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
Leprosy
Organic Compounds to Combat Neglected Tropical Diseases 141
activity far exceeding that of dapsone in the same dose [65] and in a dose of 20
mg/Kg none animals died in the control group and group treated with this
compound and dapsone [66].
More recently a macrocyclic hydrazone Schiff base (Fig. 10) was synthesized as a
series of metal complexes by reaction with Co(II), Ni(II) and Cu(II) metal salts
[67]. The compound and its complexes were screened for their antibacterial
(Escherichia coli, Staphylococcus aureus, Shigella dysentery, Micrococcus,
Bacillus subtilis, Bacillus cereus and Pseudomonas aeruginosa) and antifungal
activities.
OO
HN
N
NH
N
HO CH
3
N
NH
O
OHH
3
C
N
HN
O
Figure 10: Macrocyclic hydrazone with antimicrobial property.
The results for antibacterial activity of Shiff base and its complexes are presented
in Table 1.
Table 1: Antibacterial activity of Schiff base and its Co(II), Ni(I I) and Cu(II) complexes at 10
µg.mL
-1
concentration
Empirical Formula Activity (mm)*
E.
col
i
P.
aeruginos
a
B.
cereu
s
S.
aureu
s
S.
dysenter
y
Micrococcu
s
B.
subtili
s
C
34
H
28
N
8
O
6
16 14 16 10 16 14 20
[Co(C
34
H
26
N
8
O
6
)Cl
2
]H
2
O 10 16 16 12 14 12 12
[Ni(C
34
H
26
N
8
O
6
)Cl
2
.2H
2
O]2H
2
O
14 12 14 10 16 16 16
[Cu(C
34
H
26
N
8
O
6
)Cl
2
]2H
2
O 12 14 10 12 16 10 14
Gentamycin 20 20 20 20 20 20 20
DMF 12 12 12 12 12 12 12
*Less than 12 mm – inactive; 12–14 mm – weakly active; 14–16 mm – moderately active; above 16 mm – highly active.
Adapted from literature [67].
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
142 Organic Compounds to Combat Neglected Tropical Diseases de Lima and de Lima
The results for antibacterial activity of Shiff base and its complexes show that
these compounds are potentially active towards microbial strains. Based on the
need for continuous improvement in antileprotic drugs and the fact that various
hydrazones have application in the treatment of leprosy, continuous focus on the
chemotype may prove worthwhile in the effort to find drugs that are more
effective.
3. NATURAL PRODUCTS BEARING ANTILEPROTIC ACTIVITY
Natural products have proven to be a fertile area for research for therapeutics for
many diseases and a source of starting points and inspiration for medicinal
chemists. Many of biological active compounds are lead compounds to medicines
when transformed by synthesis. An important source of drugs is the plants given
that a wide diversity of bioactive molecules that have been isolated from them. In
a review Barbosa-Filho and co-workers [68] reported a list of 11 plants evaluated
for M. leprae inhibition. The authors also list 17 chemically defined natural
molecules reported in the literature as having antileprotic activity, although, and
four are currently clinically used to treat leprosy (Fig. 11).
(CH
2
)
11
CO
2
H
Chaulmoogric acid
CO
2
H
OAc
MeH
Me
H
HO
HO
Me
H
Fusidic acid
O
O
Me
HO
Me
Me
OMe
OH
Me
Me
Me
Me
O O
O
OMe
Me
OH
Me
O
O
OH
N(Me)
2
Me
Clarithromycin
O
NH
O
Me
MeMe
OH
HO
Me
O
O
Me
OH
OH
AcO
Me
OH
N
N
N
Me
Me
Rifampicin
Figure 11: Structures of clinically used antileprotic natural compounds.
Leprosy
Organic Compounds to Combat Neglected Tropical Diseases 143
Moreover, the review accounts for the main compounds isolated and identified
from those plants belong to the class of lipids, triterpenes, macrolides, alkaloid,
benzenoid, flavonoid, maytansinoid, proteid, and sulfur compound.
4. FINAL CONSIDERATIONS
In spite of the many approaches to synthesize and biologically evaluate several
classes of organic compounds currently summarized it is noticeable that there is
still an open avenue to work on synthesis of compounds to effectively combat
leprosy.
The possibility of solely administration is attractive to improve patient compliance
during leprosy drug treatment. Therefore, it is important to continue research
aimed at finding therapies which can eventually fulfill this need. It is possible,
either by semisynthetic or total synthesis using several methodology combination
approaches to discover a new agent that by itself or its derivatives would be a new
medicine to treat leprosy. For instance, a recent in silico study using databases and
the tools available in TDRtargets.org has generated helpful lists of potential drug
targets in tropical disease pathogens [69] that can be very useful to guide new
synthetic designs.
The new allure of drugs described above can be devised as a timely motivation for
many scientists working in different science fields to discover new therapies to
improve the quality of life for individuals suffering from leprosy. Accordingly,
governmental’ politics need to continue to invest in research related to neglected
diseases. As for M. leprae, it is an ancient enemy which needs to be eliminated
from society.
ACKNOWLEDGEMENTS
The authors are indebted to Dr. Derek Cole (Associate Director Chemistry at
Takeda San Diego, Inc., USA) for the great assistance with English review and
valuable comments and suggestions to organize this book chapter. We are also
grateful to the Universidade Federal de Mato Grosso do Sul (MS, Brazil) for all
support and encouragement to accomplish this work.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
144 Organic Compounds to Combat Neglected Tropical Diseases de Lima and de Lima
The authors dedicate this chapter to Joana Ramos de Lima and Antônio Pires de
Lima. Dênis P. de Lima also dedicates this review to Professors Alaíde Braga de
Oliveira (UFMG), Délio Soares Raslan (UFMG) and Derrick L. J. Clive
(University of Alberta-Canada) that are responsible for his solid formation in
Organic Chemistry and enthusiasm for science.
CONFLICT OF INTEREST
The authors confirm that this chapter contents have no conflict of interest.
REFERENCES
[1] Penna, M. L. F.; Wand-Del-Rey-de-Oliveira, M. L.F; Penna, G. Spatial distribution of
leprosy in the Amazon region of Brazil. Emerg. Infect. Dis. 2009, 15 (4), 650-652.
[2] Britton, W. J.; Lockwood, D. N. Leprosy. Lancet 2004, 363, 1209-1219.
[3] Moschella, S. L. An update on the diagnosis and treatment of leprosy. J. Am. Acad.
Dermatol. 2004, 51, 417-426.
[4] Margarido, L. C.; Rivitti, E. A. Hanseníase. In: Tratado de Infectolog ia, 4th ed.
;
Focacia,
R., Ed.; Atheneu: S.Paulo, 2009; Vol.1, pp1047-1082.
[5] WHO. Leprosy global situation. WER. 2001, (76), 173-180. http://www.who.int/wer
(accessed March 30, 2010).
[6] Hotez, P. J.; Molyneux, D. H.; Fenwick, A.; Kumaresan, J.; Sachs, S. E.; Sachs, J. D.;
Savioli, L. Control of neglected tropical diseases. N. Engl. J. Med. 2007, 357, 1018-1027.
[7] WHO. Leprosy global situation. WER. 2009, (84), 333-340. http://www.who.int/wer
(accessed Feb 04, 2011).
[8] WHO. Regional strategy for sustaining leprosy services and further reducing the burden of
leprosy, 2006-2010. Indian J. Lepr. 2006, 78(1): 33-47.
[9] Meima, A.; Smith, W. C.; van Oortmarssen, G. J.; Richardus, J. H.; Habbema, J. D. The
future incidence of leprosy: a scenario analysis. Bull. World Health Organ. 2004, 82 (5),
373-80.
[10] Leading edge: A day to remember leprosy. Lancet Infect. Dis. 2009, 9, 1.
[11] Senior, K. Stigma, chemoprophylaxis, and leprosy control. Lancet Infect. Dis. 2009, 9, 10.
[12] Kirchheimer, W. F.; Storrs, E. E. Attempts to establish the armadillo (Dasypus
novemcinctus Linn.) as a model for th e study of leprosy. I. Report of lepromatoid leprosy
in an experimentally infected armadillo. Int. J. Lepr. Other Mycobact. Dis. 1971, 39 (3),
693-702.
[13] Shepard, C. C. The experimental disease that follows the injection of human leprosy bacilli
into foot-pads of mice. J. Exp. Med. 1960, 112 (3), 445-454.
[14] Sco llard, D. M.; Adams, L. B.; Gillis, T. P.; Krahenbuhl, J. L.; Truman, R. W.; Williams,
D. L. The continuing challenges of leprosy. Clin. Microbiol. Rev. 2006, 19 (2), 338-81.
[15] Renault, C. A.; Ernst, J. D. Mycobacterium leprae. In Mandell, Douglas, and Bennett’s
Principles and Practice of Infectious Diseases, 7th ed.; Mandell, G. L.; Bennett, J. E.;
Dolin, R., Eds.; Churchill Livingstone Elsevier: Philadelphia, 2010; Vol. 1, pp 3165-3176.
Leprosy
Organic Compounds to Combat Neglected Tropical Diseases 145
[16] Rees, R. J. W. The microbiology of leprosy. In: Leprosy, 1st ed.; Hastings, R. C., Eds.;
Medicine in the Tropics Series; Churchill Livingstone: Edinburgh, London , Melbourne and
New York, 1985; Vol. 1, pp 31-52.
[17] Rees, R. J. Animal models in leprosy. Br. Med. Bull. 1988, 44 (3), 650-664.
[18] Shepard, C. C. The first decade in experimental leprosy. Bull. World Health Organ. 1971,
44, 821-827.
[19] Brennan, P. J.; Barrow, W. W. Evidence for species-specific lipid antigens in
Mycobacterium leprae. Int. J. Lepr. Other Mycobact. Dis. 1980, 48 (4), 382-387.
[20] Ng, V.; Zanazzi, G.; Timpl, R.; Talts, J. F.; Salzer, J. L.; Brennan, P. J.; Rambukkana, A.
Role of the cell wall phenolic glycolipid-1 in the peripheral nerve predilection of
Mycobacterium leprae. Cell 2000, 103 (3), 511-24.
[21] Goulart, I. M.; Goulart, L. R. Leprosy : diagnostic and control challenges for a worldwide
disease. Arch. Dermatol. Res. 2008, 300 (6), 269-290.
[22] Truman, R.; Fontes, A. B.; De Miranda, A. B.; Suffys, P.; Gillis, T. Genotypic variation
and stability of four variable-number tandem repeats and their suitability for discriminating
strains of Mycobacterium leprae. J. Clin. Microbiol. 2004, 42 (6), 2558-65.
[23] Shin, Y. C.; Lee, H.; Walsh, G. P.; Kim, J. D.; Cho, S. N. Variable numbers of TTC repeats
in Mycobacterium leprae DNA from leprosy patients and use in strain differentiation. J
Clin Microbiol 2000, 38 (12), 4535-8.
[24] Cole, S. T.; Eiglmeier, K.; Parkhill, J.; James, K. D.; Thomson, N. R.; Wheeler, P. R.;
Honore, N.; Garnier, T.; Churcher, C.; Harris, D.; Mungall, K.; Basham, D.; Brown, D.;
Chillingworth, T.; Connor, R.; Davies, R. M.; Devlin, K.; Duthoy, S.; Feltwell, T.; Fraser,
A.; Hamlin, N.; Holroyd, S.; Hornsby, T.; Jagels, K.; Lacroix, C.; Maclean, J.; Moule, S.;
Murphy, L.; Oliver, K.; Quail, M. A.; Rajandream, M. A.; Rutherford, K. M.; Rutter, S.;
Seeger, K.; Simon, S.; Simmonds, M.; Skelton, J.; Squares, R.; Squares, S.; Stevens, K.;
Taylor, K.; Whitehead, S.; Woodward, J. R.; Barrell, B. G. Massive gene decay in the
leprosy bacillus. Nature 2001, 409 (6823), 1007-1011.
[25] Goulart, I. M.; Bernardes Souza, D. O.; Marques, C. R.; Pimenta, V. L.; Goncalves, M. A.;
Goulart, L. R. Risk and protective factors for leprosy development determined by
epidemiological surveillance of household contacts. Clin. Va ccine Immunol. 2008, 15 (1),
101-105.
[26] Davey, T. F. The nose in leprosy: steps to a better understanding. Lepr. Re. 1974, 45 (2),
97-103.
[27] Job, C. K.; Jayakumar, J.; Kearney, M.; Gillis, T. P. Transmission of leprosy: a study of
skin and nasal secretions of household contacts of leprosy patients using PCR. Am.J.Trop.
Med. Hyg. 2008, 78 (3), 518-521.
[28] Marquet, S.; Schurr, E. Genetics of susceptibility to infectious diseases: tub erculosis and
leprosy as examples. Drug Metab. Dispos. 2001, 29 (4 Pt 2), 479-483.
[29] Mira, M. T.; Alcais, A.; Nguyen, V. T.; Moraes, M. O.; Di Flumeri, C.; Vu, H. T.; Mai, C.
P.; Nguyen, T. H.; Nguyen, N. B.; Pham, X. K.; Sarno, E. N.; Alter, A.; Montpetit, A.;
Moraes, M. E.; Moraes, J. R.; Dore, C.; Gallant, C. J.; Lepage, P.; Verner, A.; Van De
Vosse, E.; Hudson, T. J.; Abel, L.; Schurr, E. Susceptibility to leprosy is associated with
PARK2 and PACRG. Nature 2004, 427 (6975), 636-40.
[30] Zhang, F. R.; Huang, W.; Chen, S. M.; Sun, L. D.; Liu, H.; Li, Y.; Cui, Y.; Yan, X. X.;
Yang, H. T.; Yang, R. D.; Chu, T. S.; Zhang, C.; Zhang, L.; Han, J. W.; Yu, G. Q.; Quan,
C.; Yu, Y. X.; Zhang, Z.; Shi, B. Q.; Zhang, L. H.; Cheng, H.; Wang, C. Y.; Lin, Y.;
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
146 Organic Compounds to Combat Neglected Tropical Diseases de Lima and de Lima
Zheng, H. F.; Fu, X. A.; Zuo, X. B.; Wang, Q.; Long, H.; Sun, Y. P.; Cheng, Y. L.; Tian, H.
Q.; Zhou, F. S.; Liu, H. X.; Lu, W. S.; He, S. M.; Du, W. L.; Shen, M.; Jin, Q. Y.; Wang,
Y.; Low, H. Q.; Erwin, T.; Yang, N. H.; Li, J. Y.; Zhao, X.; Jiao, Y. L.; Mao, L. G.; Yin,
G.; Jiang, Z. X.; Wang, X. D.; Yu, J. P.; Hu, Z. H.; Gong, C. H.; Liu, Y. Q.; Liu, R. Y.;
Wang, D. M.; Wei, D.; Liu, J. X.; Cao, W. K.; Cao, H. Z.; Li, Y. P.; Yan, W. G.; Wei, S.
Y.; Wang, K. J.; Hibberd, M. L.; Yang, S.; Zhang, X. J.; Liu, J. J. Genomewide association
study of leprosy. N. Engl. J. Med. 2009, 361 (27), 2609-18.
[31] Yamamura, M.; Uyemura, K.; Deans, R. J.; Weinberg, K.; Rea, T. H.; Bloom, B. R.;
Modlin, R. L. Defining protective responses to pathogens: cytokine profiles in leprosy
lesions. Science 1991, 254 (5029), 277-9.
[32] Modlin, R. L. Th1-Th2 paradigm: insights from leprosy. J. Invest. Dermatol. 1994, 102 (6),
828-32.
[33] Ridley, D. S.; Jopling, W. H. Classification of leprosy according to immunity. A five-group
system. Int. J. Lepr. Other Mycobact. Dis. 1966, 34 (3), 255-73.
[34] WHO Expert Committee on Leprosy. World Health Organ. Tech. Rep. Ser. 1998, 874, 1-
43.
[35] Bryceson, A.; Pfaltzgraff, R. E. Leprosy; Third ed.; Medicine in the Tropics Series;
Churchill Livingstone: Edinburgh, New York, 1990; p 240.
[36] Harboe, M. The immunology of leprosy. In Leprosy, 1 ed.; Hastings, R. C., Ed. Churchill
Livingstone: Edinburgh, London, Melbourne, New York, 1985; Vol. 1, pp 53-87.
[37] Ranque, B.; Nguyen, V. T.; Vu, H. T.; Nguyen, T. H.; Nguyen, N. B.; Pham, X. K.; Schurr,
E.; Abel, L.; Alcais, A. Age is an important risk factor for onset and sequelae of reversal
reactions in Vietnamese patients with leprosy. Clin. Infect. Dis. 2007, 44 (1), 33-40.
[38] Pocaterra , L.; Jain, S.; Reddy, R.; Muzaffarullah, S.; Torres, O.; Suneetha, S.; Lockwood,
D. N. Clinical course of erythema nodosum leprosum: an 11-year cohort study in
Hyderabad, India. Am. J. Trop. Med. Hyg. 2006, 74 (5), 868-79.
[39] WHO. Leprosy. http://www.who.int/mediacentre/factsheets/fs101/en/index.html (accessed
July 26, 2010).
[40] Fromm, E.; Wittmann, J. Derivate des p-Nitrothiophenols. Ber. Dtsch. Chem. Ges. 1908, 41
(2), 2264-2273.
[41] Clofazimine. Tuberculosis 2008, 88 (2), 96-99.
[42] Morrison, N. E.; Morle, G. M. The mode of action of clofazimine : DNA binding studies.
Int. J. Lepr. 1976, 44, 133-135.
[43] Arbiser, J. L.; Moschella, S. L. Clofazimine: A review of its medical uses and mechanisms
of action. J. Am. Acad. Dermatol. 1995, 32 (2, Part 1), 241-247.
[44] Buu-Hoi, N. P.; Xuong, N. D.; Tien, N. B. Compounds of Potential Interest for the
Chemotherapy of Leprosy. J. Org. Chem. 1956, 21, 415-418.
[45] Zhuravlev, S. V.; Gristsenko, A. N.; Ermakova, Z. I.; Skorodumov, V. A.; Stepanova, T.
N.; Shavyrina, V. V. Synthesis of Triftazin-10-(3-(1-Methyl-4-Piperazinyl)-Propyl))-
Phenothiazine Di-HCl. Med. Prom. SSSR 1965, 70, 10-3.
[46] Ratnakar, P.; Murthy, P. S. Antitubercular activity of trifluoperazine, a calmodulin
antagonist. FEMS Microbiol Lett 1992, 76 (1-2), 73-6.
[47] Katoch, V. M.; Saxena, N.; Shivannavar, C. T.; Sharma, V. D.; Katoch, K.; Sharma, R. K.;
Murthy, P. S. Effect of trifluoperazine on in vitro ATP synthesis by Mycobacterium leprae.
FEMS Immunol. Med. Microbiol. 1998, 20 (2), 99-102.
Leprosy
Organic Compounds to Combat Neglected Tropical Diseases 147
[48] Colwell, W. T.; Chan, G.; Brown, V. H.; DeGraw, J. I.; Peters, J. H.; Morrison, N. E.
Potential antileprotic agents. 1. Inhibition of a model mycobacterial system by diaryl
sulfones. J. Med. Chem. 1974, 17 (1), 142-144.
[49] DeGraw, J. I.; Brown, V. H.; Colwell, W. T.; Morrison, N. E. Potential antileprotic agents.
2. Inhibition of mycobacterial dihydrofolic reductase. J. Med. Chem. 1974, 17, (1) , 144-
146.
[50] DeGraw, J. I.; Brown, V. H.; Colwell, W. T.; Morrison, N. E. Potential antileprotic agents.
3. Inhibition of mycobacterial dihydrofolic reductase by 2,4-diamino-5-methyl-6-
alkylquinazolines. J. Med. Chem. 1974, 17 (7), 762-764.
[51] Ruckdeschel, G.; Stransky, D.; Schonenberger, H. The relationship between structure and
tuberculostatic effect in the benzylamine group. Pharmazie 1976, 31 (6), 374-81.
[52] Meindl, W. R.; Von Angerer, E.; Schoenenberger, H.; Ruckdeschel, G. Benzylamines:
synthesis and evaluation of antimycobacterial properties. J. Med. Chem. 1984, 27 (9), 1111-
1118.
[53] Hooper, M.; Purohit, M. G. The Chemotherapy of Leprosy. In Progress in Medicinal
Chemistry, Ellis, G. P.; West, G. B., Eds. Elsevier: 1983; Vol. 20, pp 1-81.
[54] Hooper, M. The medicinal chemistry of anti-leprosy drugs. Chem. Soc. Rev. 1987, 16, 437-
465.
[55] WHO Study Group on Chemotherapy of Leprosy. Report a WHO Study Group. Geneva
1994.
[56] Davis, B.; Brandstetter, T. W.; Smith, C.; Hackett, L.; Winchester, B. G.; Fleet, G. W. J.
Tetrazoles of manno- and rhamno-fu ranoses. Tetrahedron Lett. 1995, 36 (41), 7507-7510.
[57] Muller, G. W.; Konnecke, W. E.; Smith, A. M.; Khetani, V. D. A concise two-step
synthesis of thalidomide. Org. Process Res. Dev. 1999, 3 (2), 139-140.
[58] Gütschow, M.; Hecker, T.; Thiele, A.; Hauschildt, S.; Eger, K. Aza analogues of
thalidomide: synthesis and evaluation as inhibitors of tumor necrosisfactor-[alpha]
production in vitro. Bioorg. Med. Chem. 2001, 9 (4), 1059-1065.
[59] Khanolkar-Young, S.; Rayment, N.; Brickell, P. M.; Katz, D. R.; Vinayakumar, S.;
Colston, M. J.; Lockwood, D. N. Tumour necrosis factor-alpha (TNF-alpha) synthesis is
associated with the skin and peripheral nerve pathology of leprosy reversal reactions. Clin
Exp Immunol. 1995, 99 (2), 196–202.
[60] Hess, S.; Akermann, M. A.; Wnendt, S.; Zwingenberger, K.; Eger, K. Synthesis and
immunological activity of water-soluble Thalidomide prodrugs. Bioorg. Med. Chem. 2001,
9 (5), 1279-1291.
[61] Grosset, J. H., Newer drugs in Leprosy.
Int. J. Lepr. 2001, 69 (2 Suppl.), 14-18.
[62] Xiao, Z.; Schaefer, K.; Firestine, S.; Li, P.-K. Solid-Phase Synthesis of thalidomide and its
analogues. J. Comb. Chem. 2002, 4 (2), 149-153.
[63] Capitosti, S. M.; Hansen, T. P.; Brown, M. L. Facile synthesis of an azido-labeled
thalidomide analogue. Org. Lett. 2003, 5 (16), 2865-2867.
[64] Makarov, V.; Riabova, O. B.; Yuschenko, A.; Urlyapova, N.; Daudova, A.; Zipfel, P. F.;
Mollmann, U. Synthesis and antileprosy activity of some dialkyldithiocarbamates. J.
Antimicrob. Chemother. 2006, 57 (6), 1134-1138.
[65] Urlyapova, N. G.; Yushchenko, A. A.; Daudova, A. D.; Makarov, V. A., Study of
antileprosy activities of some dialkyldithiocarbamate derivatives. Bull Exp Biol Med 2007,
143 (3), 356-8.
[66] Urlyapova, N. G.; Yuschenko, A. A.; Daudova, A. D.; Makarov, V. A. Antilepros y activity
and preliminary toxicological characteristics of some dialkyldithiocarbamate derivatives.
Bull Exp Biol Med 2008, 145 (4), 446-8.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
148 Organic Compounds to Combat Neglected Tropical Diseases de Lima and de Lima
[67] Avaji, P. G.; Vinod Kumar, C. H.; Patil, S. A.; Shivananda, K. N.; Nagaraju, C., Synthesis,
spectral characterization, in-vitro microbiological evaluation and cytotoxic activities of
novel macrocyclic bis hydrazone. Eur. J. Med. Chem . 2009, 44 (9), 3552-3559.
[68] Barbosa-Filh o, J. M.; Nascimento Júnior, F. A.; Tomaz, A. C. d. A.; Athayde-Filho, P. F.
d.; Silva, M. S. d.; Cunha, E. V. L.; Souza, M. d. F. V.; Batista, L. M.; Diniz, M. F. F. M.
Natural products with antileprotic activity. Rev. Bras. de Farmacogn. 2007, 17, 141-148.
[69] Crowther, G. J.; Shanmugam, D.; Carmona, S. J.; Doyle, M. A.; Hertz-Fowler, C.;
Berriman, M.; Nwaka, S.; Ralph, S. A.; Roos, D. S.; Van Voorhis, W. C.; Agüero, F.
Identification of attractive drug targets in neglected-disease pathogens using an in silico
approach. PLoS Negl Trop Dis. 2010, 4 (8), 1-18.
Organic Compounds to Combat Neglected Tropical Diseases, 2014, 149-17 1 149
CHAPTER 5
LYMPHATIC FILARIASIS
Therapeutic Arsenal and Drug Discovery for Lymphatic Filariasis
from a Synthetic Point of View
Gabriela Bianchi dos Santos
1
, Ana Patrícia Yatsuda Natsui
2
and Flavio da
Silva Emery
1,*
1
Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences of
Ribeirão Preto –São Paulo University, Campus USP, Av do Café s/n – Monte
Alegre, Ribeirão Preto/SP – 14040-903, Brazil;
2
Department of Clinical,
Toxicological and Bromatological Analyses, Faculty of Pharmaceutical Sciences
of Ribeirao Preto – São Paulo University, Campus USP, Av do Café s/n – Monte
Alegre, Ribeirão Preto/SP – 14040-903, Brazil
Abstract: Lymphatic filariasis (LF) is one of the most devastating neglected diseases in
terms of social and economic impact,
disabling and disfiguring infected individuals. The
infection occurs by parasitic filarial nematode worms that are transmitted between
humans by blood-sucking insects. These parasites are known to have affected
individuals in 81 countries, mostly in developing areas. Despite the epidemiological
importance of this disease, current therapies have low effectiveness and a combined
therapy has been adopted as the standard treatment. To interrupt transmission, the WHO
recommends an annual mass drug distribution in endemic areas; however, this annual
mass drug distribution program has resulted in an increase in nematode resistance. This
type of program also depends on the availability of the required drugs, such as
diethylcarbamazine, ivermectin, and albendazole. Some aspects of the production of
these drugs are described in this chapter. Although clinically well characterized, there is
an urgent need for innovative drugs for the treatment of neglected tropical diseases, and
recent findings from structural chemistry studies could lead to safe, effective, and low-
cost treatments for LF infection.
Keywords: Lymphatic filariasis, filariae, macrolides, albendazole, DEC, drug
discovery.
*Address correspondence to Flavio-da Silva Emery: Department of Pharmaceutical Sciences, Facult
of Pharmaceutical Sciences of Ribeirão Preto –São Paulo University, Campus USP, Av do Café s/n –
Monte Alegre, Ribeirão Preto/SP – 14040-903, Brazil; Tel/Fax: +55 16 3602-0658;
E-mail: flavioemery@fcfrp.usp.br
Send Orders for Reprints to reprints@benthamscience.net
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
150 Organic Compounds to Combat Neglected Tropical Diseases Santos et al.
1. EPIDEMIOLOGY
Neglected Tropical Diseases (NTDs) are caused by several infectious agents such
as ectoparasites, viruses, fungi, bacteria, protozoans and helminths, totaling 33
diseases [1]. Lymphatic Filariasis, caused by helminths, is at the top 10 of this list
due to its high prevalence: 120 million people are estimated to be infected with LF
and it is present in 81 countries with more than 1,3 billion people living at risk
areas [2] (Fig. 1). It occurs in humid tropical areas of Asia and Africa, the
Western Pacific, and some parts of the Americas [2]. Most part of the population
at risk (1.27 billion) lives either in Africa (396 million) or in the Southeast Asia,
where 874 million can be potentially infected in countries like India, Bangladesh,
Indonesia and Sri Lanka [2].
Figure 1: Countries and territories in the world where Lymphatic Filariasis is considered endemic
(according to WHO Weekly epidemiological record, No. 42, 16 October 2009). Islands are
represented out of scale and shown as square boxes for better visualization.
2. BIOLOGY
The habitat of the adult worms is the motivation for the term Lymphatic Filariasis
(LF), as the adults live in nests inside lymphatic vessels. The disease LF is caused
Соседние файлы в папке Библиотека им академика М.И. Перельмана