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Journal of Molecular Structure (Theochem) 535 (2001) 235246

www.elsevier.nl/locate/theochem

Study of electronic and structural features of thiosemicarbazone


and thiosemicarbazide derivatives demonstrating
anti-HSV-1 activity
Ah. Altun a,*, M. Kumru a, A. Dimoglo b
a

Physics Department, Faculty of Arts and Sciences, Fatih University, 34900, B. Cekmece, Istanbul, Turkey
b
Institute of Technology, PK 141, 41400, Gebze, Turkey
Received 20 December 1999; revised 13 April 2000; accepted 8 May 2000

Abstract
The structureactivity relationships (SAR) in a series of thiosemicarbazone and thiosemicarbazide derivatives (60
compounds) have been investigated by means of the Electron-Topological Method (ETM). All derivatives in the training
set are potent inhibitors of herpes simplex virus type 1 (HSV-1) replication (C. Shipman, S.H. Smith, J.C. Drach, D.L. Klayman,
Antiviral Research, 6 (1986) 197222). On the basis of geometrical and electronic data calculated for each compound and
arranged in a matrix form, two features of activity and three breaks of activity have been revealed. By means of the method of
multivariable regression a quantitative model was built to express the activity dependence on some physicochemical and
structural parameters. q 2001 Elsevier Science B.V. All rights reserved.
Keywords: Structureactivity relationships (SAR); Electron topological method (ETM); Herpes simplex virus (HSV); Inhibitory activity

1. Introduction
In 1950 Hamre et al. [2] found that derivatives of
benzaldehyde thiosemicarbazone were active against
neurovaccinial infection in mice when given orally. It
was the rst study on the antiviral activity of thiosemicarbazones that prompted further investigation of
their properties. The thiosemicarbazone of isatin was
found strongly active [3]. A clinical trial of the
N-methyl derivative of isatin-b-thiosemicarbazone
(methisazone) was carried out in India [46]. These
studies have been widely accepted as evidence of the
effective antiviral activity of methisazone in humans
[7]. Even though the drug has been used to treat
* Corresponding author.
E-mail address: aaltun@fatih.edu.tr (Ah. Altun).

patients with genital lesions caused by herpes simplex


virus (HSV), it had little effect on the severity or
duration of the lesions [8].
Sidwell and co-workers evaluated a series of purine
analogs as antiviral agents [9]. This was the rst report
of a substituted thiosemicarbazone being active
against a herpes virus. Brockman and co-workers
examined the effect of heterocyclic thiosemicarbazones such as pyridine, isochinoline, purine, and isatin
derivatives on HSV. They found that only those
compounds were active in which the thiosemicarbazide moiety was afxed to the heterocyclic ring
in the alpha position relative to the ring nitrogen
[10].
The synthesis of new compounds that can be used
as drugs in everyday life is one of the most important
tasks of molecular design. Detailed considerations

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Ah. Altun, et al. / Journal of Molecular Structure (Theochem) 535 (2001) 235246

Table 1
Skeleton types of the compounds in the training set

limited by the expenses required for experts,


laboratory equipment and millions of animals used
in experiments are necessary when testing the
compounds on bio-receptors. That is why computerized approaches are widely used for biological activities investigation at present. The so called
StructureActivity Relationship (SAR) studies are
mainly based upon establishing correlation between
structures of compounds and their activities, computer-assisted screening and the activity prognostication,
prior to experiments [11,12].
In this study, a series of thiosemicarbazones of 2acetylpyridine, 2-acetylquinoline, 1-acetylisoquinoline, and related compounds (Tables 1 and 2) have
been investigated as inhibitors of herpes simplex
virus-1 (HSV-1) by means of ETM for SAR
studies.

2. Materials and methods


SAR investigations were performed with the aid of
a modied version of the Electron Topological
Method (ETM)[1317]. ETM deals with threedimensional discrete characterizations of molecular
structures. When compared with the majority of
other approaches to SAR study, ETM shows the
following advantages:
1. ETM is capable of processing series of compounds
with quite diverse structures.
2. ETM estimates the activity qualitatively, but quantitative estimation can be also done after this, if
needed. Meanwhile in the frameworks of the
other SAR methods just quantitative study can be
applied.

Ah. Altun, et al. / Journal of Molecular Structure (Theochem) 535 (2001) 235246

3. Instead of using integral characteristics of


compounds such as molecular weight, solubility,
lipophilicity, etc. ETM pays primary attention to
their electronic structure. It uses physicalchemical and quantum-chemical characteristics alone
with conformational analysis data, which are
arranged in the form of n n matrices. The latter
are called Electron Topological Matrices of
Conjunction (ETMC) and serve as a language for
the compound structure description.
To form an ETMC, a number of selections are to be
made
1. A property for atoms (bond order, atomic charge,
valance activity, polarizability, HOMO or LUMO
energy, etc.) is to be chosen. The corresponding
values are used as diagonal elements aii.
2. A property for bonds is to be xed for off-diagonal
elements. The off-diagonal elements, aij, are of two
kinds.
(a) If i and j label two chemically bonded atoms,
then aij can be one of electronic parameters of
the (ij)-bond, such as bond order (Wiberg's
index [18]), bond energy (total, covalent or
ionic), polarizability and so on.
(b) If i and j label two nonbonded atoms, then aij
is the interatomic distance.
Since each ETMC is symmetric with respect to its
diagonal elements, only the upper half of it is kept in
the memory of the computer and processed. By
Table 2
Some substituents of the compounds in the training set

237

comparing ETMC of one of the most active


compounds (the template compound) with other
ETMCs, we obtain features responsible for the activity as submatrices of the template, that are called
Electron Topological Submatrices of Activity
(ETSA). They represent fragments of real molecular
structures.
Flexibility of molecules is taken into account by
setting initial parameters for the comparison, such as
D 1 for atoms and D 2 for bonds. These parameters are
used to establish the similarity of atoms and bonds in
molecules under comparison. Sometimes D 3 can be
used for distances at place of D 2.
The tness of the features found is determined with
respect to two probabilistic estimations known from
literature, that are given below
Pa

n1 1 1
;
n1 1 n3 1 2

n n4 2 n2 n3

aa p1
N1 N2 N3 N4

Here n1 and n2 are the numbers of molecules that


include and do not include, respectively, the features
of the activity selected by the ETM in the class of
active compounds. n3 and n4 have the same meaning
for the class of inactive ones. N1 and N2 are the
numbers of molecules in the classes of active and
inactive compounds, respectively; N3 n1 1 n3 ;
N4 n2 1 n4 : In this way, Pa evaluates the deposit of
only active molecules, while a a reects the deposit of
both active and inactive compounds in the feature of the
activity found (for this reason a a is always less than Pa in
most cases). It is quite close to 1 only in one

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Ah. Altun, et al. / Journal of Molecular Structure (Theochem) 535 (2001) 235246

Table 3
The constituents varied and viral replication values for the corresponding molecules [1]
N

Skel. type

R1

R2

C mg/ml

Skel. type

R1

R2

C m g/ml

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30

A1
A1
A1
A1
A1
A1
A1
A1
A1
A1
A1
A1
A1
A2
A2
A2
A2
A2
A2
A2
A2
A2
A2
A2
A2
A2
A2
A2
A3
A3

H
CH3
C2H3yCH2
C(CH3)2 CH2 C(CH3)2
CH2 [CH(OH)]4 CH2OH
CH2 C6H5
CH2 o(CH3)C6H4
CH2 o(C5H5N)
B1
m(F)C6H4
p(CF3)C6H4
CH3
CH3
m(CH2OH)B2
B3
B4
B5
B6
B7
B8
NHCH2CHyCH2
N(CH3)2
B4
B6
NHCH2CHyCH2
NHCH2CHyCH2
B4
B6
NHCH2CHyCH2
B4

H
H
H
H
H
H
H
H
H
H
H
CH3
C6H11
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C2H5
C3H7
CH(CH3)2
CH(CH3)2
CH(CH3)2

1.20
0.14
0.70
1.00
5.40
0.10
0.29
0.37
4.60
0.26
0.24
0.08
0.22
0.46
0.85
0.18
0.21
0.49
0.20
0.28
0.58
0.70
0.10
0.29
0.60
2.00
0.10
0.04
1.20
1.70

31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

A3
A4
A4
A4
A4
A4
A4
A5
A5
A5
A5
A5
A5
A5
A6
A6
A6
A7
A7
A7
A7
A8
A8
A9
A9
A9
A9
A10
A11
A12

B6
NHC2H5
NHC3H7(n)
N(i-C4H9)2
N(CH3)C6H4 OCH
B4
B5
N(CH3)2
N(CH3)C6H11
B9s
pCH3 B2
B10
B4
B6
NHC3H7(n)
B9
B5
NHCH2 C6H5
B11
B12
B5
B9
B5
NH2
NHC6H5
NHC6H5
B6

O
O
Se
Se

0.57
5.60
0.60
2.40
0.19
0.87
0.15
0.11
1.90
0.15
1.50
0.43
2.20
0.33
0.37
0.04
0.22
8.50
0.32
0.35
0.17
0.30
0.28
3.90
7.00
0.18
0.20
0.12
3.20
0.56

ideal case, namely, when all active compounds


and none of inactive ones include the feature
under estimation.
To nd the features of activity, the steps listed
below are to be carried out [19,20]. By this, it is
presupposed that we have a proper series of
compounds, active alone with inactive ones, whose
structures are known, activities evaluated quantitatively (or, at least, qualitatively as 1 or 0). The steps
are:
1. Make quantum chemistry calculations and geometry optimization for a training set.
2. Fix a property for atoms and a property for bonds.
Form ETMC for every compound (active or inactive), based on the results obtained at Step 1.

3. Choose a template compound (one of the most


active ones, if known).
4. Choose desirable level of activity to split all the
series into classes of activity (initially into two
classes, but, possibly, more than two) and parameters D 1 and D 2.
5. Compare the template chosen with the rest of
molecules. If the features selected are not representative enough, change some of the initial parameters or all of them (the template, D i, level of
activity, properties for atoms and bonds).
6. After obtaining satisfactory features, take a testing
set of molecules and repeat all previous steps. If the
same features of the activity are found with the
same values of probabilities as at the last step of
the training set investigation, the features are

Ah. Altun, et al. / Journal of Molecular Structure (Theochem) 535 (2001) 235246

239

Fig. 1. Conformational energies of N12 dependent on the angles of rotation w i.

considered appropriate for the activity prediction.


If not, then the more profound study of the features
violation is to be undertaken, and all the steps are to
be repeated again. If no testing series, the sliding
examination can be carried out instead.
The procedure for searching features of inactivity,
or breaks of activity, is the same as the one for the
features of activity selection. The only difference is
that the template compound is an inactive one.
In this study, the compounds whose viral replication values are smaller than 0.4 have been presupposed to be active. The training set (see Table 3)

includes 32 active and 28 inactive compounds. A


molecular mechanics program (MMX) [21] and a
semi-empirical quantum-chemical approach (CNDO/
2) [22,23] were used to determine structural and electronic parameters for each compound in the series.
Their results were used to form electron-topological
matrices of conjunction (ETMC). To validate the
features obtained, the sliding examination has been
carried out.
3. Results and discussion
Each ETMC was formed of effective charges on

Fig. 2. The feature of activity AF-I and the corresponding ETSA

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Ah. Altun, et al. / Journal of Molecular Structure (Theochem) 535 (2001) 235246

Fig. 3. Graphical representation of the dependence between Pa and D 1 when D 2 0.15.

atoms (Qii), the Wiberg's indices (Wij) for chemically


bonded atoms, and optimized distances between
chemically nonbonded atoms in molecules (Rij). The
electronic charges are given in electronic charge unit
.
e, and the distances are given in A
Structures of the molecules under study were optimized, and the rotation of separate groups of atoms
around the most labile bonds was taken into account
to make an unambiguous choice among possible
conformations. As an example, dependence of the
rotation energies on the values of rotation angles
(w 1 w 5) is shown in Fig. 1 for the molecule N12.

For w 2 and w 5 at 1808 there exists a minimum close


to the minimum at 08. The w 5 rotation of 1808 results
in the same conformation since each CH3 replaces the
other one. The w 2 rotation proceeds under high values
of energy of the internal rotation barrier. Hence, the
energy of the given conformation is less than the one
obtained when w 2 rotation is performed with 1808.
Since the rotation for w 3 is suppressed, it is more
protable to leave the system in its initial position.
For the w 1 and w 4 rotations, the given conformation
is more stable again.
After comparing all the compounds with template

Fig. 4. Graphical representation of the dependence between Pa and D 2 when D 1 0.0499.

Ah. Altun, et al. / Journal of Molecular Structure (Theochem) 535 (2001) 235246

241

Fig. 5. The feature of activity AF-2 and the corresponding ETSA.

compounds, we revealed two features of anti-HSV-1


activity. When N12 is taken as a template compound,
the feature of activity-I (AF-1) is found (see Fig. 2).
By this, the best values for D 1 and D 2 are 0.0495
and 0.155, respectively. Within the limits given, the
feature responsible for the activity is found in 25
active and 4 inactive compounds. Hence, a a and Pa
are equal to 0.47 and 0.84, respectively.
D 1 and D 2 play an important role for the features
selection. For AF-I, the effect of varying D 1 under a
xed value of D 2 on the Pa estimate is shown graphically in Fig. 3.
In a similar manner, the relation between Pa and D 1
can be seen from Fig. 4.
For small D 1 and D 2 the values of n1 and n3 are

minimal. After reaching the optimum values or ranges


of D 1 and D 2, their further growth causes the decrease
of the probability of a feature realization. It happens
because of the compounds from inactive class getting
the feature. It means that Pa diminishes while n3
grows.
Extremely exible molecules, i.e. the ones that are
capable of forming additional intramolecular bonds,
can have a few local minima. Hence, one molecule
can be found in a few stable conformations. In such
cases the limits of variation for distances go out of the
limits allowable for D 2. That is why any such conformation is to be considered as a separate molecule and
included into the series given as a self-standing
compound. If later, one of the conformations gets

Fig. 6. IF-1 and the corresponding Electron Topological Sub-matrix of Inactivity (ETSI).

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Ah. Altun, et al. / Journal of Molecular Structure (Theochem) 535 (2001) 235246

Fig. 7. IF-2 and the corresponding ETSI.

the feature of activity while others do not possess the


feature, it means that this active conformation is characteristic of the molecule in reality.
When N28 is taken as the template compound,
another feature responsible for the activity demonstration (AF-2) that is formed by four chemically
non-bonded atoms (see Fig. 5) is found. The best D 1
and D 2 for this feature are equal to 0.044 and 0.100,
respectively. This feature enters just 12 active
compounds. Hence, a a and Pa are 0.64 and 0.93,
respectively.
Some compounds in which the thiosemicarbazide
moiety is afxed to the heterocyclic ring in the b- and

g-position relative to the ring nitrogen were also of


interest for us. Since these compounds include none of
the activity features shown above, they are inactive in
accordance with the results obtained by Brockman
and co-workers [10].
After determining activity features, it may be seen
that some inactive molecules contain activity features.
It means that the presence of the activity features is a
necessary but not sufcient condition for activity
demonstration. The question whether these
compounds contain features of inactivity or not,
should be analyzed for the more complete modeling.
After taking different inactive compounds as

Fig. 8. IF-3 and the corresponding ETSI.

Ah. Altun, et al. / Journal of Molecular Structure (Theochem) 535 (2001) 235246

243

Fig. 9. Inuence of aromatic ring on the activity of compounds.

templates, three features of inactivity have been


revealed.
Inactivity feature IF-1 is found when the molecule
N55 is chosen as the template compound (see Fig. 6).
The most satisfactory result is obtained when
D 1 0.05 and D 2 0.15. This feature is found in 12
inactive compounds of the training set. None of the
active compounds includes this feature. As a result,
probabilistic estimates a a and Pa are 0.56 and 0.93,
respectively.
Inactivity feature IF-2, found when the template
compound is N32, enters just 9 inactive compound
(see Fig. 7). Hence, the probabilistic estimations a a
and Pa are 0.45 and 0.91, respectively. D 1 and D 2
appeared to be the same as in IF-1.
The third inactivity feature (IF-3) is found when the
template compound is N15 (see Fig. 8). It enters just 7
inactive compounds. D 1 and D 2 are again as in IF-1.
Probabilistic estimations a a and Pa are 0.4 and 0.89,
respectively.
Shipman et al. [1] have demonstrated that the
azomethine bond reduction in a molecule (i.e. conversion of a thiosemicarbazone to thiosemicarbazide) did
not produce a proportional decrease in the antiviral
activity. With the activity features found as a result
of the ETM application, the reason of this becomes
more understandable.
The azomethine bond (i.e. the bond between the
atoms 7 and 9 shown in Figs. 2, 5, 6 and 8) does not
affect anti-HSV-1 activity directly since both activity

features do not contain chemically bonded atoms


and all the inactivity features are not related to
that bond.
The analysis of the found features shows that the
presence of a hydrophobic part in the form of aliphatic
groups (alkanes, cycloalkanes or any their derivatives) is necessary for the activity demonstration by
a molecule. The size of the cyclic groups (R1) does not
inuence the level of activity in view. The groups'
symmetrical arrangement relative to the nitrogen
atom is the most desirable one. Obviously, the groups
are capable of hydrophobic interaction with the corresponding bio-receptor.
The other edge of the molecule can be represented
either by pyridine or chinoline ring, that can enter into
the pp interaction with the bio-receptor. The nature
of these rings does not inuence substantially the
activity investigated (see Fig. 9).
Substituents in the hydrophobic and heterocyclic
parts of the molecule, that are capable of diminishing
the strength of the interactions, essentially diminish
their activity as well. It can be seen from the example
of the molecular skeleton A3, where the CH3-group in
the pyridine ring deactivates the compound.
In this way, it can be presupposed that interaction
with the receptor can occur on account of binding with
the metalenzyme complex. The compounds can be
bonded by such tridentate ligand bonds with metal
ions. Attention has been paid to this fact earlier [21]
in the study of the anticancer activity of the given

Fig. 10. Tautomeric equilibrium characteristic of thiosemicarbazones.

244

Ah. Altun, et al. / Journal of Molecular Structure (Theochem) 535 (2001) 235246

Fig. 11. A probable mechanism of interaction with the receptor.

class of compounds. As the rst stage, the tautomerization reaction takes place (see Fig. 10).
It is worth emphasizing that replacement of the
hydrogen attached to the nitrogen atom replacement
by the CH3-group (see compound 59) deactivates the
compound, because the tautomeric form II, capable of
binding with the metalenzyme complex, is not being
formed by this. The binding can take place as shown
in Fig. 11.
In the picture we observe two ve-membered
helate-ring formation as a result of the interaction.
The construction of a QSAR model based on the
calculated physicalchemical characteristics and
features of activity is a matter of practical interest.
Table 4 contains the parameters used for multivariable
regression analysis. The molecules in the table are
ranked according to their activity.
If any activity feature enters a molecule provided
that any inactivity feature does not accompany it, the
molecule is considered to be active. Molecules
containing any of the inactivity features are inactive
even if they contain any activity feature.
Parameters in Table 4 are given for the inhibitory
concentration C in mg/ml; for the total energy ETOT in
a.u; for HOMO or LUMO energies EHOMO or ELUMO in
2.
eV; for total surface area ATOT in A
The equation of the tted model is the following:
log1=C 0:010ETOT 2 0:298EHOMO 2 0:329ELUMO
1 0:006ATOT 2 0:225AF1 2 0:371AF2
Here R 2 0.90, S 0.62 (R is the correlation coefcient, S is the standard error of log(1/C) estimate).

The increase in HOMO or LUMO energies results


in the decrease of the inhibitory activity, while the
increase in total energy or total surface area causes
the activity increase.
After nding the structural and electronic parameters by means of the molecular mechanics and
quantum-chemical calculations, AFi and IFi values
can be determined by examining whether the
compounds include activity or inactivity features,
and then the tted equation can be used to evaluate
the activity numerically.
4. Conclusions
A series of thiosemicarbazone and thiosemicarbazide derivatives that are potent inhibitors of HSV-1
replication has been investigated by means of an original approach called ETM. Two features of activity
and three breaks of activity being three-dimensional
descriptions of molecular fragments responsible for
the activity/inactivity demonstration have been
revealed. In addition, a quantitative structureactivity
relationship (QSAR) model was built by means of
multivariable regression to express the activity dependence on some physicochemical and structural parameters.
As follows from the results, in a series of
compounds with similar skeletons, a computer screening can be carried out, aiming in the series partition
into active and inactive compounds, based on the
structural features selected. The features mentioned
can be used also when planning the synthesis of
new compounds with the activity studied.

Ah. Altun, et al. / Journal of Molecular Structure (Theochem) 535 (2001) 235246

245

Table 4
Some observed and calculated data related to the compounds under study (indicator I0 takes values of 1 or 0 according to the activity found
experimentally. AF1 and AF2 comprise 1 if corresponding features of activity enter a molecule, otherwise 0. IF1, IF2 and IF3 have the same
meaning for the corresponding features of inactivity. R denotes if the activity is predicted correctly (1) by the ETM)
N

ETOT

EHOMO

ELUMO

ATOT

I0

AF1

AF2

IF1

IF2

IF3

28
46
12
6
23
27
38
58
2
40
37
51
56
16
35
57
19
17
13
47
11
10
53
20
24
7
52
49
44
50
8
45
42
14
18
60
31
21
25
33
3
22
15
36
4
29
1
41
30
39

0.04
0.04
0.08
0.10
0.10
0.10
0.11
0.12
0.14
0.15
0.15
0.17
0.18
0.18
0.19
0.20
0.20
0.21
0.22
0.22
0.24
0.26
0.28
0.28
0.29
0.29
0.3
0.32
0.33
0.35
0.37
0.37
0.43
0.46
0.49
0.56
0.57
0.58
0.60
0.60
0.70
0.70
0.85
0.87
1.00
1.20
1.20
1.50
1.70
1.90

2205.76
2185.04
2139.08
2176.00
2225.61
2234.28
2170.84
2218.86
2130.37
2186.78
2202.34
2204.13
2204.16
2216.92
2233.09
2183.94
2189.89
2172.46
2181.18
2202.38
2257.05
2194.32
2174.20
2224.57
2197.12
2184.77
2156.77
2241.07
2220.04
2244.85
2179.79
2177.66
2222.52
2190.92
2188.42
291.40
2197.12
2154.76
2163.46
2177.78
2146.21
2147.84
2165.70
2246.87
2191.19
2154.77
2121.71
2204.08
2225.60
2212.77

29.59
29.55
29.79
29.8
29.68
29.60
29.88
210.04
29.83
29.76
29.65
29.77
29.29
29.66
29.56
28.99
29.65
29.69
29.64
29.63
210.06
29.91
29.7
29.66
29.63
29.84
29.62
29.76
29.79
29.73
29.80
29.77
29.78
29.52
29.59
211.08
29.59
29.81
29.78
29.79
29.86
29.76
29.70
29.65
29.64
29.81
29.85
29.76
29.67
29.75

2.46
1.97
1.90
1.90
1.90
1.99
2.50
1.77
1.88
2.54
1.75
2.42
2.53
1.97
1.75
1.87
1.96
1.89
1.95
2.03
1.66
1.77
3.13
1.81
1.92
1.96
3.09
2.35
2.48
2.21
1.88
2.14
2.51
1.97
1.89
2.77
2.08
1.99
1.92
1.66
1.94
1.95
1.93
1.53
1.96
1.91
1.87
2.53
1.99
2.54

346
327
246
303
353
386
306
357
217
328
332
360
323
334
377
313
327
288
341
346
308
272
303
377
350
325
270
387
373
367
294
319
346
305
308
166
329
287
300
304
255
263
282
380
348
284
201
334
369
381

1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

1
1
1
0
1
0
0
1
1
0
1
1
0
1
1
1
1
1
1
1
1
1
0
1
1
1
1
0
1
1
1
1
0
0
0
0
0
1
0
0
0
1
1
0
0
0
0
0
0
0

1
0
0
1
0
0
0
0
0
0
1
1
0
0
0
0
1
1
0
1
0
0
1
0
1
1
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
0
1
0
0
1
0
0
0
1
1
1
1
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
0
1
0
0
0
1
0
1
0
1
1
1

0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
0
1
0
1
0
0
1
0
0
0
0

1
1
1
1
1
0
0
1
1
0
1
1
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
1
1
1
1
1
2
1
1
1
1
1
1
1
1

246

Ah. Altun, et al. / Journal of Molecular Structure (Theochem) 535 (2001) 235246

Table 4 (continued)
N

ETOT

EHOMO

ELUMO

ATOT

I0

AF1

AF2

IF1

IF2

IF3

26
43
34
59
54
9
5
32
55
48

2.00
2.20
2.40
3.20
3.90
4.60
5.40
5.60
7.00
8.50

2163.49
2248.50
2221.15
2147.82
2129.30
2204.38
2274.73
2169.16
2164.53
2207.71

29.84
29.77
29.58
29.69
211.14
29.60
29.70
29.82
29.19
29.95

2.09
2.48
2.20
2.74
2.48
1.94
2.02
1.68
1.43
2.35

290
367
389
263
186
337
368
292
274
360

0
0
0
0
0
0
0
0
0
0

0
0
1
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0

0
1
0
0
0
1
0
0
1
0

0
0
1
0
0
0
0
1
0
0

1
0
0
0
0
0
1
0
0
0

1
1
1
1
1
1
1
1
1
1

The correlation equation can be used to determine


the level of the activity in view within the limits of
accuracy calculated.
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