Imidazo pyridine ester III was confirmed by 1H

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Last updated: September 12, 2019

Imidazo 1, 2, ? pyridine compounds show wide range ofbiological activity like antibacterial 1, 2, antifungal 3, 4, anti-inflammatory5.

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 indrug for GABA 16, benzodiazepine receptor agonists 17,18, 19 and bradykinin B2 receptor antagonists 20. Some of the derivatives ofImidazo 1, 2, ? pyridines are also used as inhibitors like cyclin dependantKinase inhibitors 21 enzyme inhibitors like prolyl hydrolase 22. In somecases derivatives of Imidazo 1, 2, ? pyridines are used to detect braindisease like ?-Amyloid and Alzheimer’s 23, 24.

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          Considering the biological significanceof Imidazo 1, 2, ? pyridines and in continuation of our work on synthesis ofpharmacologically significant heterocycles, we herein report the synthesis piperazinylderivatives of Imidazo 1, 2, ? pyridine. Result and Discussion  ChemistryThetarget compounds were synthesized as per the synthetic scheme depicted in Figure 1. Initially, 2-amino pyridine I was condensed with chlorooxobutanoate II in ethanol to obtainpyridine ester III. The pyridineester III was confirmed by 1HNMR which showed presence of ethyl group 1.14 (-CH3) and 4.41 (-CH2-).Further compound III was hydrolysedto obtain the free acid IV. The structure of was confirmed by 1HNMR and IR which shoes the absence of ester peaks 1.

14 and 4.41 ? and presenceof carboxylic acid peak 13.24 ?. The resultant carboxylic acid IV was then coupled with different monoN-substituted piperazines in presenceof 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride (EDC) and 1-hydroxy benzotriazole (HOBt) to obtain targetderivatives Va-i in good yields. Allthe compounds were characterized by IR, 1H NMR, 13C NMRand mass spectrometric techniques. The representative 1H NMRspectrum of compound Va shows disappearanceof acid proton at ? 13.24 and change in IR frequency of acid to amide conversion1684 to1679 cm-1. The 1H NMR spectrum showeddisappearance of acid proton and appearance of piperazine protons.

  Similarly, the structures of all the otherderivatives were confirmed by analytical data, the results are presented in theexperimental part. AntibacterialActivity            Allthe synthesized imidazo1, 2, ? pyridine derivatives (IV and Va-i) were testedfor their in vitro antibacterial activityagainst clinically isolated bacterial strains such as S.aureus , E.coli, B.subtilis, P.aeruginosa, S.pyogens, K.

terrigena andK.pneumonia by using disc method and  minimum inhibitory concentration (MIC).Antibacterial results are summarized in Table1, which indicated that, most of the synthesized compounds showed good tomoderate activities against S.

aureus, P.aeruginosa, K. terrigena and E. colias compared with standard drug Chloramphenicol.

In particular, compounds IV exhibitedgood potency against E. coli and B. subtilis.Compounds Vb, Vd, Ve and Vd were active against K. pneumonia andcompounds Ve,Vf andVi showed promising activity againstB. subtilis while Ve,exhibited good activity against P. aeruginosaand K. terrigena, respectively.

Whereas, remaining compounds Va, Vc, Vgand Vh exhibited only moderate antibacterial activity as compared to the standarddrug.AntifungalActivity      All synthesized Imidazo1, 2, ? pyridinescompounds (IV and Va-i) were screened for their in vitro antifungal  activity against clinically isolatedbacterial strains such as T. viride, A.flavus, A. brasillansis and C. albicansby using disc method and minimum inhibitory concentration (MIC) at very lowconcentration 100 µg/ml. The results obtained are summarized in Table 2. Compounds Va,Vc, Vd, Ve, Vf, Vg and Viwere remarkably effective against A.

brasillansis, Vd andVg exhibited promising activity againstA. flavus and Vf and Vi were found to be active against C. albicans. revealed that compounds Vb, and Vh exhibited moderate potencyagainst E. coli, S.

aureus, P. aeruginosaand K. terrigena as compared to standared drug Nystatin. Experimental Materials and Measurements            Meltingpoints of compounds were determined in open capillary tubes in silicon oil bathusing a Veego melting point apparatus and are uncorrected. Purity of compoundswas monitored by TLC on silica F254 coated aluminum plates (Merck)as adsorbent and U.V.

light and Iodine chamber as a visualizing agent. IRspectra (KBr in cm-1) were recorded on Shimadzu Model FTIR-435. NMRspectra were recorded on a Varian mercury TH-300 operating at 300 MHz (1HNMR) and 75 MHz (13C NMR) using CDCl3 as a solvent andTMS as an internal standard (Chemical shift in ppm). All chemicals and solventsused are analytical grade.Preparation methodsSynthesis ofethyl-2-methylimidazo1, 2,?pyridine-3-carboxylate (III): 2-Amino pyridine I (15.0 g, 1.0 mol), potassiumcarbonate (26.

4 g, 1.2 mol) in absolute ethanol (80 mL) was stirred to obtainclear solution. To this clear solution, ethyl-2-chloro oxobutanoate II (31.5 g, 1.2 mol) in 15 mL ethanolwas added drop-wise.

After complete addition, the reaction mixture was refluxedfor 8-10 h. After completion of the reaction, as indicated by TLC, the reactionwas cooled to room temperature. The reaction mixture was filtered, washed withethanol (15 mL). The filtrate was evaporated and the residue was poured intocrushed ice. The product was then extracted with dichloromethane (4 x 25 mL).

The organic extract was washed with brine, water and dried over sodiumsulphate.  Dichloromethane was removedunder reduced pressure to obtain the product as off white solid. Yield 75 %; Mp61-65 °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 of2-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 refluxedfor 8-10 h. After completion of the reaction as indicated on TLC, the reactionmixture was poured into ice cold water. The resultant mixture was acidifiedwith 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 = 6.9Hz, Ar-H), 13.34 (s, 1H, COOH ). MS (m/z):177 (M+).

General procedure for thesynthesis of compoundsVa-iA mixture of carboxylicacid IV (3.5 mol), EDC (5.4 mol), HOBT (5.4 mol) in anhydrous DMF (20 mL) was stirred at roomtemperature. Substituted piperazine (3.5 mol) was then added and the mixture was further stirredat room temperature for 12 h.

After completion of the reaction as indicated byTLC, the reaction mixture was quenched in crushed ice. The precipitated solidwas washed with NaHCO3 and dil. HCl. The product thus obtained waspurified by silica gel column chromatography using hexane: ethyl acetate aseluent. Tert-butyl4-(2-methylimidazo1, 2, ?pyridine-3-carbonyl)piperazine-1-carboxylate (Va)Yield 77  %; Mp164-168 °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%; Mp178-180°C; IR (KBr, cm-1): 2924 (C-H), 2850, 1650 (C=O), 1500, 1442, 1342(C-N), 1230; 1HNMR (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, 300MHz): ? 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, 75MHz):  ? 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-methylimidazo1, 2,?pyridin-3-yl)(4-(p-tolyl)piperazin-1-yl)methanone (Ve)Yield   84 %; Mp169-173°C; IR (KBr, cm-1): 2912 (C-H), 1610 (C=O) , 1338(C-N); 1H NMR (CDCl3, 300MHz):  ?  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, 300MHz): ? 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, 300MHz): ? 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, 75MHz): ? 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-methylimidazo1, 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, 75MHz) : ? 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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