Imidazo pyridine ester III was confirmed by 1H

Imidazo 1, 2, ? pyridine compounds show wide range of
biological activity like antibacterial 1, 2, antifungal 3, 4, anti-inflammatory
5. Some of the derivatives show antiulcer 6, 7, antiviral 8, 9, 10, 11, 12, 13 and antiprotozoal 14,
15 activity. Most of the derivatives of Imidazo 1, 2, ? pyridine are used in
drug for GABA 16, benzodiazepine receptor agonists 17,
18, 19 and bradykinin B2 receptor antagonists 20. Some of the derivatives of
Imidazo 1, 2, ? pyridines are also used as inhibitors like cyclin dependant
Kinase inhibitors 21 enzyme inhibitors like prolyl hydrolase 22. In some
cases derivatives of Imidazo 1, 2, ? pyridines are used to detect brain
disease like ?-Amyloid and Alzheimer’s 23, 24.

          Considering the biological significance
of Imidazo 1, 2, ? pyridines and in continuation of our work on synthesis of
pharmacologically significant heterocycles, we herein report the synthesis piperazinyl
derivatives of Imidazo 1, 2, ? pyridine.

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 Result and Discussion

 Chemistry

The
target compounds were synthesized as per the synthetic scheme depicted in Figure 1. Initially, 2-amino pyridine I was condensed with chloro
oxobutanoate II in ethanol to obtain
pyridine ester III. The pyridine
ester III was confirmed by 1H
NMR which showed presence of ethyl group 1.14 (-CH3) and 4.41 (-CH2-).
Further compound III was hydrolysed
to obtain the free acid IV. The structure of was confirmed by 1H
NMR and IR which shoes the absence of ester peaks 1.14 and 4.41 ? and presence
of carboxylic acid peak 13.24 ?. The resultant carboxylic acid IV was then coupled with different mono
N-substituted piperazines in presence
of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide
hydrochloride (EDC) and 1-hydroxy benzotriazole (HOBt) to obtain target
derivatives Va-i in good yields. All
the compounds were characterized by IR, 1H NMR, 13C NMR
and mass spectrometric techniques. The representative 1H NMR
spectrum of compound Va shows disappearance
of acid proton at ? 13.24 and change in IR frequency of acid to amide conversion
1684 to1679 cm-1. The 1H NMR spectrum showed
disappearance of acid proton and appearance of piperazine protons.  Similarly, the structures of all the other
derivatives were confirmed by analytical data, the results are presented in the
experimental part.

 Antibacterial
Activity

            All
the synthesized imidazo1, 2, ? pyridine derivatives (IV and Va-i) were tested
for their in vitro antibacterial activity
against clinically isolated bacterial strains such as S.aureus , E.coli, B.subtilis, P.aeruginosa, S.pyogens, K.terrigena and
K.pneumonia by using disc method and  minimum inhibitory concentration (MIC).
Antibacterial results are summarized in Table
1, which indicated that, most of the synthesized compounds showed good to
moderate activities against S. aureus, P.
aeruginosa, K. terrigena and E. coli
as compared with standard drug Chloramphenicol.
In particular, compounds IV exhibited
good potency against E. coli and B. subtilis.

Compounds Vb, Vd, Ve and Vd were active against K. pneumonia and
compounds Ve,
Vf and
Vi showed promising activity against
B. subtilis while Ve,
exhibited good activity against P. aeruginosa
and K. terrigena, respectively.
Whereas, remaining compounds Va, Vc, Vg
and Vh exhibited only moderate antibacterial activity as compared to the standard
drug.

Antifungal
Activity

      All synthesized Imidazo1, 2, ? pyridines
compounds (IV and Va-i) were screened for their in vitro antifungal  activity against clinically isolated
bacterial strains such as T. viride, A.
flavus, A. brasillansis and C. albicans
by using disc method and minimum inhibitory concentration (MIC) at very low
concentration 100 µg/ml. The results obtained are summarized in Table 2. Compounds Va,
Vc, Vd, Ve, Vf, Vg and Vi
were remarkably effective against A. brasillansis, Vd and
Vg exhibited promising activity against
A. flavus and Vf and Vi were found to be active against C. albicans. revealed that compounds Vb, and 
Vh exhibited moderate potency
against E. coli, S. aureus, P. aeruginosa
and K. terrigena as compared to standared drug Nystatin.

 Experimental

 Materials and Measurements

            Melting
points of compounds were determined in open capillary tubes in silicon oil bath
using a Veego melting point apparatus and are uncorrected. Purity of compounds
was monitored by TLC on silica F254 coated aluminum plates (Merck)
as adsorbent and U.V. light and Iodine chamber as a visualizing agent. IR
spectra (KBr in cm-1) were recorded on Shimadzu Model FTIR-435. NMR
spectra were recorded on a Varian mercury TH-300 operating at 300 MHz (1H
NMR) and 75 MHz (13C NMR) using CDCl3 as a solvent and
TMS as an internal standard (Chemical shift in ppm). All chemicals and solvents
used are analytical grade.

Preparation methods

Synthesis of
ethyl-2-methylimidazo1, 2,
?pyridine-3-carboxylate (III): 2-Amino pyridine I (15.0 g, 1.0 mol), potassium
carbonate (26.4 g, 1.2 mol) in absolute ethanol (80 mL) was stirred to obtain
clear solution. To this clear solution, ethyl-2-chloro oxobutanoate II (31.5 g, 1.2 mol) in 15 mL ethanol
was added drop-wise. After complete addition, the reaction mixture was refluxed
for 8-10 h. After completion of the reaction, as indicated by TLC, the reaction
was cooled to room temperature. The reaction mixture was filtered, washed with
ethanol (15 mL). The filtrate was evaporated and the residue was poured into
crushed ice. The product was then extracted with dichloromethane (4 x 25 mL).
The organic extract was washed with brine, water and dried over sodium
sulphate.  Dichloromethane was removed
under reduced pressure to obtain the product as off white solid. Yield 75 %; Mp
61-65 °C; IR (KBr,
cm-1): 1661 (C=O) ; 1H NMR (CDCl3,  300 MHz) :  ? 1.41 (t, 3H, J = 8Hz, CH2CH3),
2.69 (s, 3H, CH3), 4.41 (q, 2H, OCH2CH3), 6.94
(m, 1H, Ar-H), 7.34 (m, 1H, Ar-H), 7.58 (d, 1H, J = 8.8Hz, Ar-H), 9.27 (d, 1H, J
= 6.9 Hz, Ar-H). MS (m/z): 205 (M+).

Synthesis of
2-methylimidazo1, 2,
?pyridine-3-carboxylic acid (IV): Compound III (15.0 g, 1.0 mol)
and NaOH (5.0 g) were taken in methanol (50 mL) and the mixture was refluxed
for 8-10 h. After completion of the reaction as indicated on TLC, the reaction
mixture was poured into ice cold water. The resultant mixture was acidified
with dil. HCl to obtain the product. Yield 89%; Mp 145-148 °C;  IR (KBr, cm-1): 1661 (C=O); 1H NMR (CDCl3,  300 MHz) :  ?  2.69 (s, 3H, CH3), 6.94 (m, 1H,
Ar-H), 7.34 (m, 1H, Ar-H), 7.58 (d, 1H, J = 8.8 Hz, Ar-H), 9.27 (d, 1H, J = 6.9
Hz, Ar-H), 13.34 (s, 1H, COOH ). MS (m/z):
177 (M+).

General procedure for the
synthesis of compounds
Va-i

A mixture of carboxylic
acid IV (3.5 mol), EDC (5.4 mol), HOBT (5.4 mol) in anhydrous DMF (20 mL) was stirred at room
temperature. Substituted piperazine (3.5 mol) was then added and the mixture was further stirred
at room temperature for 12 h. After completion of the reaction as indicated by
TLC, the reaction mixture was quenched in crushed ice. The precipitated solid
was washed with NaHCO3 and dil. HCl. The product thus obtained was
purified by silica gel column chromatography using hexane: ethyl acetate as
eluent.

Tert-butyl
4-(2-methylimidazo1, 2, ?pyridine-3-carbonyl)
piperazine-1-carboxylate (Va)

Yield 77  %; Mp
164-168 °C;  IR (KBr, cm-1): 2927
(C-H), 1680 (C=O), 1342 (C-N); 1H  NMR (CDCl3,  300 MHz) : ? 1.48 (s ,9H, tert butyl), 2.49
(s, 3H, CH3) 3.45-3.51 (m, 4H, piperazine CH2- ), 3.66 (m,
4H, piperazine CH2-), 6.84-6.89 (t, 1H, J = 6.9 Hz), 7.25 – 7.30 (t, 1H, J = 6.9,9.0 Hz,
Ar-H),
7.54 – 7.57 (d, 1H, J = 9.0 Hz, Ar-H), 8.49 – 8.51 (d, 1H, J = 6.9 Hz,
Ar-H);
13C NMR (CDCl3, 75 MHz): ? 15.25, 28.30, 43.91,
45.15, 80.40, 112.74, 115.03, 116.64, 126.32, 126.48, 144.52, 146.33, 154.42,
162.70. MS (m/z): 345 (M+).

(4-(4-chlorophenyl)
piperazin-1-yl) (2-methylimidazo 1, 2, ?pyridin-3-yl)
methanone (Vb)

Yield   94%; Mp
178-180°C; IR (KBr, cm-1): 2924 (C-H), 2850, 1650 (C=O), 1500, 1442, 1342(C-N), 1230; 1H
NMR (CDCl3, 300 MHz): ? 2.52 (s, 3H, CH3), 3.20 (m, 4H,
piperazine CH2-), 3.84  (m, 4H,
piperazine CH2-), 6.84 – 6.89 (m, 3H, Ar-H), 7.22 – 7.31 (m, 3H, Ar-H), 7.55 – 7.58 (d, 1H, J = 9.0 Hz, Ar-H), 8.51 – 8.54  (d, 1H,  J =  6.9 Hz, Ar-H). MS (m/z):
355 (M+).

(4-(4-trifluromethylphenyl)
piperazin-1-yl) (2-methylimidazo 1, 2, ? pyridin-3-yl)
methanone (Vc)

Yield   87%;
Mp 164-168°C; IR (KBr, cm-1): 2922 (C-H), 1625 (C=O), 1350(C-N) ; 1H NMR (CDCl3, 300
MHz): ? 2.53 (s, 3H, CH3), 3.30  (m, 4H, piperazine CH2-),), 3.86  (m, 4H, piperazine CH2-), 6.85 – 6.90 (t, 1H, J= 15.3 Hz, Ar-H),
7.08 – 7.16 (m, 3H, Ar-H), 7.27 – 7.31 (t, 1H, J = 14.1  Hz, Ar-H),
7.36 – 7.41 (t, 1H, J = 7.8, 15.3 Hz, Ar-H),
7.55
– 7.58 (d, 1H, J = 9.3, Ar-H), 8.51 – 8.54 (d, 1H, J = 6.9 Hz, Ar-H); 13C NMR (CDCl3, 75
MHz):  ? 15.04, 44.73, 49.09, 112.56,
114.82, 116.33, 116.50, 126.08, 126.28, 129.33, 129.44, 130.97, 144.29, 146.06,
150.73, 162.32. MS (m/z): 389 (M+).

 (2-methylimidazo 1, 2, ?pyridin-3-yl)(4-(4-nitrophenyl)piperazin-1-yl)methanone
(Vd)

Yield   78 %;
Mp 175 – 177°C; IR (KBr, cm-1): 2924 (C-H), 1605 (C=O), 
1325 (C-N);
1H NMR (CDCl3, 300 MHz): ? 2.53 (s, 3H, CH3), 3.50
– 3.59 (m, 4H, , piperazine CH2-), 
3.86 – 3.87 (m, 4H, , piperazine CH2-), 6.80 – 6.91 (m, 3H, Ar-H), 7.20 – 7.33 (t, 1H, J = 6.9 Hz, Ar-H), 7.57 – 7.60 (d, 1H, J= 9.3 Hz, Ar-H), 8.12 – 8.15 (d, 2H, J = 9.3 Hz, Ar-H), 8.54 – 8.56 (d,  1H, J =
6.9 Hz, Ar-H).
MS (m/z): 366 (M+).

(2-methylimidazo
1, 2,
?pyridin-3-yl)(4-(p-tolyl)piperazin-1-yl)methanone (Ve)

Yield   84 %; Mp
169-173°C; IR (KBr, cm-1): 2912 (C-H), 1610 (C=O) , 1338(C-N); 1H NMR (CDCl3, 300
MHz):  ?  2.28 (s, 3H, Ar-CH3), 2.58 (s, 3H,
CH3), 3.18 (m, 4H, piperazine CH2-), 3.83 (m, 4H,  piperazine CH2-), 6.83 – 6.87  (m, 3H,  Ar-H),
7.08 – 7.11 (d, 2H, J = 8.1 Hz, Ar-H),
7.23 – 7.26  (t, 1H  J =
9.0 Hz, Ar-H),
7.54 – 7.57 (d, 1H, J = 9.0  Hz,  Ar-H),
8.52 – 8.50 (d, 1H ,  J = 9.0 Hz, Ar-H); 13C NMR (CDCl3,
75 MHz): ? 15.12, 20.25, 45.08, 50.33, 112.53, 115.05, 116.42, 116.86, 126.07,
126.34, 129.58, 130.08, 144.21, 146.08, 148.52, 162.29. MS (m/z):
335 (M+).

(4-(3,
4-dichlorophenyl) piperazin-1-yl) (2-methylimidazo 1, 2, ?pyridin-3-yl) methanone
 (Vf)

Yield   76 %;
Mp 180 – 183°C; IR (KBr, cm-1): 2924 (C-H), 1627 (C=O), 1342 (C-N); 1H NMR (CDCl3, 300
MHz): ? 2.52 (s, 3H,  CH3), 3.22
(m , 4H, piperazine CH2-), 3.83 (m, 4H, piperazine CH2-),
6.75 – 6.79 ( dd , 1H , J = 8.7 Hz, Ar-H), 6.85 – 6.90 (t, 1H, J = 12.6 Hz, Ar-H), 6.98 – 6.99 (d, 1H,  Ar-H),
7.27 – 7.29  (m,  2H, Ar-H ), 7.55 – 7.58 (d, 1H, J = 8.7 Hz,
Ar-H),
8.51 – 8.53 (d, 1H, J=6.9 Hz, Ar-H). MS (m/z):
390 (M+).

(4-benzylpiperazin-1-yl)
(2-methylimidazo 1, 2, ?pyridin-3-yl)methanone(Vg)

Yield   88 %;
Mp 158-165°C; IR (KBr, cm-1) 2924 (C-H), 1622 (C=O), 1342 (C-N); 1H NMR (CDCl3,  300 MHz):  ?  2.52
(s, 3H, CH3), 2.56 – 2.60 (m, 4H , piperazine CH2-), 3.58
– 3.60 (s, 2H,  CH2-), 3.70 – 3.78
(m, 4H,  piperazine CH2-) , 6.82
– 6.87  dd, 1H, J = 6.9 and 8.1 Hz,
Ar-H),
7.22 – 7.33 (m, 6H,  Ar-H ), 7.52 – 7.55 (d, 1H,
J = 9.0 Hz, Ar-H), 8.47 – 8.49 (d, 1H, J = 6.9 Hz, Ar-H). MS (m/z):
335 (M+).

(4-(4-chlorobenzyl)
piperazin-1-yl) (2-methylimidazo 1, 2, ?pyridin-3-yl)
methanone (Vh)

Yield   77 %;
Mp 169 – 171°C; IR (KBr, cm-1): 2924 (C-H), 1620 (C=O), 1342(C-N); 1H NMR (CDCl3, 300
MHz): ? 2.46 (m, 7H,  CH3  &  piperazine CH2-), 3.68  (m, 4H,  piperazine CH2-), 4.25 (s, 2H,  CH2-) , 6.79 – 6.84  (t, 1H, J
=   6.6 Hz, Ar-H), 7.19 – 7.37 (m, 5H, Ar-H ), 7.50 – 7.53 (d, 1H, J = 8.7 Hz, Ar-H), 8.46 – 8.48 (d, 1H, J = 6.6 Hz, Ar-H); 13C NMR (CDCl3, 75
MHz): ? 15.18, 45.26, 52.01, 75.12, 112.50, 115.18, 116.50, 126.01, 126.42, 127.35,
128.97, 132.77, 141.31, 144.15, 146.08, 162.18. MS (m/z): 369
(M+).

(2-methylimidazo
1, 2,
?pyridin-3-yl) (4-(pyridin-2-yl) piperazin-1-yl) methanone
(Vi)

Yield   79 %;
Mp 175-178°C; IR (KBr,cm-1): 2920(C-H), 
1616 (C=O),
1342 (C-N);  1H NMR (CDCl3, 300 MHz):
? 2.52 (s, 3H,  -CH3), 3.64
(m, 4H , piperazine-CH2-), 3.79-3.80  (m, 4H,  piperazine-CH2-) , 6.67-6.71 (m,  2H,  Ar-H),
6.84-6.88 (t, 1H, J =  7.8, 8.1 Hz,  Ar-H),
7.25 – 7.30 (m, 1H, Ar-H),
7.49-  7.58 (m, 2H, Ar-H), 8.20-8.22 (d, 1H, J = 8.1, 9.0 Hz,  Ar-H), 8.51-8.53 (d, 1H, J=6.6 Hz, Ar-H); 13C NMR (CDCl3, 75
MHz) : ? 15.30, 45.02, 45.68, 107.39,  112.76,
114.10, 116.60, 126.34, 126.54, 137.70, 144.44, 146.29, 147.99, 158.96, 162.65.
MS (m/z): 322 (M+).

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