Synthesis and biological evaluation of benzo[d]isothiazole, benzothiazole and thiazole Schiff bases

Article abstract of DOI:10.1016/S0968-0896(03)00493-0

Three new series of benzo[d]isothiazole, benzothiazole and thiazole Schiff bases were synthesized and tested in vitro with the aim of identifying novel lead compounds active against emergent and re-emergent human and cattle infectious diseases (AIDS, hepatitis B and C, tuberculosis, bovine viral diarrhoea) or against drug-resistant cancers (leukaemia, carcinoma, melanoma, MDR tumors) for which no definitive cure or efficacious vaccine is available at present. In particular, these compounds were evaluated in vitro against representatives of different virus classes, such as a HIV-1 (Retrovirus), a HBV (Hepadnavirus) and the single-stranded RNA⁺ viruses Yellow fever virus (YFV) and Bovine viral diarrhoea virus (BVDV), both belonging to Flaviviridae. Title compounds were also tested against representatives of Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Salmonella spp.), various atypic mycobacterial strains (Mycobacterium fortuitum and Mycobacterium smegmatis), yeast (Candida albicans) and mould (Aspergillus fumigatus). None of the compounds showed antiviral or antimicrobial activity. The benzo[d]isothiazole compounds showed a marked cytotoxicity (CC ₅₀=4-9 μM) against the human CD4⁺ lymphocytes (MT-4) that were used to support HIV-1 growth. For this reason, the most cytotoxic compounds of this series were evaluated for their antiproliferative activity against a panel of human cell lines derived from haematological and solid tumors. The results highlighted that all the benzo[d]isothiazole derivatives inhibited the growth of leukaemia cell lines, whereas only one of the above mentioned compounds (1e) showed antiproliferative activity against two solid tumor-derived cell lines.

Full text of DOI:10.1016/S0968-0896(03)00493-0

Bioorganic & Medicinal Chemistry11 (2003) 4785–4789
Synthesis and Biological Evaluation of Benzo[d]isothiazole,
Benzothiazole and Thiazole Schiff Bases
Paola Vicini,a,* Athina Geronikaki,b Matteo Incerti,a Bernadetta Busonera,c
Graziella Poni,c Carla Alba Cabrasc and Paolo La Collac
a
`
Dipartimento Farmaceutico Universita degli Studi Parma, Parco Area delle Scienze 27/A, 43100 Parma, Italy
bDepartment of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki,
Thessaloniki 54006, Greece
cDipartimento di Scienze e Tecnologie Biomediche, Sez. Microbiologia e Virologia Generale e Biotecnologie Microbiche,
`
Universita di Cagliari, Cittadella Universitaria di Monserrato, S.S. 554, Km 4.500, 09042 Monserrato (CA), Italy
Received 3 January2003; accepted 22 July2003
Abstract—Three new series of benzo[d]isothiazole, benzothiazole and thiazole Schiff bases were synthesized and tested in vitro with
the aim of identifying novel lead compounds active against emergent and re-emergent human and cattle infectious diseases (AIDS,
hepatitis B and C, tuberculosis, bovine viral diarrhoea) or against drug-resistant cancers (leukaemia, carcinoma, melanoma, MDR
tumors) for which no definitive cure or efficacious vaccine is available at present. In particular, these compounds were evaluated in
vitro against representatives of different virus classes, such as a HIV-1 (Retrovirus), a HBV (Hepadnavirus) and the single-stranded
RNA+ viruses Yellow fever virus (YFV) and Bovine viral diarrhoea virus (BVDV), both belonging to Flaviviridae. Title com-
pounds were also tested against representatives of Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Salmonella
spp.), various atypic mycobacterial strains (Mycobacterium fortuitum and Mycobacterium smegmatis), yeast (Candida albicans) and
mould (Aspergillus fumigatus). None of the compounds showed antiviral or antimicrobial activity. The benzo[d]isothiazole com-
pounds showed a marked cytotoxicity (CC50=4–9 mM) against the human CD4+ lymphocytes (MT-4) that were used to support
HIV-1 growth. For this reason, the most cytotoxic compounds of this series were evaluated for their antiproliferative activity
against a panel of human cell lines derived from haematological and solid tumors. The results highlighted that all the benzo[d]i-
sothiazole derivatives inhibited the growth of leukaemia cell lines, whereas onlyone of the above mentioned compounds ( 1e)
showed antiproliferative activityagainst two solid tumor-derived cell lines.
# 2003 Elsevier Ltd. All rights reserved.
Introduction
azomethine linkage and evaluated in vitro their anti-
viral, antimicrobial and antiproliferative activities.
The twentieth centuryhas been characterised both bya
drastic reduction in the mortalitycaused byinfectious
diseases and bya rise in the control of neoplastic
pathologies. Nevertheless, microorganism and viruses,
on the one hand, and tumors, on the other, still repre-
sent a dreadful menace to men’s health and therefore,
for a more efficient control, require the steadydevelop-
ment of novel and more powerful drugs. To this end, as
a continuation of our research program on benzo[d]-
isothiazole and benzothiazole derivatives of biological
interest,1ꢀ7 we synthesized new compounds bearing an
This studyreports a comparative evaluation of benzo
[d]isothiazole, benzothiazole and thiazole Schiff bases
(azomethines) purposelydesigned to combine the het-
erocyclic ring with an arylidene moiety bearing different
substituents. The compounds synthesized for this study
are shown in Figure 1 where structures 1 and 2 represent
the benzo[d]isothiazole and the benzothiazole Schiff
bases, respectively, which were derived from the iso-
meric benzo[d]isothiazole and benzothiazole hetero-
cycles. Structures 3, related to the latter compounds, are
simple thiazole Schiff bases that can be regarded as
simplified versions of structure 2, which follows an
approach that is often applied in rational drug design.
Here we report the synthesis of the above compounds
and the evaluation of their biological activity.
*Corresponding author. Tel.: +39-0521-905051; fax: +39-0521-
905006; e-mail: pvicini@ipruniv.cce.unipr.it
0968-0896/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00493-0

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P. Vicini et al. / Bioorg. Med. Chem. 11 (2003) 4785–4789
mediates for the synthesis of the final compounds, were
prepared according to the methods described in our
previous papers.7,9 The test compounds alreadydescri-
bed had constants in agreement with the reported lit-
erature values (see Table 1). The structures of the newly
described compounds were confirmed byelemental
1
analysis and by IR, MS and H NMR spectral data.
Physical, chemical and IR relevant spectroscopic data of
the compounds are reported in Table 1.
1
Structural H NMR, complete IR data and elemental
analysis have only been given in the Experimental for
compound 1b. The complete structural data and the
elemental analysis, for all the novel compounds can be
obtained from the authors on request.
Results and Discussion
The benzo[d]isothiazole, benzothiazole and thiazole
Schiff bases were evaluated for cytotoxicity against MT-
4 cells, which was carried out in parallel with the eval-
uation of the anti-HIV-1 activity( Table 2), to determine
whether the compounds were endowed with selective
antimicrobial/antiviral activity. The compounds were
also tested for antiviral, antimicrobial and anti-
proliferative activities (Tables 3–5).
Figure 1. Structures of the benzo[d]isothiazole, benzothiazole and
thiazole Schiff bases.
Chemistry
Contraryto the benzothiazole ( 2a–g) and thiazole Schiff
bases (3a–f), the benzo[d]isothiazoles (1a–i) showed sig-
nificant cytotoxicity against MT-4 cells (Table 2). When
tested for antiviral activities, the above compounds
resulted inactive against representatives of different
virus classes, such as a Retrovirus (HIV-1), a Hepadna-
virus (HBV), Yellow fever virus (YFV) and Bovine viral
diarrhoea virus (BVDV).
The general method which is employed to prepare the
final compounds 1a–i, 2a–g and 3a–f is outlined in
Scheme 1.
The designed Schiff bases were prepared byreacting the
appropriate heteroarylamine with the selected aldehyde.
Nucleophilic addition of the NH2 group to the carbonyl
function of the aromatic aldehyde is not straightfor-
ward8 and different experimental conditions A, B, C
and D were developed to prepare the target compounds.
Difficulties connected with the poor reactivityof some
starting materials were overcome bythe use of suitable
catalysts and with azeotropical removal of water by a
Dean–Stark trap. Each of the final compound 1a–i, 2a–
g and 3a–f was purified bycrystallization using absolute
ethanol (unless otherwise noted). It emerged that anhy-
drous crystallization solvents were essential to avoid
decomposition by hydrolysis, at varying rates, of the
compounds. The various heteroarylamines, key inter-
Surprisingly, the derivatives bearing 5-nitrofurane (1e),
chlorophenyl (1a, 1g, 1h, 2b, 2e, 3b) and nitrophenyl (2c,
2d, 2f, 3c) substituents, which were expected to be
endowed with antimicrobial activity, were inactive
against bacteria and fungi (data not shown). As far as
the anti-mycobacterial activity was concerned, com-
pounds 1a–i inhibited Mycobacterium smegmatis and/
or fortuitum at concentrations close to those cytotoxic,
thus resulting poorlyselective in their anti-mycobacter-
ial activity( Table 3).
Due to the fact that the benzo[d]isothiazole Schiff bases
(1a–i) inhibited the growth of MT-4 cells, theywere also
evaluated against a panel of human cell lines derived
from haematological and solid tumors (Tables 4 and 5).
Generally, these compounds showed antiproliferative
activityin the micromolar range against both T-lym-
phoblastic and B-lymphoblastic leukaemia cells and
theydid not inhibit the proliferation of solid tumor-
derived cell lines. It is noteworthythat onlycompound
1e, which bears a 5-nitrofurane at position R1, was
active against skin melanoma and breast adenocarci-
noma cells. This result suggests that the benzo[d]-
isothiazole arylidene derivatives might be interesting
enough for further investigations on potential antitumor
effects.
Scheme 1. Reagents: (A) anhydrous benzene 5 h, reflux; (B) absolute
ethanol and acetic acid 15 min, reflux; (C) benzene and p-toluensul-
phonic acid 6 h, reflux; (D) absolute ethanol and piperidine 3 h, reflux.

P. Vicini et al. / Bioorg. Med. Chem. 11 (2003) 4785–4789
4787
Table 1. Physico-chemical data of the benzo[d]isothiazole, benzothiazole and thiazole Schiff bases 1a–i, 2a–g, 3a–f
Compd
Molecular formulaa
(Mol. Mass)
Procedure
Mp (ꢁC)
Yield (%)
IR n (cmꢀ1
Azomethine C–H
)
N¼C
Substituents
—
2964.05–2877.27 (CH3)
3522.34–3251.40 (OH)
2998.77–2826.17 (CH3)
3369.03-2981.41 (OH)
2958.27-2836.77 (CH3)
1517.70, 1346.07 (NO2)
3535.84–3316.00 (OH)
1a
1b
1c
C14H9ClN2S (272.75)
C15H12N2OS (268.33)
C15H12N2O2S (284.33)
A
A
B
122–124
87–88
70
78
75
1619.91
1599.66
1597.73
2919.70, 2838.70, 1388.50
2903.31, 2826.17, 1380.78
2930.31, 2826.17, 1382.71
145–147b
1d
C15H12N2O2S (284.33)
C
141–143b
68
1598.70
2929.34, 2838.70, 1394.28
1e
1f
C12H7N3O3S (273.27)
C15H12N2OS (268.33)
B
A
171–173b
118–120
69
40
1596.77
1601.59
2924.52, 2838.70, 1382.71
2929.34, 2838.70, 1377.89
2967.91–2822.67 (CH3)
2967.91–2812.67 (CH3)
2967.91–2812.67 (CH3)
3000.59–2823.13 (CH3)
1g
1h
1i
2a
2b
2c
2d
2e
2f
2g
3a
3b
3c
3d
3e
3f
C15H11ClN2S (286.78)
C15H11ClN2S (286.78)
C16H14N2OS (282.36)
C14H10N2S (238.31)10
C14H9ClN2S (272.75)10
C14H9N3O2S (283.31)10
C14H9N3O2S (283.31)10
C14H8ClFN2S (290.74)
C14H8FN3O2S (301.30)
C16H14N2O2S (298.36)5
C10H8N2S (188.25)8
C10H7ClN2S (222.69)11
C10H7N3O2S (233.25)8
C11H10N2OS (218.28)8
C17H14N2OS (294.37)
C18H16N2O3S (340.40)12
A
A
A
C
C
C
C
C
C
C
D
D
D
D
D
D
125–127
114–116
89–91
52
43
40
96
57
67
69
75
80
55
92
98
60
74
41
80
1599.66
1618.95
1599.66
—
—
—
2915.84, 2826.17, 1380.78
2919.70, 2838.70, 1379.82
2903.31, 2826.17, 1375.00
—
100–101
176–177
164–166
188–189
106–108
157–159
228–230
113–115
138–140
183–184
102–103
123–125
140–142
—
—
—
—
—
—
—
—
2970.8, 2908.12, 1380.81.
2968.87, 2897.54, 1390.15
—
1603.52
1605.45
—
—
—
—
—
1602.56
—
—
1527.35, 1347.03 (NO2)
—
—
—
—
—
—
—
—
—
2978.34–2815.41 (CH3)
—
2932.23, 2834.85, 1385.02
—
aKnown products are given with references, the others are new.
bCrystallized from benzene.
Table 3. Antimycobacterial activity of the benzo[d]isothiazole, ben-
zothiazole and thiazole Schiff bases 1a–i, 2a–g, 3a–f
a
c
Compd
CC50
MT-4
MIC50b/MIC90
Table 2. Cytotoxicity and anti-HIV-1 activity of the benzo[d]isothia-
zole, benzothiazole and thiazole Schiff bases 1a–i, 2a–g, 3a–f
M. smegmatis
M. fortuitum
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
2e
2f
2g
3a
3b
3c
3d
3e
9
7
6
6
4
7
8
7
5
>100
>100
78 >100
>100
42 >100
>100
>100
>100
83 >100
>100
73 >100
>100
>100
>100
>100
>100
>100
>100
>100
70 >100
57 >100
50 >100
55 >100
11\49
52 >100
>100
65 >100
55 >100
>100
>100
>100
>100
>100
>100
>100
>100
>100
a
b
Compd
CC50
(MT-4)
EC50
(HIV-1)
1a
1b
1c
1d
1e
1f
9
7
6
6
4
>9
>7
>6
>6
>4
>7
7
>100
>100
25
1g
1h
1i
8
7
5
>8
>7
>5
60
2a
2b
2c
2d
2e
2f
>100
>100
25
>100
>100
>25
>60
>100
>100
>100
>100
>100
>63
>100
>100
>100
0.01
>100
ꢂ100
ꢂ100
>100
>100
63
>100
ꢂ100
ꢂ100
60
60
>100
ꢂ100
ꢂ100
>100
>100
63
>100
ꢂ100
ꢂ100
150
>100
>100
>100
>100
0.5\8.5
>100
2g
3a
3b
3c
3d
3e
3f
>100
>100
>100
0.6\2.3
1.8\8.5
3f
Ciprofloxacind
Isoniazidd
>100
Data represent mean values for three independent determinations.
Variation among duplicate samples was less than 15%.
aCompound concentration (mM) required to reduce the viabilityof
mock-infected MT-4 cells by50%, as determined bythe MTT method.
bMinimum inhibitoryconcentration ( mM) required to reduce the
number of viable mycobacteria by50%, as determined bythe MTT
method.
AZTc
Data represent mean values for three independent determinations.
Variation among duplicate samples was less than 15%.
aCompound concentration (mM) required to reduce the viabilityof
mock-infected MT-4 cells by50%, as determined bythe MTT method.
bCompound concentration (mM) required to achieve 50% protection
of MT-4 cells from the HIV-1 induced cytopathogeneticy, as deter-
mined bythe MTT method.
cMinimum inhibitoryconcentration ( mM) required to reduce the
number of viable mycobacteria by90%, as determined bythe MTT
method.
cAzidothymidine (AZT) was used as reference drug.
dCiprofloxacin and Isoniazid were used as reference drugs.

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P. Vicini et al. / Bioorg. Med. Chem. 11 (2003) 4785–4789
assigned structure in all cases and the reported wave-
numbers are given in cmꢀ1 1H NMR spectra, in
Table 4. Antiproliferative activityagainst leukaemia-/lmy phoma-
derived cell lines of the benzo[d]isothiazole Schiff bases 1a–i
.
DMSO-d6 solutions, were recorded on a Bruker AC 300
instrument at 298 K. Chemical shifts are reported as d
(ppm) relative to TMS as internal standard. The pro-
gress of the reactions was monitored bythin-laeyr
a
Compd
IC50 (mM)
MT4b
CCRF-CEMc
WIL-2NSd
CCRF-SBe
1a
1c
1d
1e
1f
1g
1h
1i
6
5
5
2
5
3
2
4
0.1
2
2
2.5
2
2
1.5
1.5
1.5
0.3
10
10
10
6.5
6
4
5
4
5
3
3
4
4
0.3
chromatographywith F
silica-gel precoated sheets
254
(Merck) using methylene chloride/ethanol 99.5/0.5 as
eluent; UV light was used for detection. Solvents, unless
otherwise specified, were of analytical reagent grade or
of the highest qualitycommerciallyavailable. Synthetic
starting material, reagents and solvents were purchased
from Aldrich Chemical Co. and were rigorouslydried.
5
7
6.5
0.5
2A-6-MPf
Data represent mean values for three independent determinations.
Variation among duplicate samples was less than 15%.
aCompound concentration required to reduce cell proliferation by
50%, as determined bythe MTT method, under conditions allowing
untreated controls to undergo at least three consecutive rounds of
multiplication.
General procedure A for synthesis of benzo[d]isothiazol-
3-yl-(arylidene)-amines 1a,b,f–h
A solution of benzo[d]isothiazol-3-ylamine or 5-methyl-
benzo[d]isothiazol-3-ylamine (5 mmol) and the appro-
priately substituted benzaldehyde (6 mmol) in anhy-
drous benzene (25 mL) was refluxed for 6 h. The
mixture kept overnight at room temperature gave a
precipitate which was removed byfiltration and purified
byrecrystallization.
bCD4+ human T-lymphoblastoid cells.
cCD4+ human acute T-lymphoblastic leukaemia.
dHuman splenic B-lymphoblastoid cells.
eHuman acute B-lymphoblastic leukaemia.
f2-Amino-6-mercaptopurine (2A-6-MP) was used as reference drug.
Table 5. Antiproliferative activityagainst solid tumour-derived cell
lines of the benzo[d]isothiazole Schiff bases 1a–i
Experimental data of benzo[d]isothiazol-3-yl-(4-methoxy-
benzylidene)-amine 1b. Anal. calcd for C15H12N2OS
(268.33): C, 67.14; H, 4.51; N, 10.44; S, 11.95. Found:
a
Compd
IC50 (mM)
SK-MEL-28b
MCF7c
SKMES-1d
DU145e
C, 67.47; H, 4.53; N, 10.16; S, 11.65. IR (KBr) n cmꢀ1
:
3097.12–2974.05 (C–H aromatic), 2964.05–2877.27
(CH3), 2903.31, 2826.17, 1380.78 (C–H azomethine),
1606.41 (N¼C), 1573.63, 1511.92, 1259.29. 1H NMR
(300 MHz, DMSO-d6): 9.18 (s, 1H, CH), 8.19–8.16 (m,
2H, H-4,7), 8.11–8.08 (m, 2H, H-20, 60), 7.69–7.63 (m,
1H, H-5), 7.57–7.52 (m, 1H, H-6), 7.15–7.12 (m, 2H, H-
30, 50), 3.88 (s, 3H, CH3).
1a
1c
1d
1e
1f
1g
1h
1i
>20
>20
>20
6
>20
>20
>20
>20
5
>20
>20
>20
10
>20
>20
>20
>20
4
>20
>20
>20
>20
>20
>20
>20
>20
2
>20
>20
>20
>20
>20
>20
>20
>20
2
2A-6-MPf
General procedure B for synthesis of benzo[d]isothiazol-
3-yl-(arylidene)-amines 1c,e. A well stirred solution of
benzo[d]isothiazol-3-ylamine (5 mmol), the appropriate
arylaldehyde (6 mmol) and acetic acid (0.5 mL), in eth-
anol (18 mL), was heated for 15 min, until no starting
amine was detected byTLC. After cooling at room
temperature, the precipitate was collected, filtered and
washed with diethylether to give the crude product
which was purified byrecrystallisation.
Data represent mean values for three independent determinations.
Variation among duplicate samples was less than 15%.
aCompound concentration required to reduce cell proliferation by
50%, as determined bythe MTT method, under conditions allowing
untreated controls to undergo at least three consecutive rounds of
multiplication.
bHuman skin melanoma.
cHuman breast adenocarcinoma.
dHuman lung squamous carcinoma.
eHuman prostate carcinoma.
f2-Amino-6-mercaptopurine (2A-6-MP) was used as reference drug.
General procedure C for synthesis of benzo[d]isothiazol-
3-yl-(3-methoxy-4-hydroxy-benzylidene)-amine 1d and of
benzothiazol-2-yl-(arylidene)-amines 2a–g
Experimental
Chemistry
A solution of amine (5 mmol), the appropriate ary-
laldehyde (6 mmol) and p-toluenesulphonic acid (a small
amount), in anhydrous benzene (30 mL) was refluxed
for 6 h while water was removed in a Dean–Stark trap.
The solid product obtained after cooling was collected
byfiltration and purified byrecrystallisation.
Melting points (ꢁC) were determined with a Buchi 512
apparatus and are uncorrected. New compounds were
analysed in the analytical laboratory of Dipartimento
Farmaceutico, Universita di Parma, on a ThermoQuest
(Italia) FlashEA 1112 Elemental Analyzer, for C H N
and S. The found values for C H N S were
alwaysÆ0.4% of the theoretical ones.
General procedure D for synthesis of thiazol-2-yl-(aryl-
idene)-amines 3a–f
IR spectra were recorded, as KBr pellets, on a Jasco
FT-IR 300E spectrophotometer (Jasco Ltd., Tokyo,
Japan). Spectral IR data were consistent with the
The properlysubstituted thiazol-2-ylamine (5 mmol), a
slight excess of the aldehyde (6 mmol) and a few drops

P. Vicini et al. / Bioorg. Med. Chem. 11 (2003) 4785–4789
4789
of piperidine in ethanolic solution, were refluxed in a
water bath for 3 h. After cooling the final products were
precipitated, filtered and recrystallized.
18 h in the presence of serial dilutions of test com-
pounds.
Antimycobacterial assays
Microbiology
Mycobacterium tuberculosis 27294 and Mycobacterium
smegmatis 19420 are ATCC strains, Mycobacterium
fortuitum is a clinical isolate. MICs were assessed in
microtiter plates byadding 20 mL aliquots of a culture
suspension to 80 mL of Middlebrook 7H9 medium con-
taining serial dilutions of test compounds. At the end of
incubation, the number of viable mycobacteria was
Test compounds were dissolved in DMSO at 100 mM
and then diluted in culture medium.
Cytotoxicity and antiproliferative assays
+
Exponentiallygrowing human CD4
lymphocytes
13
(MT-4), babyhamster kidney(BHK-21), Madin Darby
bos kidney(MDBK) and human cell lines derived from
hematological and solid tumor were resuspended in
growth medium containing serial dilutions of the drugs.
Cell viabilitywas determined after 96 h at 37 C bythe 3
-(4,5- dimethylthiazol -2-yl)-2,5-diphenyl -tetrazolium
bromide (MTT) method13
determined bythe MTT method.
Linear regression analysis
ꢁ
Viral and tumor cell growth at each drug concentration
was expressed as percentage of untreated controls and
the concentrations resulting in 50% (EC50, EC50)
growth inhibition was determined bylinear regression
analysis.
Antiviral assay
Activityof compounds against HIV-1 was based on
inhibition of virus-induced cytopathogenicity in acutely
infected MT-4 cells at a multiplicityof infection of
0.01.14 Briefly, 50 mL of culture medium containing
1ꢃ104 cells were added to each well of flat-bottom
microtiter trays containing 50 mL of culture medium
with or without test compounds. Then 20 mL of an HIV
suspension containing 100 (HIV-1IIIB) CCID50 was
added. After a 4-dayincubation, cell viabilitywas
determined by 3-(4,5-dimethylthiazol-1-yl)-2,5-diphe-
nyl-tetrazolium bromide (MTT) method.13
Acknowledgements
This work was supported byresearch grants FIL 2001,
Universityof Parma, Italy.
References and Notes
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Med. Chem. 2002, 37, 553.
2. Geronikaki, A.; Lagunin, A.; Poroikov, V.; Filimonov, D.;
Hadjipavlou-Litina, D. J.; Vicini, P. SAR QSAR. Environ.
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