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Abstract: Quantitative structure activity relationship (QSAR) model of a series of 40 antiHIV-5-phenyl-1-Himidazole derivative were developed with the help of Quantum chemical descriptors. Molecular modeling and
geometry optimization was carried out with CAChe prosoftware .Calculation of descriptors and multilinear
regression analysis was done using Project Leader software. Various QSAR model of different combination for
each set were developed and five model has been selected on the basis of correlation coefficient .Among them
the best model is judged on the basis of values of statistical parameters such as Standard error (SE), Standard
error of estimation (SEE), t-value, p- value and Degree of freedom (DOF) that were calculated by Statistica and
secondly a direct relationship between heat of formation and observed activity is reported. Heat of formation
(Hf) can alone be helpful for searching of antiHIV-5-phenyl-1-H-imidazole derivative of reliable activities
before their synthesis.
Keyword: QSAR, AntiHIV activity, Heat of formation, Degree of freedom.
I.
Introduction
Acquired immune deficiency syndrome (AIDS) is a disease of the human immune system caused by
the human immunodeficiency virus (HIV)[1-3] .The illness interferes with the immune system making people
with AIDS much more likely to get infections, including opportunistic infections and tumors that do not affect
people with working immune systems. This susceptibility gets worse as the disease continues.
AIDS is the ultimate clinical consequence of infection with HIV, which is a retrovirus that primarily
infects vital organs of the human immune system such as CD4+ T cells (a subset of T cells), macrophages and
dendritic cells. It directly and indirectly destroys CD4+ T cells[4]. Acquired immune deficiency syndrome is most
fatal disorder for which no complete and successful chemotherapy has been developed so far. Recently, QSAR
has gained importance in the field of pharmacological sciences [5]. Quantitative structures Activity Relationships
(QSAR) are predictive tools for a preliminary evaluation of the activity of chemical compounds by using
computer-aided models. The Hohenberg and Khontheorm based DFT [6-8] provide a major boost to the
computational chemistry. The performance of DFT method in description of structural, energetic and magnetic
molecular properties has been reviewed quite substantially in recent time. DFT methods are in general capable
of generating a variety of isolated molecular properties [9-13]. QSAR techniques increase the probability of
success and reduce time and cost involvement in drug discovery process [14-15]. In this article, a Quantitative
structure Activity Relationships (QSAR) for forty derivative of anti-HIV 5-phenyl-1-H-imidazole is presented.
This study is mainly based on quantum chemical parameter and the quality of the predictions will be adjudged
by correlation coefficient and cross validation coefficient. The descriptors or the combination of descriptors
providing the best result will be recognized and employed for prediction purpose. This will be helpful in
predicting the activity of any new derivative of required activity.
II.
Experimental
We have based our QSAR study on a series of 5-phenyl-1-H-imidazole derivatives on the following reactivity
indices:
1. Molecular weight (Mw)
2. Heat of formation (Hf)
3. Total energy(TE )
4. HOMO energy(HOMO)
5. LUMO energy(LUMO)
6. Absolute hardness(
7. Electronegativity(
DOI: 10.9790/5736-08612735
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27 |Page
4
Although the Hard & Soft Acids and Bases concept was introduced more than three decades ago by
Pearson. The first unambiguous definition of Hardness and Softness was given by Parr and Pearson in early 80s
[16]
, they defined global Hardness as:
r
r
5
Where E is the total Energy, N is the number of electrons of the chemical species and v(r) is the external
potential.
The corresponding global softness S, which bears an inverse relationship with the global hardness, is
defined as in equation [17],
S r
6
The operational definition of global hardness and global softness are obtained by finite differential
approximation of eq-1[18]
= 1 / 2 (IP-EA)
7
S = 1 / (IP-EA)
8
Where IP is the Ionization Potential and EA is the Electron Affinity of the chemical. According to the
Koopmans theorem the IP is simply the eigen value of HOMO with change in sign and EA is the eigen value of
LUMO with change in sign. [19] Thus,
LUMO
9
LUMO
LUMO
LUMO
12
Parr _et.al [20] have shown that the electronegativityof any chemical species is equal to the negative
value of chemical potential . Indeed it follows rigorously that.
13
Where I and A are ionization potential and electron affinity of molecule. The equation 13 may be
written as
A = 2 - I
14
Density functional theory provides a quantum mechanical justification for electronegativity. A concept
used intuitively for a long time and validates Sanderson's postulates [21] that when two or more atoms combine to
form a molecule, their electronegativity gets equalized and a unique electronegativity exists everywhere in a
molecule. Now by putting the value of ionization potential (IP) of an atom in molecule in equation 14 we get
electron affinity (EA) of that atom of the molecule as
EA= 2IP
15
According to Koopman's theorem I and A are the eigen value of HOMO and LUMO respectively with
change in sign. Therefore from equation 11 and 15 we get
EA = (HOMO + LUMO) - (IP)
16
The forty derivatives of anti-HIV 5-phenyl-1-H-imidazole [22] used as study material are listed in Table I-II
along with their observed biological activity. For QSAR prediction, the molecular modeling and geometry
optimization have been carried out with CAChe pro software. The calculation of quantum chemical descriptors
has been done by MOPAC2007 using DFT B88-LYP method. For regression analysis, we used the Project
program associated with CAChe Pro software of Fujitsu. Various regression equations were developed for
prediction of activity.
DOI: 10.9790/5736-08612735
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28 |Page
N
R2
R
1
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29 |Page
IV.
Conclusion
The QSAR models developed by quantum chemical descriptors for the first and second set of antiHIV5-phenyl-1-H-imidazole derivatives provide higher values of correlation coefficients(r^2).The best model
between two set have been selected on the basis of values of correlation coefficient followed by other regression
quality parameters calculated by statistical software. which are indicated in Fig.2 and Fig.3 respectively.
Set no.
1
2
SE
0.0690
0.0361
SEE
0.1023
0.1001
t-value
14.2421
15.4579
p-value
0.0000
0.0000
DOF
0.9684
0.9861
VC
3
3
VU
MW, Hf ,LUMO
Hf, HOMO, LUMO
r2
0.822225
0.937130
The structural analysis of various derivatives has shown that halo group substitution at A & B generally
increases the observed activity. Secondly it has also been reported that there is a direct relationship between
reported biological activity and heat of formation (Hf).Thus, heat of formation alone can be helpful for searching
out of anti-HIV 5-phenyl-1-H-imidazole derivatives of reliable activities before their synthesis.
DOI: 10.9790/5736-08612735
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30 |Page
[12].
[13].
[14].
[15].
[16].
[17].
[18].
[19].
[20].
[21].
[22].
Table I: Structural Features and Observed Activity Data of First Set of Anti-HIV5-phenyl-1-H-imidazole
derivatives
S. No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
A
3-Cl
2-Cl
4-F
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
H
3-Br
2,5-Cl
3-NO2
3-F
3-CH3
3-CH3
3-Cl
3-CH3
3-Cl
3-OCH3
B
H
H
H
H
3-Br
4-Br
3-Cl
4-Cl
4-OCH3
H
H
H
H
H
H
H
H
H
H
H
R1
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
(CH3)2CH
C2H5
C2H5
C6H5
3-CH3
R2
SH
SH
SH
SH
SH
SH
SH
SH
SH
SH
SH
SH
SH
SH
SH
SH
SH
SH
SH
SH
Obs. Act.
1.176
0.791
0.657
0.872
1.357
1.478
1.509
1.389
1.412
0.718
1.354
0.832
1.316
0.966
1.054
1.370
1.409
1.271
1.440
1.420
Table II: Structural Features and Observed Activity Data of Second Set of Anti-HIV5-phenyl-1-Himidazole derivatives
S. No.
1
2
3
A
3-Cl
3-CH3
3-Cl
DOI: 10.9790/5736-08612735
B
3-CN
3-CN
3COCH3
R1
3-CH3
3-CH3
3-CH3
R2
SH
SH
SH
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Obs. Act.
1.003
1.341
1.172
31 |Page
3-Cl
3-CH3
4-C2H5
4-CH3S
3-Cl
3-Cl
3-Cl
H
3-CH3
4-F
4-CH3
3,5CH3
3-OCH3
3-Cl
3-CH3
3-Cl
3-CH3
3-COOH
3-COOH
H
H
H
3-Br
3-Cl
H
H
H
H
H
H
3-CN
3-CN
3-CONH2
3-CONH2
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
SH
SH
SH
SH
H
H
H
H
H
H
H
H
H
H
H
H
H
0.921
0.728
1.463
1.275
1.757
1.785
1.923
1.282
1.568
1.511
1.555
1.690
1.463
1.434
1.350
0.584
0.790
MW
314.812
314.812
298.357
314.812
393.708
393.708
349.257
349.257
344.838
280.367
359.263
349.257
327.38
298.357
294.394
322.447
328.839
308.42
376.883
310.393
Hf
134.099
47.036
97.519
117.618
122.941
98.683
109.644
98.178
71.36
140.638
139.929
67.709
164.678
97.635
227.73
219.657
112.745
225.241
152.444
95.891
TE
-145.576
-145.746
-149.72
-145.753
-155.648
-155.658
-157.524
-157.407
-164.955
-133.808
-143.927
-157.389
-167.317
-149.72
-141.27
-155.318
-152.912
-148.288
-174.781
-153.358
HOMO
-5.732
-6.39
-5.735
-5.494
-5.566
-6.706
-5.538
-6.637
-5.624
-5.643
-5.709
-4.303
-5.719
-5.786
-5.762
-5.728
-5.501
-5.62
-5.546
-5.593
LUMO
-0.724
-1.943
-0.856
-0.956
-1.134
-3.055
-1.096
-2.926
-1.706
-0.766
-1.108
-1.523
-1.248
-0.781
-0.955
-1.069
-0.954
-1.234
-0.981
-0.92
-3.228
-4.166
-3.296
-3.225
-3.35
-4.881
-3.317
-4.782
-3.665
-3.205
-3.409
-2.913
-3.483
-3.284
-3.359
-3.399
-3.227
-3.427
-3.264
-3.256
2.504
2.224
2.439
2.269
2.216
1.826
2.221
1.856
1.959
2.438
2.3
1.39
2.236
2.502
2.403
2.33
2.273
2.193
2.282
2.337
Obs. Act.
1.176
0.791
0.657
0.872
1.357
1.478
1.509
1.389
1.412
0.718
1.354
0.832
1.316
0.966
1.054
1.37
1.409
1.271
1.44
1.42
MW
339.822
339.822
374.864
358.822
352.43
308.42
326.454
283.76
362.656
318.205
249.315
263.341
267.305
263.341
277.368
279.341
308.77
288.351
326.785
306.366
Hf
154.53
154.53
37.797
29.878
131.625
126.28
142.207
95.461
103.222
176.1
188.008
178.655
144.37
178.647
168.131
151.48
217.639
212.093
70.825
52.891
DOI: 10.9790/5736-08612735
TE
-158.542
-158.543
-184.487
-175.479
-178.33
-148.156
-150.159
-137.265
-147.156
-149.032
-125.497
-132.684
-141.41
-132.685
-139.879
-144.875
-150.055
-145.473
-163.927
-159.615
HOMO
-5.679
-5.68
-5.462
-5.606
-5.885
-5.643
-5.661
-8.958
-9.028
-6.763
-6.6
-6.557
-6.664
-6.557
-6.564
-6.58
-6.908
-6.832
-9.204
-9.05
LUMO
-1.442
-1.442
-0.853
-1.35
-1.442
-0.609
-0.784
-0.495
-0.59
-4.209
-4.04
-4.039
-4.169
-4.04
-4.01
-3.994
-4.352
-4.305
-1.012
-0.648
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-3.56
-3.561
-3.157
-3.478
-3.664
-3.126
-3.222
-4.727
-4.809
-5.486
-5.32
-5.298
-5.416
-5.299
-5.287
-5.287
-5.63
-5.569
-5.108
-4.849
2.119
2.119
2.305
2.128
2.221
2.517
2.439
4.232
4.219
1.277
1.28
1.259
1.248
1.258
1.277
1.293
1.278
1.263
4.096
4.201
Obs. Act.
1.003
1.341
1.172
0.921
0.728
1.463
1.275
1.757
1.785
1.923
1.282
1.568
1.511
1.555
1.69
1.463
1.434
1.35
0.584
0.79
32 |Page
PA1
0.985
0.871
0.589
0.798
1.258
1.389
1.476
1.375
1.364
0.689
0.975
0.824
0.956
0.8974
1.045
1.27
1.35
1.125
1.232
1.356
PA2
1.145
0.745
0.642
0.789
1.236
1.365
1.457
1.345
1.345
0.568
1.347
0.984
1.342
0.9831
1.12
1.156
1.258
1.257
1.325
1.37
PA3
1.258
0.745
0.652
0.826
1.235
0.981
1.64
1.235
1.356
0.687
1.324
0.875
1.1235
0.897
1.23
1.59
1.32
1.258
1.357
1.45
PA4
1.234
0.897
0.599
0.845
1.574
1.347
1.324
1.389
1.456
0.786
1.324
0.852
1.324
0.897
1.024
1.235
1.326
1.257
1.239
1.349
PA5
1.098
0.465
0.637
0.489
0.985
1.357
1.556
1.69
1.684
0.687
1.324
0.875
1.1235
0.897
1.23
1.256
1.389
1.542
1.232
0.987
O. Activity
1.176
0.791
0.657
0.872
1.357
1.478
1.509
1.389
1.412
0.718
1.354
0.832
1.316
0.966
1.054
1.37
1.409
1.271
1.44
1.42
PA1
1.002
1.587
1.562
1.676
1.429
1.425
1.351
0.567
0.72
1.467
1.147
0.911
0.435
1.511
1.274
1.733
1.78
1.982
1.124
1.516
PA2
1.003
1.593
1.777
1.935
1.611
1.337
1.421
0.546
0.864
1.5
1.158
0.852
0.631
1.552
1.247
1.715
1.705
1.88
1.109
1.567
PA3
1.008
1.594
1.592
1.558
1.578
1.482
1.364
0.47
0.758
1.428
1.142
0.719
0.724
1.519
1.276
1.791
1.776
1.904
1.243
1.547
PA4
1.008
1.194
1.572
1.552
1.478
1.354
1.461
0.47
0.753
1.456
1.122
0.813
0.629
1.519
1.279
1.681
1.756
1.804
1.273
1.529
PA5
1.005
1.594
1.552
1.556
1.378
1.482
1.262
0.57
0.655
1.425
1.132
0.819
0.726
1.519
1.295
1.751
1.766
1.905
1.283
1.533
O.A.
1.003
1.568
1.555
1.69
1.463
1.434
1.35
0.584
0.79
1.341
1.172
0.921
0.728
1.463
1.275
1.757
1.785
1.923
1.282
1.511
SE
0.1011
0.0735
0.1153
0.0690
0.1040
SEE
0.1159
0.0853
0.1464
0.1023
0.1682
t-value
9.7230
13.7792
7.2463
14.2421
5.9487
p-value
0.0000
0.0000
0.0000
0.0000
0.0000
DOF
0.8312
0.9086
0.7305
0.9684
0.6441
VC
3
3
3
3
4
VU
Hf, MW, HOMO
Hf, MW,
Hf, MW,
MW, Hf ,LUMO
Hf, TE ,MW,
r2
0.815118
0.8204
0.819805
0.822225
0.819197
SE
0.0377
0.0361
0.0371
0.0640
0.0366
SEE
0.0679
0.1001
0.0650
0.1058
0.0594
DOI: 10.9790/5736-08612735
t-value
23.2244
15.4579
14.2941
14.5491
26.6651
p-value
0.0000
0.0000
0.0000
0.0000
0.0000
DOF
0.9659
0.9861
0.9688
0.9173
0.9739
VC
3
3
3
3
3
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VU
Hf, MW, LUMO
Hf, HOMO, LUMO
Hf, ,HOMO
Hf, HOMO,
Hf, LUMO,
r2
0.934311
0.937130
0.934136
0.932136
0.935436
33 |Page
O.A
0.791
0.832
0.966
1.389
1.409
1.44
Hf
47.036
67.709
97.635
98.178
112.745
152.444
O.A
0.657
0.872
1.176
1.316
1.37
Hf
97.519
117.618
134.099
164.678
219.657
O.A
1.412
1.42
1.478
1.509
Hf
71.36
95.891
98.683
109.644
DOI: 10.9790/5736-08612735
O.A
0.728
1.003
1.282
1.35
1.434
Hf
131.625
154.53
188.008
212.093
217.639
0.584
1.275
1.341
1.555
1.568
70.825
142.207
154.53
178.647
178.655
0.921
1.463
1.511
1.69
1.923
29.878
126.28
144.37
168.131
176.1
0.79
1.757
1.785
52.891
95.461
103.222
www.iosrjournals.org
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DOI: 10.9790/5736-08612735
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