Post Groebke-Blackburn multicomponent protocol: Synthesis of new polyfunctional imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine derivatives as potential antimicrobial agents

Article abstract of DOI:10.1016/j.ejmech.2010.09.049

New antimicrobial agents [imidazo[1,2-a]pyridine and imidazo[1,2-a] pyrimidine] have been synthesized. Their antimicrobial activities were conducted against various Gram-positive and Gram-negative bacteria including Staphylococcus aureus. Compounds 5d, 7a, 10a, 11a and 12a proved to efficiently inhibit the growth of all the Gram-positive and Gram-negative strains investigated. Results of this study showed that the nature of the substituents on the armed phenyl groups determined the extent of the activity of the fused imidazopyridine and/or imidazopyrimidine derivatives. Preliminary structure-activity observations revealed that groups with positive sigma and positive bi values (e.g. 5d, 6c, 12a, 12d) were significantly more active compared to other bioisosteres (e.g. 5b). Furthermore, increasing the molar refractivity of the substitution pattern (e.g. 5b, 6b and 6d) sharply decreased the antibacterial activity.

Full text of DOI:10.1016/j.ejmech.2010.09.049

European Journal of Medicinal Chemistry 45 (2010) 5848e5855
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Post GroebkeeBlackburn multicomponent protocol: Synthesis of new
polyfunctional imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine
derivatives as potential antimicrobial agents
,
b
,
c
Taleb H. Al-Tel a , Raed A. Al-Qawasmeh
*
a College of Pharmacy, University of Sharjah, University City Road, P.O. Box 27272, Sharjah, United Arab Emirates
b Sharjah Institute for Medical Research-Cancer Division, University of Sharjah, 27272, Sharjah, United Arab Emirates
c Department of Chemistry, University of Jordan, Amman 1194, Jordan
a r t i c l e i n f o
a b s t r a c t
Article history:
New antimicrobial agents [imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine] have been synthesized.
Their antimicrobial activities were conducted against various Gram-positive and Gram-negative bacteria
including Staphylococcus aureus. Compounds 5d, 7a, 10a, 11a and 12a proved to efficiently inhibit the
growth of all the Gram-positive and Gram-negative strains investigated. Results of this study showed
that the nature of the substituents on the armed phenyl groups determined the extent of the activity of
the fused imidazopyridine and/or imidazopyrimidine derivatives. Preliminary structureeactivity obser-
vations revealed that groups with positive sigma and positive bi values (e.g. 5d, 6c, 12a, 12d) were
significantly more active compared to other bioisosteres (e.g. 5b). Furthermore, increasing the molar
refractivity of the substitution pattern (e.g. 5b, 6b and 6d) sharply decreased the antibacterial activity.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Received 13 June 2010
Received in revised form
19 September 2010
Accepted 21 September 2010
Available online 25 September 2010
Keywords:
Oxadiazole
Benzimidazole
Phenyl imidazole
Imidazopyridine
Imidazopyrimidine
Antibacterial agents
1. Introduction
considered the last line of defense against Gram-positive infections
[4,5]. Such new treatment options are welcome additions to the
Infections caused by multi-drug resistant bacteria are of a major
health concern worldwide. Particularly important, are infections
caused by the Gram-positive bacteria Staphylococcus aureus and
species of the genus Enterococcus, due to increasing incidence of
infections caused by these microorganisms in hospitals and their
ability of developing resistance to multiple antibiotics [1].
Patients undergoing organ transplants, anticancer chemotherapy
or long treatment with antimicrobial agents, as well as patients with
AIDS are immuno suppressed and very susceptible to life threat-
ening systemic microbial infections by Candidiasis, Cryptococcosis
and Aspergillosis. New antibacterial agents to treat infections caused
by these Gram-positive bacteria have recently been introduced,
including the semi-synthetic streptogramine, quinupristin/dalfo-
pristin, daptomycin, the synthetic oxazolidinone linezolid, and
tigecycline [2,3]. For the past several years, vancomycin has been
arsenal against these invaders; however, the identification of
intrinsically resistant strains, and the serious side effects caused by
some of these new agents, makes the development of a diversified
pipeline of antimicrobials, a necessity [6]. These observations place
a new emphasis on the need to search for alternative new and more
effective antimicrobial agents with a broad spectrum of activities. In
this regard, extensive synthesis and design of new structural motifs
in order to overcome the aforementioned problems and improve
broad spectrum antimicrobial activity are highly desirable. The
engine of such a strategy, however, will be driven by the develop-
ment of novel scaffolds that will lead to a chemical space of skele-
tally diverse molecules [7e9].
As part of an ongoing program aiming at natural product
synthesis and preparation of medicinally significant structures
[10e12], we report herein an efficient process for the construction
of polyfunctionalized imidazopyridine, and pyrimidine derivatives
and their antibacterial evaluation. Recent studies from many
laboratories, implicate the role of these scaffolds in the treatment of
many of the most common human diseases, including diabetes
[13], cancers [14], infection by microorganisms [15], and an array of
neurological syndromes [16]. Furthermore, a literature search
* Corresponding author. College of Pharmacy, University of Sharjah, University
City Road, P.O. Box 27272, Sharjah, United Arab Emirates. Tel.: þ971 501732950;
fax: þ971 6 5585812.
E-mail address: taltal@sharjah.ac.ae (T.H. Al-Tel).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.09.049

T.H. Al-Tel, R.A. Al-Qawasmeh / European Journal of Medicinal Chemistry 45 (2010) 5848e5855
5849
indicated that benzimidazoles [17e19], oxadiazoles [20e22] and
phenyl imidazoles [23,24] with different substitution patterns
possess wide range of antimicrobial properties.
For the synthesis of substituted phenyl imidazoles 6aed, the
desired imidazopyridines 4aed were reacted with the proper
a
-bromoacetophenone using DIPEA at 0 ꢀC in DMF. After work up,
the crude a-ketoeasters were subjected without further purifica-
tion to standard condensation protocol with ammonia using
ACO2NH4 in refluxing acetic acid. After silica gel column chro-
matography, compounds 6aed (Table 1) were produced.
The last scaffolds, the oxadiazoles 7aed (Table 1), were visited
after the intended derivatives from 4aee were coupled with the
desired benzoylhydrazide using TBTU and DIPEA in DMF at 0 ꢀC
followed by reaction with POCl3.
After the successful synthesis of the above described derivatives,
the scope of these methodologies was extended toward the synthesis
of imidazopyrimidine scaffolds (Scheme 2). In this regard, 5-carb
oxy-2-aminopyrimidine (8) was chosen as the primary input.
Following the same reaction sequence, compounds 10ae12e (Table 1)
were produced from the [4þ1]-cycloaddition intermediates 9aee.
2. Results and discussion
2.1. Chemistry
We recently reported a protocol for the combination of Groeb-
keeBlackburn/Ugi MCRs (multicomponent reaction) to achieve higher
order seven component reaction (6CR) in one-pot [25]. Positioning the
GroebkeeBlackburn reaction [26e29] before the Ugi reaction [7,30],
was the most straightforward because the former could carry with it
an unprotected carboxylic acid group. Such a process involved the
incorporation of a functional group in one of the primary inputs of the
first MCR that does not participate in the reaction (e.g. carboxylic acid
group as in our MCRs), but does react as one of the radical components
in the second MCR. We next strove to arrive at the title motifs and
study their growth inhibitory activity against Gram-positive bacteria S.
aureus, E. faecalis and Bacillus megaterium and Gram-negative bacteria
E. coli, P. aeruginosa and E. aerogenes. These synthetic motifs were
obtained via the classical [4þ1]-cycloaddition GroebkeeBlackburn
3CR protocol of an aldehyde, aminopyridine derivatives and an iso-
cyanide. More importantly, the primary input of this reaction required
a carboxylic acid handle in order for the post GroebkeeBlackburn
product to be capable of being further differentiated and eventually
integrated to deliver the intended scaffolds. Scheme 1 shows the
general synthetic strategy followed for the arrival at compounds
5ae12e. We started our plan by using 5-carboxy-2-aminopyridine (2)
as the main component, which in turn, was subjected to condensation
with p-substituted benzaldehydes 3aeg, in the presence of a catalytic
amount of Sc(OTf)3 at rt for 45 min and subsequent reaction with
phenyl isocyanide (1) to deliver the imidazopyridines 4aeg. Having
secured pure amounts from compounds 4aeg, our synthetic plan
contemplated three types of scaffolds, 5, 6 and 7 as indicated in
Scheme 1. Thus, derivatives of type 5 were prepared through the
coupling between 4aeg and phenylene diamine using TBTU (O-(ben
zotriazol-1-yl)-N,N,N0,N0-tetramethyluronium tetrafluoroborate) and
DIPEA (N,N-diisopropylethylamine) in DMF at 0 ꢀC. After work up, the
delivered amides from this step were refluxed in acetic acid for 2 h
to produce, after chromatographic purifications, compounds 5aeg
(Table 1).
2.2. Biology
The antimicrobial activities of the compounds 5ae12e were
tested against Gram-positive bacteria S. aureus, E. faecalis and B.
megaterium and Gram-negative bacteria E. coli, P. aeruginosa and E.
aerogenes. Minimum inhibitory concentration (MIC) was measured
as described in the experimental section. Cefixime, amoxicillin and
vancomycin were used as positive controls. Solutions of different
concentrations of cefixime, vancomycin or amoxicillin and
compounds 5ae12e were prepared by dissolving them in DMSO.
Eleven serial dilutions were prepared by reducing the concentra-
tion of the stock solutions to half their original values, with an
initial concentration of (200 mg/ml). Microorganism’s suspensions
at 5 ꢁ 105 CFU (colony forming units/mL) were inoculated into the
wells. The plates were incubated at 37 ꢀC for 24 h. The MIC values
were determined using a turbidity test [31e33]. The results of in
vitro antimicrobial activities of the synthesized compounds are
listed in Table 1.
The results showed a wide range of antimicrobial activities
among the different derivatives tested with MIC values, defined as
the lowest concentration at which no visible growth is observed,
from >127
mg/ml to 0.5 mg/ml (Table 1) with the most active
compounds belonging to compounds having bromoeflouro
substituents. Derivatives 5d, 6a, 6c, 7a, 10a, 10b, 11a, 11b, and 12b
1. TBTU, DIPEA
DMF, Diaminobenzene,
0 oC, 3h.
N
N
2. AcOH, reflux
2h.
N
R1
N
H
R2
PhNH
5a-g
O
1. DIPEA, DMF,
O
HO
NC
α-bromoacetophenone,
HO
0 oC, 3h.
N
Sc(OTf)3
N
NH2
N
+
O
2
N
N
N
R1
N
H
MeOH/DCM,
rt, 12h
2. AcO2NH4,
1
PhNH
AcOH, reflux,
4h
PhNH
H
R2
6a-d
R1
4a-g
R1
3a-g
1. TBTU, DIPEA
DMF, benzoylhydrazide,
0 oC, 3h.
N
O
N
N
N
R1
2. POCl3, reflux
4h.
PhNH
R2
7a-e
Scheme 1. Synthesis of imidazopyridine derivatives 5ae7e.

5850
T.H. Al-Tel, R.A. Al-Qawasmeh / European Journal of Medicinal Chemistry 45 (2010) 5848e5855
mg/ml) of compounds 5ae12e.
Table 1
In vitro antimicrobial activity (MIC
Compd
R1
R2
E. coli
P. aeruginosa
E. aerogenes
S. aureus
E. faecalis
B. megaterium
5a
5b
5c
5d
5e
5f
5g
6a
6b
6c
6d
7a
7b
7c
7d
7e
Br
NO2
OPh
Br
F
F
OPh
CH3
F
Br
Cl
OPh
F
F
NO2
CH3
NO2
F
Cl
F
F
NO2
F
11.32 ꢂ 1.34
34.77 ꢂ 3.80
3.18 ꢂ 0.17
2.15 ꢂ 0.11
10.71 ꢂ 1.55
31.83 ꢂ 3.14
10.34 ꢂ 0.97
1.33 ꢂ 0.08
12.21 ꢂ 1.31
1.42 ꢂ 0.08
33.28 ꢂ 3.32
1.11 ꢂ 0.03
11.72 ꢂ 1.22
13.42 ꢂ 1.12
12.37 ꢂ 113
7.37 ꢂ 0.61
2.29 ꢂ 0.11
2.78 ꢂ 0.14
3.44 ꢂ 0.13
10.53 ꢂ 1.78
11.66 ꢂ 1.41
1.15 ꢂ 0.06
3.11 ꢂ 0.12
8.11 ꢂ 0.99
5.33 ꢂ 0.56
1.33 ꢂ 0.01
2.78 ꢂ 0.11
3.12 ꢂ 0.14
2.34 ꢂ 0.09
8.56 ꢂ 1.23
16.43 ꢂ 1.12
2.34 ꢂ 0.10
6.65 ꢂ 0.33
14.51 ꢂ 2.12
45.43 ꢂ 3.65
5.22 ꢂ 0.34
3.44 ꢂ 0.13
12.44 ꢂ 1.83
41.13 ꢂ 3.78
13.37 ꢂ 1.09
2.12 ꢂ 0.09
11.78 ꢂ 1.34
2.52 ꢂ 0.12
44.29 ꢂ 3.11
2.43 ꢂ 0.10
9.64 ꢂ 1.00
12.55 ꢂ 1.41
10.19 ꢂ 0.84
5.45 ꢂ 0.61
2.85 ꢂ 0.12
2.55 ꢂ 0.16
4.72 ꢂ 0.25
7.38 ꢂ 1.25
12.23 ꢂ 1.49
2.34 ꢂ 0.07
1.82 ꢂ 0.13
11.45 ꢂ 0.76
7.81 ꢂ 0.74
1.87 ꢂ 0.01
3.65 ꢂ 0.13
4.45 ꢂ 0.31
1.56 ꢂ 0.06
7.64 ꢂ 0.79
14.53 ꢂ 1.22
17.23 ꢂ 1.31
23.47 ꢂ 1.75
12.85 ꢂ 2.17
57.33 ꢂ 4.75
7.15 ꢂ 1.20
2.05 ꢂ 0.10
11.54 ꢂ 1.26
58.45 ꢂ 5.35
11.79 ꢂ 1.15
1.55 ꢂ 0.05
10.72 ꢂ 1.14
1.17 ꢂ 0.07
53.41 ꢂ 3.42
0.85 ꢂ 0.04
8.42 ꢂ 1.21
10.17 ꢂ 1.14
11.27 ꢂ 1.19
4.12 ꢂ 0.52
2.25 ꢂ 0.17
2.75 ꢂ 0.19
6.18 ꢂ 1.10
6.12 ꢂ 1.13
10.64 ꢂ 1.21
1.11 ꢂ 0.04
1.89 ꢂ 0.09
10.85 ꢂ 1.23
9.33 ꢂ 1.23
0.94 ꢂ 0.06
5.29 ꢂ 0.90
2.23 ꢂ 0.15
3.16 ꢂ 0.23
6.43 ꢂ 0.26
3.65 ꢂ 0.31
28.16 ꢂ 1.53
0.52 ꢂ 0.09
10.32 ꢂ 1.79
54.86 ꢂ 4.32
5.11 ꢂ 0.89
1.51 ꢂ 0.09
12.13 ꢂ 1.21
56.17 ꢂ 5.32
9.51 ꢂ 0.76
0.72 ꢂ 0.04
10.23 ꢂ 1.00
0.93 ꢂ 0.02
58.37 ꢂ 4.18
0.51 ꢂ 0.008
11.13 ꢂ 1.31
9.85 ꢂ 1.46
12.27 ꢂ 0.78
6.36 ꢂ 0.31
1.23 ꢂ 0.05
1.84 ꢂ 0.12
6.32 ꢂ 0.76
9.43 ꢂ 1.42
9.32 ꢂ 0.81
0.63 ꢂ 0.01
1.76 ꢂ 0.10
9.49 ꢂ 0.77
4.22 ꢂ 0.57
0.64 ꢂ 0.03
5.47 ꢂ 0.85
3.35 ꢂ 0.17
2.45 ꢂ 0.18
5.31 ꢂ 0.45
13.32 ꢂ 0.92
33.87 ꢂ 2.11
2.75 ꢂ 0.21
13.36 ꢂ 2.41
46.51 ꢂ 4.21
6.28 ꢂ 1.11
5.23 ꢂ 0.45
15.32 ꢂ 2.27
44.71 ꢂ 4.65
13.64 ꢂ 1.31
3.17 ꢂ 0.15
13.72 ꢂ 1.35
2.96 ꢂ 0.12
39.64 ꢂ 3.31
1.57 ꢂ 0.02
12.56 ꢂ 1.61
11.38 ꢂ 1.50
11.79 ꢂ 1.18
8.22 ꢂ 0.73
6.64 ꢂ 0.21
5.87 ꢂ 0.34
5.76 ꢂ 1.18
10.39 ꢂ 1.45
11.45 ꢂ 0.91
4.21 ꢂ 0.11
4.28 ꢂ 0.14
11.67 ꢂ 1.10
9.61 ꢂ 0.88
1.92 ꢂ 0.07
4.58 ꢂ 0.39
6.18 ꢂ 0.25
5.37 ꢂ 0.32
8.71 ꢂ 0.87
1.22 ꢂ 0.07
27.92 ꢂ 1.13
4.21 ꢂ 0.42
17.53 ꢂ 2.32
65.54 ꢂ 6.75
13.96 ꢂ 1.72
10.25 ꢂ 1.42
21.61 ꢂ 3.64
58.67 ꢂ 5.14
18.58 ꢂ 1.96
8.34 ꢂ 0.41
19.85 ꢂ 2.13
9.13 ꢂ 0.52
53.16 ꢂ 4.11
4.97 ꢂ 0.13
17.44 ꢂ 1.87
15.47 ꢂ 1.71
16.55 ꢂ 2.11
12.73 ꢂ 1.12
11.74 ꢂ 1.22
13.73 ꢂ 1.51
17.16 ꢂ 2.13
19.78 ꢂ 2.31
15.44 ꢂ 1.89
9.17 ꢂ 0.55
11.64 ꢂ 0.45
15.56 ꢂ 1.51
17.44 ꢂ 2.11
5.45 ꢂ 0.15
15.29 ꢂ 1.78
11.22 ꢂ 1.59
8.45 ꢂ 0.78
13.61 ꢂ 1.11
2.75 ꢂ 0.15
127.76 ꢂ 5.78
6.37 ꢂ 0.38
CH3
CH3
Br
OPh
Br
Br
Br
OPh
Br
Br
Br
OPh
CH3
Br
Br
Br
10a
10b
10c
10d
10e
11a
11b
11c
11d
12a
12b
12c
12d
12e
Amoxicillin
Cefixime
Vancomycin
Br
CH3
OPh
Br
Br
Br
Br
Br
Br
CH3
Br
Cl
CH3
NO2
F
F
NO2
Cl
Br
Br
CH3
exhibited potent activities against E. coli, E. aerogenes and S. aureus
compared to the control antibiotics amoxicillin and cefixime. Some
qualitative structureeactivity relationships could be concluded
from Table 1. The superiority of the compounds having
R1 ¼ bromine at the phenyl moiety resident on the imidazopyridine
ring and a halogen substituent on the benzimidazole rings (e.g. 5d,
6a, 6c, 12a) is obviously evident from Table 1. Furthermore, if R1 is
a methyl, and R2 is a halogen (e.g. 5c, 10c and 12b) the activity is
reduced to about three folds in all series. Interestingly, introduction
of a phenoxy group (e.g. 5b, 5e, 6b, 7b, 10d) at either side of our
motifs demolishes the activities of these compounds. Another
important finding is the activity difference between the three
different scaffolds resident on the pyridine and pyrimidine rings.
Clearly, compounds having fused benzimidazole group (e.g. 5d,
10a) are less active than compounds having substituted phenyl
imidazole moiety (e.g. 6a, 11a). The latter in turn is less active than
the substituted phenyl oxadiazole handle (e.g. 7a, 12a). Among the
most active halogenated derivatives (where R1 and R2 are halo-
gens), is the oxadiazole motifs which are two folds more active than
the imidazole analogs. The latter in turn are more potent than the
1. TBTU, DIPEA
DMF, Diaminobenzene,
0 oC, 3h.
N
N
N
N
R1
2. AcOH, ref lux
2h.
N
H
R2
PhNH
10a-e
O
1. DIPEA, DMF,
O
α-bromoacetophenone,
HO
NC
N
HO
Sc(OTf )3
N
0 oC, 3h.
N
N
N
NH2
N
+
O
8
N
N
N
R1
2. AcO2NH4,
AcOH, ref lux,
4h
MeOH/DCM,
rt, 12h
N
H
1
PhNH
PhNH
11a-d
H
R2
R1
9a-e
R1
3a-e
1. TBTU, DIPEA
DMF, benzoylhydrazide,
0 oC, 3h.
N
N
O
N
N
N
2. POCl3, reflux
4h.
R1
PhNH
12a-e
R2
Scheme 2. Synthesis of imidazopyrimidine derivatives 10ae12e.

T.H. Al-Tel, R.A. Al-Qawasmeh / European Journal of Medicinal Chemistry 45 (2010) 5848e5855
5851
benzimidazole counter parts. It is worth noting that all the deriv-
atives are more potent against B. megaterium compared to cefixime.
Moreover, all of the synthesized scaffolds showed more activity
against E. coli (except 5b, 5f and 6d) compared to amoxicillin.
However, none of these motifs exhibited good activity against B.
megaterium compared to amoxicillin. Further investigations in this
direction are currently under progress in our laboratories.
added and the resulting mixture stirred at the same temperature
for 30 min. Then the desired diaminobenzene (1.1 mmol, 1.1 equiv)
was added. The resulting mixture was stirred at 0 ꢀC for 4 h, and
then quenched with ice-water. The precipitated solid was filtered,
washed with water and dissolved in EtOAc. The organic phase was
washed with a 1 N HCl aqueous solution, then with a saturated
NaHCO3 aqueous solution, and finally H2O, dried over MgSO4, and
concentrated in vacuo, which was used in the next stage without
further purification. To this amide was added AcOH (30 mL) and the
resulting suspension was refluxed for 5 h, cooled to room temper-
ature, concentrated in vacuo and diluted with crushed ice. The
brown solid was filtered, washed thoroughly with water. The crude
was dissolved in EtOAc washed with a saturated NaHCO3 aqueous
solution and with H2O, dried over MgSO4, and concentrated in
vacuo. The crude product was purified by flash chromatography on
silica gel (DCM/AcOEt, 8/2 to 7/3) to give 1H-benzo[d]imidazol-2-
yl-N-phenylimidazo[1,2-a]pyridin-3-amine derivatives 6aee.
3. Conclusions
In summary, we have synthesized and introduced new antimi-
crobial agents with potent activity against various Gram-negative
and Gram-positive bacterial strains. Many of the synthesized motifs
showed potent antimicrobial activity compared to the control
antibiotics amoxicillin and cefixime. Characterization of the anti-
microbial spectrum of the synthesized compounds (e.g. 7a, 10a, 11a
and 12a), as shown in Table 1, indicating a broad spectrum of
antibacterial activity against the tested strains. These results form
the foundation for further investigations in our laboratories.
4.2.3. General procedure B for the synthesis of compounds 6aed
and 11aed
4. Experimental section
To a solution of 2-(4-bromophenyl)-3-(phenylamino)imidazo
[1,2-a]pyridine-6-carboxylic acid (4) (407 mg, 1.0 mmol, 1 equiv) in
DMF (10 mL) at 0 ꢀC was added DIPEA (0.21 mL,1.2 mmol,1.2 equiv).
The resulting mixture was stirred at 0 ꢀC for 30 min followed by
4.1. General methods
All reagents were used as purchased from commercial suppliers
without further purification. The reactions were carried out in oven
dried or flamed graduated vessels. Solvents were dried and purified
by conventional methods prior use. Flash column chromatography
was performed with Silica gel 60, 0.040e0.063 mm (230e400
mesh). Aluminum backed plates pre-coated with silica gel 60
(UV254) were used for thin layer chromatography. 1H, 13C spectra
were recorded on 300 MHz/75 MHz spectrometer. Splitting patterns
are designated as s, singlet; d, doublet; t, triplet; q, quartet; m,
dropwise addition of the appropriate a-bromoketone (1.1 mmol, 1.1
equiv) in DMF. The resulting mixture was stirred at 0 ꢀC for 4 h, then
quenched with ice-water. The precipitated solid was filtered,
washed with water and dissolved in EtOAc. The organic phase was
washed with a 1 N HCl aqueous solution, and then a saturated
NaHCO3 aqueous solution, then H2O, dried over MgSO4, and
concentrated in vacuo, which was used in the next stage without
further purification. To this product, AcOH (25 mL) and AcONH4
(924 mg, 12 mmol, 12 equiv) was added and the resulting suspen-
sion was refluxed for 5 h, cooled to room temperature, concentrated
in vacuo and diluted with crushed ice. The brown solid was filtered,
washed thoroughly with water. The crude cake was dissolved in
EtOAc washed with a saturated NaHCO3 aqueous solution and with
H2O, dried over MgSO4, and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel (DCM/
AcOEt, 8/2 to 7/3) to give 1H-imidazol-2-yl-N-phenylimidazo[1,2-a]
pyridin-3-amine derivatives 5aeg.
multiplet; br, broad. Chemical shifts (d) are given in ppm relative to
the resonance of their respective residual solvent peak, CHCl3
(7.27 ppm, 1H; 77.16 ppm, the middle peak, 13C). Elemental analysis
was carried out at the University of Jordan instrument. High and low
resolution mass spectroscopic analyses were conducted at the
University of Jordan using positive ion mode by Electrospray Ioni-
zation (ESI). The samples were dissolved in acetonitrile, diluted in
spray solution (methanol/water 1:1 v/v þ 0.1% formic acid) and
infused using a syringe pump with a flow rate of 2 mL/min. External
calibration was conducted using Arginine cluster in a mass range m/z
175e871.
4.2.4. General procedure C for the synthesis of compounds 7aee
and 12aee
To a solution of methyl methyl 2-(4-bromophenyl)-3-(phenyl-
amino)imidazo[1,2-a]pyridine-6-carboxylic acid (4)(407 mg,1.0 mmol,
1 equiv) in DMF (8 mL) at 0 ꢀC was added DIPEA (0.21 mL, 1.2 mmol,
1.2 equiv). After 10 min, TBTU (551 mg,1.2 mmol,1.2 equiv) was added
and the resulting mixture stirred at the same temperature for 30 min.
Then benzohydrazide (1.1 mmol, 1.1 equiv) was added. The resulting
mixture was stirred at 0 ꢀC for 6 h, and then quenched with ice-water.
The precipitated solid was filtered, washed with water and dissolved in
EtOAc. The organic phase was washed with a 1 N HCl aqueous solution,
then with a saturated NaHCO3 aqueous solution, and finally H2O, dried
over MgSO4, and concentrated in vacuo, which was used in the next
stage without further purification. To this diamide was added POCl3
(10 mL) and the resulting suspension was refluxed for 3 h, cooled to
room temperature, concentrated under vacuum and diluted with
crushed ice. The brown solid was filtered, washed thoroughly with
water. The crude was dissolved in EtOAc washed with a saturated
NaHCO3 aqueous solution and with H2O, dried over MgSO4, and
concentrated in vacuo. The crude product was purified by
flash chromatography on silica gel (DCM/AcOEt, 8/2e7/3) to give
1,3,4-oxadiazol-2-yl-N-phenylimidazo[1,2-a]pyridin-3-amine deriva-
tives 7aef (58%).
4.2. Chemistry
4.2.1. General experimental procedure A for the synthesis of
compounds 4aeg and 9aee
A mixture of aminopyridine (3.0 mmol) in MeOH-DCM (2:3,
15.0 mL) and aldehyde (3.0 mmol) containing 5 mol% of Sc(OTf)3
was stirred for 1 h at room temperature, followed by the addition of
3 mmol of the phenyl isocyanide, and the mixture was stirred for
another 12 h at rt. Then 1 mL of hexane was added and the resulting
yellowish solid was filtered, washed three times with hexaneeethyl
acetate mixture (5:1, 20 mL) and triturated with ethyl aceta-
teehexane. The crude product was used in the next step without
further purifications.
4.2.2. General procedures A for the synthesis of compounds 5aeg
and 10aee
To a solution of methyl 2-(4-bromophenyl)-3-(phenylamino)
imidazo[1,2-a]pyridine-6-carboxylic acid (4) (407 mg, 1.0 mmol,
1 equiv) in DMF (8 mL) at 0 ꢀC was added DIPEA (0.21 mL, 1.2 mmol,
1.2 equiv). After 10 min, TBTU (551 mg, 1.2 mmol, 1.2 equiv) was

5852
T.H. Al-Tel, R.A. Al-Qawasmeh / European Journal of Medicinal Chemistry 45 (2010) 5848e5855
4.2.5. 2-(4-Bromophenyl)-6-(6-nitro-1H-benzo[d]imidazol-2-yl)-
N-phenylimidazo[1,2-a]pyridin-3-amine (5a)
8.71 (s, 1H), 7.69 (m, 2H), 7.58 (d, J ¼ 8.6 Hz, 1H), 7.34e7.27 (m,
8H), 7.08e6.94 (m, 7H). 13C NMR (75 MHz, CDCl3, in ppm):
161.2,
d
This derivative was synthesized according to the general proce-
157.1, 150.5, 149.2, 141.9, 137.7, 133.8, 132.1, 130.9, 130.8, 130.5,
129.8, 129.3, 127.7, 123.6, 120.2, 119.4, 119.1, 118.7, 113.6, 104.5.
HRMS (ESI): calcd. for C32H22BrN5O [M þ Na]þ: 594.09054; found
594.09060.
dure A. Yield 66%, as white solid, m.p.197e199 ꢀC.1H NMR (300 MHz,
CDCl3, in ppm):
d
10.88 (s, 1H), 8.94 (d, J ¼ 9.6 Hz, 2H), 8.52 (s, 1H),
8.51 (d, J ¼ 2.7 Hz, 1H), 8.0 (s, 1H), 7.87 (d, J ¼ 1.2 Hz, 2H), 7.75 (d,
J ¼ 9.0 Hz, 1H), 7.56 (s, 1H), 7.31 (m, 5H), 6.98 (d, J ¼ 7.2 Hz, 1H). 13C
NMR (75 MHz, CDCl3, in ppm):
d
161.1,150.0,142.2,140.1,138.5,132.9,
4.2.11. 2-(4-Bromophenyl)-6-(6-methyl-1H-benzo[d]imidazol-
2-yl)-N-phenylimidazo[1,2-a]pyridin-3-amine (5g)
131.7, 131.2, 130.3, 128.9, 127.8, 122.1, 119.4, 119.0, 117.5, 115.9, 109.1.
HRMS (ESI): calcd. for C26H17BrN6O2 [M þ H]þ: 525.06746; found
525.06751.
This derivative was synthesized according to the general
procedure A. Yield 61%, white solid, m.p. 189e190 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
d
9.78 (s,1H), 9.14 (d, J ¼ 8.3 Hz, 2H), 8.72
4.2.6. 6-(6-Phenoxy-1H-benzo[d]imidazol-2-yl)-N-phenyl-2-p-
tolylimidazo[1,2-a]pyridin-3-amine (5b)
(bs, 1H), 8.11 (d, J ¼ 9.3 Hz, 2H), 7.87 (d, J ¼ 8.5 Hz, 1H), 7.30 (m, 8H),
7.09 (d, J ¼ 9.1 Hz, 1H), 7.00 (dd, J ¼ 5.1, 8.7 Hz, 1H), 2.39 (s, 3H). 13C
This derivative was synthesized according to the general
NMR (75 MHz, CDCl3, in ppm): d 159.5, 149.4, 141.0, 137.1, 134.0,
procedure A. Yield 71%, white solid, m.p. 168e169 ꢀC. 1H NMR
133.8, 131.9, 131.5, 130.8, 130.3, 129.6, 128.1, 120.8, 119.7, 119.5, 119.2,
117.4, 114.4, 22.3. HRMS (ESI): calcd. for C27H20BrN5 [M þ H]þ:
494.09803; found 494.09810.
(300 MHz, CDCl3, in ppm):
8.64 (s, 1H), 7.89 (dd, J ¼ 1.2, 7.2 Hz, 2H), 7.79 (s, 2H), 7.64 (s, 1H),
d
10.74 (s, 1H), 8.95 (d, J ¼ 9.6 Hz, 2H),
7.61 (s, 1H), 7.28 (m, 7H), 7.03 (m, 4H), 2.41 (s, 3H). 13C NMR
(75 MHz, CDCl3, in ppm):
d
160.4, 157.8, 150.5, 147.9, 137.1, 131.6,
4.2.12. 2-(4-Bromophenyl)-6-(5-(4-fluorophenyl)-1H-imidazol-
2-yl)-N-phenylimidazo[1,2-a]pyridin-3-amine (6a)
131.2, 130.9, 129.8, 129.2, 129.0, 127.5, 126.0, 123.2, 120.3, 129.7,
118.9, 117.5, 114.4, 104.6, 22.4. HRMS (ESI): calcd. for C33H25N5O
[M þ H]þ: 508.21374; found 508.21369.
This derivative was synthesized according to the general
procedure B. Yield 71%, white solid, m.p. 181e182 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
d
9.78 (s,1H), 8.98 (d, J ¼ 8.6 Hz,1H), 8.76
4.2.7. 6-(6-Bromo-1H-benzo[d]imidazol-2-yl)-N-phenyl-2-p-
tolylimidazo[1,2-a]pyridin-3-amine (5c)
(s, 1H), 8.06 (d, J ¼ 7.0 Hz, 2H), 7.87 (dd, J ¼ 1.4, 7.3 Hz, 2H), 7.61 (d,
J ¼ 8.9 Hz, 1H), 7.42 (s, 1H), 7.32e7.29 (m, 5H), 7.14 (d, J ¼ 3.8 Hz,
This derivative was synthesized according to the general
2H), 6.96 (s, 1H). 13C NMR (75 MHz, CDCl3, in ppm):
d 162.7, 159.9,
procedure A. Yield 58%, white solid, m.p. 199e200 ꢀC. 1H NMR
148.5, 147.2, 141.8, 137.6, 134.3, 131.5, 130.0, 129.4, 125.7, 125.2,
122.5, 120.8, 119.6, 118.3, 115.4, 114.5, 113.9. HRMS (ESI): calcd. for
C28H19BrFN5 [M þ H]þ: 524.08861; found 524.08855.
(300 MHz, CDCl3, in ppm):
d
9.66 (s, 1H), 8.92 (d, J ¼ 9.3 Hz, 2H),
8.61 (s, 1H), 7.96 (d, J ¼ 2.7 Hz, 1H), 7.88 (dd, J ¼ 1.1, 8.6 Hz, 2H), 7.74
(s, 2H), 7.38 (s, 1H), 7.26 (m, 5H), 6.88 (d, J ¼ 7.3 Hz, 1H), 2.37 (s, 3H).
13C NMR (75 MHz, CDCl3, in ppm):
d
159.8, 149.1, 141.2, 137.4, 136.7,
4.2.13. 6-(5-(4-Bromophenyl)-1H-imidazol-2-yl)-
134.1, 131.6, 130.5, 129.7, 128.4, 127.2, 125.3, 124.8, 121.5, 120.1, 119.9,
117.8, 111.6, 110.3, 21.9. HRMS (ESI): calcd. for C27H20BrN5 [M þ H]þ:
494.09803; found 494.09807.
2-(4-phenoxyphenyl)-N-phenylimidazo[1,2-a]pyridin-3-amine (6b)
This derivative was synthesized according to the general
procedure B. Yield 67%, white solid, m.p. 176e177 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
d
9.61 (s,1H), 9.21 (d, J ¼ 8.4 Hz,1H), 8.75
4.2.8. 2-(4-Bromophenyl)-6-(6-fluoro-1H-benzo[d]imidazol-2-yl)-
N-phenylimidazo[1,2-a]pyridin-3-amine (5d)
(s, 1H), 7.96 (bs, 2H), 7.87 (bs, 2H), 7.66 (s, 1H), 7.43 (bs, 3H), 7.42
(m, 4H), 7.32 (m, 4H), 7.07 (m, 3H), 7.05 (m, 2H). 13C NMR (75 MHz,
This derivative was synthesized according to the general
CDCl3, in ppm): d 158.7, 153.2, 147.9, 146.7, 141.3, 137.1, 133.2, 130.4,
procedure A. Yield 63%, white solid, m.p. 169e170 ꢀC. 1H NMR
129.5, 128.8, 125.3, 125.0, 122.1, 120.6, 119.9, 118.7, 118.3, 117.8, 113.0.
HRMS (ESI): calcd. for C34H24BrN5O [M þ Na]þ: 620.10619; found
620.10623.
(300 MHz, CDCl3, in ppm):
d
9.73 (s, 1H), 8.99 (d, J ¼ 9.3 Hz, 2H),
8.61 (s, 1H), 8.33 (d, J ¼ 8.7 Hz, 1H), 7.86 (dd, J ¼ 1.1, 7.0 Hz, 2H), 7.58
(s, 1H), 7.53 (dd, J ¼ 1.6, 8.4 Hz, 1H), 7.36e7.30 (m, 6H), 7.18 (s, 1H),
6.92 (s, 1H). 13C NMR (75 MHz, CDCl3, in ppm):
d
161.1, 158.5, 150.2,
4.2.14. 2-(4-Bromophenyl)-6-(5-(4-chlorophenyl)-1H-imidazol-
2-yl)-N-phenylimidazo[1,2-a]pyridin-3-amine (6c)
142.7, 141.1, 139.8, 137.5, 133,6, 131.7, 131.2, 130.1, 127.6, 125.3, 119.7,
119.5, 117.8, 111.3, 110.1, 105.9, 105.4. HRMS (ESI): calcd. for
C26H17BrFN5 [M þ Na]þ: 520.05490; found 520.05498.
This derivative was synthesized according to the general
procedure B. Yield 71%, white solid, m.p. 204e205 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
d
9.81 (s,1H), 8.95 (d, J ¼ 8.2 Hz,1H), 8.91
4.2.9. 6-(6-Fluoro-1H-benzo[d]imidazol-2-yl)-
(bs, 1H), 8.43 (d, J ¼ 6.6 Hz, 2H), 7.92e7.87 (m, 4H), 7.83 (d,
2-(4-phenoxyphenyl)-N-phenylimidazo[1,2-a]pyridin-3-amine (5e)
This derivative was synthesized according to the general
procedure A. Yield 79%, white solid, m.p. 179e180 ꢀC. 1H NMR
J ¼ 8.3 Hz, 1H), 7.36e7.31 (m, 8H), 7.11 (d, J ¼ 3.7 Hz, 1H). 13C NMR
(75 MHz, CDCl3, in ppm):
d 148.3, 147.4, 141.9, 133.1, 131.2, 130.6,
129.8, 125.1, 123.5, 122.8, 121.7, 120.6, 119.9, 119.6, 119.4, 113.4.
HRMS (ESI): calcd. for C28H19BrClN5 [M þ Na]þ: 562.04100; found
562.04108.
(300 MHz, CDCl3, in ppm):
d
10.02 (s, 1H), 8.93 (d, J ¼ 9.2 Hz, 2H),
8.64 (s, 1H), 8.30 (d, J ¼ 8.9 Hz, 1H), 7.91 (s, 2H), 7.85 (d, J ¼ 8.4 Hz,
2H), 7.65 (s, 1H), 7.54 (s, 1H), 7.33e7.31 (m, 4H), 7.18e7.05 (m, 8H).
13C NMR (75 MHz, CDCl3, in ppm):
d
160.3, 157.8, 157.3, 152.9, 150.2,
4.2.15. 2-(4-Bromophenyl)-6-(5-(4-phenoxyphenyl)-1H-imidazol-
2-yl)-N-phenylimidazo[1,2-a]pyridin-3-amine (6d)
143.1, 141.5, 139.2, 137.3, 132.5, 130.4, 130.1, 129.1, 127.8, 125.6, 123.4,
119.5, 119.3, 118.2, 116.7, 110.8, 110.3, 105.6, 105.1. HRMS (ESI): calcd.
for C32H22FN5O [M þ Na]þ: 534.17061; found 534.17066.
This derivative was synthesized according to the general
procedure B. Yield 73%, white solid, m.p. 187e188 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
d
10.43 (s, 1H), 9.25 (d, J ¼ 8.6 Hz, 1H),
4.2.10. 2-(4-Bromophenyl)-6-(6-phenoxy-1H-benzo[d]imidazol-
2-yl)-N-phenylimidazo[1,2-a]pyridin-3-amine (5f)
8.89 (s, 1H), 7.98 (d, J ¼ 1.1 Hz, 2H), 7.90 (dd, J ¼ 1.7, 8.3 Hz, 2H), 7.41
(bs, 1H), 7.36e7.15 (m, 17H). 13C NMR (75 MHz, CDCl3, in ppm):
This derivative was synthesized according to the general
d 158.2, 152.1, 148.3, 146.4, 141.7, 133.9, 131.6, 130.4, 129.5, 128.7,
procedure A. Yield 71%, white solid, m.p. 177e176 ꢀC. 1H NMR
125.0, 124.3, 122.2, 121.4, 120.5, 119.8, 118.7, 117.1, 112.8. HRMS (ESI):
(300 MHz, CDCl3, in ppm):
d
10.65 (s, 1H), 8.75 (d, J ¼ 8.4 Hz, 1H),
calcd. for C34H24BrN5O [M þ H]þ: 598.12425; found 598.12431.

T.H. Al-Tel, R.A. Al-Qawasmeh / European Journal of Medicinal Chemistry 45 (2010) 5848e5855
5853
4.2.16. 2-(4-Bromophenyl)-6-(5-(4-fluorophenyl)-1,3,4-oxadiazol-
1H). 13C NMR (75 MHz, CDCl3, in ppm):
d
160.0, 155.8, 155.6, 153.0,
2-yl)-N-phenylimidazo[1,2-a]pyridin-3-amine (7a)
152.7, 146.4, 141.8, 138.7, 133.4, 132.8, 132.1, 131.5, 130.6, 130.1, 129.7,
125.3, 119.9, 119.5, 112.4, 111.8, 107.1, 106.0, 94.6. HRMS (ESI): calcd.
for C25H16BrFN6 [M þ Na]þ: 521.05015; found 521.05023.
This derivative was synthesized according to the general
procedure C. Yield 70%, white solid, m.p. 197e198 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
d 9.10 (s, 1H), 8.99 (s, 1H), 8.33 (d,
J ¼ 8.9 Hz, 1H), 7.93 (dd, J ¼ 1.4, 8.3 Hz, 2H), 7.92 (s, 1H), 7.78 (bs,
4.2.22. 2-(4-Bromophenyl)-6-(6-chloro-1H-benzo[d]imidazol-
2-yl)-N-phenylimidazo[1,2-a]pyrimidin-3-amine (10b)
2H), 7.49 (dd, J ¼ 3.5, 5.1 Hz, 2H), 7.31e7.27 (m, 5H), 6.95 (dd, J ¼ 1.8,
5.3 Hz, 1H). 13C NMR (75 MHz, CDCl3, in ppm):
d
167.8, 163.2, 158.4,
This derivative was synthesized according to the general proce-
154.1, 145.8, 141.1, 137.2, 133.7, 133.2, 131.5, 130.5, 129.7, 125.9, 120.2,
119.8, 119.1, 118.0, 115.7, 111.2. HRMS (ESI): calcd. for C27H17BrFN5O
[M þ H]þ: 526.06787; found 526.06791.
dure A. Yield 70%, white solid, m.p. 202e203 ꢀC. 1H NMR (300 MHz,
CDCl3, in ppm):
d 10.71 (s, 1H), 9.22 (bs, 1H), 8.45 (s, 1H), 8.12 (d,
J ¼ 9.4 Hz, 21H), 7.93 (d, J ¼ 2.8 Hz, 1H), 7.74 (d, J ¼ 9.1 Hz, 1H),
7.50e7.42 (m, 7H), 7.13 (d, J ¼ 7.5 Hz,1H). 13C NMR (75 MHz, CDCl3, in
4.2.17. 6-(5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl)-
ppm): d 155.9, 153.1, 152.8, 146.7, 142.1, 133.9, 132.7, 132.6, 131.7, 130.8,
2-(4-phenoxyphenyl)-N-phenylimidazo[1,2-a]pyridin-3-amine (7b)
This derivative was synthesized according to the general
procedure C. Yield 65%, white solid, m.p. 172e174 ꢀC. 1H NMR
129.9, 129.4, 128.1, 122.6, 120.1, 119.8, 119.5, 115.7, 94.6. HRMS (ESI):
calcd. for C25H16BrClN6 [M þ Na]þ: 537.02060; found 537.02058.
(300 MHz, CDCl3, in ppm):
7.97e7.74 (m, 6H), 7.51(d, J ¼ 8.5 Hz, 2H), 7.37e7.32 (m, 4H), 7.12 (m,
3H), 7.10 (bs, 2H). 13C NMR (75 MHz, CDCl3, in ppm):
166.9, 163.7,
158.1, 157.5, 153.2, 145.9, 141.4, 138.6, 136.9, 130.5, 129.4, 129.2,
128.6, 126.3, 125.7, 123.8, 119.7, 119.4, 118.1, 115.9, 110.8. HRMS (ESI):
calcd. for C33H22FN5O2 [M þ H]þ: 540.18358; found 540.18361.
d
9.13 (bs, 1H), 8.31 (bd, J ¼ 3.9 Hz, 1H),
4.2.23. 6-(6-Fluoro-1H-benzo[d]imidazol-2-yl)-N-phenyl-
2-p-tolylimidazo[1,2-a]pyrimidin-3-amine (10c)
d
This derivative was synthesized according to the general
procedure A. Yield 72%, white solid, m.p. 185e186 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
d 10.14 (s, 1H), 9.31 (bs, 1H), 8.53 (d,
J ¼ 8.5 Hz,1H), 8.31 (d, J ¼ 1.3 Hz,1H), 8.13 (d, J ¼ 7.2 Hz, 2H), 7.94 (d,
J ¼ 6.4 Hz, 2H), 7.87 (dd, J ¼ 2.6, 7.3 Hz, 1H), 7.42 (m, 5H), 7.31 (m,
2H), 6.99 (dd, J ¼ 1.0, 5.6 Hz, 1H), 2.29 (s, 3H). 13C NMR (75 MHz,
4.2.18. 6-(5-(4-Nitrophenyl)-1,3,4-oxadiazol-2-yl)-N-phenyl-
2-p-tolylimidazo[1,2-a]pyridin-3-amine(7c)
CDCl3, in ppm): d 159.7, 155.9, 155.1, 153.2, 152.4, 146.8, 141.4, 139.3,
This derivative was synthesized according to the general
137.2, 133.0, 130.1, 129.9, 129.3, 126.2, 125.1, 120.7, 119.6, 112.1, 111.5,
107.3, 106.1, 93.8, 22.5. HRMS (ESI): calcd. for C26H19FN6 [M þ Na]þ:
457.15529; found 457.15533.
procedure C. Yield 60%, white solid, m.p. 209e210 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
d 8.97 (bs, 1H), 8.44 (bs, 1H), 8.34 (d,
J ¼ 8.6 Hz, 2H), 7.91(dd, J ¼ 1.0, 8.1 Hz, 2H), 7.83 (m, 3H), 7.42 (m,
4H), 6.89 (dd, J ¼ 1.2, 5.3 Hz, 1H), 2.29 (s, 3H). 13C NMR (75 MHz,
4.2.24. 6-(6-Fluoro-1H-benzo[d]imidazol-2-yl)-2-(4-
CDCl3, in ppm):
d
158.6, 153.8, 152.1, 150.5, 146.2, 141.8, 141.1, 137.4,
phenoxyphenyl)-N-phenylimidazo[1,2-a]pyrimidin-3-amine (10d)
This derivative was synthesized according to the general
procedure A. Yield 55%, white solid, m.p. 178e179 ꢀC. 1H NMR
136.7,136.1, 133.4,132.9, 130.3, 128.8, 125.4,123.7, 119.6,119.3,118.3,
110.4, 22.3. HRMS (ESI): calcd. for C28H20N6O3 [M þ Na]þ:
511.14946; found 511.14939.
(300 MHz, CDCl3, in ppm):
d 10.09 (s, 1H), 9.05 (bs, 1H), 8.61 (d,
J ¼ 8.8 Hz, 1H), 8.28 (d, J ¼ 1.2 Hz, 1H), 8.15 (bs, 2H), 7.99 (bd,
J ¼ 7.1 Hz, 2H), 77.454e7.33 (m, 4H), 7.21 (m, 2H), 7.17 (m, 2H), 7.11
(d, J ¼ 7.2 Hz, 2H), 6.74 (bd, J ¼ 6.1 Hz, 1H). 13C NMR (75 MHz, CDCl3,
4.2.19. 2-(4-Bromophenyl)-N-phenyl-6-(5-p-tolyl-1,3,4-oxadiazol-
2-yl)imidazo[1,2-a]pyridin-3-amine (7d)
This derivative was synthesized according to the general proce-
in ppm): d 159.2, 157.8, 155.7, 155.5, 153.3, 152.8, 152.4, 146.9, 141.6,
dure C. Yield 61%, white solid, m.p. 193e194 ꢀC. 1H NMR (300 MHz,
139.1, 136.3, 132.8, 130.4, 129.2, 125.1, 123.9, 119.8, 119.7, 119.2, 118.5,
111.9, 111.3, 106.1, 105.7, 93.5. HRMS (ESI): calcd. for C31H21FN6O
[M þ Na]þ: 535.16586; found 535.16579.
CDCl3, in ppm):
4H), 7.84(d, J ¼ 1.5 Hz, 1H), 7.39e7.31 (m, 8H), 6.98 (d, J ¼ 7.1 Hz,1H),
2.41 (s, 3H). 13C NMR (75 MHz, CDCl3, in ppm):
158.1, 154.2, 153.4,
d
8.82 (bs,1H), 8.23 (d, J ¼ 3.2 Hz,1H), 8.00e7.88 (m,
d
146.3, 142.6, 140.9, 137.1, 136.7, 133.9, 132.8, 131.7, 129.5, 127.6, 124.5,
124.1, 120.8, 119.7, 118.9, 117.9, 110.3, 20.6. HRMS (ESI): calcd. for
C28H20BrN5O [M þ Na]þ: 544.07489; found 544.07494.
4.2.25. 2-(4-Bromophenyl)-6-(6-nitro-1H-benzo[d]imidazol-2-yl)-
N-phenylimidazo[1,2-a]pyrimidin-3-amine (10e)
This derivative was synthesized according to the general
procedure A. Yield 75%, white solid, m.p. 194e195 ꢀC. 1H NMR
4.2.20. 2-(4-Bromophenyl)-6-(5-(4-nitrophenyl)-1,3,4-oxadiazol-
2-yl)-N-phenylimidazo[1,2-a]pyridin-3-amine (7e)
(300 MHz, CDCl3, in ppm): d 10.51 (s, 1H), 9.13 (bs, 1H), 8.71 (d,
J ¼ 2.6 Hz, 1H), 8.27 (d, J ¼ 1.5 Hz, 1H), 8.15 (bs, 1H), 8.03 (d,
This derivative was synthesized according to the general
J ¼ 7.3 Hz, 2H), 7.92 (d, J ¼ 6.9 Hz, 1H), 7.51e7.34 (m, 4H), 6.89 (d,
procedure C. Yield 57%, white solid, m.p. 186e187 ꢀC. 1H NMR
J ¼ 7.1 Hz, 1H). 13C NMR (75 MHz, CDCl3, in ppm):
d 155.7, 153.0,
(300 MHz, CDCl3, in ppm):
d
8.95 (bs, 1H), 8.46 (m, 4H), 8.32 (d,
152.6, 146.5, 142.6, 141.4, 139.8, 133.7, 132.8, 132.4, 131.3, 129.7,
129.2, 121.9, 120.2, 119.7, 118.4, 107.3, 109.1, 93.6. HRMS (ESI): calcd.
for C25H16BrN7O2 [M þ Na]þ: 548.04465; found 548.04471.
J ¼ 8.8 Hz, 1H), 7.91(dd, J ¼ 1.3, 7.1 Hz, 2H), 7.82 (dd, J ¼ 1.5, 8.7 Hz,
1H), 7.36e7.32 (m, 5H), 6.94 (dd, J ¼ 1.1, 7.1 Hz, 1H). 13C NMR
(75 MHz, CDCl3, in ppm):
d 157.9, 153.8, 152.1, 145.7, 141.4, 140.5,
136.6, 136.1, 133.5, 132.9, 132.7, 131.4, 130.5, 129.4, 125.3, 123.8,
120.2, 119.5, 118.9, 118.3, 111.0. HRMS (ESI): calcd. for C27H17BrN6O3
[M þ Na]þ: 575.04432; found 575.04428.
4.2.26. 2-(4-Bromophenyl)-6-(5-(4-fluorophenyl)-1H-imidazol-
2-yl)-N-phenylimidazo[1,2-a]pyrimidin-3-amine (11a)
This derivative was synthesized according to the general proce-
dure B. Yield 77%, white solid, m.p. 183e184 ꢀC. 1H NMR (300 MHz,
4.2.21. 2-(4-Bromophenyl)-6-(6-fluoro-1H-benzo[d]imidazol-
2-yl)-N-phenylimidazo[1,2-a]pyrimidin-3-amine (10a)
CDCl3, in ppm):
d
9.71 (s,1H), 9.21 (s,1H), 8.33 (d, J ¼ 1.4 Hz,1H), 8.11
(d, J ¼ 8.7 Hz, 2H), 8.10 (d, J ¼ 7.1 Hz, 2H), 7.61 (bs, 1H), 7.48e7.19 (m,
This derivative was synthesized according to the general proce-
6H), 7.15 (d, J ¼ 4.1 Hz, 2H), 6.81 (bd, J ¼ 6.9 Hz, 1H). 13C NMR
dure A. Yield 59%, white solid, m.p. 166e167 ꢀC. 1H NMR (300 MHz,
(75 MHz, CDCl3, in ppm):
d 162.5, 159.1, 155.1, 148.7, 147.4, 145.5,
CDCl3, in ppm):
d
9.79 (s, 1H), 9.12 (bs, 1H), 8.61 (d, J ¼ 8.3 Hz, 1H),
142.3, 134.7, 132.8, 132.4, 132.1, 131.3, 130.7, 129.5, 128.6, 125.9, 121.6,
122.0, 120.1, 114.9, 114.4, 103.6. HRMS (ESI): calcd. for C27H18BrFN6
[M þ H]þ: 525.08386; found 525.08391.
8.29 (d, J ¼ 1.4 Hz,1H), 8.11 (d, J ¼ 7.1 Hz, 2H), 7.72 (bs,1H), 7.48e7.39
(m, 4H), 7.31 (d, J ¼ 8.1 Hz, 2H), 7.10 (bs, 1H), 6.89 (dd, J ¼ 1.1, 5.2 Hz,

5854
T.H. Al-Tel, R.A. Al-Qawasmeh / European Journal of Medicinal Chemistry 45 (2010) 5848e5855
4.2.27. 2-(4-Bromophenyl)-6-(5-(4-chlorophenyl)-1H-imidazol-
2-yl)-N-phenylimidazo[1,2-a]pyrimidin-3-amine (11b)
(75 MHz, CDCl3, in ppm): d 158.1, 153.8, 151.7, 149.6, 146.9, 141.6,
136.1, 133.7, 133.0, 132.6, 131.9, 130.4, 130.2, 125.3, 119.9, 119.2, 111.3.
HRMS (ESI): calcd. for C26H16BrN7O3 [M þ Na]þ: 576.03957; found
576.03965.
This derivative was synthesized according to the general
procedure B. Yield 71%, white solid, m.p.203e204 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
d 9.82 (s, 1H), 9.181 (bs, 1H), 8.41 (d,
J ¼ 6.7 Hz, 2H), 8.31 (d, J ¼ 1.3 Hz, 1H), 8.12 (d, J ¼ 7.2 Hz, 2H), 7.84
4.2.33. 2-(4-Bromophenyl)-6-(5-(4-chlorophenyl)-1,3,4-oxadiazol-
2-yl)-N-phenylimidazo[1,2-a]pyrimidin-3-amine (12d)
(d, J ¼ 8.4 Hz, 2H), 7.55 (bs, 1H), 7.48e7.34 (m, 6H), 6.94 (bd,
J ¼ 6.8 Hz, 1H). 13C NMR (75 MHz, CDCl3, in ppm):
d
155.3, 149.8,
This derivative was synthesized according to the general
145.2, 142.1, 134.2, 133.5, 132.7, 131.2, 130.8, 129.9, 128.7, 125.6,
124.6, 123.4, 120.2, 119.6, 103.8. HRMS (ESI): calcd. for C27H18BrClN6
[M þ Na]þ: 563.03625; found 563.03619.
procedure C. Yield 72%, white solid, m.p. 189e191 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
d 9.21 (s, 1H), 8.39 (s, 1H), 8.25 (d,
J ¼ 6.7 Hz, 2H), 8.13 (d, J ¼ 7.3 Hz, 2H), 6.71 (d, J ¼ 8.2 Hz, 2H),
7.49e7.34 (m, 6H), 7.08 (bd, J ¼ 6.9 Hz, 1H). 13C NMR (75 MHz,
4.2.28. 2-(4-Bromophenyl)-N-phenyl-6-(5-p-tolyl-1H-imidazol-
2-yl)imidazo[1,2-a]pyrimidin-3-amine (11c)
CDCl3, in ppm): d 166.4, 163.1, 159.3, 154.2, 151.0, 146.8, 142.6, 134.3,
133.9,132.6,132.2,131.6,130.5,127.4,126.3, 121.5,120.6, 118.3,115.7,
110.8. HRMS (ESI): calcd. for C26H16BrClN6O [M þ Na]þ: 565.01552;
found 565.01559.
This derivative was synthesized according to the general
procedure B. Yield 74%, white solid, m.p. 196e197 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
d 9.98 (s, 1H), 9.14 (bs, 1H), 8.39 (d,
J ¼ 1.3 Hz, 1H), 8.21 (d, J ¼ 6.8 Hz, 2H), 7.91 (bd, J ¼ 7.0 Hz, 2H), 7.52
(d, J ¼ 9.6 Hz, 2H), 7.61 (bs, 1H), 7.44e7.36 (m, 6H), 6.85 (bd,
J ¼ 6.6 Hz, 1H), 2.39 (s, 3H). 13C NMR (75 MHz, CDCl3, in ppm):
4.2.34. 2-(4-Bromophenyl)-N-phenyl-6-(5-p-tolyl-1,3,4-oxadiazol-
2-yl)imidazo[1,2-a]pyrimidin-3-amine (12e)
This derivative was synthesized according to the general
d
155.0,150.4,146.4,145.3,141.2,142.1,135.1,133.1,132.3,131.1,130.5,
procedure C. Yield 71%, white solid, m.p. 193e194 ꢀC. 1H NMR
129.2, 128.4, 125.3, 121.2, 120.4, 120.0, 119.8, 103.5, 22.6. HRMS (ESI):
(300 MHz, CDCl3, in ppm): d 9.88 (s, 1H), 9.15 (bs, 1H), 8.35 (d,
calcd. for C28H21BrN6 [M þ Na]þ: 543.09088; found 543.09092.
J ¼ 1.7 Hz, 1H), 8.31 (d, J ¼ 7.1 Hz, 2H), 7.94 (bd, J ¼ 3.1 Hz, 1H), 7.72
(bs, 1H), 7.51e7.39 (m, 8H), 7.14 (bd, J ¼ 5.2 Hz, 1H), 2.37 (s, 3H). 13C
4.2.29. 2-(4-Bromophenyl)-6-(5-(4-nitrophenyl)-1H-imidazol-
2-yl)-N-phenylimidazo[1,2-a]pyrimidin-3-amine (11d)
NMR (75 MHz, CDCl3, in ppm): d 158.1, 154.2, 150.3, 146.7, 142.5,
141.8, 133.9, 133.3, 132.5, 131.7, 130.8, 129.6, 128.8, 125.7, 124.2,
120.5, 119.6, 111.3, 21.9. HRMS (ESI): calcd. for C27H19BrN6O
[M þ Na]þ: 545.07014; found 545.07021.
This derivative was synthesized according to the general
procedure B. Yield 64%, white solid, m.p. 169e170 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
d 9.95 (s, 1H), 9.18 (bs, 1H), 8.35 (d,
J ¼ 1.2 Hz, 1H), 8.20 (bs, 2H), 7.98 (d, J ¼ 6.9 Hz, 2H), 7.79e7.76 (m,
4.3. In vitro antimicrobial procedure
3H), 7.49e7.32 (m, 6H), 6.81 (bd, J ¼ 7.1 Hz, 1H). 13C NMR (75 MHz,
CDCl3, in ppm):
d 154.8, 150.0, 146.8, 145.1, 144.5, 141.0, 134.1, 133.1,
The determination of minimum inhibitory concentration [19,20]
was done with six isolates of Gram-positive bacteria S. aureus,
E. faecalis and B. megaterium and Gram-negative bacteria E. coli,
P. aeruginosa and E. aerogenes which were inoculated into Luria
broth medium containing 1% tryptone, 0.5% yeast extract, 0.5%
sodium chloride. The pH of the medium was adjusted to 7.2 with
sterile phosphate buffered saline and incubated at 37 ꢀC for 24 h.
The optical density of the bacteria from mid-log phase of growth
was measured at 540 nm and diluted in fresh medium to obtain an
optical density of 0.004 (corresponding to 5 ꢁ 105 colony forming
132.5, 131.6, 130.7, 129.5, 128.6, 125.8, 123.4, 120.1, 119.5, 119.0,
102.6. HRMS (ESI): calcd. for C27H18BrN7O2 [M þ Na]þ: 574.06030;
found 574.06028.
4.2.30. 2-(4-Bromophenyl)-6-(5-(4-fluorophenyl)-1,3,4-oxadiazol-
2-yl)-N-phenylimidazo[1,2-a]pyrimidin-3-amine (12a)
This derivative was synthesized according to the general
procedure C. Yield 68%, white solid, m.p. 178e179 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
J ¼ 6.9 Hz, 2H), 7.83 (bs, 2H), 7.52e7.35 (m, 8H), 6.91 (bd, J ¼ 6.8 Hz,
1H). 13C NMR (75 MHz, CDCl3, in ppm):
167.1, 163.5, 158.2, 153.9,
d 9.19 (s, 1H), 8.47 (s, 1H), 8.12 (d,
units/mL). To each well of the ELISA plate, 200
bacterial suspension was added and graded concentrations
(0.2e500 g/50 L) of the synthesized compounds and standard
mL of diluted
d
150.2, 146.4, 141.5, 133.8, 133.1, 132.8, 131.6, 130.8, 129.2, 126.7,
126.5, 120.0, 119.6, 117.2, 114.8, 111.0. HRMS (ESI): calcd. for
C26H16BrFN6O [M þ Na]þ: 549.04507; found 549.04511.
m
m
antibiotics (Amoxicillin, Cefixime and Vancomycin) in 20% H2O/
DMSO were added and incubated at 37 ꢀC for 24 h. At the end of
incubation the effect of the drugs on the growth of organisms was
monitored by measuring the optical density at 540 nm using an
ELISA reader. The MIC was defined as the lowest concentration of
the antibiotic or test sample allowing no visible growth.
4.2.31. 6-(5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl)-N-phenyl-
2-p-tolylimidazo[1,2-a]pyrimidin-3-amine (12b)
This derivative was synthesized according to the general
procedure C. Yield 71%, white solid, m.p. 201e202 ꢀC. 1H NMR
(300 MHz, CDCl3, in ppm):
d 9.10 (s, 1H), 8.39 (s, 1H), 8.22 (d,
Acknowledgements
J ¼ 7.1 Hz, 2H), 7.89e7.75 (m, 4H), 7.53 (dd, J ¼ 5.5, 8.7 Hz, 2H),
7.39e7.31 (m, 4H), 6.94 (bd, J ¼ 6.7 Hz, 1H), 2.43 (s, 3H). 13C NMR
The authors are grateful to the National Research Fund (UAE)
and the College of Graduate Studies and Research (University of
Sharjah) for funding this research project. Dr. Sam Victory (Trans-
tech Pharma, High Point, NC, USA) and Dr. Jareer Kassis (Transtech
Pharma, High Point, NC, USA) are greatly acknowledged for their
assistance in the in vitro data analysis, fruitful discussions and proof
reading.
(75 MHz, CDCl3, in ppm):
d 166.8, 163.7, 158.0, 153.5, 150.1, 146.8,
141.0, 136.5, 133.4, 130.6, 129.4, 129.2, 126.9, 126.7, 125.6, 119.8,
119.4, 115.7, 114.5, 111.6, 23.3. HRMS (ESI): calcd. for C27H19FN6O
[M þ Na]þ: 485.15021; found 485.15029.
4.2.32. 2-(4-Bromophenyl)-6-(5-(4-nitrophenyl)-1,3,4-oxadiazol-
2-yl)-N-phenylimidazo[1,2-a]pyrimidin-3-amine (12c)
This derivative was synthesized according to the general
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(300 MHz, CDCl3, in ppm): d 9.04 (s, 1H), 8.47e8.41 (m, 5H), 8.15 (d,
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