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Letters in Drug Design & Discovery, 2013, 10, 666-674
A Quantitative Structure-Activity Relationship Study on Some Imidazoles and 2-Aminopyridines Acting as Nitric Oxide Synthase (NOS) Inhibitors Harish Kumar1, Anees A. Siddiqui2 and Satya P. Gupta3,* 1
PDM College of Pharmacy, Bahadurgarh-124507 (Haryana), India, 2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamadard, Hamdard Nagar, New Delhi-110062, India. 3Department of Applied Sciences and Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut-250005, India Abstract: A quantitative structure-activity relationship study has been made on two different series of nitric oxide synthase (NOS) inhibitors. A series of imidazoles and some mono or bicyclic nitrogen-containing heterocycles was reported to potently act against neuronal NOS (nNOS) and a series of 2-aminopyridines to act against inducible NOS (iNOS). The QSAR model derived for the former suggested that nNOS inhibition activity of the compounds is basically controlled by electronic nature of the molecule and that the compounds having fused ring would have added advantage and the one derived for the latter suggested that iNOS inhibition activity of 2-aminopyridines is controlled by hydrophobic nature of 6substituents and the steric nature of 4-substituents. A negative effect on activity in this series was however suggested to be produced by the polarizability of the molecule.
Keywords: Nitric oxide synthase inhibitors, Imidazoles, 2-aminopyridines, QSAR study. INTRODUCTION Nitric oxide (NO) is a small gaseous molecule, which behaves as a biological messenger in the various physiological processes of the human body. It is the endotheliumderived relaxing factor [1, 2], which plays the role in various fundamental functions of the body, such as neurotransmission [3,4], blood pressure and blood flow regulation [5], platelet aggregation and inflammation [6], macrophagemediated cytotoxicity [7], gastrointestinal smooth muscle relaxation [8], and bronchodilation [9], through various pathways. The nitric oxide is synthesized by the enzyme nitric oxide synthase (NOS) which exists in three isoforms: the neuronal NOS (nNOS, also called NOS1), the inducible NOS (iNOS, also called NOS2), and the endothelial NOS (eNOS, also called NOS3). The activation of nNOS and eNOS depends on calcium, whereas iNOS is independent of calcium [10]. It has been reported that nNOS and eNOS are constitutively expressed, whereas iNOS is induced only during the immune response [11, 12]. Latest studies have shown that iNOS is constitutively expressed in neurons [13], kidney [14], liver [15], lung [16], colon [17], and keratinocytes [18], but the nNOS can be expressed at a level higher than its constitutive level under various conditions such as exercise [19], estrogen stimulation [20], hyperthermia [21], and shear stress [22, 23]. The NOS catalyzes the oxidation of a guanidino nitrogen of L-arginine to nitric oxide (NO) alongwith the formation of L-citrulline [24]. Besides, the overproduction of nitric oxide, especially by iNOS and nNOS, plays role in occurrence of various diseases, such as hypotensive crises during septic *Address correspondence to this author at the Department of Applied Sciences and Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut-250005, India; Tel: +91-9368222297; E-mail:
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shock, arthritis, colitis, tissue damage, cancer, and various kinds of inflammatory states (by iNOS) and neurodegeneration, stroke, migraine and chronic headache, Parkinson, Alzheimer, and Huntington diseases (by nNOS) [25-30]. Therefore, the different forms of NOS have become the important targets to design and develop drugs to treat these diseases. Quantitative structure-activity relationship (QSAR) methodologies are currently being applied to provide very effective rationales to drug development. The objective of this communication is therefore to make an extensive QSAR study on some series of NOS inhibitors. We have taken two different series of NOS inhibitors, a series of substituted imidazoles (1) and some mono or bicyclic nitrogen-containing heterocycles which were synthesized and characterized for their nNOS inhibitory activity by Salerno et al. [31] and a series of substituted 2-aminopyridines (2) that was synthesized and evaluated for their iNOS inhibitory activity by Hagmann et al. [32]. QSAR studies lead to find the physicochemical parameters that govern the activity of the compounds and enable us to predict new, more potent compounds. These two series were selected because they had sufficient data needed worth analysing. R1 N R2
O R
N R3
1 3 H2N
R 4
N 2
5 6
Salerno et al. selected imidazole nucleus as template because imidazole and its several imidazole derivatives were reported in the early literature as inhibitors of various
©2013 Bentham Science Publishers
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Table 1. Substituted Imidazoles Derivatives and Their Nitric Oxide Synthase Inhibitory Activity and Physicochemical Parameters. R1
R
N
Compd
O
N
R2
log(1/IC50),
Parameter
nNOS
R3
R
R1
R2
R3
Pol
σp
I
Obsd.a
Cald, Eq.(1)
1
NO2
H
H
H
24.44
0.78
0.00
3.97
4.14
2
NO2
CH3
H
H
26.19
0.78
0.00
4.13
4.18
3
NO2
CH(CH3) 2
H
H
29.77
0.78
0.00
4.64
4.25
SO2CF3
H
H
H
27.95
0.08
0.00
3.34
3.23
5b
Br
CH3
H
H
26.95
0.16
0.00
3.20
3.32
6
NO2
H
CH3
H
26.19
0.78
0.00
4.07
4.18
7
NO2
H
H
CH3
26.19
0.78
0.00
4.04
4.18
8
H
iC3H7
H
H
27.53
0.00
0.00
3.12
3.10
9
Br
iC3H7
H
H
30.53
0.16
0.00
3.34
3.39
10
NO2
C3H7
H
H
29.85
0.78
0.00
4.39
4.26
11
NO2
C6H5
H
H
34.39
0.78
0.00
4.39
4.36
12
NO2
H
C6H5
H
34.39
0.78
0.00
4.34
4.36
13
NO2
H
NO2
H
26.68
0.78
0.00
3.92
4.19
14
NO2
C2H5
CH3
H
29.77
0.78
0.00
4.12
4.25
15
NO2
H
C6H5
C6H5
44.34
0.78
0.00
4.44
4.57
16
NO2
H
H
H
24.44
0.78
0.00
4.39
4.14
17
NO2
H
H
CH3
26.19
0.78
0.00
4.20
4.18
18b
NO2
CH3
H
CH3
27.95
0.78
0.00
4.18
4.21
NO2
25.06
0.78
0.00
3.63
4.15
NO2
23.82
0.78
0.00
4.32
4.12
30.12
0.78
1.00
4.44
4.59
NO2
30.12
0.78
1.00
4.64
4.59
NO2
30.74
0.78
1.00
4.48
4.60
4
b
O
19c
N
O
20
N
b
N
N
N
21
NO2 O
N
N O
22
N N N O
23
N N
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Table 1. contd…
R1
R
N
Compd
O
N
R2
log(1/IC50),
Parameter
nNOS
R3
R
R1
R2
R3
Pol
σp
I
Obsd.a
Cald, Eq.(1)
32.98
0.78
1.00
4.17
4.65
O NO2
N
24b
N NO2 R1
O
N
R
X R2
X
Y
R
R1
R2
b
CH
CH
H
H
H
28.49
0.00
1.00
3.31
3.45
26
CH
CH
NO2
H
H
30.74
0.78
1.00
4.33
4.60
27
CH
CH
NO2
CH3
CH3
34.25
0.78
1.00
4.86
4.68
28
CH
N
NO2
H
H
30.12
0.78
1.00
4.49
4.59
29
N
CH
NO2
H
H
30.12
0.78
1.00
4.90
4.59
25
a
N
Y
Taken from ref. [31].
b
Taken for test set.cNot included in the derivation of Eq.(1) as it was an outlier.
isoforms of NOS [33, 34]. On this basis, a series of imidazole-based inhibitors substituted at N-1 with an arylethanone chain were previously studied by Salerno et al. [35-37] to find that they were interesting inhibitors of nNOS. As a follow up of these studies, Salerno et al. [31] studied not only imidazoles but also other mono or bicyclic nitrogencontaining heterocycles and evaluated their inhibitory activity against nNOS and eNOS. Majority of them were found to be active against only nNOS and not eNOS. These heterogeneous group of compounds were of great interest to us for QSAR analysis. As imidazoles, 2-aminopyridines were also identified as potent inhibitors of NOS. A compound 2-amino-4methylpyridine (2, R = 4-methyl) has been studied in detail for its in vivo and in vitro properties. Therefore, Hagmann et al. [32] studied a large series of 2-aminopyridine derivatives and found that they were specifically good inhibitors of iNOS. We therefore proposed to make a QSAR study on them also. MATERIALS AND METHODS The two series described above are listed in Tables 1 and 2, respectively, along with their NOS inhibitory activity and the physiochemical and topological parameters which were found to govern their activity. The various physicochemical parameters used in this study were calculated by Chemsketch version 11.0 or Dragon, or taken from the literature [40].
RESULTS AND DISCUSSION Table 1 contains 29 compounds in total. This set was divided into two subsets, the training set comprising of 23 compounds and the test set comprising of 6 compounds. Compounds for the test were selected keeping in mind the wide structural diversity and span in the activity data. The compounds of test set are given in bold and with superscript ‘b’ in Table 1. When a multiple regression analysis was performed on the training set, the best correlation that we could find was: log(1/ IC50 ) = 0.022(±0.020)Pol + 1.413(±0.433) ! p + 0.328(±0.190)I + 2.501(±0.665) n = 22, r = 0.908, r 2 cv = 0.70, r 2 pred = 0.89, s = 0.19, F 3, 18 = 28.36(5.09)
(1)
where Pol represents the polarizability of the compounds and σp is Hammett’s electronic constant used for the parasubstituent at the phenyl ring of N-substituent of heterocycles. ‘I’ is an indicator variable used with a value of unity for the compounds containing fused rings. ‘I’is zero for the other compounds. Among the statistical parameters, n is the number of data points, r is the correlation coefficient, r2cv is the square of cross-validated correlation coefficient obtained from leave-one-out (LOO) jackknife procedure, s is the standard deviation, F is the F-ratio between the variances of calculated and observed activities, and the data within the parentheses with ± sign are 95% confidence intervals. The fig-
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Training Set
669
Test Set
log(IC50), Cald. (Eq. 1)
5.5 5 4.5 4 3.5 3 2.5 3
3.5
4
4.5
5
5.5
6
log(IC50), Obsd. Fig. (1). A plot between observed and predicted activities of compounds of Table 1.
ure within the parenthesis following the F-value is the standard F-value at 99% level. The values of these statistical parameters exhibit that the correlation obtained is quite significant. Its internal and external validity can be judged by its r2cv and r2pred values, which are 0.70 and 0.89, respectively, each one being greater than desired (r 2cv > 0.60; r 2pred > 0.50). The r2cv is calculated as: r2cv = 1 – [ Σi(Yi,obsd – Yi,pred)2/ Σi( Yi,obsd – Yav,obsd)2]
(2)
where Yi,obsd and Yi,pred are the observed and predicted (from LOO) activity values of compound i, respectively, and Yav,obsd is the average of the observed activities of all compounds used in the correlation. Similarly, the r2pred is calculated as: r2pred = 1 – [ Σi(Yi,obsd – Yi,pred)2/ Σi( Yi,obsd – Yav,obsd)2]
(3)
where Yi,obsd is the observed activity of compound i in the test set and Yi,pred is its activity predicted from the model obtained. Yav,obsd is same as in Eq.(2).The activity values predicted from Eq. (1) for both training and test sets are given in Table 1. A comparison shows that these predicted values are in very good agreement with the corresponding observed ones. These observations can be better visualized in the graph drawn between the predicted and observed activities for training as well as test sets (Fig. 1). In deriving Eq. (1), however, a compound 19 was not included as it showed aberrant behaviour. The aberrant behaviour of this compound is not hard to explain. Its observed activity (3.63) is much lower than its predicted activity (4.15). This difference in the activities may be attributed to the replacement of imidazole ring by pyrrole ring. Equation (1) suggests that the activity of compounds is governed by their polarizability. This indicates that the drugreceptor interaction involves strong dispersion interaction. Further, the positive coefficient of σp indicates that an electron-withdrawing para-substituent at the phenyl ring of N-
substituent of heterocycles will further add to the activity. This substituent might participate in some electronic interaction with some site of the receptor. Further, the positive coefficient of the indicator variable ‘I’ indicates that a compound having fused ring would be better than the other compounds. A fused ring may have better electronic interaction with the receptor than a single ring. Using Eq. (1) we have predicted some new compound as shown in Table 3. The activities of these compounds are higher than any compound in the existing series (Table 1). While choosing the compounds, the modifications in structures were made such that the values of favourable parameters in the model are increased or remain conducive to the activity. Thus, a fused ring was retained, an SO2CN was selected for the para-position of the phenyl ring because it has quite high value of σp and is of moderate size unlikely to create any steric problem, and the fused ring was substituted with groups of moderate size to avaoid any steric problem but capable of increasing the Pol value of the molecule. The next series which contains 23 2-aminopyridines (Table 2) has also been treated in the same way by dividing it into two subsets, the training set and test set. In Table 2 also, the test set compounds are shown in bold and with superscript ‘b’. The remaining compounds were considered in training set. The QSAR analysis of training set revealed a correlation as shown by Eq. (4) where π6 refers to the hydrophobic coefficient of 6-position substituents, Eig1p is the leading eigenvalue from polarizability weighted distance matrix, and ‘I’ is an indicator parameter used with a value of 1 for any substituent present at the 4-position of the pyridine ring. This correlation, therefore, expresses that the iNOS inhibition activity of this series of compounds is governed by the hydrophobic property of the 6-position substituents and a positive coefficient of π6 indicates that these substituents might be involved in some hydrophobic interaction with any hydrophobic site of the receptor.
670 Letters in Drug Design & Discovery, 2013, Vol. 10, No. 7
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Table 2. 2-Aminopyridines and Their Nitric Oxide Synthase Inhibitory Activity and Physicochemical Parameters.
Compound
R
1
Eig1p
log(1/IC50), iNOS
I Obsd
Cald, Eq. (4)
Pred (LOO)
H
0.00
13.03
0.00
5.72
5.53
5.43
2
b
3-CH3
0.00
13.72
0.00
6.02
5.47
-
3
b
4-CH3
0.00
13.94
1.00
6.76
6.92
-
4c
5-CH3
0.00
16.18
0.00
6.22
5.25
-
5
6-CH3
0.56
17.11
0.00
5.70
5.75
5.76
6
3,4-(CH3)2
0.00
18.83
1.00
7.12
6.48
6.36
7
3,5-(CH3)2
0.00
19.05
0.00
4.84
4.99
5.07
8
4,5-(CH3)2
0.00
19.11
1.00
6.09
6.46
6.52
4,6-(CH3)2
0.56
20.16
1.00
6.96
6.95
6.95
5,6-(CH3)2
0.56
17.42
0.00
5.14
5.72
-
11
4-C2H5
0.00
20.35
1.00
6.63
6.35
6.30
12
4-CF3
0.00
40.10
1.00
4.88
4.57
4.18
13
9 10
b
3-C2H5, 4-CH3
0.00
22.98
1.00
5.57
6.11
6.19
14
b
3-n-C3H7 , 4-CH3
0.00
26.05
1.00
4.46
5.83
-
15
c
3-NH2 , 4-CH 3
0.00
19.92
1.00
7.22
6.39
-
16
5-C2H5 , 4-CH3
0.00
23.49
1.00
5.89
6.06
6.08
17
6-C2H5 , 4-CH3
1.02
25.35
1.00
6.48
6.97
7.03
18
6-n-C3H7 , 4-CH3
1.68
31.49
1.00
6.96
7.11
7.11
19
6-i-C3H7 , 4-CH 3
1.53
29.81
1.00
6.96
7.10
7.10
b
6-n-C4H9 , 4-CH3
2.13
34.53
1.00
7.33
7.31
-
21
6-i-C4H9 , 4-CH 3
1.98
36.72
1.00
7.55
6.95
6.80
22
6-i-C5H11 , 4-CH3
2.63
44.47
1.00
7.12
6.94
6.86
23
6-(CH2)3 Ph , 4-CH 3
3.64
70.19
1.00
4.90
5.68
5.73
20
a
π6
Taken from ref. [32].
b
Taken for test set.cNot included in the derivation of Eq.(4) as they were outliers
Table 3. Some Proposed Compounds Belonging to the Series of Table 1 and their Predicted Activities from Eq. (1). S.No
Compound
Pol
σp
I
log (1/IC50)
SO2CN
35.71
1.26
1.00
5.39
SO2CN
37.53
1.26
1.00
5.43
SO2CN
37.19
1.26
1.00
5.42
N 1
N O
NH2 N 2
N O
CN
N 3
N NO2
O
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Table 3. contd… S.No
Compound
Pol
σp
I
log (1/IC50)
SO2CN
40.63
1.26
1.00
5.50
SO2CN
39.98
1.26
1.00
5.48
SO2CN
36.70
1.26
1.00
5.41
SO2CN
44.90
1.26
1.00
5.59
SO2CN
37.45
1.26
1.00
5.43
SO2CN
40.85
1.26
1.00
5.50
SO2CN
37.53
1.26
1.00
5.43
N 4
N O
SCN
N 5
N O
SNO2 N 6
N O
CH3 N 7
N O
C6H5
N
8
N O
COOH
N 9
N O
C2H4NO2
N
10
N CH2NH2
O
Table 4. Some Proposed Compounds Belonging to the Series of Table 2 and their Predicted Activities from Eq. (4). S.No
Compounds
π6
Eig1p
I
1og(1/IC50)
1.12
16.18
1
7.90
1.50
20.76
1
7.88
0.86
16.62
1
7.59
CH3 1
H2N
N
I
CH3 2
H2N
N
CH2I
CH3 3
H2N
N
Br
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Table 4. contd… S.No
Compounds
π6
Eig1p
I
1og(1/IC50)
1.53
26.17
1
7.43
0.71
17.04
1
7.38
1.51
27.44
1
7.29
CH3 4
N
H2N
CH(CH3)2 CH3
5
H2N
N
Cl
CH3 6
H2N
N
CBr3
8 Training Set
7.5
Test Set log(IC50), Cald. (Eq. 4)
7 6.5 6 5.5 5 4.5 4 4
4.5
5
5.5
6
6.5
7
7.5
8
log(IC50), Obsd. Fig. (2). A plot between observed and predicted activities of compounds of Table 2.
log(1/IC50 ) =1.049( ± 0.364)! 6 – 0.090( ± 0.028) Eig1p + 1.477( ± 0.603) I + 6.707( ± 0.644) n = 16, r = 0.918, r 2 cv = 0.70, r 2 pred = 0.57, s = 0.39, F 3,12 = 21.51(5.95)
(4)
A positive coefficient of the indicator parameter ‘I’ indicates that any substituent present at the 4-position will have an added advantage and this may be probably due to some steric interaction of this substituent with any site of the receptor. The parameter Eig1p is indicative of the polarizability of the molecule, hence its negative coefficient indicates that highly polarized molecule will not be conducive to the activity. The highly polarized molecule might have some repulsive interaction with the receptor. From the values of r2cv and r2pred, Eq. (4) also seems to be quite valid for prediction. The activity values predicted from this equation for both training and test sets are found to be in good agreement with the observed ones (Table 2). The matching of predicted
activity values from this equation with observed ones for both training and test sets can be visualised by the graph in Fig. (2). In deriving Eq. (4), however, compounds 4 and 15 were not included as they behaved as outliers. Their this behaviour can be explained as follows. Compound 4 has a 5methyl group which might produce a positive effect due its hydrophobic nature, in the absence of any bulky substituent in the neighbour that might create steric hinderance. This positive hydrophobic effect 5-methyl could not be accounted for by any parameter in the equation, hence the equation predicted its low activity as compared to its observed activity. The higher observed activity of compound 15 as compared to its predicted activity can be attributed to its 3-NH 2 group which is capable of forming a hydrogen bond with the receptor. Using Eq. (4), we have predicted some new compounds for this series as shown in Table 4. All predicted compounds have the higher potency than any compound in the existing
A Quantitative Structure-Activity Relationship Study
series. In this case also, the modifications in structures have been made such that they have favourable π6, decreased Eig1p, and I = 1.
Letters in Drug Design & Discovery, 2013, Vol. 10, No. 7 [13] [14]
CONCLUSION The results and discussion as presented above lead to conclusion that nNOS inhibition potency of imidazoles and other mono or bicyclic nitrogen-containing heterocycles will be affected by the electronic nature of the compounds where the polarizability of the whole molecule, the electronwithdrawing para-substituent of the phenyl ring of Nsubstituent of heterocycles, and fused rings will be crucial. However, the iNOS inhibition activity of 2-aminopyridines is shown to be adversely affected by the polarizability of the molecule but to be controlled by the hydrophobic nature of 6-substituent with specific effect of 4-position substituent. This 4-position substituent might have steric interaction with some site of the receptor. This leads to suggest that different isoforms of NOS may have different nature of interactions with the inhibitors.
[15]
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CONFLICT OF INTEREST
[20]
The authors confirm that this article content has no conflicts of interest.
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ACKNOWLEDGEMENTS
[22]
Declared none. REFERENCES [1] [2]
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