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
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 101
Foroumadi and coworkers reported the synthesis of two types of chalconoids by
Claisen-Schmidt condensation of chomenes with different acetophenones or
aldehydes to afford (6-chloro-2H-chromen-3-yl)propen-1-ones. A 3.0 μM IC
50
value of the tested compounds indicated that all of them exhibited high activity
against L. major. Compounds 232 and 233, which contain 2-chlorophenyl and 2-
bromophenyl substituents, proved to be the most potent compounds, with IC
50
values of 1.22 and 1.33 μM, respectively [135].
Sauvain and coworkers reported the synthesis and in vitro screening of
polysubstituted chalcones against L. amazonensis amastigotes. The compounds
that showed better activity were also evaluated against a macrophage-infected
model of L. amazonensis, L. braziliensis and L. peruviana. Their IC
50
values
range from 0.9-29.7, 1.4-237, 4.0-290 μM, respectively. The five most active and
selective chalcones were studied in vivo, and the chalcones 234 and 235 reduced
the parasite burden by 92% and 74%, respectively [136].
A new set of synthesized chalcones was evaluated against the L. braziliensis
promastigote form. Among the compounds synthesized, 236 was the most active
with an IC
50
value of 3.9 μM. The authors concluded that methoxy groups in the
phenyl ring A, especially in the di-ortho position, and a chlorine atom at phenyl
ring B seem to be important for antileishmanial activity [137].
OH
3
CO
O
O
OCH
3
H
3
CO
O
O
O
O
O
O
CH
3
H
3
C
H
3
C
Cl
O
OBr
Cl
OCl
Cl
O
OH
3
CO
O
OH
H
3
CO
OCH
3
OCH
3
OCH
3
A
B
(236)
(232)
(233)
(234)
(235)
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
102 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
2.17. Quinone Derivatives
Cavalli and coworkers reported the synthesis of 2-phenoxy-1,4-naphthoquinone
and 2-phenoxy-1,4-anthraquinone derivatives in a one-pot reaction of 2-
bromoquinones 237 with phenoxides 238. The compounds were tested against the
axenic amastigote form of L. donovani and exhibited IC
50
values between 0.28-
2.37 μM. The most potent compound in this series was the derivative 2-(2,4-
difluoro-phenoxy)-1,4-anthraquinone (239) [138].
O
O
Br
OH
F
F
(i)
O
O
O
F
F
+
(237)
(238)
(239)
Reagents and conditions: (i) phenol, K
2
CO
3
, DMF, 30 min, bromoquinone, rt, 3 h.
Jiménez-Alonso and coworkers have prepared a new series of bis-
pyranobenzoquinones through a double intramolecular domino Knoevenagel
hetero Diels-Alder reaction. The Knoevenagel condensation of 2,5-dihydroxy-1,4-
benzoquinone (240) and the corresponding aldehydes containing an alkene in the
presence of a catalytic amount of ethylenediammonium diacetate (EDDA) was
carried out. The reactive intermediates underwent a double intramolecular hetero
Diels-Alder reaction with the dienophile moieties yielding the corresponding bis-
pyranobenzoquinones (241 and 242). Studies have been performed on the drug
resistance reversal effect of bis-pyranobenzoquinones in a multidrug resistant
(MDR) L. tropica line. The results indicated that compounds 241 and 242 cause
approximately 100% cell growth inhibition of MDR parasites [139].
OH
HO
O
O
O
O
O
O
O
O
H
H
H
H
OCH
3
OCH
3
O
O
O
H
H
O
O
O
H
H
(241)
(242)
(240)
(i)
(i)
Reagents and conditions: (i) aldehydes, EDDA, EtOH, reflux, 25 min.
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 103
Mantyla and coworkers reported potent in vitro activity for buparvaquone (243)
and its phosphate prodrugs 244 and 245 against the Leishmania species that cause
CL and VL. The synthesis of buparvaquone prodrugs was achieved from
hydroxynaphthoquinone treated with NaH followed by appropriately protected
chlorophosphates. The protecting groups were removed to yield the respective
prodrugs. The ED
50
values for promastigotes indicated that buparvaquone and its
prodrugs have potent in vitro activity (0.002 to 0.124 μM) and, in many cases,
have greater activity than amphotericin B [140].
O
O
OH
O
O
O
P
HO OH
O
O
O
O
O
P
HO OH
O
(i)
(ii)
(245)
(244)
(243)
Reagents and conditions: (i) a) NaH, (EtO)
2
POCl, THF, N
2
, overnight; b) TMS-Br, DCM, rt, 4h.
(ii) a) NaH, n-Bu
4
NI, (t-BuO)
2
P(O)OCH
2
Cl, DMF, N
2
, 0
o
C - 50
o
C, 3 days; b) HCl/EtOAc, 0
o
C,
1h.
2.18. Alkylphosphocholine and Bisphosphonate Derivatives
Ether/alkyl-phosphocholine analogs originally used as anticancer agents have bee n
found to be the most effective oral compounds. These act as membrane synthetic
ether-lipid analogs and contain alkyl chains in the lipid portions. The most promising
compounds are miltefosine (5), edelfosine (246) and i lmofosine (247). Since 2002,
when 5 was approved in India for the treatment of visceral leishmaniasis, many
derivatives have been developed for similar purposes. Alkylphosphocholines
showed more potent antileishmanial activity than miltefosine against the
promastigote forms of both L. donovani and L. infantum [141].
OO
P
O
N
O
O
O
CH
3
-
+
SO
P
O
N
O
O
O
CH
3
-
+
(246) (247)
A wide variety of bisphosphonates inhibited the farnesylpyrophosphate synthase
enzyme (FPPS) of L. major and L. donovani [142, 143].
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
104 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
The reaction of 4,4’-bisbromomethylbenzophenone (248) with an excess of the
corresponding phosphine was used to synthesize a set of benzophenone-derived
bisphosphonium salts (249). These derivatives were assayed against L. donovani
promastigotes and exhibited IC
50
values in a range of 1.09-19.31 μM and
presented IC
50
values in a range of 0.97-14.01 μM against L. pifanoi amastigote
[144].
O
Br Br
O
P+ P
R
3
R
2
R
1
R
3
R
1
R
2
Br
Br
(i)
R
1
= R
2
= Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, n-C
5
H
11
, c-C
6
H
11
, n-C
8
H
17
, Ph, 2-furanyl
R
3
= Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, n-C
5
H
11
, c-C
6
H
11
, n-C
8
H
17
, Ph,
2
-pyridyl, o-tolyl, p-tolyl, 2-furany l
(248) (249)
Reagents and conditions: (i) R
1
R
2
R
3
P, DMF or toluene, 110
o
C.
Acuña and coworkers reported the synthesis of a series of compounds in which a
4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorescent group was
inserted in the drug alkyl chain. The synthesis was carried out by the condensation
of the appropriate hydroxyundecyl pyrrole (250) with the suitable 2-formyl-
pyrrole in the presence of POCl
3,
yielding a dipyrromethene intermediate that was
converted in situ into the corresponding BODIPY compounds (251) by reaction
with BF
3
.OEt
2
. The phosphocholine group was introduced into the respective
alcohols by reaction with 2-chloro-1,3,2-dioxa-phospholane-2-oxide to yield the
miltefosine fluorescent analogs (252). The in vitro leishmanicidal activity of
BODIPY analogs 252 against L. donovani promastigotes was equivalent to
miltefosine under similar conditions, with LD
50
(drug concentration required to
inhibit 50% parasite proliferation) values of 4.3-5.2 µM [145, 146].
N
H
OH
B
NN
FF
R
OH
-
O
B
NN
FF
R
OP
O
O
N
(i)
(ii)
R= H, Et
(251)
(252)
11
11
11
(250)
Reagents and conditions: (i) 2-formyl pyrroles, POCl
3,
CH
2
Cl
2
, Ar, 5 h, then DIPEA, BF
3
.OEt
2
, 20
min; (ii) 2-chloro-1,3,2-dioxaphospholane-2-oxide, Me
3
N, MeCN, Ar, pressure tube, 78
o
C, 3 h,
then 80
o
C, 4 h.
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 105
Romeo and coworkers described the synthesis and activity of edelfosine analogs.
The alkylglycerol portion of edelfosine (246) was modified, and the
phosphocholine group was kept constant in the synthesis of the analogs. The
octadecyl chain was substituted by aromatic groups and the methyl group was
replaced by long or short aliphatic chains as well as aromatic groups. The in vitro
activity of edelfosine analogs showed that compound 253 was the most active
when tested against L. donovani axenic amastigote forms, with an IC
50
value of
0.66 µM. In infected macrophages, compound 253 was appreciably mor e active
than the reference drug miltefosine [147].
N
O
P
O
O
O
N
O
O
N
N
-
(253)
New substituted ether phospholipids 254 and 255 were synthesized, and their
antileishmanial activity was evaluated. The most potent compounds were the
adamantyl-substituted 254, which exhibited an IC
50
value of 16.2 μM against
L. infantum amastigotes, and the derivative 5-cyclopentadecylpentylphosphocholine
(255), which had IC
50
values of 1.4, 0.9 and 0.7 µM for L. infantum, L. donovani
promastigotes and L. infantum intracellular amastigote forms, respectively [148, 149].
O
P
O
O
O
N
O
P
O
O
O
N
O
(254)
10
(255)
2.19. Trioxane Artemisinin Derivatives
Artemisinin derivatives are used, alone or in combination, to treat malaria. These
compounds have also been studied for their anticancer, antifungal and
antileishmanial activities. A series of artemisinin derivatives has been assayed by
Avery and coworkers against L. donovani promastigotes [150].
Galal and coworkers described the synthesis of a series of dimers by reacting
dihydroartemisinin (256) with a series of aliphatic and cycloaliphatic glycols
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
106 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
using BF
3
.OEt
2
as a catalyst. Compounds 257 were tested against L. donovani
promastigotes and showed IC
50
values ranging from 5.0-10.4 µM; pentamidine
and amphotericin B were used as controls [151].
O
O
H
H
H
OH
O
O
O
O
H
H
H
O
O
R
O
O
H
H
H
O
O
OO
OH
O
O
O
OO
OO
R=
(i)
(256)
(257)
Reagents and conditions: (i) HOCH
2
CH
2
OH, BF
3
.OEt
2
, Ar, rt.
2.20. Miscellaneous
Vasconcelos and coworkers described the strong antileishmanial activity of a
series of Baylis-Hillman adducts. The compound 258 represented one of the most
selective compounds of the series against the amastigote form of L. amazonensis,
inhibiting 84.3% of parasite growth with an IC
50
value of 12.5 µM [152-156]. The
dinitrodiphenylthioether derivative (259) was prepared by Copper-catalyzed
Ullmann condensation. Compound 259 was tested against the parasites in vitro,
exhibiting an IC
50
value of 0.67 µM, and in vivo against L. donovani -infected
BALB/c mice at 25 mg/kg/day for 5 days, causing a 28% reduction of parasitemia
[157].
OH
CN
Br
S
H
3
CO O
2
NCN
NO
2
(258)
(259)
Werbovetz and coworkers reported the synthetic modifications of trifluralin (260)
and oryzalin (261), generating a series of derivatives with activity against
L. donovani [158-160]. Trifluralin is an antimicrotubule herbicide that inhibited
promastigote proliferation and amastigote infectivity of all Leishmania species
that were tested and, as a topical ointment, reduced the size of cutaneous lesions
on BALB/c mice [161]. However, not all of the treated lesions remained closed,
and trifluralin does not present good pharmacokinetic properties [162]. To
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 107
improve the solubility of trifluralin, the analog oryzalin was developed, in which
the trifluoromethyl group was replaced by a sulfonamide group.
Another analog of trifluralin was developed and evaluated in vitro against both the L.
infantum and L. donovani promastigote form as well as against the L. infantum
intracellular form (IC
50
0.5-9.1 µM). Compound 262 exhibited approximately 11-fold
and 14-fold higher activity than miltefosine against the L. infantum and L. donovani
promastigote forms, with IC
50
values of 2.2 and 0.6 µM, respectively [163].
CF
3
O
2
NNO
2
N
S
O
2
NNO
2
N
O
O
NH
2
CF
3
O
2
NNO
2
HN
OH
(260)
(261)
(262)
Another series of nitroaromatic compounds was synthesized and evaluated as
potential antileishmanial agents. However, compound 263 showed low
antileishmanial activity in vitro against the promastigote form of L. amazonensis,
with IC
50
value of 50.6 μM [164].
Eifler-Lima described the synthesis and in vitro activity of R(+)-limonene
derivatives against L. braziliensis promastigotes. The derivative 264 was the most
active of the series, with an IC
50
value of 11.5 μM, and was also one of the most
active of the series against the L. amazonensis promastigote form, with an IC
50
value of 89.75 μM [165].
Abad-Grillo and coworkers described the synthesis of a set phenalen-1-one
derivatives. Compound 265 was the only compound from this series that
significantly inhibited both L. amazonensis and L. donovani with IC
50
values of
3.73 and 1.02 µg/mL, respectively [166].
NC
O
N
H
Cl
O
O
2
N
Cl
N
H
(263)
(264)
(265)
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
108 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
A series of new heterocycles derived from betulin triterpene was synthesized by
Yli-Kauhaluoma and coworkers and tested against L. donovani amastigotes. The
most effective derivative was the heterocycloadduct 266 with a GI
50
value of 8.9
μM [167].
Férézou and coworkers described the synthesis of a family of macrocyclics and
acyclics prepared from commercial ivermectin. Compound 267 was very active
against promastigotes with an IC
50
value of 2.8 µM, which is more potent than the
control drug amphotericin B, and 267 was also active against amastigotes with an
IC
50
value of 4.6 µM [168].
N
N
N
H
AcO
O
O
OAc
O
O
O(elo-L)
2
O
HO
Et
O
H
OH
H
OH
OH
HO
O
O
OH
H
(266)
(268)
(267)
Euglobals and other structural analogs were synthesized in four steps from
phloroglucinol. Compound 268, which contains an isovaleryl moiety and a formyl
group at the β-position to the pyran oxygen, was the most potent against
L. donovani promastigotes with an IC
50
value of 2.8 µg/mL [169, 170].
CONCLUSIONS
Here, we presented various synthetic compounds that were described from 2002
to 2012, tested against Leishmania spp. and could be considered possible
prototype drugs for this disease. They were organized into 20 chemical classes of
compounds.
As described in the literature, several functional groups and heterocyclic rings
have been associated with leishmanicidal activity. Groups such as amidine,
diamidine, guanidine, sulfonamide, hydrazide, hydrazine and polyamine as well
as small heterocyclic moieties including imidazole, pyrazole, thiadiazole, triazole,
oxazole, and piperazine were frequently found in leishmanicidal compounds.
Activity has also been associated with quinolines, quinones, pyrazolopyrimidines,
imidazopyrimidine, trioxanes, benzoazoles, acridine, naphthoquinones and others.
Leishmaniasis
Organic Compounds to Combat Neglected Tropical Diseases 109
Chalcones are natural products that belong to the flavonoid family. Chemically,
they consist of open-chain flavonoids in which the two aromatic rings are bonded
by a three-carbon α,β-unsaturated carbonyl system. Many of these
polyhydroxylated compounds have been synthesized and possess interesting
antileishmanial activity. Methoxy groups in the phenyl ring A, especially at the di-
ortho position and a chlorine atom at phenyl ring B seem to be important for
antileishmanial activity.
Based on the activity of miltefosine, an ether/alkyl-phosphocholine analog that
was approved as an oral drug approved in 2002 in India, many derivatives have
been developed, and a wide variety of bisphosphonates analogs have
demonstrated inhibition of the farnesylpyrophosphate synthase enzyme (FPPS)
from L. major and L. donovani.
With this comprehensive review, we hope to add more knowledge about the
various classes of compounds with activity against Leishmania and contribute to
the search for the new alternative treatments that could cure this disease.
ACKNOWLEDGEMENTS
The authors thank the National Council of R&D of Brazil (CNPq) and Foundation
for Research of the State of Rio de Janeiro (FAPERJ) for the fellowships and
support granted.
CONFLICT OF INTEREST
The authors confirm that this chapter contents have no conflict of interest.
REFERENCES
[1] World Health Organization, Control of the leishmaniasis: report of a meeting of the WHO
Expert Committee on the Control of Leishmaniases, Geneva, 22-26 March 2010.
[2] Glew, R. H.; Saha, A. K.; Das, S.; Remaley, A. T. Biochemistry of the Leishmania species.
Microbiol. Rev., 1988, 52, 412-432.
[3] Cavalli, A.; Bologn esi, M. L. Neglected Tropical Diseases : Multi-Target-Directed Ligands
in the Search for Novel Lead Candidates against Trypanosoma and Leishmania. J. Med.
Chem., 2009, 52, 7339-7359.
[4] Chang, K. P.; Fong, D.; Bray, R. S. Biology of Leishmania and Leishmaniais, p. 1-30. In K.
P. Chang and R. S. Bray (Eds.), Elsevier Biomedical Press, Amsterdam, 1985; Vol. 14, 1-
30.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
110 Organic Compounds to Combat Neglected Tropical Diseases Boechat and Pinheiro
[5] Tiuman, T. S.; Santos, A. O.; Ueda-Nakamura, T.; Filho, B. P. D.; Nakamura, C. V. Recent
advances in leishmaniasis treatment. Int. J. Infect. Dis. 2011, 15, e525-e532.
[6] Croft, S. L.; Yardley, V. Chemotherapy of Leishmaniasis. Curr. Pharm. Des. 2002, 8, 319-
342.
[7] Mishra, B. B.; Singh, R. K.; Srivastava, A.; Tripathi, V. J.; Tiwari, V. K. Fighting Against
Leishmaniasis : Search of Alkaloids as Future True Potential Anti-Leishmanial Agents.
Mini-Rev. Med. Chem., 2009, 9, 107-123
[8] Berman, J. Clinical status of agents being developed for leishmaniasis. Expert Opin. Invest.
Drugs, 2005, 14, 1337-1346.
[9] Micheletti, A. C.; Beatriz, A. Progressos Recentes na Pesquisa de Compostos Orgânicos
com Potencial Atividade Leishmanicida. Rev. Virtual Quim., 2012, 4, 268-286.
[10] Richard, J. V.; Werbovetz, K. A. New antileishmanial candidates and lead compounds.
Curr. Opin. Chem. Biol. 2010, 14, 447-455.
[11] Silva-López, R. E. Proteases de Leishmania : Novos Alvos para o Desenvolvimento
Racional de Fármacos. Quim. Nova, 2010, 33, 1541-1548.
[12] Rath, S.; Trivelin, L. A.; Imbrunito, T. R.; Tomazela, D. M.; Jesús, M. N.; Marzal, P. C.;
Junior, H. F. A.; Tempone, A. G. Antimoniais Empregados no Tratamento da
Leishmaniose: Estado da Arte. Quim. Nova, 2003, 26(4), 550-555.
[13] Croft, S. L.; Sundar, S.; Fairlamb, A. H. Drug resistance in leishmaniasis. Clin. Microbiol.
Rev. 2006, 19, 111-126.
[14] Sundar, S.; More, D. K.; Singh, M. K.; Singh, V. P.; Sharma, S.; Makharia, A.; Kumar, P.
C.; Murray, H. W. Failure of pentavalent antimony in visceral leishmaniasis in India: report
from the center of the Indian epidemic. Clin. Infect. Dis., 2000, 31, 1104-1107.
[15] Sundar, S.; Thakur, B. B.; Tandon, A. K.; Agrawal, N. R.; Mishra, C. P.; Mahapatra, T. M.;
Singh, V. P. Clinicoepidemiological study of drug resistance in Indian kala-azar. BMJ,
1994, 308, 307.
[16] Sundar, S. Drug resistance in Indian visceral leishmaniasis. Trop. Med. Int. Health, 2001, 6,
849-854.
[17] Perez-Victoria, J.M.; Di-Pietro, A.; Barron, D.; Ravelo, A. G.; Castanys, S.; Gamarro, F.
Multidrug resistance phenotype mediated by the P-glycoprotein-like transporter in
leishmania: a search for reversal agents. Curr. Drug. Targets, 2002, 3, 311-333.
[18] Mishra, M.; Biswas, U. K.; Jha, D. N.; Khan, A. B. Amphotericin versus pentamidine in
antimony-unresponsive kala-azar. The Lancet, 1992, 340, 1256-1257.
[19] Thakur, C. P.; Singh, R. K.; Hassan, S. M.; Kumar, R.; Narain, S.; Kumar, A.
Amphotericin B deoxycholate treatment of visceral leishmaniasis with newer modes of
administration and precautions: a study of 938 cases. Trans. R. Soc. Trop. Med. Hyg., 1999,
93, 319-323.
[20] Sundar, S.; Rai, M.; Chakravarty, J.; Agarwal, D.; Agrawal, N.; Vaillant, M.; Olliaro, P.;
Murray, H. W. New treatment approach in Indian visceral leishmaniasis: single-dose
liposomal amphotericin B followed by short-course oral miltefosine. Clin. Infect. Dis.,
2008, 47, 1000-1006.
[21] Thakur, C. P. A single high dose treatment of kala-azar with ambisome (amphotericin B
lipid complex): a pilot study. Int. J. Antimicrob. Agents, 2001, 17, 67-70.
[22] Sundar, S.; Jha, T. K.; Thakur, C. P.; Mishra, M.; Singh, V. P.; Buffels, R. Single-dose
liposomal amphotericin B in the treatment of visceral leishmaniasis in India: a multicenter
study. Clin. Infect. Dis., 2003, 37, 800-804.
Соседние файлы в папке Библиотека им академика М.И. Перельмана