Prenyloxyphenylpropanoids as a novel class of anticonvulsive agents

Article abstract of DOI:10.1016/j.bmcl.2009.07.110

In this study, we synthesized some natural and semi-synthetic prenyloxyphenylpropanoids (e.g., acetophenones, benzoic and cinnamic acids, chalcones, and coumarins), and we assessed their in vivo neuroprotective activity, using the mouse maximal electrosho

Full text of DOI:10.1016/j.bmcl.2009.07.110

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5419–5422
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Prenyloxyphenylpropanoids as a novel class of anticonvulsive agents
b
c,d
Salvatore Genovese a, Francesco Epifano a, , Massimo Curini , Monika Dudra-Jastrzebska
,
*
Jarogniew J. Luszczki c,d
a Dipartimento di Scienze del Farmaco, Università ‘G. D’Annunzio’ di Chieti-Pescara, Via dei Vestini 31, 66013 Chieti Scalo (CH), Italy
b Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Università degli Studi di Perugia, Via del Liceo, 06123 Perugia, Italy
c Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland
d Department of Physiopathology, Institute of Agricultural Medicine, Jaczewskiego 2, PL 20-950 Lublin, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, we synthesized some natural and semi-synthetic prenyloxyphenylpropanoids (e.g.,
acetophenones, benzoic and cinnamic acids, chalcones, and coumarins), and we assessed their in vivo
neuroprotective activity, using the mouse maximal electroshock-induced seizure model (MES test). 7-Iso-
pentenyloxycoumarin and (2E)-3-{4-[(3-methylbut-2-enyl)oxy]phenyl}prop-2-enoic acid, administered
ip at a dose of 300 mg/kg, suppressed MES-induced seizures in mice in a time- and dose-dependent
manner.
Received 15 June 2009
Revised 22 July 2009
Accepted 23 July 2009
Available online 26 July 2009
Keywords:
Mes test
Ó 2009 Elsevier Ltd. All rights reserved.
Neuroprotective activity
Prenyloxyphenylpropanoids
Neurodegenerative syndromes represent a widely differenti-
ated group of diseases affecting the nervous system, including
the brain, the spinal cord, and peripheral nerves, arising from
several causes, many of which are still unknown.1 Due to their
incidence, morbidity, and mortality, neurodegenerative diseases
represent nowadays a huge problem from a medical, social,
and financial point of view for the human society all over the
world. Pathologically, neurodegeneration result from abnormali-
ties in the functionality of specific regions of the central and
the peripheral nervous systems and/or specific populations of
neurons. Depending on which cluster of cells begins to undergo
pathological changes, this will lead to the clinical phenotype of
that particular illness. Recent studies allowed to identify a cer-
tain number of genes responsible for several neurodegenerative
diseases. Moreover, during last years, valuable animal models
were developed to study factors and mechanism underlying
the etiology and pathogenesis of these syndromes. Currently
used therapeutic approaches are able to treat the symptoms
for a limited period of time but, as progression of the disease ad-
vances, these treatments become ineffective. Different therapeu-
tic approaches were proposed, depending on which biological
target is triggered. Drugs commonly used in such situations are
able to restore the imbalance in neurotransmitters functionality
that characterize the most part of neurodegenerative diseases.
combination with DOPA-decarboxylase inhibitors in the treat-
ment of Parkinson’s disease and (b) the use of cholinomimetics
and acetylcholinesterase inhibitors in the therapy of Alzheimer’s
disease. Other drugs that were proposed in the therapeutic man-
agement of neurodegenerative disorders include inhibitors of key
enzymes like COX-2,2 MAO-B,3 iNOS,4 and caspase,5 heavy metal
chelators,6 radical and reactive oxygen species scavengers,7,8
statins,9 and finally the most recent approaches are genetic10
and stem-cell11 based therapies.
In recent years natural products have been re-discovered as a
valuable source of novel agents exerting positive effects in the
treatment of cancer and microbial infections, against which syn-
thetic drugs failed due to progressively increasing pharmacological
resistance. In addition several natural compounds were seen in the
last decade to efficiently interfere at different levels with the devel-
opment and progress of many neurodegenerative disorders. These
include ferulic acid,12 oleamide,13 polyphenols,14 tocopherols,15
curcumin,16 folate,17 and coumarins.18
In the last five years our research group studied extensively
chemical and biological properties of secondary metabolites of
phenylpropanoid biosynthetic origin, and containing a sesqui-
terpenyl, monoterpenyl, and semiterpenyl chains attached to a
phenol group. These represent quite a rare group of natural prod-
ucts.19 As a continuation of our studies aimed at evaluating phar-
macological properties of prenyloxyphenylpropanoids, we wish
to report herein the activity of natural compounds belonging to se-
lected subcategories (e.g., acetophenones, benzoic and cinnamic
acids, chalcones, and coumarins) as in vivo neuroprotective
Explicative examples to this aim are (a) the use of L-DOPA in
* Corresponding author.
E-mail address: fepifano@unich.it (F. Epifano).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.07.110

5420
S. Genovese et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5419–5422
anticonvulsant agents using the mouse maximal electroshock-in-
duced seizure model (MES test). The following secondary metabo-
lites were synthesized and evaluated: the acetophenones 1-{2-
hydroxy-4-[(3-methylbut-2-enyl)oxy]phenyl}ethanone (1) and 1-
(4-{[(2E)-3,7-dimethylocta-2,6-dienyl]oxy}-2-hydroxyphenyl)-
ethanone (2), both isolated from Melicope spp.20 and Euodia merrilli
Kanehira & Sasaki ex Kanehira21 (Fam. Rutaceae); the vanillic acid
derivatives 3-methoxy-4-[(3-methylbut-2-enyl)oxy]benzoic acid
(3) and 4-{[(2E)-3,7-dimethylocta-2,6-dienyl]oxy}-3-methoxyben-
zoic acid (4), both obtained as methyl esters from the liverwort Tri-
chocolea lanata (Ehrh.) Dumm. (Fam. Trichocolaceae);22 the p-
coumaric and ferulic acids derivatives (2E)-3-{4-[(3-methylbut-2-
enyl)oxy]phenyl}prop-2-enoic acid (5), isolated from Esenbeckia
hieronymi (Fam. Rutaceae),23 boropinic acid (6), extracted from
Boronia pinnata Sm. (Fam. Rutaceae),24 (2E)-3-(4-{[(2E)-3,7-dim-
ethylocta-2,6-dienyl]oxy}phenyl)prop-2-enoic acid (7), and (2E)-
3-(4-{[(2E)-3,7-dimethylocta-2,6-dienyl]oxy}-3-methoxyphenyl)-
prop-2-enoic acid (8), both obtained from Acronychia baueri Schott.
(Fam. Rutaceae),25 3-{4-[(3-methylbut-2-enyl)oxy]phenyl}propa-
noic acid (9) and 3-(4-{[(2E)-3,7-dimethylocta-2,6-dienyl]oxy}ph-
enyl)propanoic acid (10), both isolated as methyl esters from
Zanthoxylum pistaciiflorum Hayata (Fam. Rutaceae);26 the chal-
cones cordoin (11), extracted from Millettia erythrocalyx Gagnep.,27
Cordoa placa,28 and Derris spp. (Fam. Leguminosae),29 p-hydroxy-
cordoin (12), isolated from C. placa,30 and 40-geranyloxyisoliquiri-
tigenin (13), obtained from Millettia spp.;31 finally the coumarins
7-isopentenyloxycoumarin (14), auraptene (15), widespread in
the genus Citrus (Fam. Rutaceae), collinin (16), isolated from Zanth-
oxylum schinifolium Siebold & Zucc. (Fam. Rutaceae), 7-hydroxy-8-
isopentenyloxycoumarin (17), extracted from Melampodium diva-
ricatum DC. (Fam Asteraceae), and lacinartin (18), obtained from
Z. schinifolium, Artemisia and Diosma spp. (Fam. Rutaceae).32
R''
O
O O
R'
14 R' = H, R'' = H
15 R' = isopentenyl, R'' = H
16 R' = isopentenyl, R'' = OCH3
17 R' = H, R'' = OH
18 R' = H, R'' = OCH3
in 76% and 68% yields, respectively, from 2,4-dihydroxyacetophe-
none by selective alkylation with 3,3-dimethylallyl bromide and
geranyl bromide promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), followed by crystallization from n-hexane (Fig. 1).34
Cordoin (11) was obtained in 93% yield from acetophenone (1)
and benzaldehyde by an aldol condensation in a basic hydroalco-
holic medium, followed by acidic work-up, and crystallization from
n-hexane (Fig. 2).
The two other chalcones, p-hydroxycordoin (12), and 40-gera-
nyloxyisoliquiritigenin (13) were obtained from acetophenones
(1) and (2), and p-hydroxybenzaldehyde in 32% and 35% yield,
respectively, by a slight modification of the synthetic scheme of
cordoin (11) (Fig. 3).35
Finally, coumarins (17) and (18) were obtained by the same
procedure reported for compounds 14–16 in 84% and 62% yields,
respectively.34
Compounds 1–18 were then evaluated in vivo for their neuro-
protective anticonvulsant properties, using the mouse maximal
electroshock-induced seizure model (MES test). Procedures involv-
ing animals and their care were carried out in accordance with cur-
rent European Community and Polish legislation on animal
experimentation. Additionally, all efforts were made to minimize
animal suffering and to use only the number of animals necessary
to record reliable scientific data. The experimental protocols and
procedures described in this manuscript were approved by the Lo-
cal Ethics Committee at the Medical University of Lublin (Licenses
no.: 20/2008 and 26/2008), and complied with the European Com-
munities Council Directive of 24 November 1986 (86/609/EEC). All
compounds were administered intraperitoneally (ip) at a dose of
300 mg/kg. Results from the mouse MES model are reported in
Table 1.
O
R
O
OH
1 R = H
2 R = isopentenyl
R'
R'''
O
R''
The anticonvulsant effects were considered of pivotal impor-
tance if at least 50% of the animals tested were protected against
MES-induced seizures. As shown in Table 1, a well defined and
distinguished pattern of results was recorded. The results partly
confirm data already obtained in an in vitro study in which 7-isopen-
tenyloxycoumarin was found to protect neuronal cells against
NMDA-induced excitotoxicity.35 Results obtained herein indicated
that the compounds (5), (8), (14), and (17) considerably protected
the animals against MES-induced seizures, possessing the definite
anticonvulsant properties, at the respective pretreatment times in
the mouse MES model. In particular for 7-isopentenyloxycoumarin
(14) and (2E)-3-{4-[(3-methylbut-2-enyl)oxy]phenyl}prop-2-enoic
acid (5) the maximum of anticonvulsant activity was reached within
a very short time after ip administration, leading to a dose and
time-dependent protection of all animals treated. The dose–
3 R' = COOH, R'' = OCH3, R''' = H
4 R' = COOH, R'' = OCH3, R''' = isopentenyl
5 R' = CH=CH-COOH, R'' = H, R''' = H
6 R' = CH=CH-COOH, R'' = OCH3, R''' = H
7 R' = CH=CH-COOH, R'' = H, R''' = isopentenyl
8 R' = CH=CH-COOH, R'' = OCH3, R''' = isopentenyl
9 R' = CH2CH2-COOH, R'' = H, R''' = H
10 R' = CH2CH2-COOH, R'' = H, R''' = isopentenyl
O
R'
O
OH
R''
11 R' = H, R'' = H
12 R' = H, R'' = OH
13 R' = isopentenyl, R'' = OH
Compounds 3–8 and 14–16 were synthesized as already
reported.33 Acids (9) and (10) were obtained by the same environ-
mentally friend procedure reported for compounds 3–8 in 77% and
83% yield, respectively, and using commercially available 3-(4-
hydroxyphenyl)propionic acid as the starting material. Acetophe-
nones (1) and (2) were both synthesized in a single step procedure,
O
O
a,b
R
HO
OH
O
OH
Figure 1. Reagents and conditions: (a) 3,3-dimethylallyl bromide [geranyl bro-
mide] (1 equiv), DBU (1 equiv) acetone, rt, 24 h; (b) crystallization.

S. Genovese et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5419–5422
5421
Table 2
O
Dose–response relationships of compounds 5, 8, and 14 against MES-induced seizures
in mice
a,b
1
O
OH
Compd
Time (min)
ED50 (mg/kg)
na
228.4 9.8*
261.7 20.6*
311.5 11.5*
>> 350
16
16
16
—
Figure 2. Reagents and conditions: (a) PhCHO (1.05 equiv), KOH (aq) 99%, EtOH, rt,
24 h; (b) crystallization.
5
5
15
30
60
8
14
*
5
15
30
60
225.1 26.3*
224.1 10.7*
223.5 20.9*
>>350
24
24
24
—
O
a,b
1
O
OH
OH
5
15
30
60
>>350
—
238.0 18.9*
221.2 21.4*
>>350
16
32
—
O
a,b
2
O
OH
OH
p <0.05 at Student’s t test.
n = number of animals at those doses whose anticonvulsant effects ranged
Figure 3. Reagents and conditions: (a) p-OHPhCHO (1.05 equiv), KOH (aq) 60%,
EtOH, 100 °C?rt, 24 h; (b) crystallization.
a
between 16% and 84%.
seems also that the presence of a free carboxylic acid moiety or a
lactone ring do not modify the anticonvulsant effect. The only
notable exception to the above reported preliminary structure–
activity relationship (SAR) consideration is (2E)-3-(4-{[(2E)-3,7-
dimethylocta-2,6-dienyl]oxy}-3-methoxyphenyl)prop-2-enoic
acid (8), that, although possessing a C10 carbon skeleton and a
disubstituted aromatic ring, is almost equal in potency to 7-isopen-
tenyloxycoumarin (14) and to (2E)-3-{4-[(3-methylbut-2-enyl)ox-
y]phenyl}prop-2-enoic acid (5). Trying to explain this discrepancy,
it could be hypothesized that these compounds exerted the ob-
served effects acting by different mechanisms of action. Compound
(14) is an ingredient of a patented coumarin-based pharmaceutical
preparation showing a high degree of acetylcholinesterase (Ach-ase)
inhibition.39 Moreover 7-isopentenyloxycoumarin was seen to
interfere on excitable cells, acting as a myorelaxant at a concentra-
Table 1
Time-course of anticonvulsant effects of compounds 1–18 against MES-induced
seizures in mice
Entry
Time (min)
5
P/T
15
P/T
30
P/T
60
P/T
120
P/T
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
0/8
0/8
0/8
0/8
8/8
0/8
0/8
2/8
0/8
3/8
0/8
0/8
0/8
6/8
0/8
2/8
4/8
0/8
0/8
0/8
0/8
0/8
6/8
0/8
0/8
7/8
0/8
3/8
0/8
0/8
0/8
8/8
0/8
0/8
1/8
0/8
0/8
0/8
0/8
0/8
3/8
0/8
0/8
6/8
0/8
1/8
0/8
0/8
0/8
7/8
0/8
0/8
0/8
0/8
0/8
0/8
0/8
0/8
2/8
0/8
0/8
2/8
0/8
1/8
0/8
0/8
0/8
2/8
0/8
0/8
0/8
0/8
0/8
0/8
0/8
0/8
0/8
0/8
0/8
0/8
0/8
1/8
0/8
0/8
0/8
0/8
2/8
0/8
0/8
0/8
tion of 100 lM on the KCl (60 mM)-induced contraction in the rat
thoracic aorta, yielding a 80% inhibitory effect.40 In addition, cou-
marins, structurally resembling compound (14), were reported to
decrease spontaneous beating of cultured myocardial cells due to
Ca+2 overload, and to be potent and selective inhibitors of key en-
zymes like Ach-ase and monoamino oxidase B (MAO-B). Inhibition
of these enzymes was claimed to be among the main factors con-
tributing to neuroprotection.36–38 On the other hand (2E)-3-(4-
{[(2E)-3,7-dimethylocta-2,6-dienyl]oxy}-3-methoxyphenyl)prop-
2-enoic acid (8) was reported to be an inhibitor of COX-2 and
iNOS.41 Also these two enzymes were found to play a crucial role
in neuroprotection.42,43 It is also well known that natural p-couma-
ric acid derivatives structurally resembling compound (5), contain-
ing one or more prenyl side chains attached to the aromatic ring,
exerted a valuable neuroprotective effect through the antioxidant
activity.44 Hence, it is conceivable that compounds (5), (8), and
(14) could share the same effect but with different mechanisms
of action. However the ones underlying the observed neuroprotec-
tive effects will require further efforts to be clearly depicted, and
studies to this aim are currently in progress in our laboratories.
In conclusion, the findings described herein indicate that pre-
nyloxyphenylpropanoids could be regarded as potential com-
Data are presented as number of animals protected against maximal electroshock
(MES)-induced seizures out of 8 animals per group. The MES test was performed at
various pretreatment times (5, 15, 30, 60 and 120 min) after systemic (ip) admin-
istration of the investigated compounds in a fixed dose of 300 mg/kg. P = number of
animals protected against MES-induced seizures; T = number of animals tested.
response relationships of the most active compounds 5, 8, and 14 are
reported in Table 2.
All natural products taken in consideration are lipophilic, so in
principle able to pass through the blood-brain barrier (BBB). The
outcome that only a restricted number of compounds exhibited
an appreciable anticonvulsant activity led us to hypothesize that
they may trigger specific biological targets inside the CNS. From
data reported in Table 1, it is evident that whole classes of com-
pounds, like acetophenones, benzoic acid derivatives, and chal-
cones are totally inactive. Comparing data and structures of
active and non-active products from other classes (e.g., cinnamic
acids and coumarins), it arises that three structural requirements
may be necessary for the observed activity: an isopentenyloxy side
pounds of
a novel class of anticonvulsant and in general
neuroprotective agents. Considering that all tested compounds
were easily synthesized from widely available and non toxic start-
ing materials, by high-yielding, environmentally friend, and cheap
synthetic routes, and that some of the active natural products are
commonly extracted from edible fruits and vegetables, the present
study could be considered as a topic for future studies aiming at
evaluating dietary feeding chemopreventive effects on acute and
chronic neurological disorders. Moreover our study may represent
chain, a para-monosubstituted benzene ring, and an
a,b-unsatu-
rated carbon–carbon double bond conjugated to a carboxylate.
In fact it can be seen that both increasing the length of the O-
side chain to a geranyl one, and saturating the conjugated double
bond, led to a significant decrease or complete lack of activity. It

5422
S. Genovese et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5419–5422
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This study was supported by a grant (PW555/09) from the Med-
ical University of Lublin (Lublin, Poland). The authors express their
thanks to Anna Zadrozniak and Aleksandra Wlaz for their technical
assistance. F.E. wish to thank Delia Pia Ravallese and Adelaide Var-
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.07.110.
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