Bioorganic&MedicinalChemistryLetters

Synthesisandantibacterialactivityevaluationofmetronidazoletriazole
conjugates
Beena,aNitinKumar,aRajeshK.Rohilla,bN.Roy,bDiwanS.Rawat*a

a
DepartmentofChemistry,UniversityofDelhi,Delhi110007,India
b
DepartmentofBiotechnology,NationalInstituteofPharmaceuticalEducationand
Research,SASNagar,Punjab160062,India

SupportingInformation
Experimental Section

AllofthechemicalsusedinthesyntheseswerepurchasedfromSigmaAldrichandwereusedassuch.
Thin layer chromatography was used to monitor the progress of the reactions. The compounds were
purified by silica gel column. Melting points were determined on a melting point apparatus and are
uncorrected.IR(KBr)spectrawererecordedusingPerkinElmerFTIRspectrophotometerandthevalues
are expressed as max cm1. Mass spectral data were recorded in waters micromass LCT Mass
Spectrometer/Data system. The 1H NMR and 13C NMR spectra were recorded on Bruker Spectrospin
spectrometerat300MHzand75.5MHz,respectivelyusingTMSasaninternalstandard.Thechemical
shiftvaluesarerecordedon scaleandthecouplingconstants(J)areinHz.Elementalanalysiswere
performedonaCarloErbaModelEA1108elementalanalyzeranddataofC,HandNiswithin0.4%of
calculatedvalues.

Synthesisofmetronidazoletriazoleconjugates(6a6o;7a7f):Toavigorouslystirredsolutionof1- (2-
azido-ethyl)-2-methyl-5-nitro-1H-imidazole (5), (2.5mmol)andappropriatealkynes(2.5mmol)in tert
butylalcoholwasaddedasolutionofCuSO4.5H2O(0.51mmol)andsodiumascorbate(1.02mmol)in
distilledwater.Theamountoftertbutylalcoholanddistilledwaterwaskept1:1(v/v).Thedeepyellow
mixturewasstirredvigorouslyatroomtemperatureandprogressofreactionwasmonitoredbythinlayer
chromatography.After2hrreactionwascompletedandcrudereactionmixturewasextractedwithCHCl 3

1
(5 10mL)anddriedoveranhydrousNa2SO4.Excessofsolventwasremovedundervacuo.Thecrude
mixturewaspurifiedoverSiO2columnusingethylacetate/hexaneasaneluent.
{1[2(2Methyl5nitroimidazol1yl)ethyl]1H[1,2,3]triazol4yl}methanol (6a): Yield: 64%; mp
152154oC;IR(cm1,KBr):3341,2924,1525,1457,1430,1371,1268,1197,1147,1012,825;1HNMR
(300MHz,CDCl3):2.12(s,3H,CH3),2.14(brs,1H,OH),4.784.80(m,6H),7.28(s,1H),8.0(s,1H); 13C
NMR(75.5MHz,DMSOd6):12.76,46.2,48.5,54.8,123.5,133.1,138.3,148.4,151.2;HRMScalcdfor:
C9H12N6O3:252.2302,found:253.2310(M++H);Anal.calcdforC9H12N6O3:C,42.86;H,4.80;N,33.32;
found:C,42.99;H,4.96;N,33.58.

4Methoxymethyl1[2(2methyl5nitroimidazol1yl)ethyl]1H[1,2,3] triazole (6b): Yield: 67%;

mp116118oC;IR(cm1,KBr):2926,1628,1527,1463,1371,1267,1198,1102,1051; 1HNMR(300
MHz,DMSOd6):1.83(s,3H),3.20(s,3H),4.83(s,2H),4.69(t,2H),4.80(s,2H),7.95(s,1H),8.02(s,
1H);ESIMS(m/z):266.20(M+).

Propionic acid 1[2(2methyl5nitroimidazol1yl)ethyl]1H[1,2,3]triazol4ylmethyl ester (6c):

Yield:58%;mp116118 oC;IR(cm1,KBr):2979,1732,1530,1467,1425,1372,1263,1174,1143; 1H
NMR(300MHz,DMSOd6):1.02(t,J=6Hz,3H),1.83(s,3H),2.32(q,J=6Hz,2H),4.70(m,2H),4.83
(m,2H),5.09(s,2H),8.01(s,1H),8.06(s,1H);ESIMS(m/z):308.21(M+).

1[2(2Methyl5nitroimidazol1yl)ethyl]4phenoxy methyl1H[1,2,3]triazole (6e): Yield: 54%;

mp146148oC;IR(cm1,KBr):2932,1527,1466,1428,1367,1252,1196,1049; 1HNMR(300MHz,
DMSOd6):1.80(s,3H),4.71(t,2H),4.85(t,2H),5.12(s,2H),6.927.08(m,3H),7.267.31(m,2H),8.04
(s,1H),8.11(s,1H);ESIMS(m/z):329.23(M++H);Anal.calcdforC15H16N6O3:C,54.87;H,4.91;N,
25.60;found:C,54.98;H,5.08;N,25.79.

1[2(2Methyl5nitroimidazol1yl)ethyl]4otolyloxymethyl1H[1,2,3]triazole (6f): Yield: 60%;

mp134136oC;IR(cm1,KBr):2924,1526,1461,1430,1268,1243,1006;1HNMR(300MHz,DMSO
d6):1.74(s,3H),2.09(s,3H),4.71(brs,2H),4.83(brs,2H),5.10(s,2H),6.84(m,1H),7.067.13(m,3H),
8.03(s,1H),8.08(s,1H);ESIMS(m/z):342.22(M +);Anal.calcdforC16H18N6O3:C,56.13;H,5.30;N,
24.55;found:C,56.33;H,5.55;N,24.73.

1[2(2Methyl5nitroimidazol1yl)ethyl]4ptolyloxymethyl1H[1,2,3] triazole (6g): Yield: 52%;

mp142oC;IR(cm1,KBr):2924,2854,1509,1465,1369,1235,1190; 1HNMR(300MHz,DMSOd6):
1.78(s,3H),2.21(s,3H),4.70(brs,2H),4.82(brs,2H),5.05(s,2H),6.84(d,J=8Hz,2H),7.04(d,J=
8Hz,2H),8.02(s,1H),8.07(s,1H);13CNMR(75.5MHz,DMSOd6):12.7,20.1,48.7,60.9,114.6,125.2,

2
129.5,129.8,133.2,138.4,143.3,151.2,155.7;ESIMS(m/z):342.22(M +);Anal.calcdforC16H18N6O3:C,
56.13;H,5.30;N,24.55;found:C,56.33;H,5.45;N,24.77.

1[2(2Methyl5nitroimidazol1yl)ethyl]4mtolyloxymethyl1H[1,2,3]triazole(6h): Yield:58%;
mp108110oC;IR(cm1,KBr):2924,2873,1528,1465,1364,1262,1155,1039,824;1HNMR(300MHz,
DMSOd6):1.82(s,3H),2.22(s,3H),4.74(brs,2H),4.88(brs,2H),5.10(s,2H),6.776.91(m,2H),7.09
7.22(m,2H),8.08(s,1H),8.12(s,1H);ESIMS(m/z):342.20(M+).

1[2(2Methyl5nitroimidazol1yl)ethyl]4(2nitrophenoxymethyl)1H[1,2,3]triazole (6i): Yield:

66%;mp144146oC;IR(cm1,KBr):3012,1603,1526,1469,1430,1358,1281,1265,1190,1144,1092;
1
HNMR(300MHz,DMSOd6):1.93(s,3H),4.794.84(m,4H),5.34(s,2H),7.067.11(m,1H),7.237.26
(m,1H),7.517.58(m,2H),7.84(s,1H),7.99(s,1H);ESIMS(m/z):373.21(M+).

1[2(2Methyl5nitroimidazol1yl)ethyl]4(4nitrophenoxymethyl)1H[1,2,3]triazole(6j):Yield:
54%;mp196198oC;IR(cm1,KBr):3127,2916,1593,1502,1457,1361,1259,1186,1044; 1HNMR
(300MHz,CDCl3):1.99(s,3H),4.82(brs,4H),5.26(s,2H),7.04(d,J=9Hz,2H),7.36(s,1H),8.00(s,
1H),8.20(d,J=9Hz,2H);HRMScalcdforC15H15N7O5:373.3238,found:373.3228(M+).

2{1[2(2Methyl5nitroimidazol1yl)ethyl]1H[1,2,3]triazol4ylmethoxy}benzaldehyde (6k):
Yield:60%;mp180182oC;IR(cm1,KBr):3141,2870,1679,1599,1534,1475,1370,1261,1241,1187,
1049;1HNMR(300MHz,DMSOd6):1.78(s,3H),4.72(brs,2H),4.87(brs,2H),5.33(s,2H),7.087.13
(m,1H),7.40(d,J=6Hz,1H),7.657.72(m,2H),8.04(s,1H),8.19(s,1H),10.33(s,1H);HRMScalcd
forC16H16N6O4:356.3363;found:356.3358(M+).

4{1[2(2Methyl5nitroimidazol1yl)ethyl]1H[1,2,3]triazol4ylmethoxy}benzaldehyde (6l):
Yield:60%;mp170172oC;IR(cm1,KBr):2924,2854,1683,1601,1577,1524,1454,1370,1261,1221,
1172,826;1HNMR(300MHz,DMSOd6):1.83(s,3H),4.76(t,2H,NCH2),4.93(t,2H),5.32(s,2H),
7.23(d,J=8Hz,2H),7.95(d,J=8Hz,2H),8.09(s,1H),8.20(s,1H),9.93(s,1H,CHO); 13CNMR(75.5
MHz,DMSOd6):12.7,46.1,48.8,61.2,115.2,129.8,131.7,133.2,138.3,142.4,151.2,162.7,191.3;ESI
MS(m/z):356.22(M+);Anal.calcdforC16H16N6O4:C,53.93;H,4.53;N,23.58;found:C,54.09;H,4.70;
N,23.78.

1(4{1[2(2Methyl5nitroimidazol1yl)ethyl]1H[1,2,3] triazol4ylmethoxy}phenyl)ethanone
(6m):Yield:54%;mp168170oC;IR(cm1,KBr):3115,2918,1673,1602,1526,1460,1367,1264,1192,
1042;1HNMR(300MHz,DMSOd6):1.78(s,3H),2.49(s,3H),4.68(brs,2H),4.84(brs,2H),5.22(s,

3
2H),7.08(d,J=8Hz,2H),7.89(d,J=8Hz,2H),8.03(s,1H),8.12(s,1H);HRMScalcdforC 17H18N6O4:
370.3629;found:370.3618(M+).

4(2Chlorophenoxymethyl)1[2(2methyl5nitroimidazol1yl)ethyl]1H[1,2,3] triazole (6n):

Yield:63%;mp140142oC;IR(cm1,KBr):3133,2924,1525,1460,1430,1366,1264,1195,1037; 1H
NMR(300MHz,CDCl3):1.98(s,3H),4.79(brs,4H),5.15(s,2H),6.666.75(m,2H),7.017.05(m,1H),
7.33(brs,1H),8.00(s,1H);EIMS(m/z):362.32(M+).

4(4Chlorophenoxymethyl)1[2(2methyl5nitroimidazol1yl)ethyl]1H[1,2,3]triazole (6o):
o 1
Yield:57%;mp103106 C;IR(cm ,KBr):3128,2927,1526,1495,1464,1428,1368,1267,1245,1196,
1050;1HNMR(300MHz,DMSOd6):1.78(s,3H),4.70(brs,2H),4.83(brs,2H),5.11(s,2H),7.02(d,J=
9Hz,2H),7.32(d,J=8Hz,2H),8.02(s,1H),8.09(s,1H); 13CNMR(75.5MHz,DMSOd6):12.7,46.1,
48.8,61.1,116.54,124.6,125.4,129.2,133.2,138.3,142.8,151.2,156.7;EIMS(m/z):362.18(M+);Anal.
calcdforC15H15ClN6O3:C,49.66;H,4.17;N,23.17;found:C,49.89;H,4.28;N,23.42.

2{1[2(2Methyl5nitroimidazol1yl)ethyl]1H[1,2,3]triazol4yl}ethanol (7a): Yield: 57%; mp

115116oC;IR(cm1,KBr):3325,3127,2924,1530,1463,1428,1365,1265,1192,1052;1HNMR(300
MHz,DMSOd6):1.82(s,3H),2.69(t,2H),3.51(brs,1H),3.55(t,2H),4.664.68(m,4H),7.72(s,1H),
8.02(s,1H);EIMS(m/z):266.18(M+).

4Bromomethyl1[2(2methyl5nitroimidazol1yl)ethyl]1H[1,2,3]triazole (7b): Yield: 52%; mp

108110oC;IR(cm1,KBr):3127,2947,1526,1461,1429,1369,1268,1199,1117,1028;1HNMR(300
MHz,DMSOd6):1.83(s,3H),3.73(s,2H),4.594.81(m,4H),7.95(s,1H),8.03(s,1H);EIMS(m/z):
314(M+),316(M++2).

1[2(2Methyl5nitroimidazol1yl)ethyl]4phenyl1H[1,2,3]triazole (7c): Yield:59%; mp 178

180oC;IR(cm1,KBr):3124,1527,1460,1367,1263,1192,1149,1082,825,771; 1HNMR(300MHz,
DMSOd6):1.92(s,3H),4.77(brs,2H),4.88(brs,2H),7.317.36(m,3H),7.757.77(m,2H),8.06(s,1H),
8.43(s,1H);HRMScalcdforC14H14N6O2:298.3002;found:298.3001(M+).

2{1[2(2Methyl5nitroimidazol1yl)ethyl]1H[1,2,3]triazol4yl}pyridine(7d): Yield:58%; mp
194196oC;IR(cm1,KBr):2924,2854,1597,151,1461,1424,1367,1268,1191,1087; 1HNMR(300
MHz,DMSOd6):1.89(s,3H),4.76(brs,2H0,4.88(s,2H),7.307.35(m,1H),7.847.89(m,1H),7.97
8.00(m,1H),8.03(s,1H),8.508.57(m,2H);13CNMR(75.5MHz,DMSOd6):12.9,46.1,48.9,119.4,
123.1,124.2,133.2,137.2,138.4,147.4,149.6,151.1;EIMS(m/z):299.11(M+).

4
3{1[2(2Methyl5nitroimidazol1yl)ethyl]1H[1,2,3]triazol4yl}pyridine (7e): Yield: 53%; mp
180182oC;IR(cm1,KBr):2923,2853,1510,1464,1364,1186,1067; 1HNMR(300MHz,CDCl3):2.06
(s,3H),4.844.93(m,4H),7.367.40(m,1H),7.59(s,1H),8.03(s,1H),8.118.15(m,1H),8.598.61(m,
1H),8.94(brs,1H);EIMS(m/z):299.11(M+).