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: (salonimishr12@gmail.com, dwivedi.sheela@yahoo.co.in)

Mo. No. 00919793453310, 00915352203387

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 QSAR Studies on Dihydroxypyrimidine-4-carboxamides and

Analogues as Novel Potent HIV Integrase Inhibitor

ABSTRACT: - The QSAR studies have been carried out on Dihydroxypyrimidine-4-

carboxamides 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

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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.

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 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

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Co. Substitution Values of the Hansch -log IC50
No. parameters used

Ar R ArF Rπ ArR RF Obs. Cal.** Cal.***

S
1. CH2Ph 0.10 2.4 0.04 0.04 1.0969 1.5122 1.44966
4

2*. S
Ph 0.10 1.9 0.04 0.08 0.0000 5.2532 5.49636
0

3*. S
CH2 hexyl 0.10 0.2 0.04 0.00 -1.6988 19.573 20.9457
3 3

4. S
(S)CHCH3Ph 0.10 2.9 0.04 -0.06 -1.6988 -1.4184 -1.7327
8

5#. S
(R)CHCH3Ph 0.10 2.7 0.04 0.00 0.3010 -0.4052 -0.628
5

6. S
CH2CH2Ph 0.10 2.7 0.04 0.00 -0.6989 0.9627 -0.628
5

7. S
CH2C6H4(4F) 0.10 2.5 0.04 0.00 1.6989 1.4182 1.34102
2

8. S
CH2C6H4(4F) 0.10 1.7 0.04 0.47 2.0000 1.3344 1.33339
3

9. H CH2C6H4(4F) 0.00 1.7 0.00 0.47 1.2218 1.2086 1.21965

3
10* Me CH2C6H4(4F) -0.04 1.7 -0.13 0.47 1.2218 1.1254 1.14611
. 3

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11. iPr CH2C6H4(4F) -0.05 1.7 -0.10 0.4 1.000 1.122 1.1431
3 7 0 6
12* PhCH2 CH2C6H4(4F) -0.08 1.7 -0.01 0.4 1.301 0.857 0.91458
. 3 7 0 3
13. p-tolyl CH2C6H4(4F) -0.08 1.7 -0.01 0.4 1.698 1.443 1.13407
* 3 7 9 3
14. 2-thiazolyl CH2C6H4(4F) 0.36 1.7 -0.29 0.4 1.698 1.418 1.52235
3 7 9 2
15. 2-pyridyl CH2C6H4(4F) 0.5 1.7 -0.09 0.4 1.301 1.753 1.71701
3 7 0 6
16. CH2C6H4(4F) 0.18 1.7 -0.52 0.4 1.154 1.263 1.27875
3 7 9 9

OMe
MeO
17* CH2C6H4(4F) 0.44 1.7 -1.03 0.4 0.823 1.413 0.7642
. 3 7 9 9
MeO

18. CH2C6H4(4F) 0.02 1.7 -0.93 0.4 0.698 0.962 1.01165

3 7 9 7

19. CH2C6H4(4F) 0.03 1.7 -0.82 0.4 0.823 1.005 1.0491

3 7 9 9
N

20. CH2C6H4(4F) -0.23 1.7 -0.88 0.4 0.823 1.413 1.42343

3 7 9 4
N

21. CH2C6H4(4F) 0.03 1.7 -0.91 0.4 1.301 0.979 1.02696

3 7 0 9

O
22. CH2C6H4(4F) -0.12 1.7 -0.77 0.4 1.000 0.844 0.90859
3 7 0 8

23* CH2C6H4(4F) -0.04 1.7 -0.76 0.4 1.000 0.944 0.99113

. 3 7 0 3
NH

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24 CH2C6H4(4F) -0.04 1.7 -0.76 0.4 0.0969 0.9433 0.99113
. 3 7

N
H
25 CH2C6H4(4F) -0.04 1.7 -0.76 0.4 -0.0899 0.9433 0.99113
. 3 7
HN

26 CH2C6H4(4F) -0.08 1.7 -0.89 0.4 0.6989 0.8601 0.91759

. 3 7
N

27 CH2C6H4(4F) -0.11 1.7 -0.86 0.4 1.0000 0.8345 0.8938

. 3 7
N

28 CH2C6H4(4F) -0.16 1.7 -0.96 0.4 0.6989 0.7485 0.81725

. 3 7
N

29 CH2C6H4(4F) 0.12 1.7 -2.10 0.4 0.6382 0.7388 0.82773

N
. 3 7
N

30 CH2C6H4(4F) 0.07 1.7 -1.03 0.4 1.5228 0.9909 1.039

. O 3 7
N

31 CH2C6H4(4F) -0.04 1.7 -0.76 0.4 0.9208 0.9433 0.99113

. 3 7
N

32 CH2C6H4(4F) 0.11 1.7 -2.07 0.4 1.0000 0.7360 0.82472

. N 3 7
N

33 CH2C6H4(4F) -0.09 1.7 -0.86 0.4 1.3010 1.7536 1.71701

. 3 7

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