Qsar Studies On Dihydroxypyrimidine
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QSAR Studies on Dihydroxypyrimidine-4-carboxamides and Analogues as Novel Potent HIV Integrase Inhibitor SALONI MISHRA*, SHEELA DWIVEDI and J.P.MISHRA Department of Chemistry, Feroze Gandhi College, Raebareli-229001, U.P., India, Email: ([email protected], [email protected]) Mo. No. 00919793453310, 00915352203387
1
QSAR Studies on Dihydroxypyrimidine-4-carboxamides and Analogues as Novel Potent HIV Integrase Inhibitor ABSTRACT: - The QSAR studies have been carried out on Dihydroxypyrimidine-4carboxamides and Analogues which were reported as inhibitor of HIV. The present study was undertaken with a hope to identify the important physico chemical parameters that affect the anti HIV activity of the given series of drug molecules. The best QSAR model thus obtained, have high statistical significance (>99.9%) and moderate correlation coefficient (r=0.841) led us to know that in the pool of descriptors, taken for study, resonance effect and field effect affects positively influencing the aromatic moiety in the meanwhile the electronic effect and field effect of aliphatic moiety affects the biological activity negatively. KEYWORDS: - QSAR, Dihydroxypyrimidine-4-carboxamides and Analogues, Multiparameter Regression, Descriptors
INTRODUCTION Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS), which is one of the world’s most serious health problems. FDA-approved therapies target primarily two viral enzymes, HIV reverse transcriptase1 and HIV protease2, to block the viral life cycle. Multidrug cocktails consisting of a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with two nucleoside reverse transcriptase inhibitors (HAART, highly active
2
antiretroviral therapy) is now the standard for treatment. HIV-1 integrase catalyzes the insertion of the viral DNA into the genome of the host cell 3, which is an essential step in the viral replication cycle, and thus HIV-1 integrase is an attractive target for novel chemotherapy. Integration is a multistep process consisting of three biochemical steps: (i) assembly of a complex with specific DNA sequences at the end of HIV-1 long terminal repeat (LTR) regions, (ii) endonucleolytic processing of the viral DNA to remove the terminal dinucleotide from each 3’ end, and after nuclear entry, (iii) strand transfer, in which the viral DNA 3’ ends are covalently linked to the cellular DNA. Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes required for replication, is a rational target for chemotherapeutic intervention in the treatment of AIDS that has also recently been confirmed in the clinical setting. The present work is on N-benzyl- 5, 6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV integrase-catalyzed strand transfer process4. Thus the main objective of present studies is to design specific inhibitors in the hope that these molecules may be further powerful against HIV. These studies may help for the design and synthesis of better selective inhibitors.
3
EXPERIMENTAL In our study, a set of forty five molecules collected from reference 4 was investigated, the structures of which are displayed in the Table 1. The biological activities of these compounds were reported as the concentration capable of inhibiting 50% of HIV-1 integrase catalytic strand transfer activity (IC50). The inhibitory activity of the compounds was expressed as IC50 value in the micromolar range (μM). The IC50 values were converted into -logIC50 for the use in the QSAR studies. The data set was randomly divided into two subsets; test set and training set which is also marked in the Table 1. Hence all the molecules were first arranged in increasing order of IC50 values and every 4th molecule was selected for test set and the remaining ones for the training set (34 molecules).
OH OH N H N Ar
N
R O
4
Co. No.
Substitution
Ar
Values of the Hansch parameters used
-log IC50
R
ArF
Rπ
ArR
RF
Obs.
Cal.**
Cal.***
CH2Ph
0.10
2.4 4
0.04
0.04
1.0969
1.5122
1.44966
Ph
0.10
1.9 0
0.04
0.08
0.0000
5.2532
5.49636
CH2 hexyl
0.10
0.2 3
0.04
0.00
-1.6988
19.573 3
20.9457
(S)CHCH3Ph
0.10
2.9 8
0.04
-0.06 -1.6988
-1.4184
-1.7327
(R)CHCH3Ph
0.10
2.7 5
0.04
0.00
0.3010
-0.4052
-0.628
CH2CH2Ph
0.10
2.7 5
0.04
0.00
-0.6989
0.9627
-0.628
CH2C6H4(4F)
0.10
2.5 2
0.04
0.00
1.6989
1.4182
1.34102
CH2C6H4(4F)
0.10
1.7 3
0.04
0.47
2.0000
1.3344
1.33339
1.7 3 1.7 3
0.00
0.47
1.2218
1.2086
1.21965
-0.13
0.47
1.2218
1.1254
1.14611
S 1.
2*.
3*.
4.
5#.
6.
7.
8.
S
S
S
S
S
S
S
9.
H
CH2C6H4(4F)
0.00
10* .
Me
CH2C6H4(4F)
-0.04
5
11.
iPr
CH2C6H4(4F)
-0.05
12* . 13. * 14.
PhCH2
CH2C6H4(4F)
-0.08
p-tolyl
CH2C6H4(4F)
-0.08
2-thiazolyl
CH2C6H4(4F)
0.36
15.
2-pyridyl
CH2C6H4(4F)
0.5
CH2C6H4(4F)
0.18
CH2C6H4(4F)
16.
1.7 3 1.7 3 1.7 3 1.7 3 1.7 3 1.7 3
-0.10
0.4 7 0.4 7 0.4 7 0.4 7 0.4 7 0.4 7
1.000 0 1.301 0 1.698 9 1.698 9 1.301 0 1.154 9
1.122 6 0.857 3 1.443 3 1.418 2 1.753 6 1.263 9
1.1431
0.44
1.7 3
-1.03
0.4 7
0.823 9
1.413 9
0.7642
CH2C6H4(4F)
0.02
1.7 3
-0.93
0.4 7
0.698 9
0.962 7
1.01165
CH2C6H4(4F)
0.03
1.7 3
-0.82
0.4 7
0.823 9
1.005 9
1.0491
CH2C6H4(4F)
-0.23
1.7 3
-0.88
0.4 7
0.823 9
1.413 4
1.42343
CH2C6H4(4F)
0.03
1.7 3
-0.91
0.4 7
1.301 0
0.979 9
1.02696
CH2C6H4(4F)
-0.12
1.7 3
-0.77
0.4 7
1.000 0
0.844 8
0.90859
CH2C6H4(4F)
-0.04
1.7 3
-0.76
0.4 7
1.000 0
0.944 3
0.99113
-0.01 -0.01 -0.29 -0.09 -0.52
0.91458 1.13407 1.52235 1.71701 1.27875
OMe
17* .
MeO
MeO
18.
N
19. N
20. N
21.
N
O
22.
N
23* . NH
6
24 .
CH2C6H4(4F)
-0.04
1.7 3
-0.76
0.4 7
0.0969
0.9433 0.99113
CH2C6H4(4F)
-0.04
1.7 3
-0.76
0.4 7
-0.0899 0.9433 0.99113
CH2C6H4(4F)
-0.08
1.7 3
-0.89
0.4 7
0.6989
0.8601
0.91759
CH2C6H4(4F)
-0.11
1.7 3
-0.86
0.4 7
1.0000
0.8345
0.8938
CH2C6H4(4F)
-0.16
1.7 3
-0.96
0.4 7
0.6989
0.7485
0.81725
CH2C6H4(4F)
0.12
1.7 3
-2.10
0.4 7
0.6382
0.7388
0.82773
CH2C6H4(4F)
0.07
1.7 3
-1.03
0.4 7
1.5228
0.9909
1.039
CH2C6H4(4F)
-0.04
1.7 3
-0.76
0.4 7
0.9208
0.9433
0.99113
CH2C6H4(4F)
0.11
1.7 3
-2.07
0.4 7
1.0000
0.7360
0.82472
CH2C6H4(4F)
-0.09
1.7 3
-0.86
0.4 7
1.3010
1.7536
1.71701
N H
25 .
HN
26 . N
27 . N
28 . N
29 .
N N
30 .
O N
31 . N
32 .
N N
33 . N
7
8
1
QSAR Studies on Dihydroxypyrimidine-4-carboxamides and Analogues as Novel Potent HIV Integrase Inhibitor ABSTRACT: - The QSAR studies have been carried out on Dihydroxypyrimidine-4carboxamides and Analogues which were reported as inhibitor of HIV. The present study was undertaken with a hope to identify the important physico chemical parameters that affect the anti HIV activity of the given series of drug molecules. The best QSAR model thus obtained, have high statistical significance (>99.9%) and moderate correlation coefficient (r=0.841) led us to know that in the pool of descriptors, taken for study, resonance effect and field effect affects positively influencing the aromatic moiety in the meanwhile the electronic effect and field effect of aliphatic moiety affects the biological activity negatively. KEYWORDS: - QSAR, Dihydroxypyrimidine-4-carboxamides and Analogues, Multiparameter Regression, Descriptors
INTRODUCTION Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS), which is one of the world’s most serious health problems. FDA-approved therapies target primarily two viral enzymes, HIV reverse transcriptase1 and HIV protease2, to block the viral life cycle. Multidrug cocktails consisting of a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with two nucleoside reverse transcriptase inhibitors (HAART, highly active
2
antiretroviral therapy) is now the standard for treatment. HIV-1 integrase catalyzes the insertion of the viral DNA into the genome of the host cell 3, which is an essential step in the viral replication cycle, and thus HIV-1 integrase is an attractive target for novel chemotherapy. Integration is a multistep process consisting of three biochemical steps: (i) assembly of a complex with specific DNA sequences at the end of HIV-1 long terminal repeat (LTR) regions, (ii) endonucleolytic processing of the viral DNA to remove the terminal dinucleotide from each 3’ end, and after nuclear entry, (iii) strand transfer, in which the viral DNA 3’ ends are covalently linked to the cellular DNA. Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes required for replication, is a rational target for chemotherapeutic intervention in the treatment of AIDS that has also recently been confirmed in the clinical setting. The present work is on N-benzyl- 5, 6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV integrase-catalyzed strand transfer process4. Thus the main objective of present studies is to design specific inhibitors in the hope that these molecules may be further powerful against HIV. These studies may help for the design and synthesis of better selective inhibitors.
3
EXPERIMENTAL In our study, a set of forty five molecules collected from reference 4 was investigated, the structures of which are displayed in the Table 1. The biological activities of these compounds were reported as the concentration capable of inhibiting 50% of HIV-1 integrase catalytic strand transfer activity (IC50). The inhibitory activity of the compounds was expressed as IC50 value in the micromolar range (μM). The IC50 values were converted into -logIC50 for the use in the QSAR studies. The data set was randomly divided into two subsets; test set and training set which is also marked in the Table 1. Hence all the molecules were first arranged in increasing order of IC50 values and every 4th molecule was selected for test set and the remaining ones for the training set (34 molecules).
OH OH N H N Ar
N
R O
4
Co. No.
Substitution
Ar
Values of the Hansch parameters used
-log IC50
R
ArF
Rπ
ArR
RF
Obs.
Cal.**
Cal.***
CH2Ph
0.10
2.4 4
0.04
0.04
1.0969
1.5122
1.44966
Ph
0.10
1.9 0
0.04
0.08
0.0000
5.2532
5.49636
CH2 hexyl
0.10
0.2 3
0.04
0.00
-1.6988
19.573 3
20.9457
(S)CHCH3Ph
0.10
2.9 8
0.04
-0.06 -1.6988
-1.4184
-1.7327
(R)CHCH3Ph
0.10
2.7 5
0.04
0.00
0.3010
-0.4052
-0.628
CH2CH2Ph
0.10
2.7 5
0.04
0.00
-0.6989
0.9627
-0.628
CH2C6H4(4F)
0.10
2.5 2
0.04
0.00
1.6989
1.4182
1.34102
CH2C6H4(4F)
0.10
1.7 3
0.04
0.47
2.0000
1.3344
1.33339
1.7 3 1.7 3
0.00
0.47
1.2218
1.2086
1.21965
-0.13
0.47
1.2218
1.1254
1.14611
S 1.
2*.
3*.
4.
5#.
6.
7.
8.
S
S
S
S
S
S
S
9.
H
CH2C6H4(4F)
0.00
10* .
Me
CH2C6H4(4F)
-0.04
5
11.
iPr
CH2C6H4(4F)
-0.05
12* . 13. * 14.
PhCH2
CH2C6H4(4F)
-0.08
p-tolyl
CH2C6H4(4F)
-0.08
2-thiazolyl
CH2C6H4(4F)
0.36
15.
2-pyridyl
CH2C6H4(4F)
0.5
CH2C6H4(4F)
0.18
CH2C6H4(4F)
16.
1.7 3 1.7 3 1.7 3 1.7 3 1.7 3 1.7 3
-0.10
0.4 7 0.4 7 0.4 7 0.4 7 0.4 7 0.4 7
1.000 0 1.301 0 1.698 9 1.698 9 1.301 0 1.154 9
1.122 6 0.857 3 1.443 3 1.418 2 1.753 6 1.263 9
1.1431
0.44
1.7 3
-1.03
0.4 7
0.823 9
1.413 9
0.7642
CH2C6H4(4F)
0.02
1.7 3
-0.93
0.4 7
0.698 9
0.962 7
1.01165
CH2C6H4(4F)
0.03
1.7 3
-0.82
0.4 7
0.823 9
1.005 9
1.0491
CH2C6H4(4F)
-0.23
1.7 3
-0.88
0.4 7
0.823 9
1.413 4
1.42343
CH2C6H4(4F)
0.03
1.7 3
-0.91
0.4 7
1.301 0
0.979 9
1.02696
CH2C6H4(4F)
-0.12
1.7 3
-0.77
0.4 7
1.000 0
0.844 8
0.90859
CH2C6H4(4F)
-0.04
1.7 3
-0.76
0.4 7
1.000 0
0.944 3
0.99113
-0.01 -0.01 -0.29 -0.09 -0.52
0.91458 1.13407 1.52235 1.71701 1.27875
OMe
17* .
MeO
MeO
18.
N
19. N
20. N
21.
N
O
22.
N
23* . NH
6
24 .
CH2C6H4(4F)
-0.04
1.7 3
-0.76
0.4 7
0.0969
0.9433 0.99113
CH2C6H4(4F)
-0.04
1.7 3
-0.76
0.4 7
-0.0899 0.9433 0.99113
CH2C6H4(4F)
-0.08
1.7 3
-0.89
0.4 7
0.6989
0.8601
0.91759
CH2C6H4(4F)
-0.11
1.7 3
-0.86
0.4 7
1.0000
0.8345
0.8938
CH2C6H4(4F)
-0.16
1.7 3
-0.96
0.4 7
0.6989
0.7485
0.81725
CH2C6H4(4F)
0.12
1.7 3
-2.10
0.4 7
0.6382
0.7388
0.82773
CH2C6H4(4F)
0.07
1.7 3
-1.03
0.4 7
1.5228
0.9909
1.039
CH2C6H4(4F)
-0.04
1.7 3
-0.76
0.4 7
0.9208
0.9433
0.99113
CH2C6H4(4F)
0.11
1.7 3
-2.07
0.4 7
1.0000
0.7360
0.82472
CH2C6H4(4F)
-0.09
1.7 3
-0.86
0.4 7
1.3010
1.7536
1.71701
N H
25 .
HN
26 . N
27 . N
28 . N
29 .
N N
30 .
O N
31 . N
32 .
N N
33 . N
7
8
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