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_5490_Библиотеки_им_академика_М_И_Перельмана
.pdf
Chagas Disease
Organic Compounds to Combat Neglected Tropical Diseases 11
oxothiazolylhydrazons (ATZ) ligands, deemed to be non-classical bioisosters of
thiosemicarbazones. This second ligand possesses great ability to interact with
biological targets by hydrophobic interaction and provides chemical stability to
the metal complex. In almost all cases, the organometallic compound was more
active than the ligand alone on trypomastigotes and epimastigotes of T. cruzi, and
many of them were more effective than benznidazole and nifurtimox. The most
active compound was 11 (Fig. 4), with an IC
50
of 1.8 μM over the epimastigote
form and it can be considered as a prototype for an antitrypanosomal drug.
Figure 4: Active ruthenium complexes.
The control of T. cruzi infection in vertebrate hosts is dependent on the activation
of macrophages and NO production, which is involved in intracellular parasite
destruction. Thus, the pharmacological modulation of the host’s immune response
against T. cruzi through control of the levels of NO has been gaining substantial
interest as a potentially valuable chemotherapeutic approach. Silva et al. [19] have
prepared a new class of ruthenium NO donors, cis-[Ru(NO)(bpy)
2
L]
n+
, cis-
[Ru(H
2
O)(bpy)
2
L]
n+
and cis-[Ru(NO
2
)(bpy)
2
L]
n+
where L = imidazole (imN), 1-
methylimidazole (1-miN) or sulphite ion (SO
3
2-
), and evaluated their effects in
cell cultures and animal models. Ruthenium NO donors are able to lyse
trypomastigotes of T. cruzi present in the bloodstream (BT), by an NO-dependent
mechanism, and can also inhibit the glyceraldehyde-3-phosphate dehydrogenase
(GAPDH), a key enzyme in the glycolytic cascade that has been implicated in
intracellular events mediated by NO. The enzyme possesses important structural
differences when compared to the homologous protein from the mammalian host
O
O
2
N
N
NH
NHR
S
N
N
H
NH
R
S
Ru
R= H, methyl, ethyl or phenyl
N
NNH
R
S-
Ru
S
N
Ru
NH
Br
N
S
O
Cl
Cl
HL
L
(10)
(11)
12 Organic Compounds to Combat Neglected Tropical Diseases Micheletti et al.
(about 45% sequence identity) and, because of that, is an attractive target for the
development of novel antitrypanosomatid agents. In vitro and in vivo trypanocidal
compounds were those which effectively donate NO, and one of the possible
mechanisms responsible for this effect is the inhibition of GAHPD (IC
50
values
from 89 (cis-[Ru(NO)(bpy)
2
imN](PF
6
)
3
) to 153 M - in vitro assay). But, because
these complexes react easily with glutathione and potentially with trypanothione,
it is reasonable to suggest that they can also act through the trypanothione/
trypanothione reductase system.
Benítez and coworkers have reported, in the last few years, three series of vanadyl
complexes (V
IV
), using diverse polypyridyl [17, 20, 21] and salicylaldehyde
semicarbazones [17, 21] as ligands. Metabolic pathways of kinetoplastid parasites
(Trypanosomaparasites) are similar to those present in tumor cells leading to a
correlation between anti-trypanosomal and anti-tumor activities. In addition, it has
been proposed that compounds that efficiently interact with DNA in an
intercalative mode, like polypyridyl chelators (Npy,Npy donors) capable of
intercalating DNA, could also show anti-trypanosomal activity [17].
First, the authors studied a polypyridyl system as ligand, the dipyrido[3,2-a:2’, 3’
-c]phenazine (dppz), together with salicylaldehyde semicarbazones (Salsem -2H), as
coligands. The latter are versatile ligands which present a wide range of bioactivity
[17]. 2,2’-Bipyridine (bipy) was also used as a polypyridyl system, but in this case,
the complexes had just moderate activity. Compounds containing both dppz and
salicylaldehyde semicarbazone or 5-bromosalicylaldehyde semicarbazone ligands
showed IC
50
values of 13 and 19 μM on epimastigotes of the Dm28c strain of
T. cruzi, respectively, by interacting with DNA, and introducing conformational
changes of the biomolecule. Then, dppz was used agai n, in a complex with formula
[VO(SO
4
)(H
2
O)
2
(dppz)].2H
2
O (12, Fig. 5). The compound was significantly
trypanocidal, with an IC
50
of 3 μM and, in addition, showed the ability to stimulate
apoptosis in tumor human cell lines by an interaction with DNA [20]. Changi ng the
pyridine moiety to 1,10-phenantroline and using another pool of semicarbazones,
with methoxy, ethoxy and bromine groups substituting the ortho- and para-positions
of the phenolic ring, the group has synthesized another five vanadyl complexes
[VO(salsen-2H)(phen)], much more active than the others, with IC
50
values between
1.6 and 3.8 μM (13, Fig. 5) [21].
Chagas Disease
Organic Compounds to Combat Neglected Tropical Diseases 13
N
N
N
N
V
O
OH
2
O
4
S
OH
2
N
O
O
N
NH
2
O
V
N
O
N
CH
3
(12)
(13)
Figure 5: Active vanadyl complexes.
Other metals and ligands have been used in recent years to prepare trypanocidal
compounds, and examples are summarized in Table 1.
Table 1: Other trypanocidal complexes
Metal
(Reference)
Ligands Molecular Formula IC
50
(μM) Mode of Action
Pt (II)
[22]
3-(5-nitrofuryl)acrolein
thiosemicarbazones
[PtCl
2
(HL)]
T. cruzi Talahuen
2: 8.6 - > 25
T. cruzi Dm28c:
24.40 – 63.23
Production of free
radicals and
interaction with
DNA
Pt (II)
[22]
3-(5-nitrofuryl)acrolein
thiosemicarbazones (14,
Fig. 6)
[Pt(L)
2
]
T. cruzi Talahuen
2: 9.1 - >25
T. cruzi Dm28c:
5.89 – 48.22
Production of free
radicals and
interaction with
DNA
Ni (II)
[23]
Anionic form of 4,6-
dimethyl-1,2,3-
triazolo[4,5-
d]pyrimidin-5,7-dione
(dmax – 15, Fig. 6)
Ni(dmax)
2
(A)
n
(H
2
O)
m
A= aliphatic or
aromatic amine
<1 – 90
(epimastigotes)
Metabolic changes in
production of
succinate and
acetate, due to the
disturbance of the
enzymes involved in
sugar metabolism
inside mitochondria
Pd
[24]
N,N-dimethyl-1-
phenethyl-amine
(DMPA), 1,2-ethane-bis
(diphenylphosphine)
(DPPE) (16, Fig. 6)
[Pd
2
(S(−)C
2
,N-
DMPA)
2
(m-
DPPE)]Cl
2
15x10
-3
Apoptosis-like death
and causes
mitochondrion
disruption
Mn (II)
[25]
Nitrobenzaldehyde,
nitroacetophenone and
nitrobenzophenone
thiosemicarbazones (17,
Fig. 6)
[Mn(L)
2
Cl
2
]
19,21 - > 200
(trypomastigotes)
-
L= ligand.
14 Organic Compounds to Combat Neglected Tropical Diseases Micheletti et al.
Figure 6: Active metallic complexes and ligands.
2.4. Nitrogen Heterocycles
Among the synthesized nitrogen compounds with potential antichagasic activity
there are the polynuclear aromatic heterocycles, like quinolines, quinolones,
isoquinolines, quinoxalines, benzofuraxans and imidazoles.
Polysubstituted quinolines, such as compound 18 (Fig. 7), have been shown to be
active not only against epimastigotes (IC
50
=3.4 μM), but also against amastigote
(IC
50
=3.1 μM) and trypomastigote (IC
50
=12.8 μM) forms of T. cruzi, which are
the stages of the parasite in mammals [26]. Quinolones also represent structures
with potential antichagasic activity. A series of phenoxy, benzyloxy and
phenylthio quinolone analogues were synthesized by Romeiro et al. [27]. Most
compounds with hydroxyl and thiol groups on the aromatic moiety exhibited
moderate to high inhibitory activity in vitro against T. cruzi, but the 7,8-
dibenzyloxy quinolone 19 (Fig. 7) demonstrated the most significant
antitrypanosomal activity, with an IC
50
value of 1.3 μg/mL.
O
N
N
NH
S
O
2
N
O
N
N
HN
S
NO
2
Pt
CH
3
CH
3
P
H
2
C
H
2
C
P
Pd Pd
N
+
Cl
N
+
Phe Phe Phe
Phe
Cl
CH
3
CH
3
CH
3
CH
3
H
H
CH
3
CH
3
N
N
N
N
-
N
O
O
CH
3
CH
3
N
H
N
H
N
S
CH
3
O
2
N
(14)
(15)
(16)
(
17
)
Chagas Disease
Organic Compounds to Combat Neglected Tropical Diseases 15
Figure 7: Chemical structures of 18 and 19.
Tipifarnib (20, Fig. 8) kills the causative agent of Chagas disease, T. cruzi, by
blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14α-
demethylase (Tc-L14DM) [17]. Ergosterol is a constituent of the parasite’s
membranes, which cannot be replaced by mammalian host cell derived cholesterol
[28]. Tipifarnib (20) is also an inhibitor of human protein farnesyltransferase
(PTF) [29], were the amino group is part of a hydrogen bond network in the active
site of human PTF, which does not exist in the parasite’s sterol demethylase [28].
Thus, in the search for analogues of 20 that display reduced affinity for human
PFT to reduce toxicity while increasing affinity for parasite Tc-L14DM, Kraus
et al. [29] prepared analogues by modifying atom X, Ring-1 and Ring-2 (Fig. 8).
The quinolone analogue, which comprises a mixture of rotamers, with an
additional methyl group (R
1
) and a chlorine atom (R
2
) in Ring-2 (Fig. 8) was the
first analogue with a methoxyl group in the same position as the amino group of
tipifarnib (20), and it showed trypanocidal activity at picomolar concentrations in
vitro [29, 30]. From this result, other significant effects were observed by
modifications on Ring-2. Among them, the most potent activity was observed for
quinolone 21 (IC
50
value of 0.31 nM) with very low inhibitory activity on
mammalian protein farnesyltransferase [29].
The carbonyl and N-methyl portions of the amide of the quinoline ring of
Tipifarnib (20) interact only with enzyme surface residues, and this kind of
interaction is usually not strong. The quinolone ring could be replaced with a
quinoline ring, but, as quinolines are well-known to be susceptible to oxidative
N
O
COOH
OBn
BnO
F
CH
3
N
Cl COOH
H
N
N
H
COOMe
(19)
(18)
16 Organic Compounds to Combat Neglected Tropical Diseases Micheletti et al.
metabolism in which carbon-2 is hydroxylated leading to the quinolone ring after
tautomerization of the 2-hydroxyquinoline, Chennamaneni et al. [28] made
isoquinoline analogs, such as compounds 22 and 23 (Fig. 9), which exhibited
interesting activities of growth arrest of T. cruzi amastigotes at nanomolar
concentration (IC
50
value of 0.9 and 1.3 nM, respectively).
Figure 8: Tipifarnib (20) and its analogue 21.
N
MeO
N
N
CH
3
Cl
Cl
N
MeO
N
N
CH
3
Cl
FF
(22)
(23)
Figure 9: Tipifarnib analogues 22 and 23.
The quinoxalines, including their fused-ring derivatives, display diverse
pharmacological activities, and their 1,4-dioxides have demonstrated excellent
anti-T. cruzi properties. In Fig. 10, the quinoxaline 1,4-dioxides 24a and 24b
are considered active (IC
50
value of 12 and 7.5 μM, respectively) and have
shown excellent parasite/mammal cell selectivity indexes [9]. The analysis of
Ring-1
N
NH
2
N
N
CH
3
O
Cl
Cl
CH
3
N
X
N
N
CH
3
O
CH
3
R
R
Ring-2
(20)
Structural
Modifications
(21)
N
MeO
N
N
CH
3
OC
l
CH
3
FF
Chagas Disease
Organic Compounds to Combat Neglected Tropical Diseases 17
the free sterols from parasites incubated with these compounds showed that
none of them are able to accumulate squalene [9]. Halogenated quinoxaline 1,4-
dioxides with amide and cyano substituents have proved to be interesting
structures for the preparation of bioactive compounds. The quinoxaline 25 (Fig.
10) is an example of this class, and was the most active derivative in the series
synthesized by Ancizu et al. [31] against the Tulahuen 2 strain of T. cruzi, with
IC
50
values of the same order as the reference compound, nifurtimox (1). A
series of quinoxalines similar to 25, substituted with benzyl or thiophene rings
at the 4 position of the quinoxaline scaffold, exhibited good trypanocidal
activity. Among them, the analogues with a thiophene group were the most
active, like 26 (Fig. 10), with an IC
50
value of 7.1 μM, making them valid as
new lead compounds. Two quinoxaline-N-acylhydrazones synthesized by
Romeiro et al. [23] (27 and 28, Fig. 10) had in vitro IC
50
values on
epimastigote forms of T. cruzi between 15 and 20 μM. The compounds were
non-toxic at the highest assayed concentration, showed good selectivity
indexes, and inhibited cruzain, the primary cysteine protease expressed by
T. cruzi during infection. It is a cysteine protease of the papain-like family and
plays a vital role at every stage of the parasite’s life cycle; it is involved in
protein degradation for nutrition, host cell remodeling, and evasion of host
defense mechanisms [27, 32].
The quinazoline class has been designed as inhibitors of the parasite reductase
enzymes such as trypanothione reductase (TR, the enzyme responsible for
keeping trypanotione in the reduced form, maintaining the intracellular
reducing environment) and dihydrofolate reductase (DHFR, that catalyzes the
reduction of dihydrofolate to tetrahydrofolate, the precursor of folate cofactors
required for one-carbon transfer reactions) [33-35]. A series of quinazoline
derivatives was made, compound 29 (Fig. 10) being one of the most active
against the parasite (IC
50
value of 3.7 μM) and in the assay of TR inhibition.
The series of diaminoquinoxalines synthesize d by Schorman et al. [35], based
on the structure of the antifolate drug trimetrexate (30, Fig. 10), that inhibits the
growth of amastigote and trypomastigote forms of T. cruzi in vitro, were
characterized as inhibitors of Tc DHFR, but also show high degree of inhibitory
activity against the human enzyme.
18 Organic Compounds to Combat Neglected Tropical Diseases Micheletti et al.
Figure 10: Trypanocidal quinoxalines 23 to 28, and quinazoline 29.
The dialkyl imidazoles 31 and 32 (Fig. 11) are promising anti-Chagas disease
candidates, because they are the most highly active compounds already tested in
vitro on T. cruzi amastigotas, showing nanomolar potency (IC
50
values of 0.4 and
1.2 nM, respectively). They are inhibitors of Tc-L14DM and in studies on mice
displayed excellent pharmacokinetic properties including oral availability and
reasonable stability in mouse plasma, besides being effective in acute Chagas
disease, with efficacy comparable to that of posaconazole [36].
N
+
N
+
N
H
S
O
F
F
N
O
-
O
-
N
+
N
+
O
O
CH
3
O
-
O
-
N
H
N
H
N
CH
2
S
CH
3
N
+
N
+
O
O
CH
3
O
-
O
-
N
H
N
H
N
CH
2
S
N
N
N
H
CH
3
N
O
H
OH
N
N
N
H
N
O
H
OH
N
+
N
+
Cl
N
O
-
O
-
S
N
NN
N
O
O
NH
2
O
CH
3
O
CH
3
N
N
N
H
NH
2
H
2
N
CH
3
O
O
O
CH
3
CH
3
CH
3
(25)
(24a)
(24b)
(27)
(28)
(26)
(29)
(30)
Chagas Disease
Organic Compounds to Combat Neglected Tropical Diseases 19
Among a number of different substitution patterns of 2H-benzimidazole
synthesized, the spiro benzimidazole 1,3-dioxides, like 33 (Fig. 11) exhibited a
very high selectivity index and provoked an important diminution of amastigotes
in Vero cells [3]. The benzimidazole 1,3-dioxides prepared by Gerpe et al. [9]
were shown to be T. cruzi membrane sterol biosynthesis inhibitors and had high
selectivity indexes. The most active compound among this class was that
substituted with a thiosemicarbazone group, 34 (Fig. 11) (ID
50
value of 7.2 μM).
H
N
Cl
N
N
NH
2
H
N
N
N
NH
2
S
N
N
N
O
O
CH
3
N
N
CH
3
CH
3
O
O
N
H
N
H
N
CH
2
S
(31)
(32)
(33)
(34)
Figure 11: Trypanocidal imidazoles 31 to 34.
The benzofuroxans are another kind of structure that represents the class of
nitrogenated heterocyclic compounds. Various isomeric vinylthio-benzofuroxans
were synthesized by Castro et al. [37], the compounds 35 and 36 (Fig. 12) showed
tripanocidal activity against Tulahuen 2 strain (T2) and CL Brener clone (CLB)
(IC
50
values ranged from 1.0 to 3.2 μM), but no clear relationship between
geometric isomerism and activity was observed. However, as deoxygenated
derivatives with benzofurazans possess less trypanosomicidal activity than the
corresponding N-oxide analogues, it is clear that the N-oxide moiety is essential
for adequate anti-T. cruzi activity.
20 Organic Compounds to Combat Neglected Tropical Diseases Micheletti et al.
1,2,4-Oxadiazole derivatives are important heterocyclic compounds due to their
various bioactivities, such as tyrosine kinase inhibition, and anti-inflammatory
and antitumor activity. The oxadiazole heterocycle is well known for its
antiparasitic properties and, due to its chemical stability and ability to act as an
amide bioisoster, the oxadiazole structure is emerging as a valuable scaffold for
anti-protozoal drug design [4]. Durust et al. [4] synthesized various
5-azidomethyl-3-aryl substituted-1,2,4-oxadiazol compounds. They showed only
modest growth inhibitory potential towards T. cruzi, and the IC
50
values were
within the range of 36.6 (37, Fig. 12) - 62.4 µg/mL. 1,2,4-Oxadiazole
N-acylhydrazones synthesized by Filho et al. [38], such as 38 (Fig. 12), proved to
be potent antitrypanosomal agents and showed low toxicity both in vitro and in
vivo. They were found to be as potent as the reference drug, benznidazole [38].
Cl
S
N
+
O
N
O
-
F
S
O
N
O
N
+
O
-
H
N
N
N
H
O
N
O
N
H
CH
3
O
N
N
O
N
N
N
N
O
O
H
H
CH
3
CH
3
(35)
(36)
(38)
(37)
Figure 12: Active benzofuroxans and oxadiazoles.
Tetrahydro-1-benzazepine derivatives have been extensively investigated
synthetically and pharmacologically. Compounds containing this heterocyclic unit
Соседние файлы в папке Библиотека им академика М.И. Перельмана