Synthesis and evaluation of pharmacological properties of some new xanthone derivatives with piperazine moiety

Article abstract of DOI:10.1016/j.bmcl.2013.05.062

A series of new xanthone derivatives with piperazine moiety [1-7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α₁ and β₁ adrenergic as well as 5-HT_1A, 5-HT

Full text of DOI:10.1016/j.bmcl.2013.05.062

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4419–4423
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of pharmacological properties of some new
xanthone derivatives with piperazine moiety
a
a
b
c
d
d
A. M. Waszkielewicz a, , A. Gunia , N. Szkaradek , K. Pytka , A. Siwek , G. Satała , A. J. Bojarski ,
⇑
E. Szneler e, H. Marona a
a Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland
b Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-060 Krakow, Poland
c Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland
d Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Sme˛tna Street, Krakow, Poland
e Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new xanthone derivatives with piperazine moiety [1–7] was synthesized and evaluated for
their pharmacological properties. They were subject to binding assays for a1 and b1 adrenergic as well
as 5-HT1A, 5-HT6 and 5-HT7b serotoninergic receptors. Five of the tested compounds were also evaluated
for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-
yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic
5-HT1A receptors (Ki = 24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-
{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED50 determined
in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with
piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral
administration.
Received 4 April 2013
Revised 16 May 2013
Accepted 17 May 2013
Available online 29 May 2013
Keywords:
5-HT
Adrenergic receptors
Anticonvulsant activity
Epilepsy
Ó 2013 Elsevier Ltd. All rights reserved.
1,4-Piperazine derivatives
MES
Serotoninergic receptors
Xanthone
The xanthone skeleton consists of the
c
-pyron moiety con-
terms of anti-arrhythmic, hypotensive,
blocking properties.9,13
In the present Letter we report on synthesis and biological
activity of seven new xanthone derivatives. Pharmacological stud-
a1- and b1-adrenoreceptor
densed with two benzene rings. Its derivatives constitute an
important class of compounds which are found in higher plants,
fungi and lichens. Especially the Guttiferae family is known for
being rich in these substances, which occur mostly in forms of
polyphenolic derivatives.1 Xanthone derivatives are also an inter-
esting group of compounds in the field of medicinal chemistry.
They proved to possess several beneficial heterogeneous pharma-
cological properties, for example, analeptic,2 antiallergic,3 antilipi-
ies include in vitro binding to a1, b1, and 5-HT1A, 5-HT6 and 5-HT7b
receptors as well as in vivo anticonvulsant assays (for five com-
pounds). All tested substances possessed both xanthone skeleton
and an N-substituted piperazine moiety joined by a methylene lin-
ker. Combining of those moieties was an attempt of rational design
of new potentially active substances. Especially incorporation of N-
(2-methoxyphenyl)piperazine seemed to be promising due to the
fact that this moiety is considered an important element for bind-
ing to adrenergic as well as serotoninergic receptors.14 Typical
examples of drugs containing this group are urapidil and naftopidil
(Fig. 1).15,16 Moreover, a1 and b1 receptors constitute important
targets for antihypertensive and antiarrhytmic drugs.17–19 On the
other hand, 5-HT1A ligands with agonist or partial agonist activity
seem to possess antianxiety, antidepressant, antiaggressive, and
probably neuroprotective properties.20 As an example, naluzotan
(Fig. 1) as an N-arylpiperazine derivative and a 5-HT1A ligand,
has been developed for various CNS disorders including epi-
lepsy.21,22 5-HT6 and 5-HT7 receptors play role in depression,
demic,4
diuretic,5
antitumor,6
antimycobacterial,7
and
antimicrobial.8,9 In recent years we have reported their anticonvul-
sant activity, especially in the in vivo maximal electroshock (MES)
seizure model.10 The most promising compounds were (R,S)-, (R)-
and (S)-6-chloro-2-(1-hydroxypropan-2-ylamino)methyl-9H-xan-
then-9-one (Fig. 1) with MES ED50 (median effective dose) values
of 56.2, 77.44, and 72.97 mg/kg b.w. (mice, i.p.), respectively.11,12
Our former research also proved their cardiovascular activity in
⇑
Corresponding author. Tel.: +48 126205576.
E-mail addresses: awaszkie@cm-uj.krakow.pl, am.waszkielewicz@interia.pl
(A.M. Waszkielewicz).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.05.062

4420
A. M. Waszkielewicz et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4419–4423
O
H3C
O
N
H
N
O
CH3
N
CH3
N
H
N
N
O
O
S
N
H
N
O
N
N
N
CH3
O
Urapidil
Naluzotan
O
CH3
CH3
∗
O
OH
N
H
OH
Cl
O
6-chloro-2-(1-hydroxypropan-2-ylamino)methyl-
9H-xanthen-9-one
Naftopidil
Figure 1. Structures of urapidil, naftopidil, naluzotan, and 6-chloro-2-(1-hydroxypropan-2-ylamino)methyl-9H-xanthen-9-one.
memory deficits, anxiety, as well as other disorders characterized
by change of cholinergic neurotransmission.23
structures are consistent with this rule (calculated values are in
the range 36.687–56.915 Å2). None of the compounds exhibited
any violations from the Lipinski rule of five,28 making them poten-
tially promising drug-like agents.
Considering anticonvulsant assays, we were interested how
piperazine moiety with a methylene linker could affect the activity
of formerly synthesized derivatives of xanthone, and––as a conse-
quence––our aim was to compare the achieved results. Since many
pathomechanisms contribute to presence of seizures, it was inter-
esting whether there was a correlation between affinities to the
above mentioned receptors and anticonvulsant activity.
The first step of the research was calculation of several physico-
chemical parameters by means of Molinspiration online toolkit.24
Such calculations are important at early stage of drug discovery
process in terms of predicting essential parameters and facilitating
rational drug design. The parameters include miLogP, topological
polar surface area TPSA, molecular volume, as well as violations
from the Lipinski rule of five. The results are presented in Table 1.
The first calculated parameter, miLogP, exhibits optimum value for
CNS active compounds of about 2 and 3 and was found in the range
3.239–4.98.25 The most beneficial value of TPSA should be <120 Å2
for orally administered drugs and <60–70 Å2 for compounds de-
signed to penetrate blood–brain barrier,26,27 and all proposed
General way of preparation of compounds 1–7 is shown in
Scheme 1 and their structures are presented in Table 1. The mul-
tistage synthesis was performed according to previously published
procedures.12 The first step was the Ullmann’s condensation of
substituted chlorbenzoic acid and appropriate cresol followed by
cyclization resulting in corresponding 9H-xanthen-9-one with
methyl residue.29,30 Next step constituted methanolysis in case
of synthesis of 3–6. It was performed with a portion of 9H-xan-
then-9-one methyl derivative. Then all intermediate compounds
were subject to free-radical bromination with little excess of
N-bromosuccinimide (NBS). The last reaction constituted aminoly-
sis of the appropriate bromo-substituted derivative by means of
appropriate piperazine derivatives.9,31 Some portions of amines
were converted into hydrochlorides. All compounds were purified
by means of recrystallization from appropriate solvents mixtures.
The structures were further confirmed using 1H NMR and 13C
NMR spectra.
Table 1
Chemical structures of the tested compounds 1–7
O
O
1
8
7
2
R2
R1
3
4
6
5
Compd
R1
Position of R2
4
R2
nHCl
miLogP
TPSA [Å]
36.687
Volume
301.41
N
N
N
Cl
1
1a 2HCl
3.871
N
CH3
Cl
2
3
4
4
2a 2HCl
3a HCl
3.239
4.956
56.915
55.155
326.471
393.814
N
OH
CH3
H3C
O
O
O
N
H3C
N
4
5
2
2
4a 2HCl
5a 2HCl
3.274
4.673
45.921
45.921
313.42
385.07
N
CH3
O
H3C
H3C
N
N
O
O
N
N
CH3
CH3
6
7
2
2
6a HCl
7a HCl
4.98
55.155
45.921
393.814
368.268
H
N
O
N
4.947

A. M. Waszkielewicz et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4419–4423
4421
O
O
serve as ‘gold standards’ in screening for potential anticonvulsants,
giving premises for activity in human grand mal or petit mal
epilepsy, respectively. The procedures are routinely carried on at
National Institutes of Neurological Disorders and Stroke, NINDS,
National Institutes of Health NIH (Rockville, MD, USA) within Anti-
convulsant Screening Project ASP and the procedures have been
published.36,37
8
5
1
4
Ullmann's condesation
cyclization
2
7
+
OH
CH3
CH3
CH3
3
R
O
R
6
HO
1 6
R - Cl for
-
or H for 7
methanolysis
NBS (CCl4, hν)
for 1, 2, 7
CH3ONa, CH3OH
for 3-6
Many antiepileptic drugs exhibit significant toxicity. Therefore,
the ASP program includes a screening model for neurotoxicity–
rotarod. The ability of an animal to stay on a slowly rotating rod
(6 rpm) without falling is measured (3 times within 1 min). If it
falls after 0.5 or 4 h of a dose of 30 mg/kg b.w. (mice, i.p.), the min-
imal motor impairment observed for the compound excludes it
from further testing (class 4 ASP, Table 3).36,37
O
O
O
O
NBS
(CCl4, hν)
CH3
CH2Br
H3C
O
R1
aminolysis
(toluene, K2CO3)
Five of the synthesized compounds were tested for their anti-
convulsant activity within the ASP program and the results are pre-
sented in Tables 3–5. Preliminary screening included
intraperitoneal (i.p.) administration to mice at 0.5 or 4 h before
the test. The doses 30, 100, and 300 mg/kg b.w. were used. Preven-
tion of seizures is considered protection.
O
O
R2
R1
1-7
Compounds
Compounds 2a, 4 and 5 exhibited protection in MES. 2a and 4
were especially active, but their neurotoxicity was noticeable.
Thus, 5 proved better properties because it showed no neurotox-
icity at two test time points. It was active in MES while tested at
4 h after administration at the doses of 100 and 300 mg/kg. 2a, 4
and 5 were also tested at the dose of 30 mg/kg in rats after oral
administration for activity in MES and neurotoxicity. The results
are presented in Table 4. This kind of test enables to evaluate to
some extent the bioavailability in p.o. route which is most popular
way of administration of drugs. 2a and 5 proved to be more active
than 4. Compound 5 showed activity at 4 time points and it was
used in quantitative assay. Time to peak effect (TPE) was shown
to be 4 h after administration. Its median effective dose (dose of
the compound which gives protection against seizures in 50% of
tested animals, ED50) was determined at the value of 105 mg/kg
while median toxic dose (dose of the compound which produces
neurotoxicity in 50% of tested animals, TD50) was greater than
Scheme 1. Chemical procedure of preparation of compounds 1–7.
Table 2
Results of binding to serotoninergic and adrenergic receptors of reference and tested
compounds 1–7
Compd
Ki [nM]
a
a
a
b
b
5-HT1A
5-HT6
5-HT7b
a1
b1
1a
2a
3a
4a
5a
6a
7a
13340
4503
24
15840
1671
429
117
12
19460
14420
9363
19100
8836
13600
5939
––
10490
17420
195
16950
13500
1145
426
650
3930
170
490
310
380
3660
––
n.a.
n.a.
n.a.
n.a.
n.a.
>30,000
>10,000
––
Buspiron
Clozapine
Phentolamine
Propranolol
––
143
––
––
4
––
––
18
––
––
––
18
––
––
––
7
300 mg/kg which resulted in protection index (PI = TD50/ED50
)
more than 2.86.
n.a.––Compound did not bind to receptor at 50 lM, inhibition constants (Ki) were
In conclusion, in the present paper we report on preliminary
pharmacological properties of seven new xanthone derivatives.
They all possessed additional pharmacophore forming fragment
that is, arylpiperazine moiety. In spite of former encouraging data
of pharmacological activity of compounds from that group9,13 the
title compounds did not show satisfactory binding affinities to a1
and b1 adrenoreceptors or to 5-HT1A receptors. Even though intro-
ducing of N-(2-methoxyphenyl)piperazine moiety resulted in some
improvement of binding properties to a1 receptor which was seen
in case of compound 3a, of which Ki value was the lowest among
the tested series.
It is consistent with known facts that if a compound exhibits
some affinity towards a1 receptor, it is likely to bind to 5-HT1A
receptors as well. A good example in our study is 3a––Ki for a1
and 5-HT1A are 170 nM and 24 nM, respectively.
calculated according to the equation of Cheng and Prusoff31. Radioligand binding
assays to rats brain tissues using [3H]8-OH-DPAT for 5-HT1A, [3H]-LSD for 5-HT6,
[3H]-5-CT for 5-HT7, [3H]prazosin for a1 and [3H]CGP-12177 for b1.
a
n = 3.
n = 2.
b
In vitro pharmacological profile of the new compounds was
evaluated by radioligand binding assays. The inhibition constants
(Ki) were calculated from the Cheng–Prusoff equation.32 Mem-
brane preparation and general assay procedures for cloned recep-
tors were adjusted to 96-microwell format on the basis of
protocols described previously.33–35 The obtained results are pre-
sented in Table 2. Compound 3a showed the highest affinity for
serotoninergic 5-HT1A receptors expressed in HEK293 (Ki = 24 nM)
as well as for a1 receptors (Ki = 195 nM). Compounds 2a, 4a, 5a, 6a
Another observation is that substitution with piperazine moiety
in position four of the xanthone structure is more beneficial than in
position two (compound 3a was clearly more active than 6a and
7a). Compound 3a exhibited the best affinity to 5-HT1A receptors
which suggest that it could be scheduled to further pharmacolog-
ical testing for its antianxiety and/or antidepressant activity.
The most promising results concern anticonvulsant activity of
five compounds. The activity showed in maximal electroshock
was encouraging. However, 3a which was the most active ligand
in the binding studies did not exhibit optimum in vivo activity.
In fact, it did not prevent seizures and it was neurotoxic at
300 mg/kg b.w. (mice, i.p.). Other compounds: 2a, 4 and 5 were ad-
and 7a displaced [3H]8-OH-DPAT from HEK293 serotonin binding
sites in moderate concentration range (Ki = 117–15840 nM). None
of tested compounds inhibited [3H]CGP12177 binding to cortical
b1-adrenoreceptors.
Preclinical research and discovery of potential antiepileptic
drugs rely heavily on the use of animal models of seizures. The
explanation of this fact is that there is no single pathomechanism
related with development of epilepsy. As a consequence, most of
existing antiepileptic drugs have been discovered with use of
either of the anticonvulsant in vivo tests: maximal electroshock
(MES) or subcutaneous metrazole (ScMet). These two methods

4422
A. M. Waszkielewicz et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4419–4423
Table 3
Results of anticonvulsant activity evaluation (mice, ip) of compounds 2a–6
Compd
Dose mg/kg
MESa
ScMeta
TOXb
ASP classc
0.5 h
4 h
0.5 h
4 h
0.5 h
4 h
2a
3a
4
30
0/1
3/3
––
0/1
0/3
––
0/1
0/1 (1d)
––
0/1
0/1 (1d)
––
0/4
5/8
4/4 (4)*
0/4
0/8
3/4
0/4
1/8
4/4
0/4
0/8
0/4
0/4
3/8
0/4
0/2
0/4
––
1
3
1
1
3
100
300
30
100
300
30
100
300
30
100
300
30
0/1
0/3
0/1
0/1
4/7
4/5
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
1/1
0/1
1/3
1/1
0/1
0/3
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/2
0/4
0/2
0/2
0/4
1/2(1)*
0/2
0/4
0/2
0/2
0/4
0/2
5
6
100
300
a
b
c
Number of animals protected/number of animals tested in the MES and ScMet tests.
Number of animals displaying motor impairment/number of animals used in the rotarod test.
ASP classification: (1)––anticonvulsant activity at doses 100 mg/kg or less; (2)––anticonvulsant activity at doses greater than 100 mg/kg; (3)––compound inactive at
300 mg/kg; (4)––compound either active or inactive but toxic at doses of 30 mg/kg. ‘––’The compound was not tested in the particular case.
*
Number of animals which died during test are stated in brackets.
Table 4
xanthone substitution, because the best anticonvulsant properties
Results of anticonvulsant activity evaluation for compounds 2a, 4 and 5 (rats, p.o.)
are observed for 2a: 6-chloro-4-[4N-(2-hydroxyethyl)piperazi-
nyl]methyl-9H-xanthen-9-one and 5: 6-methoxy-2-[4N-(2-
methoxyphenyl)piperazinyl]methyl-9H-xanthen-9-one, which are
xanthones substituted in positions 4, 6 and 2, 6, respectively.
Currently reported compounds differ in the structure from our
previous studies. A substituted piperazine moiety was used instead
of aminoalkanol residue. As a result, the change in the structure
caused increase of bioavailability after oral administration which
means that further modification could result in discovering more
potent anticonvulsants.
Compd
Test
Dose [mg/kg]
Time [h]
1.0
0.25
0.5
2.0
4.0
2a
4
MESa
TOXb
MESa
TOXb
MESa
TOXb
30
30
30
30
30
30
0/4
0/4
0/4
0/4
0/4
0/4
2/4
0/4
0/4
0/4
2/4
0/4
2/4
0/4
0/4
0/4
2/4
0/4
0/4
0/4
0/4
0/4
3/4
0/4
4/4
0/4
1/4
0/4
3/4
0/4
5
a
Number of animals protected/number of animals tested in the MES test.
Number of animals displaying motor impairment/number of animals used in
b
neurotoxicity test.
Acknowledgments
The authors thank Professors James P. Stables and Tracy Chen
Ph.D. from National Institute of Neurological Disorders and Stroke
(NIH, Rockville, USA) for providing the results of anticonvulsant
vanced to evaluation in rats after oral (p.o.) administration. All of
them proved some activity without neurotoxicity during the whole
study (Table 4). Although the ED50 value of 105 mg/kg b.w. for 5
(Table 5) seem high, the important thing is the oral route of admin-
istration to rats which justifies this dose. Orally administered drugs
are most preferable for patients, therefore, compounds which are
characterized by good absorption are the most appreciated. For-
merly reported compounds were evaluated in quantitative assays
after i.p. administration in mice, for example, (R,S)-, (R)- and (S)-
6-chloro-2-(1-hydroxypropan-2-ylamino)methyl-9H-xanthen-9-
one with anti-MES ED50 values of 56.2, 77.44, and 72.97 mg/kg
b.w., respectively.11,12 Therefore, still bearing in mind change in
species from mice to rats, due to this improvement of route of
administration, compound 5 should be considered superior.
Another conclusion is that–unlike in the binding results–
anticonvulsant properties are not so correlated with position of
´
evaluation and Professor Katarzyna Kiec-Kononowicz for coordina-
tion of the cooperation between the National Institute of Neurolog-
ical Disorders and Stroke and the Faculty of Pharmacy Jagiellonian
University Medical College.
The publication is supported by Jagiellonian University Medical
College (Grant No K/ZDS/003328). Radioligand binding experi-
ments 5-HT1A, 5-HT6 and 5-HT-7) were financially supported by
the Norwegian Financial Mechanism as part of the Polish–Norwe-
gian Research Fund, Grant No. PNRF–103–AI-1/07.
The research was carried out with the equipment purchased
thanks to the financial support of the European Regional Develop-
ment Fund in the framework of the Polish Innovative Economy
Operational Program.
Table 5
Results of anticonvulsant quantification of compound 5 (rats, p.o.)
ED50 MESa [mg/kg] (confidence interval)
ED50 ScMeta [mg/kg]
>250d
TD50 [mg/kg]
>300c
b
Compd
5
105d
(34.01–319.03)
PI > 2.86
a
b
c
Dose of the compound which gives protection against seizures in 50% of tested animals; 95% confidence interval is shown in brackets.
Dose of the compound which produces neurotoxicity in 50% of tested animals; PI = TD50/ED50
.
Results observed after 0.0 h of administration of the compound.
Results observed after 4.0 h of administration of the compound.
d

A. M. Waszkielewicz et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4419–4423
4423
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.
05.062. These data include MOL files and InChiKeys of the most
important compounds described in this article.
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