Analgesic activity of cyclic imides: 1,8-Naphthalimide and 1,4,5,8- naphthalenediimide derivatives

Article abstract of DOI:10.1016/S0014-827X(00)00027-6

In early studies, we have reported the synthesis and biological activities of several cyclic imides. The present study describes the analgesic activity of 1,8-naphthalimide and 1,4,5,8-naphthalenediimide derivatives in a standard murine model of analgesia. The pharmacological results show that all compounds studied, given intraperitoneally, produced significant inhibition of acetic acid-induced abdominal constrictions. At the ID₅₀ (μmol/kg) level, these cyclic imide derivatives were about 40-270- fold more potent in this assay than aspirin and acetaminophen, two well-known and widely used analgesics. These results extend previous studies on the analgesic activity of cyclic imides. (C) 2000 Elsevier Science S.A.

Full text of DOI:10.1016/S0014-827X(00)00027-6

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 319–321
Short Communication
Analgesic activity of cyclic imides: 1,8-naphthalimide and
1,4,5,8-naphthalenediimide derivatives
Adriano Defini Andricopulo a,*, Luciane A. Mu¨ller b, Valdir Cechinel Filho b,
Graziela S. Cani b, Juliana F. Roos b, Roge´rio Correˆa b, Adair Roberto S. Santos b,
Ricardo Jose´ Nunes a, Rosendo Augusto Yunes a
a Department of Chemistry, Uni6ersidade Federal de Santa Catarina (UFSC), 88040-900 Floriano´polis, SC, Brazil
b Nu´cleo de In6estigac¸o˜es Qu´ımico-Farmaceˆuticas (NIQFAR)/CCS Uni6ersidade do Vale do Itaja´ı (UNIVALI), 88302-202 Itaja´ı, SC, Brazil
Received 6 July 1999; accepted 16 February 2000
Abstract
In early studies, we have reported the synthesis and biological activities of several cyclic imides. The present study describes the
analgesic activity of 1,8-naphthalimide and 1,4,5,8-naphthalenediimide derivatives in a standard murine model of analgesia. The
pharmacological results show that all compounds studied, given intraperitoneally, produced significant inhibition of acetic
acid-induced abdominal constrictions. At the ID50 (mmol/kg) level, these cyclic imide derivatives were about 40–270-fold more
potent in this assay than aspirin and acetaminophen, two well-known and widely used analgesics. These results extend previous
studies on the analgesic activity of cyclic imides. © 2000 Elsevier Science S.A. All rights reserved.
Keywords: Cyclic imides; Analgesic activity; Naphthalimides; Writhing test
1. Introduction
2. Results and discussion
Previously, our research group has studied the chem-
ical and biological properties of cyclic imides, which
were synthesized using phyllantimide, an alkaloid ex-
tracted from Phyllantus sellowianus [1], as a model.
Several analogues were obtained that exhibit a spec-
trum of biological activities [2–8], including analgesic
action [9–13].
In order to extend our research program concerning
the biological properties of cyclic imides, we have now
evaluated a series of 1,8-naphthalimide and 1,4,5,8-
naphthalenediimide derivatives as analgesics. Previous
studies provide evidence that these compounds exerted
analgesic action at 10 mg/kg in mice [12].
In order to extend our research program to discover
molecules which could be used as starting points for the
discovery of new analgesic drugs, a series of 1,8-naph-
thalimides and 1,4,5,8-naphthalenediimides was pre-
pared and their analgesic properties evaluated by using
the writhing test in mice. For comparison, we have also
included the analgesic effects of aspirin and ac-
etaminophen [14]. The compounds studied here are
shown in Scheme 1. The substituent group in the
aromatic ring was selected according to the Topliss
method [15], which aids in the prediction of new, more
active compounds.
Table 1 shows the analgesic potency of these com-
pounds, and of aspirin and acetaminophen. As can be
seen, all of them exhibit potent and structure-dependent
analgesic effects, being several times more potent than
aspirin and acetaminophen, two comparative standard
drugs used in our studies. The most active compound
(10) is approximately 270-fold more active on a molar
* Corresponding author. Present address: College of Pharmacy,
University of Michigan, 428 Church Street, Ann Arbor, MI 48109-
1065, USA. Tel.: +1-734-6151281; fax: +1-734-7632022.
E-mail address: aandrico@umich.edu (A.D. Andricopulo).
0014-827X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(00)00027-6

320
A.D. Andricopulo et al. / Il Farmaco 55 (2000) 319–321
Scheme 1.
basis than the standard drugs. Comparison of the
1,4,5,8-naphthalenediimides 6 and 10 indicates that the
introduction of an electron-donating methoxy group in
position 4 of the aromatic ring significantly increased
the analgesic activity. This suggests that resonance do-
nation plays a significant role in the binding of these
molecules, and results in enhanced inhibition of the
acetic acid-induced abdominal constrictions in mice.
Similarly, comparison between 1,8-naphthalimides 1
and 3 confirms that the introduction of a 4-methoxy
group improves the analgesic potency.
The distance between the aromatic and the imido
ring seems to be another important factor related to
analgesic activity of the 1,4,5,8-naphthalenediimides.
Comparing data for structures 6–8, the compound
containing the aromatic ring directly attached to the
imido ring (6) is the most potent. It was, therefore, used
as a point of departure to achieve more active deriva-
tives, such as compound 10, the most potent cyclic
imide synthesized by our research group to the present
time.
3.2. Pharmacological analysis: writhing test
Female Swiss mice (25–30 g) were kept at an auto-
matically controlled temperature (2392°C) with 12 h
light–dark cycles. Food and water were freely avail-
able. The abdominal constriction induced by intraperi-
toneal injection of acetic acid (0.6%; 15 ml/kg) was
carried out according to the procedures described previ-
ously [16]. Animals were pretreated with the com-
pounds
(0.06–30
mg/kg;
0.21–97.7
mmol)
intraperitoneally 30 min before the acetic acid injection.
Control animals received a similar volume of 0.9%
NaCl (10 ml/kg). All experiments were carried out at
20–22°C. After challenge, pairs of mice were placed in
separate boxes and the number of abdominal constric-
tions was cumulatively counted over a period of 20
min. The results are reported in Table 1.
Table 1
Analgesic effects of a series of 1,8-naphthalimides and 1,4,5,8-naph-
thalenediimides given intraperitoneally, against acetic acid-induced
abdominal constriction in mice a
The promising analgesic effects demonstrated here
for these cyclic imides suggest that this class of organic
compounds may be useful for the design of novel cyclic
imides having improved analgesic activity. This com-
munication confirms previous studies concerning the
activity of cyclic imides [10–13]. Studies are currently in
progress to evaluate these compounds in other pharma-
cological models of pain as well to characterize their
mechanism of analgesic action.
Comp.
ID50 (mmol/kg) ID50 (mg/kg)
MI (%)
1
2
3
4
5
6
7
8
9
10
11
12
1.69 (1.28–2.27) 0.46 (0.35–0.62) 8898
0.60 (0.21–1.18) 0.17 (0.06–0.34) 9991
0.79 (0.40–0.99) 0.24 (0.12–0.30) 9991
3.20 (2.08–5.28) 0.98 (0.64–1.62) 9392
1.00 (0.79–1.37) 0.34 (0.27–0.48) 9294
1.00 (0.67–1.48) 0.42 (0.25–0.63) 9093
1.50 (0.29–1.91) 0.67 (0.13–0.85) 9891
1.29 (0.69–2.40) 0.61 (0.33–1.14) 9192
1.19 (0.62–2.42) 0.53 (0.28–1.10) 9991
0.48 (0.40–0.79) 0.23 (0.19–0.38) 9991
1.60 (0.99–2.89) 0.78 (0.48–1.41) 9296
1.10 (0.79–1.69) 0.61(0.44–0.94) 9096
133.0 (73–243) 24.0 (13.1–43.8) 8392
125.0 (104–150) 18.8 (15.7–22.6) 8891
3. Experimental
Aspirin [14]
Acetaminophen
[14]
3.1. Chemical procedures
Compounds were prepared by adding the appropri-
ate aniline or aniline derivative to a solution of the
respective anhydride in acetic acid, as previously de-
scribed [12].
a ID50 values are accompanied by 95% confidence limits. MI indi-
cates the maximal inhibition (%) of abdominal constrictions (at 30
mg/kg). Each group represents the mean of six to ten animals.

A.D. Andricopulo et al. / Il Farmaco 55 (2000) 319–321
321
[4] A.B. Cruz, R.C. Cruz, V. Cechinel Filho, D.A. Junior, R.J.
Nunes, R.A. Yunes, Evaluation of the antibacterial effects of
N-aryldichloromaleimides and N-arylphthalimides. Structure–
activity relationship, Rev. Latioamer. Qu´ım. 26 (1996) 10; Chem.
Abstr. 127 (1997) 329e.
[5] V. Cechinel Filho, T.R. Pinheiro, R.J. Nunes, R.A. Yunes, E.F.
Queiroz, E.O. Lima, Synthesis of N-alkylphenylmaleimides and
N-alkylarylmaleimides with antifungal activity, Qu´ım. Nova. 19
(1996) 590.
3.3. Drugs
The cyclic imides were dissolved in Tween 80 (Merck)
plus 0.9% NaCl solution. The final concentration of
Tween 80 did not exceed 5% and did not cause any
effect per se.
[6] R. Correˆa, P.W. Rosa, A.B. Cruz, A.O. Savi, V. Cechinel Filho,
R.J. Nunes, Synthesis and antibacterial activity of citracon-
imides, Pharm. Sci. 2 (1996) 353.
3.4. Statistical analysis
The results are presented as mean9SEM, except the
ID50 values (the dose of compound that reduced re-
sponses by 50% relative to control value) which are
reported as geometric means followed by their corre-
sponding 95% confidence limits. The statistical signifi-
cance between groups was calculated by means of
analysis of variance followed by Dunnett’s multiple
comparison test. P values less than 0.05 were consid-
ered as indicative of significance. The ID50 values were
determined by linear regression from individual experi-
ments using linear regression GraphPad software.
[7] A.D. Andricopulo, A.O. Savi, R. Correˆa, A.B. Cruz, R.A.
Yunes, R.J. Nunes, V. Cechinel Filho, Synthesis and antibacte-
rial activity of cyclic imides: 3,4-dichloromaleimides and 3-
chloro-4-substituted-maleimides, Qu´ım. Nova 21 (1998) 573.
[8] E.O. Lima, E.F. Queiroz, A.D. Andricopulo, R.J. Nunes, R.A.
Yunes, R. Correˆa, V. Cechinel Filho, Evaluation of antifungal
activity of N-aryl-maleimides and N-phenylalkyl-3,4-dichloro-
maleimides, Bol. Soc. Chil. Qu´ım. 44 (1999) 185.
[9] R. Correˆa, V. Cechinel Filho, V. Schlemper, P.W. Rosa, P.I.
Pereira, R.J. Nunes, Synthesis of new succinimides and
sulphonated derivatives with analgesic action in mice, Pharm.
Sci. 3 (1997) 67.
[10] V. Cechinel Filho, R. Correˆa, Z. Vaz, J.B. Calixto, R.J. Nunes,
T.R. Pinheiro, A.D. Andricopulo, R.A. Yunes, Further studies
on analgesic activity of cyclic imides, Farmaco 53 (1998) 55.
[11] A.D. Andricopulo, A.W. Filho, R. Correˆa, A.R.S. Santos, R.J.
Nunes, R.A. Yunes, V. Cechinel Filho, Analgesic activity of
3,4-dichloromaleimides: structure–activity relationships, Phar-
mazie 53 (1998) 7.
[12] A.D. Andricopulo, R.A. Yunes, V. Cechinel Filho, R. Correˆa,
A.W. Filho, A.R.S. Santos, R.J. Nunes, Synthesis and analgesic
properties of cyclic imides: naphthalimide and bis-naphthalimide
derivatives, Acta Farm. Bon. 17 (1998) 219; Chem. Abstr. 130
(1999) 282003e.
Acknowledgements
We are grateful to Dr Eugene H. Cordes (University
of Michigan, USA) for helpful discussions. This work
was supported by grants from ProPPEX/UNIVALI
and CNPq (Brazil).
[13] A.D. Andricopulo, R.A. Yunes, V. Cechinel Filho, R.J. Nunes,
J.W. Frazer, E.H. Cordes, Development of a predictive statistical
model for the analgesic activity of a family of imides, Pharmazie
54 (1999) 698.
References
[1] M.S. Tempesta, D.G. Corley, J.A. Beutler, C.J. Metral, R.A.
Yunes, C.A. Giacomozzi, J.B. Calixto, Phyllantimide, a new
alkaloid from Phyllanthus sellowianus, J. Nat. Prod. 3 (1988) 617.
[2] V. Cechinel Filho, A. Bella Cruz, E. Moretto, T. Pinheiro, R.J.
Nunes, R.A. Yunes, Antibacterial activity of N-phenyl-
maleimides, N-phenylsuccinimides and related compounds.
Structure–activity relationships, Farmaco 49 (1994) 675.
[3] V. Cechinel Filho, R.J. Nunes, J.B. Calixto, R.A. Yunes, Inhibi-
tion of guinea-pig ileum contraction by phyllanthimide ana-
logues: structure–activity relationships, Pharm. Sci. 1 (1995) 399.
[14] Z.R. Vaz, V. Cechinel Filho, R.A. Yunes, J.B. Calixto, Antinoci-
ceptive action of 2-(4-bromobenzoyl)-3-methyl-4,6-dimethoxy
benzofuran, a novel xanthoxyline derivative, on chemical and
thermal models of nociception in mice, J. Pharmacol. Exp. Ther.
278 (1996) 304.
[15] J.G. Topliss, A manual method for applying the Hansch ap-
proach to drug design, J. Med. Chem. 20 (1977) 463.
[16] R.F. Collier, H.O.J. Dinnen, C.A. Johnson, C. Schneider, The
abdominal constriction response and its suppression by analgesic
drugs in the mouse, Br. J. Pharmacol. 32 (1968) 295.
.