IndianDrugs,45(1),2008,1625

SpectroscopicandInterMolecularStudiesofAntiAIDSDrug:3'Azido2'deoxythymidine
Y.P.Singha*andRatneshDasb

aDepartmentofPhysics,Govt.WomensPolytechnicCollege,Sagar(MP)470001
INDIA,.Email:Y_P_S_2k@Yahoo.com
bDepartmentofChemistry,Dr.H.S.GourUniversity,Sagar(MP),INDIA,470001,
Email:ratnesh_das@breakthru.com

ABSTRACT
The vibrational absorption spectra of 3'Azido2'deoxythymidine (Zidovudine) have been studied. The
spectrawereanalysedbasedonsemiempiricalquantummechanical(AM1)and(PM3)calculations.AssumingCs
point symmetry, vibrational assignments for the observed frequencies have been proposed. The spectra exhibit
distinct features originating from low frequency vibrational modes caused by intermolecular motion. Normal
modeshavebeencalculatedandanassignmentoftheobservedspectrahasbeenproposed.

Keywords:Zidovudine,FTIRSpectra,Antiaidsdrug,HIV,AM1andMP2calculations

INTRODUCTION

1988.InthesolidstateAZTformsahydrogenbond
network4.

AIDS has ceased to be a mere health

problem and has now acquired dimensions which
perhaps have very few parallels in the history of
mankind. In reality AIDS1 is , not a disease but a
collectionofseventyormoreconditionswhichresult
from the damage done to the immune system and
other parts of the body as a result of infection by
HIV.

Thestudyofdrugcomplexeshaveassumed

much importance, the chemistry of life involves, in

an essential and indispensible way many of the
chemical elements5, 6. The word AIDS inspires fear,
widespread diffusion of information about this
diseasehasmadepeopleawareofitslethaleffects.
Nodal research in the medicinal and biological
sciencesarebeingpersuedallovertheworldwitha

Thereareanumberofdrugsthathavebeen

consideredastobeantiHIV.Thedrugslike3'Azido
2'deoxythymidine (AZT) and ribavirin appear most
promising because both cross the bloodbrain
barrierandcanbetakenorally,andinearlytraities
theydonotcauseserioussideeffects.

viewforachievimgbetterunderstandingofAIDS,its
causes, symptoms, mode of spreading, diagnostic
treatment and possible cure. Spectroscopis studies
of antiAIDS drug have made a significant
contribution of this noble endeavor of striving to
eliminatethefearofthisdreadfuldisease.

AZTZidovudine,wasthefirstdrugapprovedforthe
treatment of AIDS and HIV infection. Jerome
2

Horowitz first synthesized AZT in 1964 . The crystal

3

structure of AZT was reported by Alan Howie in

Thecalculationofvibrationalfrequenciesby

computational methods is becoming increasingly

important in many areas7. Infra red and Raman

The accuracy of the measurements was

spetraofmoleculesintheirgroundelectronicstates
8

werepredictedbymolecularorbitaltheory .

estimatedtobewithin3cm1andtheresolutionwas

Conformational analysis of AZT structure and other

betterthan2cm1throughtheentirespectra.

related drugs have been previously reported at

semiempirical and ab initio levels of theory

79

O17
C1

N2

H30
O15

studyofthedipolepolarizabilityofAZTdrug.

H31

H20

H29
C13
H24

O9
H 2 5H 2 8

N16

H26
N 32

view to understand the spectroscopy of this drug

H27
C6

C12
N14

Thusthepresentstudyhasbeenundertakenwitha

H23

C5
N4

O 19

Hernndez10 at al reported an ab initio HF and DFT

C8
C7

C3

H22

H21

H18

3'Azido2'deoxythymidineorZidovudine

and we compared experimental results with

EmpiricalFormula

C10H13N5O4

MolecularWeight

267.24

calculated frequencies using force matrix method

andMOPACmethod.
Thus the present study has been

Figure1:StructureandFormulaofZidovudine

undertaken with a view to understand the

spectroscopy of this drug and we compared

RESULTSandDISCUSSIONS

experimental results with calculated frequencies

using force matrix method and MOPAC method.
Probably,thisisthefirsttimewhenwearereporting
experimental frequencies with AM1 and PM3
calculatedfrequenciesbecausewehadsurveyedlot
ofliteraturebutwefoundnothing.
EXPERIMENTAL
All the chemicals used to prepare
experimental sets were of Analar/BDH grade.
ZidovudinewaspurchasedfromCiplaIndiaLtd.

I.R. Spectrum has been recorded using KBr

disc in solid phase in the range 4004000cm1 on

PerkinElmerspectrometerModel397.
Preparation of KBr Pallets: A small amount
of finally grounded solid sample was intimately
mixedwithabout100timesormorethanitsweight
of Potassium bromide powder. The finely ground
mixture was than pressed under very high pressure
in a press (about 10/cm2) to form a small pallet
(about12mmthickand1cmindiameter).

Zidovudineisoneofthecomplexstructured
drugs. The infra red spectrum of this drug is
presentedinfigure2.

The theoretical prediction of vibrational

spectra is of practical importance for the

identification of known and unknown compounds,
and has become an important part of spectro
chemicalandquantumchemicalinvestigations11.

Wecangetinformationfromcomputational

vibrational spectra only when we compare it with

experimentalspectrum.Thevaluesofbondanglein
angstroms, bond angles in degrees and Cartesian
coordinates are presented in Table 1. The
experimental results are compared with those
obtained by AM1 and PM3 method. These
calculationsaredoneonthebasisofpreciseset.The
calculated bond distances and bond angles comes
outtobeinagreementwiththeexperimentaloneas
reportedbyRoeyetal12.

The vibrational infrared frequencies were

ACKNOWLEDGEMENTS

alsocalculatedonthebasisofAM1andPM3precise
set of MOPAC as shown in table 3. 3'Azido2'
deoxythymidinecontains32atomssothatithas90
normal modes. The calculated normal modes are
distributed among 60 a and 30 a species of Cs

The authors are grateful to Director, DTE

Madhya Pradesh, Bhopal and Head, Department of
Chemistry, Dr. H.S.Gour University, Sagar (MP),
India.
REFRENCES

symmetrygroup.
The table 3 also shows that PED

1.

contributions for 90 normal modes. These

2.

assignments are partly based on the calculated

3.

frequencies. As the table 3 is selfexplanatory, we

shalldiscusshereonlysomeimportantpoints.

4.

Only the frequencies from 300cm1 to

2200cm1 have been taken into consideration. The

experimentalbandsareshowninfigure2.Allspectra

5.

exhibit fine structures. Experimental OH stretching

bands are not shown; only theoretically calculated
frequenciesaretakenintoaccount.

Figure 3 and 4 shows agreement between

the experimental and calculated wave numbers

(AM1 and PM3). The graph is linear which shows
thattheoreticalandexperimentalresultsareingood
agreement.

6.

7.

8.

CONCLUSIONS
Theoretical

semiempirical

quantum

mechanical AM1 and PM3 calculations of the

9.

geometry and vibrational frequencies of the AZT

drugarepresentedinthispaperandcomparedwith

10.

infrared spectra. The calculated geometries and

frequencies agree well with the experimental ones,
buttherearesomedifferencesbetweenfrequencies
mainly

due

to

intermolecular

interactions,

anharmonicityandcomputationalbasisset.

11.

DossierP,AIDSandThirldWorld,ThePanon
InstituteofLondon(1988)
Yarchoan R, Mitsuya H, Broder S. AIDS
therapies.SciAm,259(4):1109,(1988)
AlanHowie,r.a.howie@abdn.ac.uk,
www.abdn.ac.uk/chemistry/research/rah/r
ah.hti,(2006)
I.D.Dyer,J.N.Low,P.T.Tollin,H.R.Wilsonand
R. Alan Howie; Structure of 3'Azido2'
deoxythymidine, AZT; Acta Crystal,; C44,
767769,(1988)
A.P.Scott, L.J.Radom,; Harmonic vibrational
frequencies: An evaluation of HF, MP,
Quadratic configuration Interaction, DFT
and Semiempirical scale factors; J. Phys
ChemA;;100,1650216513,(1996)
M.W.Wong;
Vibrational
frequencies
predictionusingDFT;ChemPhys.Lett;;256,
391399,(1996)
M. Sabio, S. Topiol; A conformational
analysis of 3'Azido2'deoxythymidine; J.
Comput.Chem,13,478491,(1992).
M. T. Baumgartner, M. I. Motura, R. H.
Contreras, A. B. Pierini, M. C. Brin;
Conformational
studies
of
novel
antiretroverial analogs of Zidovudine;
Nucl.eos. Nucleot. & Nucleic Acids, 22, 45
62,(2003).
H. Xinjuan, H. Mingbao, Y. Dayu; Density
functionof3'Azido2'deoxythymidine;Sci.
China Serie B: Chemistry, 45, 470474,
(2002).
Javier Hernndez, Humberto Soscn,and
Alan Hinchliffe, The dipole polarazibility of
the most stable conformation of 3'Azido
2'deoxythymidine; Internet Electronic
Journal of Molecular Design, Volume 2,
Number9,Pages589598,(2003).
M. Szafran, J. Koput, Z. Dega, A. Katrusiak ,
M.PankowskiandK.Stobiecka;Xray,MP2,
DFTstudiesofthestructureandvibrational

spectraoftrigonelliniumchloride;Chemical
Physics,289,201219,(2003)
12. V.P. Roey, J.M. Salerno, W.L. Duax, C.K.Chu,
M.K.Ahn, R.F. Schinazi; Solid state
conformation
of
anti
human

immunodeficiency virus type1 agents:

Crystal structure of three AZT; J. Am. Soc,
110,22772282,(1988)

Fig2:I.R.Spectraof3'Azido2'deoxythymidine/Zidovudine(AZT)
Table1.Optimizedbonddistances(inAngstrom),bondanglesandtorsionangles(indegrees)ofAZT.
BondAngle(Degree)

Bondlength(A )
14

Bond

Experimental

AM1
Calculation

PM3Calculation

C1N2
N2C3
C3N4
C5N4
C5C7
C7C1
C1O17
C7C8
C8H21
N2H18
C3O19
C5H20
N4C10
C10O9
C10C6
C6C12
C12C11
C11O9
C11C13
C13O15
C12N14
N14N16
N16N32
N32N14

1.384
1.368
1.372
1.386
1.332

1.197
1.503

1.201

1.463
1.391
1.535
1.529

1.414
1.515
1.405
1.467
1.231
1.100

1.391
1.391
1.391
1.391
1.391
1.391
1.107
1.542
1.694
1.095
1.095
1.095
1.456
1.401
1.598
1.581
1.946
1.511
1.591
1.483
1.492
1.316
1.245
1.729

1.391
1.391
1.391
1.391
1.391
1.391
1.113
1.557
1.703
1.109
1.116
1.115
1.498
1.451
1.603
1.608
1.993
1.549
1.612
1.506
1.507
1.359
1.281
1.937

Table2:CartesianCoordinates

BondAngle

C1N2C3
C1N2H18
N2C1O17
N2C3O19
C3N4C5
C7C8H21
H21C8H22
C7C5H20
C5N4C10
N4C10H27
N4C10O9
H27C10C6
C11O9C10
C10C6C12
C10C6H26
O9C11C12
C11C12C6
C11C13O15
C13O15H31
H30C13O15
C6C12N14
C5C7C1
C5C7C8
C13C11O9
N4C10C6
N14N16N32
N16N32N14
N32N14N16
N2C3N4

Experimental14

AM1Calculation

PM3Calculation

130.4

123.1

119.1

117.9

107.8

110.2
98.8

104.7
105.6
113.5

111.1
120.0
120.0
120.4
162.3

113.0

120.000
120.000
120.000
120.000
120.000
77.245
69.517
120.000
118.953
120.269
108.329
77.519
111.538
99.157
106.681
103.184
105.995
114.382
141.357
39.462
113.346
121.634
119.924
120.996
160.534
57.165
69.378
56.00
110.0

120.000
120.000
120.010
120.00
120.060
78.058
70.349
121.658
119.359
121.647
109.264
76.927
112.327
100.062
106.992
104.194
104.367
115.216
140.581
40.421
114.624
120.347
120.068
120.624
159.458
58.619
70.058
55.0274
111.621

AM1
NO.ATOMXYZ

1C.0000.0000.0000
2N1.4008.0000.0000
3C2.10061.2117.0000
4N1.40022.4246.0000
5C.00102.4250.0000
6C4.20362.5236.7786
7C.69941.2119.0000
8C1.80251.2121.0000
9O4.71451.14461.2160
10C5.09833.52911.5247
11C6.22871.36731.3141
12C6.33432.73961.9949
13C5.8960.02701.3141
14N7.21374.13691.9949
15O6.58821.00341.3141
16N6.48515.24081.9949
17O.5515.9553.0000
18H1.9522.9554.0000
19O3.20371.2117.0000
20H.55043.3804.0000
21H2.3927.3261.0000
22H2.93861.4685.0000
23H2.71412.1686.0000
24H7.14331.61331.3141
25H5.84772.2723.3594
26H5.10782.5105.3594
27H5.29264.39521.5247
28H3.66863.8305.7786
29H5.1802.85741.3141
30H4.9213.25901.3141
31H7.92811.60391.3141
32N5.00706.08411.9949

Table3

PM3
NO.ATOMXYZ

1C.0000.0000.0000
2N1.4008.0000.0000
3C2.10061.2117.0000
4N1.40022.4246.0000
5C.00102.4250.0000
6C2.24673.4319.8402
7C.69941.2119.0000
8C1.80251.2121.0000
9O2.83232.28891.6796
10C3.46684.2561.3927
11C4.13311.9632.9355
12C4.69623.3511.5971
13C4.57361.1318.9355
14N5.34583.6474.5971
15O5.5266.6188.9355
16N5.10564.8577.5971
17N4.54774.4753.5971
18O.5515.9553.0000
19H1.9522.9554.0000
20O2.70781.1640.0000
21H.55043.3804.0000
22H1.7139.0315.0000
23H2.3664.4990.0000
24H2.08731.9235.0000
25H4.73432.5012.9355
26H3.99692.8504.5971
27H3.08753.5391.2340
28H3.85124.6240.3927
29H2.66793.9207.8402
30H3.7636.7315.9355
31H5.29041.4621.9355
32H6.4823.6999.9355

Experimental,CalculatedFrequenciesandPotentialDistributioninZidovudine(AZT)

Assignment

Experimental
Frequencies
(incm

MOPACCalculatedFrequencies(incm
AM1

PM3

PotentialEnergy
Distributionb

AtomPair/Energy
Contribution
a
(in%)

Speciesa
1
2
3
4
5

3468.99
3451.41
3331.98
3190.12
3143.81

3485.70
3356.85
3294.36
3166.24
3087.32

6
7
8

3142.39
3094.79
3084.79

3077.40
3073.82
3069.05

9
10

3072.90
3055.24

2993.62
2988.79

11

3039.39

2907.71

12

3020.78

2805.41

13

3015.48

2639.90

14

2512.86

2622.94

15
16

2170
1887

2162.78
1842.68

2163.94
1949.16

17

1801

1811.70

1894.66

18

1725

1728.36

1720.75

19

1623

1653.82

1605.83

20

1552.48

1543.15

21

1549.01

1532.50

22

1539.82

1500.53

23

1483

1479.92

1472.42

24

1476.10

1469.10

O15H31(99.5)
N2H18(99.3)
015H31(99.5)
C10H27(97.7)
C8H22(32.9)
C8H21(29.2)
C8H23(24.7)
C5H20(86.0)
C11H24(54.9)
C6H26(70.1)
C6H28(28.4)
C13H29(92.1)
C8H22(55.8)
C8H21(39.2)
C8H23(66.4)
C8H21(26.5)
C11H24(38.8)
C6H28(68.4)
C6H26(29.8)
N16N32(71.7)
N14N16(28.0)
C12N14(23.6)
C10H27(42.2)
C12N14(16.7)
C11C12(15.5)
C5C7(21.7)
C3C5(15.7)
C3N4(10.7)
C3N4(19)
C3O19(14.1)
C3N4(14.8)
C3O19(18.1)

s(HydroxylGroup)
a(ThymineRing)
a(HydroxylGroup)
a(AzideRing)

s(ThymineRing)

s(ThymineRing)
s
s(FurancoseRing)

s(HydroxylGroup)
s(ThymineRing)

a(ThymineRing)

a(FurancoseRing)
a(FurancoseRing)
a(AzideRing)
s(FurancoseRing)
s+s+s
(FurancoseRing)

s+s+s
(ThymineRing)

s+s
(ThymineRing)
a+a
(ThymineRing)

N4C5(24.1)
C5C7(15.6)
O15H31(50.3)
C13H29(11.5)
C13O15(11.1)
C12N14(35.3)
N14N16(29.4)
C13O15(22.6)
C11C13(18.4)
C13H29(15.5)

s+s
(ThymineRing)
s+s+s
(HydroxylGroup)

s+s
(AzideRing)
a+a+a
(HydroxylGroup)

C7C8(25.7)
C1C7(15.0)
C5C7(13.2)

s+s+s
(ThymineRing)

25

1460.51

1451.15

C6H26(20.1)
C6C10(16.8)
C6H28(15.8)
N2H18(29.2)
N2C3(10.4)
C11C12(21.5)
C1C7(13.1)
C8H22(10.7)
N2H18(10.6)
C6H28(12.5)
C6H26(12.4)

26

1437.58

1425.70

27
28

1414

1436.61
1412.89

1419.17
1429.43

29

1395.64

1382.55

30

1384.84

1377.64

C11H24(17.9)

31

1377.14

1370.14

C11H24(14.9)

32

1376.39

1364.90

33
34

1324

1372.71
1320.69

1360.08
1330.35

35

1318.57

1316.84

36

1286.42

1280.66

37

1281.31

1278.95

38

1275.97

1269.91

39

1172.30

1174.33

40

1151

1171.21

1169.71

41

1118.52

1112.05

42

1106

1103.83

1110.50

43

1072.51

1062.79

44

1058.95

1049.28

45

1050.84

1034.86

46

1013

1012.02

1006.45

47

1001

966.26

976.38

48
49

927

922.03
854.58

931.15
863.26

C8H22(34.9)
C8H23(21.5)
C3O19(11.5)
C13H29(25.1)
C11C13(13.8)
C1N2(30.0)
C1O17(13.3)
C1C7(12.6)
C5H20(28.1)
N2C3(12.7)
N4C5(11.7)
C13H29(17.6)
C12N14(14.2)
C6H28(23.8)
C13H29(22.6)
C13H29(19.6)
C6H28(10.0)
C11H24(16.9)
C11C13(14.0)
C11C13(18.9)
C11H24(17.8)
C5H20(22.5)
C1N2(14.4)
C3N4(14.3)
C8H23(36.6)
C8H21(21.0)
C8H22(17.3)
C8H23(11.5)
C8H21(24.7)
C8H22(26.8)
C6C10(19.5)
C10H27(10.6)
C6C10(18.6)
C6H26(17.2)
C6H28(15.9)
C11H24(24.1)
C11C12(19.2)
C1C7(12.9)
C5C7(13.6)

50

694.90

715.21

C6C10(11.0)

s+s+s
(FurancoseRing)

s+s
(ThymineRing)
s(FurancoseRing)
s+s+s
(ThymineRing)

s+s
(FurancoseRing)

s(FurancoseRing)

a(FurancoseRing)

U(ThymineRing)

s(ThymineRing)
s+s
(HydroxylGroup)
s+s+s
(ThymineRing)
s+s+s
(ThymineRing)

s(HydroxylGroup)
s(AzideRing)
s(FurancoseRing)
s(HydroxylGroup)
a(FurancoseRing)
a(HydroxylGroup)
s(FurancoseRing)
s(HydroxylGroup)
a(HydroxylGroup)
a(FurancoseRing)
s+s+s
(ThymineRing)
s+s+s
(ThymineRing)
a+a+a
(ThymineRing)
s+s
(FurancoseRing)
s+s+s
(FurancoseRing)

s+s
(FurancoseRing)
s(ThymineRing)
a(ThymineRing)

s(FurancoseRing)

51

574

574.24

562.87

52
53
54
55
56
57

482

311

490.62
456.07
417.19
367.44
322.41
305.67

450.83
417.07
402.02
354.55
362.60
317.91

58

236.18

225.89

59

144.79

15.47

60

112.24

77.84

Assignment

Experimental
Frequencies
(incm

C13O15(18.7)
C11C13(16.2)
C1C7(10.5)
O15H31(22.4)
N14N16(11.8)
C3015(37.0)
N14N16(21.9)
C6C10(14.5)
C6H28(21.1)
C6H26(18.9)
C6C10(24.5)
C6H28(20.1)
C6H26(19.9)
C6C10(13.4)
C10H27(13.0)
C7C8(24.5)
C8H21(21.2)
C8H22(20.5)

MOPACCalculatedFrequencies(incm
AM1

PM3

rocking
(HydroxylGroup)
s(ThymineRing)
s(HydroxylGroup)
s(AzideGroup)
s(HydroxylGroup)
a(AzideGroup)
s+s+s
(FurancoseRing)
a+a+a
(FurancoseRing)
s+s
(FurancoseRing)
a+a
(ThymineRing)

PotentialEnergy
Distribution

AtomPair/Energy
Contribution(in%)

Speciesa
1

1387

1381.07

1373.55

1350.60

1363.73

1246.77

1274.74

1191

1213.16

1206.15

5
6
7

914

817

944.84
857.71
815.85

981.27
885.26
813.62

741

752.51

797.30

696.64

699.38

10
11

607

696.22
624.34

671.40
647.93

12

563.95

562.70

C8H21(47.9)
C8H23(35.4)
C6H28(17.3)
C6H26(15.0)
C13H29(54.1)
O15H31(12.7)
C6H26(27.1)
C10H27(11.8)
C13H29(11.8)
C5H20(65.0)
C6C10(11.9)
C10H27(24.8)
C6H26(13.9)
C6H28(13.7)
C1C7(31.7)
C1N2(21.6)
C1O17(21.5)
C3N4(27.3)
N2C3(21.3)
C3O19(20.8)
N2H18(80.2)
C1N2(21.1)
N2C3(14.8)
C1C7(13.8)
C3C5(14.5)

13

537.38

555.47

C6C10(11.6)

s(ThymineRing)

s(FurancoseRing)

s+s(Hydroxyl
Group)
a(FurancoseRing)
a(HydroxylGroup)

s(ThymineGroup)
s(FurancoseRing)
s(Furancosering)

s(ThymineGroup)

s(ThymineGroup)

s(ThymineGroup)
a(ThymineGroup)

Rocking(Thymine
Ring)
a(FurancoseRing)

14

486.23

489.36

C11H24(11.3)

15

461.91

453.46

16

441

448.37

432.65

17

406

427.19

412.02

C12N14(12.0)
C11C12(10.2)
N16N32(52.0)
N14N16(41.6)
N14N16(11.8)

18

355

344.89

394.32

19

337.41

377.95

20

180.47

191.89

21

167.09

183.81

22

106.61

116.5

23
24

81.07
50.97

71.33
47.41

25

38.55

33.11

26

29.21

27.21

27

28.56

26.8

28

17.86

18.42

29
30

12.50
10.10

13.6
10.8

O15H31(21.8)
N14N16(13.2)
C7C8(20.5)
N4C5(13.0)
O9C110(12.1)
O9C11(11.4)
C1N2(20.3)
N2C3(20.0)
N2H18(17.7)
C11C12(21.4)
C11C13(20.6)
C11H24(18.8)
C3O19(13.6)
C13O15(19.0)
C11C13(16.2)
O15H31(11.9)
C13O15(17.5)
C11C13(12.9)

C7C1(19.8)
C7C5(17.3)
C7C8(12.6)
C10O9(18.6)
C10C6(16.5)
C10H27(12.9)
C8H21(15.6)
C8H23(14.9)
C8C7(11.60

sScissoring
(FurancoseRing)
aScissoring
(FurancoseRing)
sScissoring
(AzideRing)
aScissoring
(AzideRing)
s(HydroxylGroup)
s(AzideRing)
s(ThymineRing)

s(FurancoseRing)

a(ThymineRing)

s(FurancoseRing)

s(ThymineRing)
a(HydroxylGroup)

Rocking
(HydroxylGroup)
Rocking
(ThymineRing)
Rocking
(AzideRing)
Rocking
(ThymineRing)
Twisting
Twisting

Onlycontributions>10%arelisted
=stretching,=inplanebending,=outofplanebending,s=symmetric,a=asymmetric

Fig3:CorrelationDiagramforExperimentalVsCalculatedFrequencies(AM1method)

Fig:4CorrelationDiagramforExperimentalVsCalculatedFrequencies(PM3method)