Anti-inflammatory activity of isobornylphenol derivatives

Full text of DOI:10.1007/s10600-010-9651-0

Chemistry of Natural Compounds, Vol. 46, No. 3, 2010
ANTI-INFLAMMATORY ACTIVITY OF ISOBORNYLPHENOL DERIVATIVES
1*
1
1
I. Yu. Chukicheva, I. V. Fedorova, E. V. Buravlev,
UDC 547.563.4’599+615.276
1
2
2
A. E. Lumpov, Yu. B. Vikharev, L. V. Anikina,
V. V. Grishko, and A. V. Kuchin
2
1
Nonsteroidal anti-inflammatory drugs and non-narcotic analgesics are widely used to treat various inflammatory
diseases of infectious and noninfectious nature [1].
The development of new drugs based on terpenophenols, which have a unique set of pharmacological properties [2],
is highly promising. The literature teaches that phenols with a bicyclic isobornyl moiety exhibit anti-infection activity [3].
The series of studies performed by us on the synthesis and investigation of terpenophenols showed that some alkylphenols
exhibit hemorheological properties and improve brain blood flow [4, 5]. Thus, the synthesis of terpenophenols is critical for
further studies of their physiological properties.
Herein we present results from a study of the anti-inflammatory activity of the synthesized terpenophenols and their
aminomethyl derivatives.
A series of isobornylphenols (1a–e) with various substituents in the aromatic ring were prepared earlier via alkylation
of phenols by the natural monoterpenoid camphene in the presence of the corresponding aluminum phenolates [6–8].
OH
OH
OH
H C
3
H
H
H
H
CH
3
1a
1c
1b
OH
OH
HO
O
H
H
1d
1e
Continued functionalization of the terpenophenols by introducing aminomethyl moieties using the Mannich reaction
synthesized the previously prepared compounds 2a, 2b, and 2d [9] and newly synthesized 2c, the structure of which was
13
confirmed by IR, PMR, and C NMR spectral data.
21'''
9
7
OH
22'
20'''
19'
N
18
10
12
13
21''
R
20''
20'
21'
1
19
H
5
N
N
3
20
21
15
(n-C H ) N
9 2
4
O
CH
3
17
22
c
2a - d
a
b
d
The anti-inflammatory activity of terpenophenols 1–2 was studied using a formalin-induced acute inflammation
model in mice [10] (Table 1). Compounds 1a and 2a exhibited reliable anti-inflammatory activity upon parenteral administration.
Compound 1a was less active and showed only 10% more inhibition than this control group.
1) Institute of Chemistry, Komi Scientific Center, Ural Branch, Russian Academy of Sciences, 167982, Russia,
Syktyvkar, fax: +7 (8212) 21 84 77, e-mail: chukicheva-iy@chemi.komisc.ru; 2) Institute of Technical Chemistry, Ural Branch,
Russian Academy of Sciences, 614013, Russia, Perm, ul. Akad. Koroleva, 3. Translated from Khimiya Prirodnykh Soedinenii,
No. 3, pp. 402–403, May–June, 2010. Original article submitted November 2, 2009.
©
478
0009-3130/10/4603-0478 2010 Springer Science+Business Media, Inc.

TABLE 1. Anti-inflammatory Activity of Isobornylphenols
Mass increase of
inflamed paw, %
Degree of edema
inhibition, %
Mass increase of
inflamed paw, %
Degree of edema
inhibition, %
Compound
Compound
2
–8
–4
–
–6
–2
–
1c
2a
2b
2c
Control 2
1b
2d**
Control 3
61.22ꢄ3.83
39.95ꢄ5.14*
74.31ꢄ2.24
71.46ꢄ2.95
33
22
–
5
–6
10
Sodium diclofenac
ꢄ
ꢄ
46.41 4.83*
68.99 1.79
Control 1
59.81ꢄ2.49
65.84ꢄ2.09
72.95ꢄ2.83
64.73ꢄ6.49
61.94ꢄ2.87
1d
1e
1a
ꢄ
60.77 3.16
ꢄ
62.09 1.53*
______
*p ꢅ 0.05 relative to the corresponding control; **using 2d·HCl.
Edema of an inflamed paw was reduced by 33% compared with the control upon administration of 2a. The anti-
inflammatory activity of 2a was studied upon i.p. administration because of its high hydrophobicity. However, it did not
exhibit anti-inflammatory activity for this model at a dose of 50 mg/kg. This indicated that it was poorly assimilated from the
GI tract.
A toxicity study gave LD values for 1–2 that were greater than 500 mg/kg. This meant that these compounds had
50
class 3 toxicity and hazard (GOST 12.1007-76).
Synthesis of the Amine (2c). 2-Isobornyl-4-methylphenol (0.86 g, 3.5 mmol) and paraformaldehyde (0.13 g,
4.2 mmol) were stirred in anhydrous benzene (15 mL) at room temperature for 30 min, treated with dicyclohexylamine
(0.83 mL, 4.2 mmol), and refluxed for 6 h. Upon completion of the reaction, the excess of solvent was evaporated at reduced
pressure. The mixture was separated over a column of silica gel (Alfa Aesar, 70/230 ꢀ) with elution by petroleum ether:Et O
2
with increasing fraction of the latter to afford 2c (1.45 g, 95%).
2-((Dicyclohexylamino)methyl)-4-methyl-6-(1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yl)phenol (2c). Colorless
–1
crystals, mp 161–163°C, C H NO. IR spectrum (KBr, ꢁ, cm ): 3437 (OH), 2930, 2855, 1468, 1381, 1605. PMR spectrum
30 47
(300 MHz, CDCl , ꢂ, ppm, J/Hz): 0.76 (3H, s, Me-10), 0.82 (3H, s, Me-9), 0.90 (3H, s, Me-8), 1.04–1.62 and 1.74–1.89 (16H
3
and 10H, both m, H-3, H-4, CH -5, CH -6, CH -20, CH -20ꢃ, CH -20ꢃꢃ, CH -20ꢃꢃꢃ, CH -21, CH -21ꢃ, CH -21ꢃꢃ, CH -21ꢃꢃꢃ,
2
2
2
2
2
2
2
2
2
2
CH -22, CH -22ꢃ), 2.14-2.21 (1H, m, H-3), 2.23 (3H, s, Me-17), 2.68 (2H, t, J = 11.6, H-19, H-19ꢃ), 3.28 (1H, t, J = 9.1, H-2),
2
2
3.78 and 3.95 (2H, both d, J = 14.5 and J = 14.5, CH -18), 6.58 and 6.97 (2H, both s, H-14, H-16), 11.79 (1H, br.s, OH).
2
13
C NMR spectrum (75 MHz, CDCl , ꢂ, ppm): 11.85 (C-10), 20.28 (C-9), 20.94, 21.51 (C-8, C-17), 26.09, 26.17 (C-21,
3
C-21ꢃ, C-21ꢃꢃ, C-21ꢃꢃꢃ), 27.54 (C-5), 29.63 (C-22, C-22ꢃ), 31.68 (C-20, C-20ꢃ, C-20ꢃꢃ, C-20ꢃꢃꢃ), 33.59 (C-3), 39.48 (C-6), 44.39
(C-2), 45.77 (C-4), 47.87 (C-7), 49.46 (C-18), 49.78 (C-1), 57.15 (C-19, C-19ꢃ), 121.72, 126.35, 129.90 (C-11, C-13, C-15),
126.12, 127.19 (C-14, C-16), 155.28 (C-12).
Anti-inflammatory Properties of 1–2. We used mongrel white male mice (mass 22-24 g) for the formalin test. The
tested compounds were injected i.p. at a dose of 50 mg/kg in physiological solution with added Tween-80. The reference drug
was sodium diclofenac at a dose of 8 mg/kg [11]. Compound 2a had the highest anti-inflammatory activity and was also
studied upon oral administration. The control group of animals received physiological solution. Inflammation was
induced 1 h after injecting the compounds using formalin solution (3%) that was injected (0.05 mL) into the aponeurosis of the
right hind paw.
ACKNOWLEDGMENT
The work was supported by the Russian Academy of Sciences (Basic Research Integration Project carried out in RAS
institutions of the Ural Branch, RAS).
REFERENCES
1.
2.
P. Brooks, Am. J. Med., 104, No. 3, S9 (1998).
E. V. Kuzakov and E. N. Shmidt, Khim. Prir. Soedin., 198 (2000).
479

3.
4.
M. Cirri, P. Mura, and P. Corvi Mora, Int. J. Pharm., 30, 84 (2007).
M. B. Plotnikov, V. I. Smolꢃyakova, I. S. Ivanov, A. V. Kuchin, I. Yu. Chukicheva, and E. A. Krasnov, Byull. Eksp.
Biol. Med., 145, No. 3, 296 (2008).
5.
M. B. Plotnikov, E. A. Krasnov, V. I. Smolꢃyakova, I. S. Ivanov, A. V. Kuchin, I. Yu. Chukicheva, and
E. V. Buravlev, RF Pat. No. 2,347,561 (2009); Byull. No. 6 (2009).
6.
7.
I. Yu. Chukicheva, I. V. Timusheva, L. V. Spirikhin, and A. V. Kuchin, Khim. Prir. Soedin., 205 (2007).
I. Yu. Chukicheva, A. V. Kuchin, L. V. Spirikhin, O. Ya. Borbulevich, A. V. Churakov, and A. I. Belokonꢃ, Khim.
Kompꢃyuternoe Model. Butler. Soobshch., No. 1, 9 (2003).
8.
9.
10.
I. Yu. Chukicheva and A. V. Kuchin, Ross. Khim. Zh., 48, 21 (2004).
E. V. Buravlev, I. Yu. Chukicheva, K. Yu. Suponitskii, and A. V. Kuchin, Zh. Obshch. Khim., No. 7, 1177 (2008).
P. G. Winyard and D. A. Willoughby (eds.), Methods in Molecular Biology, 225: Inflammation Protocols, Humana
Press, Totowa, 2003.
11.
R. D. Syubaev, M. D. Mashkovskii, G. Ya. Shvarts, and V. I. Pokryshkin, Khim.-farm. Zh., No. 1, 33 (1985).
480