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ABSTRACT
The synthesis of a series of euphorbol derivatives is described, starting from euphorbol isolated from fresh latex
of Euphorbia resinifera Berg. Their structures have been established on the basis of spectral data. All
compounds were evaluated for antibacterial activities against Escherichia coli and Staphyloccus aureus strains
and antifungal activity against Candida albicans and Aspergillus niger strains by using serial dilution method.
Keywords: Synthesis; euphorbol; latex; Euphorbia resinifera Berg, derivatives; antibacterial activities;
antifungal activity
INTRODUCTION
The synthesis of new compounds to dead with
resistant bacteria and fungi has become one of the
most important areas of antibacterial and antifungal
research today, since resistance of pathogenic
bacteria and fungi toward available antimicrobial
drug is rapidly becoming a major problem
worldwide. So the discovery of novel and potent
antibacterial as well as antifungal agent is more
demanding. Despite great effort from the
pharmaceutical industry to manage the resistance
problem, the discovery and development of new
mechanistic classes of antibiotics has found with
very little success [1]. The difficulty of this task is
demonstrated by the fact that only two antibiotics
of new classes, linezolid and daptomycin, have
been successfully developed in the past three
decades [2]. As part of our ongoing valorisation of
Euphorbia species native to Morocco, we have
investigated the antimicrobial and antifungal
semisynthetic terpenoid derivatives from euphorbol
(1). The results of this study are discussed in this
paper.
MATERIAL AND METHODS
General experimental procedures: Reactions were
monitored by TLC on Merck 60 F254 (0.25 mm)
*Corresponding Author Address: Dr. Hanane Farah, Laboratoire de Chimie Applique et Environnement, Facult des Sciences et
Techniques de B.P 577 Settat. Morocco, Tel.: +212 662796559; fax: +212 (0) 5 23 40 09 69, E-mail: hanane.farah@gmail.com
Semisynthesis
of
euphorbol-3-(3-methoxybenzoate) (3): To a solution of euphorbol (500 mg,
469.44 g/mol, 1.06 mmol) in dry toluene (7 mL), 3methoxy benzoic acid (381 mg, 180.04 g/mol, 2.12
mmol, 2 equivalents), DMAP (262 mg, 2.12 mmol,
2 equivalents) and DCC (454 mg, 2.12 mmol, 2
equivalents) were added. After stirring at 90C for
4 h, the reaction was worked up by filtration. The
precipitate was washed with toluene, and the
filtrates were treated with 5% NaHCO3 and dried
(Na2SO4). After evaporation, the residue was
purified by gravity CC on silica gel (25 g,
petroleum ether-EtOAc 9:1 as eluant) to afford 505
mg (83%) of compound (3) as a brown-yellowish
84
13 (44.1), C-14 (50.0), C-15 (29.8), C-16 (28.1), C17 (50.1), C-19 (20.2), C-20 (36.3), C-21 (18.8), C22 (35.0), C-23 (31.3), C-24 (156.9), C-25 (33.8),
C-26 (22.0), C-27 (21.9), C-28 (28.0), C-29 (15.5),
C-30 (24.4), C-31 (105.9), C=O (168.2), C1(132.5), C-2(107.3), C-3(162.2), C-4(104.4),
C-5(162.2), C-6(107.2), C-OCH3 (56.2), C-OCH3
(56.2); CI-EIMS: m/z [M+ H]+ 605 [C40H60O4 +
H]+.
Semisynthesis
of
euphorbol-3-(3-methoxyphenylacetate) (6): To a solution of euphorbol (500
mg, 469.44 g/mol, 1.06 mmol) in dry toluene (7
mL), 3-methoxy-phenylacetic acid (352 mg, 166.06
g/mol, 2.12 mmol, 2 equivalents), DMAP (262 mg,
2.12 mmol, 2 equivalents) and DCC (454 mg, 2.12
mmol, 2 equivalents) were added. After stirring at
85
Semisynthesis
of
euphorbol-3-(3-methoxyphenylpropionate) (9): To a solution of euphorbol
(500 mg, 469.44 g/mol, 1.06 mmol) in dry toluene
(7 mL), 3-methoxy-phenylpropic acid (382 mg,
180.08g/mol, 2.12 mmol, 2 equivalents), DMAP
(262 mg, 2.12 mmol, 2 equivalents) and DCC (454
mg, 2.12 mmol, 2 equivalents) were added. After
stirring at 90C for 4 h, the reaction was worked up
by filtration. The precipitate was washed with
toluene, and the filtrates were treated with 5%
NaHCO3 and dried (Na2SO4). After evaporation,
the residue was purified by gravity CC on silica gel
(25 g, petroleum ether-EtOAc 9:1 as eluant) to
afford 530 mg (83%) of compound (9) as a brownyellowish powder Rf : 0.31 (petroleum etherEtOAc 9:1). Boiling point: 139 C; IR (KBr): 1720
(CO), 889 (C=C); 1H NMR (CDCl3 , 300 MHz): H1 [1.21 (), 1.77 ()], H-2 [1.67 (), 1.57 ()], H-3 [
3.24 (dd, J = 4.3, 11.6 Hz)], H-5 [1.12 (dd, J ) 1.8,
12.5 Hz)], H-6 [1.69 (), 1.42 ()], H-7 [2.08
(2H)], H-11 [2.06 (), 1.92 ()], H-12 [1.72 (2H)],
H-15 [1.52 (), 1.18 ()], H-16 [1.32 (), 1.94 ()],
H-18 [0.76 (s)], H-19 [0.96 (s)], H-21 [0.93 (d, J )
6.4 Hz)], H-22 [1.12, 1.55], H-23 [1.88, 2.12], H25 [2.24 (s, J= 6.7 Hz)], H-26 [1.02 (d, J = 6.8
Hz)], H-27 [1.03 (d, J ) 7.0 Hz)], H-28 [1.00 (s)],
H-29 [0.80 (s)], H-30 [0.88 (s)], H-31 [4.66 and
4.72 ( s)], H-CH2 (2.55), H-CH2 (2.92), H-2(7.5),
H-4(6.86), H-5(7.2), H-6(7.53), H-OCH3 (3.73);
13
C NMR (75 MHz, CDCl3): C-1 (35.3), C-2
(27.9), C-3 (85.4), C-4 (38.9), C-5 (51.0), C-6
(18.9), C-7 (27.7), C-8 (133.5), C-9 (134.1), C-10
(37.3), C-11 (21.5), C-12 (30.8), C-13 (44.1), C-14
(50.0), C-15 (29.8), C-16 (28.1), C-17 (50.1), C-19
(20.2), C-20 (36.3), C-21 (18.8), C-22 (35.0), C-23
(31.3), C-24 (156.9), C-25 (33.8), C-26 (22.0), C27 (21.9), C-28 (28.0), C-29 (15.5), C-30 (24.4), C31 (105.9), C=O (169.2), C-CH2 (36.2), C1(132.5), C-2(116.3), C-3(165.2), C-4(119.4),
C-5(130.2), C-6(123.2), C-OCH3 (59.2); CIEIMS: m/z [M+ H]+ 603 [C41H62O3 + H]+.
MHz): H-1 [1.21 (), 1.77 ()], H-2 [1.67 (), 1.57
()], H-3 [ 3.24 (dd, J = 4.3, 11.6 Hz)], H-5 [1.12
(dd, J ) 1.8, 12.5 Hz)], H-6 [1.69 (), 1.42 ()], H-7
[2.08 (2H)], H-11 [2.06 (), 1.92 ()], H-12 [1.72
(2H)], H-15 [1.52 (), 1.18 ()], H-16 [1.32 (),
1.94 ()], H-18 [0.76 (s)], H-19 [0.96 (s)], H-21
[0.93 (d, J ) 6.4 Hz)], H-22 [1.12, 1.55], H-23
[1.88, 2.12], H-25 [2.24 (s, J= 6.7 Hz)], H-26 [1.02
(d, J = 6.8 Hz)], H-27 [1.03 (d, J ) 7.0 Hz)], H-28
[1.00 (s)], H-29 [0.80 (s)], H-30 [0.88 (s)], H-31
[4.66 and 4.72 ( s)], H-CH2 (2.91), H-CH2 (2.56),
H-2(7.06), H-4(6.51), H-6(7.1), H-OCH3 (3.73),
H-OCH3 (3.73); 13C NMR (75 MHz, CDCl3): C-1
(35.3), C-2 (27.9), C-3 (85.4), C-4 (38.9), C-5
(51.0), C-6 (18.9), C-7 (27.7), C-8 (133.5), C-9
(134.1), C-10 (37.3), C-11 (21.5), C-12 (30.8), C13 (44.1), C-14 (50.0), C-15 (29.8), C-16 (28.1), C17 (50.1), C-19 (20.2), C-20 (36.3), C-21 (18.8), C22 (35.0), C-23 (31.3), C-24 (156.9), C-25 (33.8),
C-26 (22.0), C-27 (21.9), C-28 (28.0), C-29 (15.5),
C-30 (24.4), C-31 (105.9), C=O (168.2), C-CH2
(36.2), C-CH2 (31.5), C-1(132.5), C-2(107.3), C3(162.2), C-4(104.4), C-5(162.2), C-6(107.2),
C-OCH3 (56.2), C-OCH3 (56.2); CI-EIMS: m/z
[M+ H]+ 633 [C42H64O4 + H]+.
CONCLUSION
Various new derivatives of euphorbol (2-10) have
been semisynthesized from the condensation of
natural euphorbol isolated from fresh latex of
Euphorbia resinifera Berg., and the commercial
aromatic acids, the reactions were carried put in
toluene in presence of DCC and DMAP. To
improve the yield, we increased the temperature of
reaction to 90C. The structure of the compounds
2-10 has been characterized by IR, 1H NMR, 13C
NMR and mass spectral data. The novel
compounds were subjected to anti-microbial
screening. The compounds showed moderate to
good antibacterial and antifungal activities.
ACKNOWLEDGEMENT
We thank Dr. Francesco Maneri (department of
pharmacy, university of Novara, Italy) for help and
the ministry of education, higher education and
scientific research, Morocco, for support.
Table 1. Antimicrobial activity of compounds (200 g/8 mm disk), the broad-spectrum antibacterial drug
ampicillin trihydrate (100 g/8 mm disk) and the antifungal drug Clotrimazole (100 g/8 mm disk) against S.
aureus ATCC 19433 (SA), B. subtilis ATCC 6633 (BS), E. coli ATCC 25922 (EC), P. aeruginosa ATCC 27853
(PA), and C. albicans ATCC 753 (CA).
Cpd
MIC (g/mL)
SA
BS
EC
PA
CA
100
100
100
100
100
2
55
53
111
116
115
3
17
21
57
106
58
4
56
105
106
113
113
5
58
56
50
110
102
6
19
15
52
55
104
7
57
58
105
106
107
8
54
54
51
105
105
9
19
16
33
102
108
10
< 7.5
< 7.5
< 7.5
< 7.5
NT
Ampicillin
NT
NT
NT
NT
12.8
Clotrimazole
NT, not tested.
12
13
11
1
2
10
HO
9
8
5
4
12
17
15
13
11
16
14
DCC
DMAP
10
15
9
8
5
4
17
16
14
R-COOH
7
6
R
1
2:R=
5:R=
3:R=
8:R=
6:R=
9:R=
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
4: R =
7:R=
OCH3
10 : R =
OCH3
OCH3
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