Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5732_Библиотеки_им_академика_М_И_Перельмана
.pdf
Schistosomiasis
Organic Compounds to Combat Neglected Tropical Diseases 211
the intermediate (3’) in 80% overall yields. This latter compound was subjected to a
SmI
2
-promoted Evans-Tishenko reduction to give the alcohol (4’) with a 95% yiel d.
Ozolysis of the alkene (4’) followed by a Barbier-like reaction involving prenyl
bromide, afforded, after separation of the diastereisomers, diol (5’) with a yield o f
29%. Further protection of the diol group and reduction of the ethyl ester of (5’)
resulted in the alcohol (6’) in 89% yield. The Mitsunobu reaction involving ( 6’) and
4-methoxyphenol introduced the protecting group and right stereochemistry at the
same time. The product (7’) was then subjected to a palladium-catalyzed
alkoxicarbonylation to provide (8’) in 75% yield as a single isomer. Glycosilation of
(8’) with (9’) gave (10’) in 62% yield. Further treatment of (10’) with CAN, resulted
in the cyanolide A precursor (11’), which can be converted in the natural cyanolide
A (48) in two steps following Hong`s protocol [32].
In 2011, the groups of Pabbaraja, Jennings and Rychnovsky, in independent
works, published three alternative syntheses of cyanolide A aglicone, employing
different strategies [34-36]. Pabbaraja and co-workers [34] designed a synthesis
based upon a sequence of one pot Wittig olefination/Michael addition, with an
aldol reaction, Corey-Bakshi-Shibata (CBS) Reduction and dimerization. The
retrosynthetic approach for this strategy is illustrated in Scheme 3.
N
S
N
O
OCH
3
O
O
OH
S
O
O
OH
N
O
O
OH
O
O
O
O
O
O
O
O
O
O
MeO
MeO
MeO
O
OMe
OMe
OMe
(44)
LC
100
= 10 mg/mL
(27.7 M)
(45)
B. glabrata
LD
50
= 9.0 µg/mL or 31.6 µM
(46)
LD
50
= 8.3 µM
(47)
LD
50
= 6.0 µM
LD
50
= 1.2 µM
Cyanolide A
(48)
Figure 20: Molluscicidal activity of marine-derived small molecules (MDSMs).
The strategy published by Jennings and Sharpe [35] started with a Ruthenium-
catalyzed cross-metathesis between the alkenes (1’’) and (2’’) to afford the
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
212 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira and Neves-Filho
intermediate (3’’) in 72% yield. Compound (3’’) was submitted to a hemiketal
formation/ intramolecular Michael addition cascade in the presence of benzaldehyde
to produce (4’’) in 60% yield. This compound was reduced to the respective
aldehyde and submitted to a Mukuyama aldol reaction involving the gem-dimethyl
sylil ketene acetal (5’’). This protocol produced t he advanced intermediate (6’’) in
60% overall yield. The compound (6’’) was protected with MOMCl and subjected to
a hydrogenolisis in the presence of Pearlman`s catalyst followed by acid catalyzed
lactonization resulting in lactone (7’’) with a 57% yield over the two steps. This
compound was alkylated with allylmagnesium bromide, followed by a tandem
stereoselective oxocarbenium/TFA and Et
3
SiH reduction sequence to result in the
glycoside (8’’) in 56% yield. Ozonolysis of this latter intermediate with respective
Lindgren-Kraus-Pinnick oxidation gave the hydroxi-acid (9’’), which was submitted
to a Yamaguchi lactonization, to afford the advanced precursor (10’’) in 45% yield.
Deprotection of the MOM-ethers in the presence of LiBF
4
resulted in the desired
cyanolide A aglicone in 68% yield (Scheme 4).
O
O
O
O
O
O
O
O
R
R
O
O
O
OO
O
O
O
R
R
O
OMe
OMe
OMe
S
S
HO
O
PMBO
H
(I)
(II)
Dimerization
Asymmetric
ethylaton
Glycosilation
Tandem
Oxidation/Michael
Cyanolide A
R =
10 steps
22% yields
(48)
(48)
Scheme 1: First total synthesis of cyanolide A.
Rychnovsky and co-workers [36] explored a protective-group-free strategy to
accomplish the synthesis of cyanolide A aglicone. Their approach was based on
the addition of 1,3-dithiane followed by oxidation, Yamagushi esterification and
Sakurai dimerization (Scheme 5).
Schistosomiasis
Organic Compounds to Combat Neglected Tropical Diseases 213
O
S
S
OOH
O
Et OH
OH O
MeO
OMe
OOHOH
PMP
CO
O
MeO
OMe
SPh
MeO
O
MeO
2
C
O
O
PMP
O
OMe
OMe
OMe
CAN
MeCN:H
2
O
O
MeO
2
C
O
OH
PMP
OOH
O
Et
OH O O
O
MeO
2
C
HO
O
O
OMe
OMe
OMe
SmI
2
, EtCHO
THF
95%
1'
2'
3'
4'
5'
80%
6'
4-methoxyphenol
1) DIAD, PPh
3
, THF
2) 1N HCl
PdCl
2
, CuCl
2
MeCN, MeOH
9
Ref. 32
7'
8'
10'
11'
1) O
3
, CH
2
Cl
2
2) Prenyl bromide, Zn
3) separation of the
diastereoisomers , 29%
78%
75%
62%
80%
1) BuLi, THF
2) I
2
, CaCO
3
Cyanolide A (48)
1) TsOH (cat.), CH
2
Cl
2
2) LiAlH
4
, THF, 89%
MeOTf, MS 4A
Et
2
O, 25
o
C, 48h
Scheme 2: Second approach for the synthesis of cyanolide A.
O
O
O
OH
O
O
O
HO
O
O
O
HO O
O
O
OH
D
i
m
e
r
i
z
a
t
i
o
n
C
B
S
r
e
d
u
c
t
i
o
n
O
n
e
p
o
t
W
i
t
t
i
g
o
l
e
f
i
n
a
t
i
o
n
/
M
i
c
h
a
e
l
a
d
d
i
t
i
o
n
Aldol react ion
Cyanolide A
aglicone
Scheme 3: Recent strategy for synthesis of cyanolide A.
2.2. Synthetic Compounds
In 2004, de Souza and co-workers synthesized a series of dihydro-pyran-2,4-
diones containing molluscicidal activity [37]. Caloverticicilic acid (49) (Fig. 21),
a natural product isolated from Calophyllumverticillatum displayed pronounced
activity against snails of Biomphalaria glabrata [38] and was a source of
inspiration for the target compounds.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
214 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira and Neves-Filho
OH
OTMS
OEt
O
OR
OOHO
Ph
O
OEt
OH O
OR
PhCHO
O
O
O
O
O
O
MOMO
OMOM
OH
OMOM
O
BrMg
Cl
3
PhCOCl
O
HO
2
C
HO
OMOM
OO
OR
O
Ph
OH
OMOM
O
O
Grubbs` II
Cyanolide A
aglicone
t-BuOK, THF
60%
1) MOMCl, DIPEA, 78%
2) H
2
, Pd(OH)
2
then TFA
1''
2''
3''
4''
6''
72%
7''
4-methoxyphenol
1)
2) TFA / Et
3
SiH
1
) O
3
, CH
2
Cl
2
2) NaClO
2
,
NaH
2
PO
4
1) LiBF
4
, MeCN
/ H
2
O, 68%
9''
1) DIBAL, CH
2
Cl
2
, 94%
2) BF
3
OEt
2
, CH
2
Cl
2
56%
65%
8''
10''
DMAP, toluene
45%
5''
Scheme 4: Synthesis of cyanolide A aglycone.
O
O
O
OH
O
O
O
HO
O
O
O
HO O
O
O
OH
Addition/
Oxidation
Yamagushi
esterification
Sakurai dimerization
Cyanolide A
aglicone
Scheme 5: New approach for synthesis of cyanolide A aglycone.
O
O
O
CO
2
H
OH
(49)
Figure 21: Structure of caloverticilic acid.
Schistosomiasis
Organic Compounds to Combat Neglected Tropical Diseases 215
The synthesis of the desired compound started from the aldol condensation
between ethyl acetoacetatedianion (51) and aldehydes (52) to produce the δ-
hydroxy-β-ketoesters. These intermediates were saponified and treated under
acidic conditions to achieve the desired lactones (53) with 42-80% yields (Scheme
6). The synthesized compounds presented significant molluscicidal activity
against B. glabrata egg masses. The most active compound bears a propenyl
group attached to the C-6. In the series of dihydro-pyran-2,4-diones containing
aryl substituents at C-6, it was observed that the more the number of methoxy
groups attached to the phenyl ring, the weaker the molluscicidal activity. The
reason for this trend has not been clarified so far.
O
O
OR
O
O
OPh
EtO
O
O
OEt
OO
1) NaH, THF, 0
o
C
2) n-BuLi, 0
o
C
3) RCHO
4) NaOH, H
2
O, r.t.
5) HCl, 0
o
C
42-80%
LC
50
< 100 ppm
LC
90
= 24.7 ppm
52
51
50
53
(129.9 M)
Scheme 6: Molluscicidal activity of lactones against B. glabrata snails.
Abass and co-workers evaluated the molluscicidal activity of a series of
enaminones derived from 4-hydroxiquinolinones [39]. The synthesis of the most
active compounds (57) and (58) is illustrated in Scheme 7. The key precursor (54)
was used as the starting material for the synthesis of both target compounds.
Hydrazinolysis of (54) yielded the 3-(pyrazolinyl)quinolinones (55), which was
converted in the target enaminone (57) in 81% yield through the condensation
with DMF-DMA in refluxing xylene. In order to achieve the enaminone (58),
compound (54) was simultaneously saponified and decarboxylated to produce the
intermediate (56). This latter compound was then condensed with DMF-DMA in
the presence of 4-aminoantipyrine to result in the desired target enaminone (58).
The synthesized compounds displayed potent activity against snails from two
different species, B. alexandrina and L. natalensis. Other molluscicidal azoles
containing enaminones, reported by Nawwar and co-workers, were also
synthesized following a similar protocol as that depicted in Scheme 7 [40].
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
216 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira and Neves-Filho
N
OH
O
O
N
OH
O
NH
N
O
N
OH
O
NH
N
O
N
N
OOH
O
N
N
O
O
OH
O
N
2
H
4
.H
2
O, DMF,
reflux, 1h
n.r.y
NaOH (15%), H
2
O
reflux, 2h
n.r.y
DMF-DMA, p-xylene
reflux, 2h
81%
4-aminoantipyridine
DMF-DMA, toluene
110
o
C, 2h
88%
IC
50
(ppm)
B. alexandrina - 47.51 ppm
L. natalensis - 40.41 ppm
IC
50
(ppm)
B. alexandrina - 15.80 ppm
L. natalensis - 66.21 ppm
54 55
56
57
58
Scheme 7: Molluscicidal azole derivatives.
Ph
OO
S KPhHN
S
PhNH
O
Ph
O
Ph
S
PhNH
O
OH
O
Ph
S
PhNH
O
OEt
O
Ph
S
PhNH
O
O
Ph
NN
S
Ar
Ph
O
O
O
Ph
N
H
N
PhNH
O
Ph
Ph
OO
N-NHAr
Br
O
Ph
1) KOH / DMF
2) PhNCS
ClCH
2
COCl
DMF, r.t.
ClCH
2
COMe
DMF, r.t.
1) HCl
2 )
NH
2
NH
2
Et
3
N, EtOH, r.t.
PhCOCH
2
Br
DMF, r.t.
BrCH(COOEt)
2
DMF, r.t.
n.r.y
65%
70%
59%
45%
35-87%
76%
IC
50
= 15.6 ppm
IC
50
= 18.0 ppm
IC
50
= 19.0 ppm
IC
50
= 5.5-8 ppm
IC
50
= 13.0 ppm
IC
50
= 16.0 ppm
59
60
61
61
62
63
64
65
Scheme 8: Molluscicidal thiadiazole derivatives against B. alexandrina snails.
Fadda and co-workers screened several thiophene, thiadiazole and pyrazole
derivatives as molluscicidal agents [41]. The key reagent for the synthesis of the
above mentioned heterocyclic compound is the salt (59), which can be easily
generated by the base-catalyzed condensation of the β-diketone (60) and phenyl
isothiocyanate. The thiophene derivatives were synthesized by alkylation of the
sulphide moiety with an α-halogenated carbonyl compound followed by
Schistosomiasis
Organic Compounds to Combat Neglected Tropical Diseases 217
intermolecular aldol condensation. The yields of this process are in general good.
Depending on the structure of the employed eletrophile, it is possible to generate
different thiophene scaffolds like (61-64). The intermediate (59) can also be
employed in the synthesis of other heterocyclic compounds. For example the
reaction between (59) and hydrazine afforded pyrazole (65) in 76% yield. The
thermal condensation involving (59) and arylazophenacyl bromides produced a
series of thiadiazole derivatives (65) in moderate to good yields. All the synthesized
compounds presented molluscicidal activities against B alexandrina snails. The
thiadiazole derivatives had the highest potency of the series with LC
50
values below
10 ppm (Scheme 8). It has been supposed that the higher activity of this series might
be related to the basicity of the heterocyclic ring. Furthermore, snails exposed to
these compounds effused a gelatinous material before dying. Based upon this fact,
the authors proposed that the tested substances might cause physical inter ference in
the cell membranes, causing hemolysis and subsequently death.
Three years later, Kanawade and co-workers synthesized a series of thiophene
compounds (67) and (68) with high activity against Indoplonorbis exustus snails
[42]. The designed compounds were synthesized from the precurs or (66) via acidic
hydrolysis or acetylation with excellent yields. These compounds presented ample
molluscicidal properties with IC
50
ranging from 0.61 to 0.76 ppm (Scheme 9).
S
NH
2
Ar
CN
NC
S
NH
2
Ar
O
O
H
2
N
NH
2
S
CN
NC
N
H
Ar
O
conc., H
2
SO
4
r.t., 4-6h
90-94%
Ac
2
O, H
2
SO
4
r.t., 1-1.5h
85-90%
LC
50
0.61 - 0.75 ppm
LC
50
0.65 - 0.76 ppm
66
67
68
Scheme 9: Molluscicidal thiophene derivatives against Indoplonorbis exustus snails.
Barsoum and co-workers developed the synthesis and investigation of the
molluscicidal activity of a large number of bis(1-aryl-2-pyrazoline) compounds
(71) [43]. The synthesis started with the aldol condensation involving the bis
benzaldehydes (69) and the ketones (R
1
COCH
3
) in the presence of KOH in
refluxing methanol. This protocol gave the corresponding bis-2-propen-1-ones
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
218 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira and Neves-Filho
(70) in 80% yields. It is noteworthy that the reaction was efficient with
thermodynamic control and only the 2E,2’E- isomers were formed. These
intermediates were then placed in a reaction with hydrazine in refluxing formic or
acetic acid to produce the target compounds in suitable yields (Scheme 10). The
synthesized compounds presented molluscicidal activity against B. alexandrina.
Although no IC
50
value was shown, the most active compounds displayed a
potency of about 20 ppm.
1,4-Thiazine and pyridine compounds incorporating a benzofuran moiety (75) and
(76) also exhibited molluscicidal activity (Scheme 11) [44]. The synthesis of these
substances started with an aldol condensation between aldehyde (72) and ketone
(73). The adduct (74) was reacted with hydrazine in refluxing methanol to
produce (75) in 70% yield. The same precursor (74) was also condensed with
malonitrile to produce pyridines (76) in a yield of 65%. The target compounds
presented significant molluscicidal activity against B. alexandrina in preliminary
assays. Other heterocyclic compounds were also synthesized from the
intermediate (74) but did not display significant activity. Interestingly, the most
active compound of this series was the chalcone precursor (74).
O
O
O
O
R
1
O
O
O
OR
1
R
1
O
OO
N
N
N
N
O
O
R
2
R
2
R
1
R
1
R
2
O
OH
NH
2
NH
2
, EtOH
reflux, 6h
70%
KOH, EtOH
reflux, 4h
80 %
69
70 71
Scheme 10: Molluscicidal bis(aryl-pyrazoline) compounds against B. alexandrina snails.
Ar
N
N
H
Ar
1
Ar
O
N
Ar
NH
2
CN
Ar
1
Ar =
O
O
N
N
Ph
HAr
1
O
PhNHNH
2
Ar
1
O
Ar
CH
2
(CN)
2
,NH
4
OAc
reflux , 5h
65%
Ar
1
=
NH
2
NH
2
, EtOH
reflux, 6h
70%
+
NaOH, EtOH
reflux, 4h
80 %
72
73
74
75
76
Scheme 11: Synthesis of molluscicidal 1,4-thiazine and pyridine derivatives.
Schistosomiasis
Organic Compounds to Combat Neglected Tropical Diseases 219
Silva and co-workers investigated the molluscicidal activity of compounds
derived from lapachol (30) [45], a natural product known for its molluscicidal
properties [46]. Scheme 12 presents the synthesis of the most promising
synthesized compounds. The 1-aza-anthraquinone (79) was prepared via
nucleophilic displacement of 2-methoxylapachol (77) with n-butylamine in 85%
yield. The derivative (78) was synthesized in a quantitative yield by the catalytic
hydrogenation of Lapachol under high pressure. The compounds (78) and (79)
exhibited strong molluscicidal activity against B. glabrata snails. The authors
observed that for the synthesized series, molluscicidal activity was closely related
to the hydrophobic character of the aminoalkyl side-chain moiety. Nevertheless,
some exceptions to this trend were also found.
The same research group investigated the molluscicidal properties of 1-aza-
anthraquinones derived from norlapachol (81) (Scheme 12) [47]. The desired
compounds were synthesized by following the same procedure employed for the
synthesis of compound (79). Norlapachol derivatives (81) presented similar
biological profile in comparison with the analogs derived from lapachol (30).
Moreover, a close relation has also been observed for this series between the
lipophilic character and the molluscicidal activity of the synthesized molecules.
Scheme 12: Synthesis of molluscicides norlapachol and lapach ol derivatives.
The molluscicidal activity of many 1,4-naphtoquinone derivatives has been
investigated by the groups of Camara, Sant’Ana and Goulart in independent
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
220 Organic Compounds to Combat Neglected Tropical Diseases de Oliveira and Neves-Filho
works. Camara and co-workers investigated a series of sixteen 1,4-
naphtoquinones derived from lawsone [48]. This compound presents a similar
structure to lapachol (30) and norlapachol but without the prenylated side chain. It
has been found that the bioactivity of these compounds is very similar to that
exhibited by (30) and (80). This suggests that the prenylated side chain has little
or no effect on molluscicidal activity. Among the tested compounds, two of them,
(82) and (83), presented pronounced higher toxicity. This enhancement has been
attributed to the presence of the bromo and azido substituents (Fig. 22). One year
later, Goulart and co-workers investigated the molluscicidal properties of 5-
substituted 1,4-naphtoquinones [49]. For this series they reported an increase in
the lipophilic character of the tested compounds leading to an enhancement in
molluscicidal activity. This trend is illustrated in Fig. 22, where the most polar
compound (84) shows the highest LC
50
(µg/mL) value in comparison with the
more lipophilic analogs (85), (89) and (90). They also observed that the 3-bromo
and 5-bromo substituted 5-methoxy 1,4-naphtoquinones presented similar
activities, which suggests that the position of attachment of the halogen atom does
not influence the toxicity of the tested compound significantly.
O
O
N
3
O
O
Br
OMe
O
OOH
Br
O
OOAc
Br
O
OOMe
Br
O
O
Br
Br
LC
50
= 6.71
LC
50
= 37.18
LC
50
= 0.75
LC
50
= 2.49
LC
50
= 0.89
LC
50
= 0.48
82
83 84
85
89
90
Figure 22: Molluscicidal activity of 1,4-naphthoquinone derivatives in µg/mL.
In an attempt to rationalize the biological mechanism of compound 1,4-
naphtoquinone compound action, the same research group carried out cyclic
voltammetry studies on a series of twenty four natural and synthetic 1,4-
naphtoquinones [50]. Although similar studies conducted a year before for the
niclosamide and analogs appeared inconclusive [51], this investigation revealed
that the easily reducible quininones were more active against B. glabrata, while
Соседние файлы в папке Библиотека им академика М.И. Перельмана