13C NMR (126 MHz, CDCl3) d 141.95, 132.96, 131.54,
131.48, 129.37, 128.73, 128.28, 127.86, 126.44, 126.28, 125.28,
123.54, 122.65, 117.92, 111.86, 48.16, 31.79, 30.06, 29.11, 29.10,
26.56, 22.70, 14.22. MS (ESI) calcd for C29H31N3, m/z 421.25, found
422.27 (M+H)+.
3.1.34. Compound 5g: N-(adamantan-1-yl)-2-(anthracen-9-yl)
imidazo[1,2-a]pyridin-3-amine (46 mg, 43%)
1H NMR (500 MHz, CDCl3) d 8.52 (s, 1H), 8.45 (dt, J = 6.9, 1.1 Hz,
1H), 8.08–8.03 (m, 2H), 7.87 (d, J = 8.8 Hz, 2H), 7.65 (dt, J = 9.0,
1.0 Hz, 1H), 7.44 (dddd, J = 10.0, 7.9, 6.5, 1.3 Hz, 4H), 7.23 (ddd,
J = 9.0, 6.7, 1.3 Hz, 1H), 6.88 (td, J = 6.8, 1.1 Hz, 1H), 2.66 (s, 1H),
1.65 (s, 3H), 1.34 (d, J = 12.1 Hz, 3H), 1.19 (d, J = 11.4 Hz, 3H),
1.13 (d, J = 2.5 Hz, 6H). 13C NMR (126 MHz, CDCl3) d 142.80,
137.17, 131.51, 131.15, 129.27, 128.82, 127.68, 126.39, 126.35,
125.99, 125.17, 123.99, 123.87, 117.61, 111.43, 55.78, 43.30,
36.03, 29.50. MS (ESI) calcd for C31H29N3, m/z 443.24, found
444.26 (M+H)+.
3.1.40. Compound 7b: 2-(anthracen-9-yl)-N,N-
dioctylimidazo[1,2-a]pyridin-3-amine (7 mg, 20%)
1H NMR (500 MHz, CDCl3) d 8.54 (s, 1H), 8.30 (d, J = 6.8 Hz, 1H),
8.04 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.7 Hz, 3H), 7.46–7.40 (m, 2H),
7.31 (ddd, J = 8.6, 6.5, 1.1 Hz, 2H), 7.26–7.21 (m, 1H), 6.90 (td,
J = 6.8, 1.0 Hz, 1H), 2.51–2.45 (m, 4H), 1.32–1.19 (m, 8H), 1.19–
1.08 (m, 8H), 1.08–0.93 (m, 8H), 0.85 (t, J = 7.2 Hz, 6H). 13C NMR
3.1.35. Compound 5h: 2-(anthracen-9-yl)-N-(4-methoxyphenyl)
imidazo[1,2-a]pyridin-3-amine (36 mg, 36%)
(126 MHz, CDCl3)
d 142.02, 135.49, 132.12, 131.84, 131.45,
1H NMR (500 MHz, CDCl3) d 8.50 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H),
7.90–7.83 (m, 3H), 7.74 (d, J = 9.1 Hz, 1H), 7.46–7.39 (m, 2H), 7.38–
7.28 (m, 3H), 6.87 (td, J = 6.8, 1.0 Hz, 1H), 6.61–6.56 (m, 2H), 6.37–
6.29 (m, 2H), 5.29 (s, 1H), 3.63 (s, 3H). 13C NMR (126 MHz, CDCl3) d
153.58, 142.85, 137.63, 136.25, 131.45, 131.34, 128.69, 128.04,
127.61, 126.28, 126.18, 125.19, 124.47, 123.39, 123.21, 118.11,
115.45, 114.84, 112.22, 55.69. MS (ESI) calcd for C28H21N3O, m/z
415.17, found 416.19 (M+H)+.
129.90, 128.41, 127.72, 127.10, 125.49, 125.20, 123.93, 123.19,
117.77, 111.74, 54.71, 31.92, 29.51, 29.38, 29.16, 27.09, 22.75,
14.25. MS (ESI) calcd for C37H47N3, m/z 533.38, found 534.38
(M+H)+.
3.1.41. Synthesis of compound 7c: N-(2-(anthracen-9-yl)
imidazo[1,2-a]pyridin-3-yl)-2,2,2-trifluoro acetamide
To a solution of compound 6 (10 mg, 0.024 mmol) in anhydrous
CH2Cl2, was added trifluoroacetic anhydride (4 lL, 0.03 mmol) and
3.1.36. Compound 5i: 2-(anthracen-9-yl)-N-(2-chloro-6-
methylphenyl)imidazo[1,2-a]pyridin-3-amine (11 mg, 11%)
1H NMR (500 MHz, CDCl3) d 8.38 (s, 1H), 8.21 (dt, J = 6.8, 1.1 Hz,
1H), 7.94 (d, J = 8.4 Hz, 2H), 7.75 (ddd, J = 15.6, 8.3, 4.8 Hz, 3H),
7.41–7.35 (m, 2H), 7.34–7.28 (m, 3H), 6.97 (td, J = 6.8, 1.1 Hz,
1H), 6.61 (dd, J = 7.9, 1.0 Hz, 1H), 6.41–6.35 (m, 1H), 6.29 (t,
J = 7.7 Hz, 1H), 5.43 (s, 1H), 1.48 (s, 3H). 13C NMR (126 MHz, CDCl3)
d 142.20, 139.32, 137.26, 131.22, 129.58, 128.96, 128.51, 127.69,
127.36, 126.96, 126.32, 125.86, 124.98, 124.43, 124.33, 122.77,
121.59, 118.07, 112.53, 18.14. MS (ESI) calcd for C28H20ClN3, m/z
433.13, found 434.15 (M+H)+.
the reaction mixture was stirred for 12 h. The solvent was then re-
moved under vacuum and the residue was purified using column
chromatography (3% methanol/CH2Cl2) to obtain the compound
7c (10 mg, 73%). IR (CHCl3) mmax (cmꢁ1): 1730, 1494, 1355, 1315,
1240, 1195, 1157. 1H NMR (500 MHz, MeOD) d 8.89 (s, 1H), 8.76
(d, J = 6.8 Hz, 1H), 8.28–8.14 (m, 3H), 8.10 (d, J = 9.0 Hz, 1H), 7.77
(d, J = 8.5 Hz, 2H), 7.72 (dd, J = 10.0, 4.0 Hz, 1H), 7.59 (ddt, J = 9.9,
6.6, 3.9 Hz, 4H). 13C NMR (126 MHz, MeOD) d 161.71, 161.41,
161.11, 160.82, 159.55, 159.23, 158.92, 158.61, 140.74, 135.66,
132.62, 132.61, 132.47, 130.22, 129.81, 129.06, 127.34, 127.00,
125.58, 118.91, 118.54, 113.88. MS (ESI) calcd for C23H14F3N3O,
m/z 405.11, found 406.12 (M+H)+.
3.1.37. Synthesis of Compound 6: 2-(anthracen-9-yl)
Compound 8a–8c were synthesized similarly as compound 1a.
imidazo[1,2-a]pyridin-3-amine
Compound 5e (50 mg, 0.12 mmol) was stirred in a solution of
4 M HCl/dioxane for 3 h, followed by removing the solvent under
vacuum. The residue was then purified using column chromatogra-
phy to obtain the compound 6 in quantitative yield. 1H NMR
(500 MHz, CDCl3) d 8.55 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 8.07 (d,
J = 8.4 Hz, 2H), 7.87 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 9.1 Hz, 1H),
7.49–7.45 (m, 2H), 7.44–7.38 (m, 2H), 7.23–7.17 (m, 1H), 6.91
(td, J = 6.8, 0.9 Hz, 1H), 3.07 (s, 2H). 13C NMR (126 MHz, CDCl3) d
141.49, 131.62, 131.32, 130.44, 128.77, 127.97, 127.79, 126.54,
3.1.42. Compound 8a: 2-([1,1’-biphenyl]-4-yl)-N-(2,4,4-
trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine (60 mg,
63%)
1H NMR (500 MHz, CDCl3) d 8.27 (d, J = 6.9 Hz, 1H), 7.99–7.95
(m, 2H), 7.71–7.65 (m, 4H), 7.61 (d, J = 9.0 Hz, 1H), 7.46 (dd,
J = 10.5, 4.8 Hz, 2H), 7.38–7.33 (m, 1H), 7.21–7.15 (m, 1H), 6.82
(dd, J = 6.6, 6.2 Hz, 1H), 3.29 (s, 1H), 1.61 (s, 2H), 1.05 (s, 9H),
0.99 (s, 6H). 13C NMR (126 MHz, CDCl3) d 140.75, 140.14, 128.92,
128.78, 128.70, 127.31, 127.27, 127.26, 127.00, 126.96, 124.63,

5862
N. M. Shukla et al. / Bioorg. Med. Chem. 20 (2012) 5850–5863
123.66, 123.48, 117.04, 111.69, 60.86, 57.09, 31.86, 31.76, 29.02.
Compound 11 was synthesized similarly as compound 1a.
MS (ESI) calcd for C27H31N3, m/z 397.25, found 398.25 (M+H)+.
3.1.47. Compound 11: 2-(anthracen-9-yl)-6-bromo-N-(2,4,4-
trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine
3.1.43. Compound 8b: 2-(phenanthren-9-yl)-N-(2,4,4-
trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine (79 mg,
78%)
(150 mg, 63%). 1H NMR (500 MHz, CDCl3) d 8.54–8.51 (m, 2H),
8.08–8.04 (m, 2H), 7.82 (dd, J = 8.6, 0.9 Hz, 2H), 7.56 (dd, J = 9.4,
0.7 Hz, 1H), 7.49–7.41 (m, 4H), 7.30 (dd, J = 9.4, 1.9 Hz, 1H), 2.91
(s, 1H), 0.96 (s, 2H), 0.68 (s, 6H), 0.50 (s, 9H). 13C NMR (126 MHz,
CDCl3) d 141.22, 138.24, 131.56, 131.08, 128.94, 128.70, 127.97,
127.51, 127.30, 126.66, 126.08, 125.26, 124.04, 118.41, 106.62,
59.88, 55.93, 31.31, 31.07, 28.78. MS (ESI) calcd for C29H30BrN3,
m/z 499.16, found 500.18 (M+H)+.
1H NMR (500 MHz, CDCl3) d 8.78 (d, J = 8.2 Hz, 1H), 8.74 (d,
J = 8.1 Hz, 1H), 8.37 (dt, J = 6.9, 1.1 Hz, 1H), 8.04 (dd, J = 8.2,
1.0 Hz, 1H), 7.92 (dd, J = 7.9, 1.2 Hz, 1H), 7.90 (s, 1H), 7.68 (dddd,
J = 8.3, 6.9, 4.2, 1.4 Hz, 2H), 7.65–7.56 (m, 3H), 7.21 (ddd, J = 9.0,
6.7, 1.3 Hz, 1H), 6.86 (td, J = 6.8, 1.1 Hz, 1H), 3.21 (s, 1H), 1.26 (s,
2H), 0.78 (s, 6H), 0.73 (s, 9H). 13C NMR (126 MHz, CDCl3) d
142.35, 139.07, 131.88, 131.67, 131.27, 130.82, 130.44, 129.27,
128.91, 127.17, 126.89, 126.83, 126.72, 126.63, 125.55, 124.24,
123.90, 123.18, 122.72, 117.53, 111.59, 60.24, 56.39, 31.63, 31.45,
28.78. MS (ESI) calcd for C29H31N3, m/z 421.25, found 422.26
(M+H)+ and 444.25 (M + Na)+.
Compound 12 was synthesized similarly as compound 10.
3.1.48. Compound 12: 2-(anthracen-9-yl)-N6-(3-
(dimethylamino)propyl)-N3-(2,4,4-trimethylpentan-2-
yl)imidazo[1,2-a]pyridine-3,6-diamine (21 mg, 40%)
1H NMR (500 MHz, MeOD) d 8.61 (s, 1H), 8.11 (d, J = 8.2 Hz, 2H),
7.83 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 1.9 Hz, 1H), 7.52–7.42 (m, 4H),
7.39 (d, J = 9.5 Hz, 1H), 7.04 (dd, J = 9.5, 2.1 Hz, 1H), 3.18 (t,
J = 6.8 Hz, 2H), 2.60–2.54 (m, 2H), 2.34 (s, 6H), 1.98–1.90 (m, 2H),
0.93 (s, 2H), 0.73 (s, 6H), 0.46 (s, 9H). 13C NMR (126 MHz, MeOD)
d 140.23, 138.50, 136.47, 133.04, 132.49, 130.41, 129.86, 128.71,
128.35, 127.41, 127.33, 126.29, 121.96, 117.07, 103.72, 60.35,
58.54, 56.85, 45.44, 43.56, 31.78, 31.70, 29.50, 27.45. MS (ESI) calcd
for C34H43N5, m/z 521.35, found 522.36 (M+H)+.
3.1.44. Compound 8c: 2-(pyren-4-yl)-N-(2,4,4-trimethylpentan-
2-yl)imidazo[1,2-a]pyridin-3-amine (47 mg, 44%)
1H NMR (500 MHz, CDCl3) d 8.40 (dt, J = 6.9, 1.1 Hz, 1H), 8.28 (d,
J = 7.8 Hz, 1H), 8.23–8.16 (m, 4H), 8.11 (dd, J = 12.1, 5.0 Hz, 3H),
8.02 (t, J = 7.6 Hz, 1H), 7.67 (dt, J = 9.0, 0.9 Hz, 1H), 7.23 (ddd,
J = 9.0, 6.7, 1.3 Hz, 1H), 6.87 (td, J = 6.8, 1.1 Hz, 1H), 3.24 (s, 1H),
1.20 (s, 2H), 0.73 (s, 9H), 0.67 (s, 6H). 13C NMR (126 MHz, CDCl3)
d 142.45, 139.49, 131.39, 131.00, 130.94, 130.62, 129.17, 128.39,
128.17, 127.55, 127.46, 125.92, 125.48, 125.20, 125.05, 125.01,
124.95, 124.79, 124.06, 123.77, 117.46, 111.40, 60.22, 56.27,
31.54, 31.32, 28.53. MS (ESI) calcd for C31H31N3, m/z 445.25, found
446.26 (M+H)+ and 468.25 (M + Na)+.
Compound 13 was synthesized similarly as compound 1a.
3.1.49. Compound 13: N-(tert-butyl)-2-(10-chloroanthracen-9-
yl)imidazo[1,2-a]pyridin-3-amine (242 mg, 84%)
1H NMR (500 MHz, CDCl3) d 8.60 (d, J = 8.8 Hz, 2H), 8.40 (dt,
J = 6.9, 1.1 Hz, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 9.0 Hz, 1H),
7.60 (ddd, J = 8.8, 6.5, 1.1 Hz, 2H), 7.48 (ddd, J = 8.7, 6.5, 1.1 Hz,
2H), 7.28–7.23 (m, 1H), 6.90 (td, J = 6.8, 1.1 Hz, 1H), 2.63 (s, 1H),
0.65 (s, 9H). 13C NMR (126 MHz, CDCl3) d 142.88, 136.60, 131.47,
129.77, 129.12, 128.75, 127.13, 126.76, 126.72, 126.67, 125.36,
124.42, 123.78, 117.69, 111.71, 55.76, 29.90. MS (ESI) calcd for
Compound 9 was synthesized similarly as compound 1a.
3.1.45. Compound 9: 2-(10-chloroanthracen-9-yl)-N-(2,4,4-
trimethylpentan-2-yl)imidazo[1,2-a]pyridin-3-amine (128 mg,
59%)
1H NMR (500 MHz, CDCl3) d 8.60 (d, J = 8.8 Hz, 2H), 8.41 (d,
J = 6.9 Hz, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 9.0 Hz, 1H),
7.62–7.57 (m, 2H), 7.50–7.45 (m, 2H), 7.28–7.25 (m, 1H), 6.90 (t,
J = 6.8 Hz, 1H), 2.83 (s, 1H), 0.96 (s, 2H), 0.68 (s, 6H), 0.52 (s, 9H).
13C NMR (126 MHz, CDCl3) d 142.73, 136.53, 131.45, 129.61,
129.14, 128.64, 127.24, 127.01, 126.69, 126.58, 126.55, 125.21,
124.28, 123.73, 117.53, 111.57, 59.62, 55.90, 31.20, 31.00, 28.67.
MS (ESI) calcd for C29H30ClN3, m/z 455.21, found 456.23 (M+H)+.
C
25H22ClN3, m/z 399.15, found 400.17 (M+H)+.
Compound 14 was synthesized similarly as compound 10.
3.1.50. Compound 14: N1-(10-(3-(tert-butylamino)imidazo[1,2-
a]pyridin-2-yl)anthracen-9-yl)octane-1,8-diamine Red solid
(20 mg, 32%)
1H NMR (500 MHz, MeOD) d 9.01 (d, J = 6.8 Hz, 1H), 8.55 (d,
J = 8.8 Hz, 2H), 8.15–8.08 (m, 1H), 7.99 (dd, J = 13.0, 4.8 Hz, 3H),
7.85 (dd, J = 8.4, 7.0 Hz, 2H), 7.80–7.71 (m, 2H), 7.67 (dd, J = 10.0,
4.0 Hz, 1H), 3.79 (dd, J = 16.7, 8.6 Hz, 2H), 2.94 (dd, J = 14.0,
6.6 Hz, 2H), 2.00–1.91 (m, 2H), 1.72–1.63 (m, 2H), 1.46–1.38 (m,
6H), 0.81 (s, 9H). 13C NMR (126 MHz, MeOD) d 139.74, 135.47,
135.36, 132.83, 130.52, 129.36, 129.01, 128.07, 127.63, 127.26,
127.03, 125.59, 123.03, 118.21, 113.15, 56.34, 54.29, 40.75, 30.28,
30.13, 29.99, 28.55, 27.62, 27.38, 27.35. MS (ESI) calcd for
3.1.46. Synthesis of compound 10: N1,N1-dimethyl-N3-(10-(3-
((2,4,4-trimethylpentan-2-yl)amino)imidazo[1,2-a]pyridin-2-
yl)anthracen-9-yl)propane-1,3-diamine
To a solution of compound 9 (50 mg, 0.11 mmol) in anhydrous
dioxane, were added potassium tert-butoxide (38 mg, 0.34
mmol), N1,N1-dimethylpropane-1,3-diamine (69
lL, 0.55 mmol)
and catalytic amounts of tris(dibenzylideneacetone)-dipalladium
[Pd2(dba)3] and 2-dicyclohexylphosphino-20-(N,N-dimethylamino)
biphenyl [DavePhos]. The reaction was heated in a sealed tube at
80 °C for 4 h. The solvent was then removed under vacuum and
the residue was purified using column chromatography to obtain
the compound 10 (15 mg, 26%). 1H NMR (500 MHz, MeOD) d 8.53
(dt, J = 6.9, 1.0 Hz, 1H), 8.47 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.5 Hz,
2H), 7.60v7.56 (m, 1H), 7.51–7.45 (m, 2H), 7.44–7.35 (m, 3H),
7.04 (td, J = 6.8, 1.1 Hz, 1H), 3.45 (t, J = 7.1 Hz, 2H), 2.57–2.52 (m,
2H), 2.30 (s, 6H), 2.02–1.91 (m, 2H), 0.95 (s, 2H), 0.74 (s, 6H),
0.45 (s, 9H). 13C NMR (126 MHz, MeOD) d 144.90, 143.81, 137.83,
133.18, 128.54, 127.84, 127.32, 126.52, 126.46, 125.51, 125.31,
125.08, 124.09, 117.18, 113.25, 60.30, 58.65, 56.77, 51.56, 45.43,
44.86, 32.49, 31.81, 31.76, 29.47, 29.44. MS (ESI) calcd for
C
33H41N5, m/z 507.34, found 508.35 (M+H)+.
Compound 15 was synthesized similarly as compound 1a.
3.1.51. Compound 15: nthracen-9-yl)-6-bromo-N-(tert-
butyl)imidazo[1,2-a]pyridin-3-amine (260 mg, 81%)
1H NMR (500 MHz, CDCl3) d 8.54–8.52 (m, 2H), 8.08–8.04 (m,
2H), 7.83 (d, J = 8.6 Hz, 2H), 7.56 (dd, J = 9.4, 0.6 Hz, 1H), 7.49–
7.42 (m, 4H), 7.30 (dd, J = 9.4, 1.9 Hz, 1H), 2.68 (s, 1H), 0.64 (s,
9H). 13C NMR (126 MHz, CDCl3) d 141.20, 138.13, 131.52, 130.96,
128.97, 128.47, 128.04, 127.60, 127.27, 126.67, 125.99, 125.25,
123.94, 118.41, 106.67, 55.85, 29.83. MS (ESI) calcd for C25H22BrN3,
m/z 443.10, found 444.10 (M+H)+.
C
34H43N5, m/z 521.35, found 522.37 (M+H)+.
Compound 16 was synthesized similarly as compound 10.

N. M. Shukla et al. / Bioorg. Med. Chem. 20 (2012) 5850–5863
5863
3.1.52. Compound 16: N6-(8-aminooctyl)-2-(anthracen-9-yl)-N3-
Supplementary data
(tert-butyl)imidazo[1,2-a]pyridine-3,6-diamine Brown solid
(55 mg, 47%)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2012.07.052.
1H NMR (500 MHz, MeOD) d 8.81 (s, 1H), 8.20 (dd, J = 6.5,
2.3 Hz, 2H), 7.85–7.80 (m, 2H), 7.72–7.56 (m, 7H), 3.23 (t,
J = 7.0 Hz, 2H), 2.97–2.90 (m, 2H), 1.80 (dt, J = 14.5, 7.1 Hz, 2H),
1.72–1.64 (m, 2H), 1.59–1.51 (m, 2H), 1.45 (s, 6H), 0.78 (s, 9H).
13C NMR (126 MHz, MeOD) d 141.50, 141.40, 134.23, 132.75,
132.52, 131.64, 130.29, 128.91, 128.20, 127.68, 126.85, 126.05,
121.64, 112.69, 104.55, 56.28, 45.40, 40.78, 30.46, 30.35, 30.30,
29.46, 28.65, 28.27, 27.52. MS (ESI) calcd for C33H41N5, m/z
507.34, found 508.35 (M+H)+.
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Acknowledgments
This work was supported by NIH/NIAID contract
HHSN272200900033C.