Bioprospection of Potential Trypanocidal Drugs

Chapter 9

Bioprospection of Potential Trypanocidal Drugs: A Scientific Literature Survey over the Period 2000–2010 Liliana V. Muschietti, Valeria P. Su¨lsen and Virginia S. Martino Ca´tedra de Farmacognosia, IQUIMEFA (UBA-CONICET), Facultad de Farmacia y Bioquı´mica, Universidad de Buenos Aires, Buenos Aires, Argentina

Chapter Outline Introduction Methods Search Strategy Criteria for Selection of Articles Data Extraction Data Interpretation

297 299 299 299 299 299

Results Databases Search Discussion Concluding Remarks References

299 299 300 327 328

INTRODUCTION Chagas disease or American trypanosomiasis is a parasitic disease that affects nearly 10 million people in Latin America [1]. It is known as a “neglected disease” because it persists exclusively among the poorest and the most marginalized communities. For this reason, low attention is paid to them, remaining outside of the pharmaceutical market. The causative agent of Chagas disease is the hemoflagellate protozoan parasite Trypanosoma cruzi transmitted by the hematophagous insect known as “vinchuca” in Argentina. Chagas disease has two sequential clinical phases: the acute phase, which is usually asymptomatic and starts soon after parasite infection, lasting up to 2 months and the chronic phase, in which 30–40% of infected patients develop cardiac and/or digestive damage after a silent period lasting from several years to decades [2]. Studies in Natural Products Chemistry, Vol. 39. http://dx.doi.org/10.1016/B978-0-444-62615-8.00009-6 © 2013 Elsevier B.V. All rights reserved.

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The nitroheterocyclic compounds nifurtimox and benznidazole, which were developed more than four decades ago, remain the current treatments for American trypanosomiasis. These drugs are considered far from ideal because they cause multiple side effects and present limited efficacy, especially in patients with the chronic form of the disease. Moreover, a wide range of susceptibility of different strains of T. cruzi has been reported [3]. Despite the long list of compounds tested against this parasite, only few drugs have been assayed in clinical trials. Among these, the antifungal triazole derivatives, E-1224 (a prodrug of ravuconazole) and TAK-187, have completed preclinical studies and phase I testing, thus becoming promising candidates [4]. Natural products for the treatment of human illnesses have been used for decades, and the majority of new drugs have been developed from natural products and from compounds derived from this source. In recent years, the introduction of combinatorial chemistry and high-throughput synthesis has precipitated a global decline in the screening of natural products. Nevertheless, this situation has been reverted, due to unrealistic expectations, and the interest in natural products has been rekindled mainly in the antimicrobial and anticancer therapeutic areas [5]. To date, many compounds obtained from medicinal plants and their analogues have proved to be clinically useful drugs. The most interesting characteristic of natural products is the one associated with their structural complexity as a result of the presence of multiple chiral centers, heterocyclic substituents, and polycyclic structures which cannot be easily synthesized in the laboratory. The influence of natural products as leads or sources of drugs over the period 1981–2006 has been pointed out by Newman [6]. Natural products, compounds derived from natural products, and synthetic compounds derived from a natural pharmacophore comprise 50.6% of the total small-molecule lead drugs. Bioprospection of antimicrobial agents (antibacterial, antifungal, and antiparasitic) and anticancer drugs has been particularly successful. Of about 14 antiparasitic drugs reported in the period 1981–2006, nine are natural derived compounds. Among them, artemisinin and its derivatives, artesunate, artether, and artemether, and quinine and its derivatives can be mentioned as effective natural antiparasitic drugs [7]. It is estimated that around 250,000 flowering plant species are reported to occur globally. Approximately half of these species are found in the tropical forests. Only a small portion of the available biodiversity has been explored so far, and the potential for finding new compounds is enormous, for only about 1% of tropical species have been studied for their pharmaceutical potential. The search among natural products, particularly from higher plants, is a unique opportunity for finding new bioactive compounds [8]. In this chapter, an analysis of the scientific literature concerning the trypanocidal activity of natural products of plant origin, over the period 2000–2010, will be presented. Data will be discussed under a critical point of view which may be useful for the development of new trypanocidal drugs.

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Bioprospection of Potential Trypanocidal Drugs

299

METHODS Search Strategy A literature survey was carried out using SCOPUS and MEDLINE databases from January 1, 2000 to December 31, 2010. The search was performed using the following combination of keywords: trypanocidal, T. cruzi, antiparasitic, and antitrypanosomal, each combinated with medicinal plants, plant extracts, and natural compounds. The results were limited for English language. All articles were assessed by title/abstract in MEDLINE and for title/ abstract/keywords in SCOPUS.

Criteria for Selection of Articles The selection of articles was limited to those corresponding only to higher plants and T. cruzi. References related to other parasites and natural compounds from other origins (animals, marine organisms, fungus, and microorganisms) were excluded. Articles concerning natural product analogues were included. If no bioactivity was found for both plant extracts or isolated compounds, data were excluded. When the information extracted from the abstract was insufficient, the full text was read. The three authors of the present review performed the selection independently.

Data Extraction Data on botanical source (genus, species, and family), ethnomedical uses of plants, search approaches for the identification of bioactive compounds (screening and bioassay-guided fractionation, phytochemical analysis/biological activity), and class of bioactive compounds and bioassays (in vitro/vivo) were collected.

Data Interpretation The extracted data were analyzed and discussed looking out for different approaches and strategies applied in a trypanocidal drug discovery process.

RESULTS Databases Search The databases search identified a total of 1621 articles that matched the combination of keywords described in the search strategy. After the application of the selection criteria, a total of 191 articles (11.8%) were finally selected Fig. 1.

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Total records (n = 1621)

Identified by literature search in MEDLINE (n = 268)

Identified by literature search in SCOPUS (n = 1353)

Exclusion criteria • Parasites other than Trypanosoma cruzi • Natural compounds from origins other than higher plants (animals, marine organisms, fungus, microorganisms) • Duplicate records • No activity reported for Trypanosoma cruzi • Incomplete information/no full text available

Articles selected (n = 191) FIGURE 1 Articles selection process.

The 191 references matching the search criteria are shown in Table 1. This table includes all data on botanical sources and class of bioactive compounds of only those species which were stated as “actives” by the authors. Data included in Table 1 were analyzed for the most representative plant families and the most representative class of bioactive compounds, including their semisynthetic analogues. Results are shown in Figs. 2 and 3. The analysis shows that the most frequently reported active families are Asteraceae, Fabaceae, Rutaceae, Annonaceae, and Lamiaceae. Terpenoids were the most represented class of trypanocidal compounds representing a 32% of the total, followed by alkaloids and flavonoids 17% each (Fig. 3). Further analysis within the terpenoid subclasses (monoterpenes, sesquiterpenes, diterpenes, triterpenes, sesquiterpene lactones (STLs), and steroids) showed that triterpenes (26%) and STLs (24%) were the major ones (Fig. 4).

DISCUSSION One of the most important steps in any drug discovery program from higher plants is the selection of plant species to be collected. There are different approaches that can be applied: search within plants selected for their traditional use, plants from promising families from which bioactive compounds have been reported, plants known to contain characteristic compounds of proven trypanocidal potential, or plants selected at random. These strategies

TABLE 1 Results of the Search Strategy Matching the Selection Criteria First Author/Year of Publication

Plant Species

Family

Class of Bioactive Compounds

Abe/2002

Annona reticulata

Annonaceae

Lignans

Annona muricata

Annonaceae

Aristolochia taliscana

Aristolochiaceae

Cecropia obtusifolia

Cecropiaceae

Chenopodium graveolens

Chenopodiaceae

Artemisia ludoviciana

Asteraceae

Bidens odorata

Asteraceae

Muntingia calabura

Elaeocarpaceae

Calophyllum brasiliense

Clusiaceae

Garcinia intermedia

Clusiaceae

Mammea americana

Clusiaceae

Persea americana

Lauraceae

Gliricidia sepium

Fabaceae

Haematoxylum brasiletto

Fabaceae

Senna hirsuta

Fabaceae

Zornia thymifolia

Fabaceae

Piper sp.

Piperaceae

Pouteria sapota

Sapotaceae

References [9]

Continued

TABLE 1 Results of the Search Strategy Matching the Selection Criteria—Cont’d First Author/Year of Publication

Plant Species

Family

Class of Bioactive Compounds

Abe/2002

Rosmarinus officinalis

Lamiaceae

Terpenoids

[10]

Abe/2003

Garcinia subelliptica

Clusiaceae

Xanthones

[11]

Abe/2004

Garcinia intermedia

Clusiaceae

Benzophenones

[12]

Calophyllum brasiliense

Clusiaceae

Xanthones

Persea americana

Lauraceae

Aliphatic compounds

Spondias mombin

Anacardiaceae

Annona cherimola

Annonaceae

Annona muricata

Annonaceae

Annona purpurea

Annonaceae

Annona reticulata

Annonaceae

Aristolochia grandiflora

Aristolochiaceae

Aristolochia taliscana

Aristolochiaceae

Alnus acuminate

Betulaceae

Parmentiera aculeata

Bignoniaceae

Heliopsis longipes

Asteraceae

Piqueria trinervia

Asteraceae

Tanacetum parthenium

Asteraceae

Abe/2005

References

[13]

Equisetum giganteum

Equisetaceae

Gaultheria acuminate

Ericaceae

Hippocratea excelsa

Hyppocrateaceae

Amphipterygium adstringens

Julianaceae

Hyptis stellulata

Lamiaceae

Marrubium vulgare

Lamiaceae

Acacia farnesiana

Fabaceae

Lonchocarpus guatemalensis

Fabaceae

Lonchocarpus phenthaphylus

Fabaceae

Smilax aristolochiifolia

Liliaceae

Smilax xalapensis

Liliaceae

Talauma mexicana

Liliaceae

Psidium guajava

Myrtaceae

Adiantum princeps

Polypodiaceae

Phlebodium aureum

Polypodiaceae

Coluania Mexicana

Rosaceae

Solanum hispidum

Solanaceae

Chiranthodendron pentadactylon

Sterculiaceae

Taxodium macronatum

Taxodiaceae Continued

TABLE 1 Results of the Search Strategy Matching the Selection Criteria—Cont’d First Author/Year of Publication

Plant Species

Family

Class of Bioactive Compounds

References

Ternstroemia sylvatica

Theaceae

Eryngium carlinae

Umbelliferae

Lippia dulcis

Verbenaceae

Larrea tridentate

Zygophylaceae

Abe/2006

Physalis angulata

Solanaceae

Terpenoids

[14]

Abegaz/2002

Bulbine frutescens

Asphodelaceae

Quinones

[15]

Albernaz/2010

Spiranthera odoratissima

Rutaceae

[16]

Ali/2002

Gardenia lutea

Rubiaceae

[17]

Pamianthe peruviana

Amaryllidaceae

Amal Nour/2009

Xanthium brasilicum

Asteraceae

Terpenoids

[18]

Ambro´sio/2008

Viguiera arenaria

Asteraceae

Terpenoids

[19]

Ambrozin/2004

Almeidea coerulea

Rutaceae

Almeidea rubra

Rutaceae

Conchocarpus heterophyllus

Rutaceae

Galipea carinata

Rutaceae

Trichilia ramalhoi

Meliaceae

[20]

Flavonoids

Aponte/2008

Iryanthera juruensis

Myristicaceae

Flavonoids and analogues

[21]

Aponte/2010

Plagiochila distichia

Plagiochillaceae

Terpenoids

[22]

Ambrosia peruviana

Asteraceae

Azorella compacta

Umbelliferae

Terpenoids

[23]

Flavonoids

[24]

Araya/2003 Arioka/2010

Quinones Asaruddin/2001

Desmos dasymachalus

Annonaceae

Alkaloids

[25]

Asaruddin/2003

Michelia alba

Magnoliaceae

Terpenoids

[26]

Astelbauer/2010

Glycosmis sp.

Rutaceae

Sulfur compounds

[27]

Balde´/2010

Pavetta crassipes

Rubiaceae

Alkaloids

[28]

Barbosa/2008

Arrabidaea chica

Bignoniaceae

Barreto-Menna/2008

Pterodon pubescens

Fabaceae

Terpenoids

[30]

Batista/2008

Piper gaudichaudianum

Piperaceae

Chromanes

[31]

Piper aduncum

Piperaceae

Neurolaena lobata

Asteraceae

Terpenoids

[32]

Lignan analogues

[33]

Berger/2001 Bernardes/2006

[29]

Biavatti/2001

Raulinoa echinata

Rutaceae

Terpenoids

[34]

Biavatti/2001

Raulinoa echinata

Rutaceae

Coumarins

[35]

Terpenoids Continued

TABLE 1 Results of the Search Strategy Matching the Selection Criteria—Cont’d First Author/Year of Publication

Plant Species

Family

Class of Bioactive Compounds

Biavatti/2002

Raulinoa echinata

Rutaceae

Terpenoids

Billo/2005

Amborella trichopoda

Amborellaceae

Glochidion billardieri

Euphorbiaceae

Erythrina variegata

Fabaceae

Smilax orbiculata

Smilacaceae

Cerberiopsis candelabra

Apocynaceae

Pagiantha cerifera

Apocynaceae

Bolognesi/2008

References [36] [37]

Quinone analogues

[38]

Borges-Arga´ez/2007

Lonchocarpus spp.

Fabaceae

Flavonoids

[39]

Borges-Arga´ez/2009

Lonchocarpus xuul

Fabaceae

Flavonoids and analogues

[40]

Bradacs/2010

Baccaurea stylaris

Phyllantaceae

Dysoxylum arborescens

Meliaceae

Intsia bijuga

Fabaceae

Gyrocarpus americanus

Hernandiaceae

Tabernaemontana pandacaqui

Apocynaceae

Macropiper latifolium

Piperaceae

Dunalia brachyacantha

Solanaceae

Bravo/2001

[41]

Terpenoids

[42]

Brengio/2000

Artemisia douglasiana

Asteraceae

Terpenoids

[43]

Bringmann/2000

Ancistrocladus ealaensis

Ancistrocladaceae

Alkaloids

[44]

Bringmann/2002

Ancistrocladus congolensis

Ancistrocladaceae

Alkaloids

[45]

Bringmann/2002

Dioncophyllum thollonii

Dioncophyllaceae

Alkaloids

[46]

Bringmann/2002

Ancistrocladus griffithii

Ancistrocladaceae

Alkaloids

[47]

Bringmann/2003

Ancistrocladus likoko

Ancistrocladaceae

Alkaloids

[48]

Bringmann/2003

Ancistrocladus tanzaniensis

Ancistrocladaceae

Alkaloids

[49]

Bringmann/2004

Ancistrocladus tanzaniensis

Ancistrocladaceae

Alkaloids

[50]

Bringmann/2004

Ancistrocladus benomensis

Ancistrocladaceae

Alkaloids

[51]

Bringmann/2008

Ancistrocladus taxon

Ancistrocladaceae

Alkaloids

[52]

Cabral/2010

Nectandra glabrescens

Lauraceae

Lignans

[53]

Ocotea cymbarum

Lauraceae

Acnistus arborescens

Solanaceae

Scoparia dulcis

Scrophulariaceae

Maianthemum paludicola

Convallariaceae

Chromolaena leivensis

Asteraceae

Annona muricata

Annonaceae

Argemone subfusiformis

Papaveraceae

Caesalpinia paraguariensis

Fabaceae

Piper barbatum

Piperaceae

Caldero´n/2010

[54]

Continued

TABLE 1 Results of the Search Strategy Matching the Selection Criteria—Cont’d First Author/Year of Publication

Plant Species

Family

Class of Bioactive Compounds

Calis/2006

Astragalus baibutensis

Fabaceae

Terpenoids

[55]

Quinones

[56]

Camacho/2004

References

Alkaloids Campos/2005

Bertholletia excelsa

Lecythidaceae

Terpenoids

[57]

Campos/2010

Croton cajucara

Euphorbiaceae

Terpenoids

[58]

Cardona Zuleta/2003

Calycophyllum spruceanum

Rubiaceae

Iridoids

[59]

Carmona/2010

Pentalinon andrieuxii

Apocynaceae

Terpenoids

[60]

Chaves/2007

Mikania hoehnei

Asteraceae

Mikania stipulacea

Asteraceae

Mikania cordifolia

Asteraceae

Mikania camporum

Asteraceae

Mikania lasiandrae

Asteraceae

Mikania micrantha

Asteraceae

Che´rigo/2005

Nectandra lineata

Lauraceae

Lignans

[62]

Cunha/2003

Miconia fallax

Melastomataceae

Terpenoids

[63]

Miconia stenostachya

Melastomataceae

Miconia sellowiana

Melastomataceae

Terpenoids

[64]

Miconia ligustroides

Melastomataceae

Cunha/2006

[61]

da Silva Filho/2004

Baccharis dracunculifolia

Asteraceae

Flavonoids

[65]

Organic acids de Fatima/2006

Pyranone analogues

[66]

de Marchi/2004

Coumarin analogues

[67]

Annona crassiflora

Annonaceae

Duguetia furfuracea

Annonaceae

Casearia sylvestris

Flacourtiaceae

de Moura/2001

Tabebuia spp.

Bignoniaceae

Quinone analogues

[69]

de Oliveira/2001

Bauhinia bauhinioides

Fabaceae

Proteins

[70]

Lignan analogues

[71]

de Mesquita/2005

de Oliveira/2006

[68]

del Olmo/2001

Notholaena nivea

Pteridaceae

Stilbenoids and analogues

[72]

do Nascimento/2004

Calea uniflora

Asteraceae

Acetophenones

[73]

dos Santos/2001

Tecoma heptaphylla

Bignoniaceae

Quinones and analogues

[74]

Duarte/2000

Macfadyena unguis-cati

Bignoniaceae

Flavonoids

[75]

Terpenoids Erosa-Rejo´n/2010

Bourreria pulchra

Boraginaceae

Chromanes

[76]

Espindola/2004

Casearia sylvestris

Flacourtiaceae

Terpenoids

[77]

Faria/2007

Erythrina speciosa

Fabaceae

Feresin/2003

Oxalis erythrorhiza

Oxalidaceae

Quinones

[79]

Ferreira/2007

Zanthoxylum chiloperone

Rutaceae

Alkaloids

[80]

[78]

Continued

TABLE 1 Results of the Search Strategy Matching the Selection Criteria—Cont’d First Author/Year of Publication

Plant Species

Family

Ferreira da Silva/2008 Fournet/2007

Ocotea lancifolia

Lauraceae

Galarreta/2008 Ganapaty/2008

Tephrosia pumila

Fabaceae

Garro/2010

Class of Bioactive Compounds

References

Alkaloid analogues

[81]

Alkaloids

[82]

Heterocyclic compounds

[83]

Flavonoids

[84]

Alkaloids

[85]

Gerscht/2003

Phyllanthus piscatorum

Euphorbiaceae

Lignans

[86]

Gohari/2003

Dracocephalum kotschyi

Lamiaceae

Flavonoids

[87]

Gohari/2008

Rubus hyrcanum

Rosaceae

Salvia sclera

Lamiaceae

Gonza´lez/2006 Gonza´lez-Coloma/2002

Grael/2000

Rollinia membranacea

Annonaceae

Annona cherimola

Annonaceae

Annona glabra

Annonaceae

Lychnophora granmongolense

Asteraceae

[88]

Alkaloids

[89]

Acetogenins

[90]

Terpenoids

[91]

Flavonoids Grael/2005

Lychnophora pohlii

Asteraceae

Terpenoids Flavonoids Phenolics

[92]

Guzma´n/2008

Senna villosa

Fabaceae

Hamilton/2006

Aliphatic compounds

[93]

Alkaloid analogues

[94]

Hay/2007

Pseudocedrela kotschyi

Meliaceae

Terpenoids

[95]

Heilmann/2000

Amomum aculeatum

Zingiberaceae

Spiroacetals

[96]

Heilmann/2001

Amomum aculeatum

Zingiberaceae

Spiroacetals

[97]

Herrera/2001

Cyrtanthus elatus

Amaryllidaceae

Alkaloids

[98]

Herrera/2008

Cranolaria annua

Bignoniaceae

Terpenoids

[99]

Izumi/2008

Tanacetum parthenium

Asteraceae

Terpenoids

[100]

Janua´rio/2005

Dipteryx odorata

Fabaceae

Flavonoids

[101]

Jimenez-Coello/2010

Senna villosa

Fabaceae

Aliphatic compounds

[102]

Terpenoids

[103]

Jimenez-Ortiz/2005 Jime´nez-Romero/2007

Stylogyne turbacensis

Myrsinaceae

Phenolics

[104]

Jorda˜o/2004

Lychnophora salicifolia

Asteraceae

Terpenoids

[105]

Flavonoids Karioti/2009

Anthemis auriculata

Asteraceae

Terpenoids

[106]

Kiuchi/2002

Chenopodium ambrosioides

Chenopodiaceae

Terpenoids

[107]

Kiuchi/2002

Combretum quadrangulare

Combretaceae

Sophora flavescens

Fabaceae

Paris polyphylla

Liliaceae

[108]

Continued

TABLE 1 Results of the Search Strategy Matching the Selection Criteria—Cont’d First Author/Year of Publication

Plant Species

Family

Class of Bioactive Compounds

Alpinia galanga

Zingiberaceae

Phenolics

Pogostemon cablin

Lamiaceae

Vitex trifolia

Lamiaceae

Dendrobium nobile

Orquidaceae

Kiuchi/2004

Pogostemon cablin

Lamiaceae

Terpenoids

[109]

Labran˜a/2002

Narcissus angustifolius

Amaryllidaceae

Alkaloids

[110]

Leite/2006

Arrabidaea triplinervia

Bignoniaceae

Terpenoid analogues

[111]

Leite/2009

Cedrela fissilis

Meliaceae

Cipadessa fruticosa

Meliaceae

Trichilia ramalhoi

Meliaceae

Rapanea lancifolia

Myrsinaceae

Flavonoids

Cipadessa fruticosa

Meliaceae

Terpenoids

Lia˜o/2009

Cheiloclinium cognatum

Hippocrateaceae

Terpenoids

Lirussi/2004

Pueraria lobata

Fabaceae

Mahonia bealei

Berberidaceae

Dictamnus dasycarpus

Rutaceae

Leite/2010

References

[112] Flavonoids

[113]

[114] [115]

Kochia scoparia

Chenopodiaceae

Sophora flavescens

Fabaceae

Ligustrum lucidum

Oleaceae

Lithospermum erythrorhizon

Boraginaceae

Saussurea lappa

Asteraceae

Melia toosendan

Meliaceae

Cinnamomum cassia

Lauraceae

Baccharis trı´mera

Asteraceae

Cymbopogon citratus

Panicoideae

Matricaria chamomilla

Asteraceae

Mikania glomerata

Asteraceae

Piper regnellii

Piperaceae

Stryphnodendron adstringens

Fabaceae

Tanacetum parthenium

Asteraceae

Tanacetum vulgare

Asteraceae

Luize/2006

Piper regnellii

Piperaceae

Lignans

[117]

Luize/2006

Piper regnellii

Piperaceae

Lignans

[118]

Machocho/2004

Crinum kirkii

Amaryllidaceae

Alkaloids

[119]

Luize/2005

[116]

Continued

TABLE 1 Results of the Search Strategy Matching the Selection Criteria—Cont’d First Author/Year of Publication

Plant Species

Family

Mafezoli/2000

Almeidea coerulea

Rutaceae

Conchocarpus gaudichaudianus

Rutaceae

Conchocarpus ovobatus

Rutaceae

Conchocarpus inopinatus

Rutaceae

Pilocarpus spicatus

Rutaceae

Zanthoxylum minutiflorum

Rutaceae

Mahiou/2000

Guatteria boliviana

Annonaceae

Alkaloids

[121]

Martı´nez/2009

Castela coccinea

Simaroubaceae

Alkaloids

[122]

Martins/2003

Piper solmsianum

Piperaceae

Lignans

[123]

Mbwambo/2004

Vismia orientalis

Clusiaceae

Quinones

[124]

Mbwambo/2006

Garcinia livingstonei

Clusiaceae

Xanthones

[125]

Mendes do Nascimento/2004

Mikania stipulacea

Asteraceae

Terpenoids

[126]

Mikania hoehnei

Asteraceae

Terpenoids

Menezes/2003 Mesia/2008

Piptadenia africanum

Chrysochlamys tenuis

Fabaceae

Clusiaceae

References [120]

Coumarins

Mezenceb/2009 Molinar-Toribio/2006

Class of Bioactive Compounds

[127] [128]

Indole phytoalexins

[129]

Xanthones

[130]

Montenegro/2007

Clidemia sericea

Anacardiaceae

Mosquitoxylon jamaicense

Anacardiaceae

Mota da Silva/2009

Peperomia obtusifolia

Piperaceae

Muelas-Serrano/2000

Mikania cordifolia

Asteraceae

Philodendron bipinnatifidum

Araceae

Cecropia pachystachya

Moraceae

Solanum pilcomayense

Solanaceae

Scutia buxifolia

Rhamnaceae

Curcuma longa

Zingiberaceae

Mimosa tenuiflora

Fabaceae

Neurolaena lobata

Asteraceae

Manilkara achras

Sapotaceae

Muscia/2008

Flavonoids

[131]

Chromanes

[132] [133]

Alkaloid analogues

[134]

Nagafuji/2004

Physalis angulata

Solanaceae

Terpenoids

[135]

Nakayama/2001

Galipea longiflora

Rutaceae

Alkaloids

[136]

Navarro/2003

Acalypha guatemalensis

Euphorbiaceae

Smilax spinosa

Smilacaceae

Ndjakou Lenta/2007

Albizia zygia

Fabaceae

Nkwengoua/2009

Enantia chlorantha

Annonaceae

[137]

[138] Alkaloids

[139] Continued

TABLE 1 Results of the Search Strategy Matching the Selection Criteria—Cont’d First Author/Year of Publication

Plant Species

Family

Class of Bioactive Compounds

References

Nour/2010

Ageratum conyzoides

Asteraceae

Flavonoids

[140]

Osorio/2007

Annona muricata

Annonaceae

Rollinia exsucca

Annonaceae

Rollinia pittieri

Annonaceae

Xylopia aromatica

Annonaceae

Osorio/2010

Phaedranassa dubia

Amaryllidaceae

Alkaloids

[142]

Paveto/2004

Camellia sinensis

Theaceae

Phenolics

[143]

Phenolics and analogues

[144]

Terpenoids

[145]

Quinone analogues

[146]

Pereira/2008 Pinheiro/2009

Annona amazonica

Annonaceae

Pinto/2000

[141]

Baccharis platypode

Asteraceae

Eugenia jambolana

Myrtaceae

Polygala sabulosa

Polygalaceae

Polygala cyparissias

Polygalaceae

Trichilia catigua

Meliaceae

Ramirez/2003

Cissampelos pareira

Menispermaceae

Flavonoids

[148]

Regasini/2009

Piper arboretum

Piperaceae

Alkaloids

[149]

Piper tuberculatum

Piperaceae

Pizzolatti/2002

[147]

Reyes-Chilpa/2008

Mammea americana

Clusiaceae

Rosas/2007

Ampelozizyphus amazonicus

Rhamnaceae

[151]

Rosella/2007

Gaillardia cabrerae

Asteraceae

[152]

Gaillardia megapotamica

Asteraceae

Rubio/2005

Pinus oocarpa

Pinaceae

Terpenoids

[153]

Ruiz-Mesia/2005

Remijia peruviana

Rubiaceae

Alkaloids

[154]

Saeidnia/2004

Dracocephalum kotschyi

Lamiaceae

Terpenoids

[155]

Saedinia/2005

Dracocephalum subcapitatum

Lamiaceae

Terpenoids

[156]

Saeidnia/2007

Satureja macrantha

Lamiaceae

Terpenoids

[157]

Saeidnia/2008

Nepeta cataria

Lamiaceae

Essential oil

[158]

Salvador/2002

Blutaparon portulacoides

Amaranthaceae

Flavonoids

[159]

Sanchez/2006

Salvia gilliessi

Lamiaceae

Terpenoids

[160]

Santoro/2007

Origanum vulgare

Lamiaceae

Thymus vulgaris

Lamiaceae

Terpenoids

Santoro/2007

Cymbopogon citratus

Poaceae

Essential oil

[162]

Santoro/2007

Syzygium aromaticum

Myrtaceae

Terpenoids

[163]

Ocimum basilicum

Lamiaceae

Achillea millefolium

Asteraceae

Cassia fistula

Fabaceae

Flavonoids

[164]

Sartorelli/2009

Coumarins

[150]

[161]

Continued

TABLE 1 Results of the Search Strategy Matching the Selection Criteria—Cont’d First Author/Year of Publication

Plant Species

Family

Class of Bioactive Compounds

References

Sartorelli/2010

Aristolochia cymbifera

Aristolochiaceae

Terpenoids

[165]

Terpenoid analogues

[166]

Sau´de-Guimara˜es/2007 Angelica dahurica

Apiaceae

Angelica pubescens

Apiaceae

Angelica sinensis

Apiaceae

Astragalus membranaceus

Fabaceae

Coptis chinensis

Ranunculaceae

Haplophyllum hispanicum

Rutaceae

Scutellaria baicalensis

Lamiaceae

Phellodendron amurense

Rutaceae

Ranunculus sceleratus

Ranunculaceae

Schinor/2004

Moquinia kingii

Asteraceae

Flavonoids

[168]

Schinor/2006

Chresta exsucca

Asteraceae

Flavonoids

[169]

Schinor/2007

Chresta scapigera

Asteraceae

Flavonoids

[170]

Schmeda-Hirschmann/2001

Cryptocarya alba

Lauraceae

Pyranones

[171]

Schmidt/2002

Arnica sp.

Asteraceae

Terpenoids

[172]

Scio/2003

Kielmeyera albopunctata

Clusiaceae

Coumarins

[173]

Schinella/2002

[167]

Scio/2003

Alomia myriadenia

Scotti/2010

Different sources

Senn/2007

Cussonia zimmermannii

Araliaceae

Su¨lsen/2006

Ambrosia scabra

Asteraceae

Ambrosia tenuifolia

Asteraceae

Baccharis spicata

Asteraceae

Eupatorium buniifolium

Asteraceae

Lippia integrifolia

Verbenaceae

Mulinum spinosum

Apiaceae

Satureja parvifolia

Lamiaceae

Ambrosia tenuifolia

Asteraceae

Flavonoids

Eupatorium buniifolium

Asteraceae

Flavonoids

Su¨lsen/2008

Ambrosia tenuifolia

Asteraceae

Terpenoids

[179]

Su¨lsen/2010

Ambrosia tenuifolia

Asteraceae

Terpenoids

[180]

Takeara/2003

Lychnophora staavioides

Asteraceae

Flavonoids

[181]

Taketa/2004

Ilex affinis

Aquifoliaceae

Terpenoids

[182]

Ilex buxifolia

Aquifoliaceae

Chromolaena hirsuta

Asteraceae

Flavonoids

[183]

Quinones

[184]

Su¨lsen/2007

Taleb-Continil/2004 Tasdemir/2006

Asteraceae

Terpenoids

[174]

Flavonoids

[175]

Polyacetylenes

[176] [177]

[178]

Continued

TABLE 1 Results of the Search Strategy Matching the Selection Criteria—Cont’d First Author/Year of Publication

Plant Species

Family

Class of Bioactive Compounds

References

Tasdemir/2008

Scrophularia cryptophila

Scrophulariaceae

Resins

[185]

Tempone/2005

Annona coriacea

Annonaceae

Annona crassiflora

Annonaceae

Cissampelos ovalifolia

Menispermaceae

Duguetia furfuracea

Annonaceae

Siparuna guianensis

Siparunaceae

Xylopia emarginata

Annonaceae

Guatteria australis

Annonaceae

Duguetia lanceolata

Annonaceae

Neoraputia magnifica

Rutaceae

Tomazela/2000

[186]

Flavonoids

[187]

Chalcones Torres Mendoza/2003

Myrospermum frutescens

Fabaceae

Terpenoids

[188]

Truiti/2005

Cayaponia podantha

Cucurbitaceae

Melochia arenosa

Sterculiaceae

Uchiyama/2002

Laurus nobilis

Lauraceae

Terpenoids

[190]

Uchiyama/2003

Dracocephalum komarovi

Lamiaceae

Terpenoids

[191]

Uchiyama/2004

Dracocephalum komarovi

Lamiaceae

Terpenoids

[192]

[189]

Valde´s/2008

Simarouba glauca

Simaroubaceae

Verza/2009

Viguiera arenaria

Asteraceae

Lignans

[194]

Vieira/2001

Almeidea coerulea

Rutaceae

Coumarins

[195]

Pilocarpus spicatus

Rutaceae

Conchocarpus obovatus

Rutaceae

Monnieira trifolia

Rutaceae

Ravenia infelix

Rutaceae

Harpalyce brasiliana

Fabaceae

Flavonoids

[196]

Acnistus arborescens

Solanaceae

Quinones

Physalis angulata

Solanaceae

Terpenoids

Cordia globosa

Boraginaceae

Protium amplum

Burseraceae

Marila laxiflora

Clusiaceae

Guarea polymera

Meliaceae

Otoba novogranatensis

Myristicaceae

Otoba parviflora

Myristicaceae

Conobea scoparioides

Scrophulariaceae

Vieira/2008

Weniger/2001

Weniger/2006 Yanes/2004

[193]

[197]

Flavonoids Azadirachta indica

Meliaceae

Melia azedarach

Meliaceae

[198] [199]

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45 40 35 30 25 20 15 10 5 Amar Anac Anci Anno Apia Apoc Aris Aste Bign Bora Chen Clus Euph Faba Lami Laur Lilia Mela Meli Myri Myrt Pipe Rubi Ruta Scro Sola Zing

0

FIGURE 2 Most representative plant families for which trypanocidal activity has been reported in the period 2000–2010. Only plant families with three or more citations were included. (Data derived from Table 1, repeated species were not considered). Amaryllidaceae (Amar), Anacardiaceae (Anac), Ancistrocladaceae (Anci), Annonaceae (Anno), Apiaceae (Apia), Apocynaceae (Apoc), Aristolochiaceae (Aris), Asteraceae (Aste), Bignoniaceae (Bign), Boraginaceae (Bora), Chenopodiaceae (Chen), Clusiaceae (Clus), Euphorbiaceae (Euph), Fabaceae (Faba), Lamiaceae (Lami), Lauraceae (Laur), Liliaceae (Lilia), Melastomataceae (Mela), Meliaceae (Meli), Myristicaceae (Myri), Myrtaceae (Myrt), Piperaceae (Pipe), Rubiaceae (Rubi), Rutaceae (Ruta), Scrophulariaceae (Scro), Solanaceae (Sola), and Zingiberaceae (Zing).

3%

9%

5%

17%

32%

6% 11%

17%

Lignans

Terpenoids

Flavonoids

Other phenolics

Quinones

Alkaloids

Coumarins

Miscellaneous

FIGURE 3 Most represented class of trypanocidal bioactive compounds for which trypanocidal activity has been reported in the period 2000–2010.

can be used alone or in combination. Within the period 2000–2010, all of them have been applied. More than 70% of the investigated species are medicinal plants, but only three are reported as being specifically used for the treatment of American Trypanosomiasis, that is, Annona crassiflora, Oxalis erythrorhiza, and Guatteria

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3%

15%

24% 10%

22%

26% Monoterpenes

Sesquiterpenes

Diterpenes

Triterpenes

STLs

Steroids

FIGURE 4 Subclasses of terpenoid compounds with trypanocidal activity reported in the period 2000–2010. STLs, sesquiterpene lactones.

australis [68,79,186]. In general, this pathology is not recognized as a specific disease by people, so traditional therapeutic practices, involving medicinal plants, are used to treat symptomatologies (fatigue, depression, constipation, gastric pains) or heart complains rather than as antiparasitics [200]. This is the reason why there are very few examples of medicinal plants reported to be specifically used to treat Chagas disease. The antitrypanosomal activity of the species A. crassiflora and G. australis, both belonging to the Annonaceae family, was concentrated in the total alkaloid fractions. It has been reported that this family produces isoquinoline alkaloids, which are strongly implicated in the inhibition of the trypanothione reductase (TryR), an essential antioxidant enzyme of T. cruzi [201]. From the species O. erythrorhiza, Feresin et al. have identified the benzoquinone embelin as an active molecule against T. cruzi trypomastigotes and with cytotoxicity above the trypanocidal concentration [79]. When considering the different classes of bioactive compounds most frequently isolated and identified, in the same period, terpenoids, alkaloids, and flavonoids seem to be the most promising ones as new “lead molecules” with trypanocidal activity. Biological screening is generally the starting point in an investigation process in the search of bioactive compounds from plant origin. From the total number of selected references, 18 papers concerning with the screening of trypanocidal activity of plants were found (considering “screening” the analysis of five or more species). In five of these, the authors reported the screening and the isolation of active compounds within the same paper. Trypanocidal compounds of different classes have been thus reported: lignans from Aristolochia taliscana, aliphatic compounds from Persea americana, phenolics from Alpinia galanga, and several natural coumarins such as chalepin isolated from different species of Rutaceae [9,13,108,195]. Flavonoids from Conchocarpus heterophyllus showed only moderate trypanocidal activity [20].

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Other bioactive compounds isolated from plants previously screened have also been reported in the period: coumarins from Mammea americana and Almeidea coerulea, terpenoids from Neurolaena lobata and Pogostemon cablin, STLs from Tanacetum parthenium and Ambrosia tenuifolia, flavonoids from A. tenuifolia and Eupatorium bunnifolium, lignans from Piper regnellii, xanthones from Calophyllum brasiliense, and benzophenones from Garcinia intermedia, and essential oils from Cymbopogon citratus [12,32,100,109,118,150,162, 178,179,195]. These results indicate that biological screening can be considered a successful strategy in the search of trypanocidal compounds. According to Pieters and Vlietinck, bioassay-guided fractionation can still be considered a valuable approach to obtain new lead compounds from plants [202]. Frequently, this methodology is perceived as rate limiting and resource consuming. However, this process can be improved, in terms of speed, by the implementation of robotics used in other drug discovery processes [203]. The bioassay-guided fractionation strategy was found to be applied in about 30% of the selected articles. Most of the investigations were carried out using whole parasites in vitro (97.4%) and were mainly performed using trypomastigote and epimastigote forms. Works dealing with in vitro assays on amastigotes, the intracellular form of the parasite, are scarce. Several investigations have been performed with parasites transfected with reporter genes encoding b-galactosidase, enabling an easy and rapid detection of the antiparasitic activity. In vivo assays represent only a 2.6% [64,80,102,136,179]. The latter observation is particularly important since many medicinal plant projects never go beyond the in vitro analysis [204]. One of the strategies for the development of trypanocidal drugs involves the identification of specific targets within key metabolic pathways. In the past two decades, an improved understanding of the biology and biochemistry of T. cruzi has led to the identification of various targets for chemotherapy to treat Chagas disease [205]. The main promising ones involve proteinases (cysteine proteases), sterol biosynthetic pathways, and thiol-dependent redox metabolism. Polyamine metabolism and transport pathways, enzymes of the glycolytic and pentose biosynthetic pathways, and some organelles functions including DNA modulation in nucleus and kinetoplast have also been extensively studied. In T. cruzi, the fourth enzyme of the pathway that catalyzes the production of orotate from dihydroorotate, the dihydroorotate dehydrogenase, differs markedly from the human enzyme [206]. Recently, this enzyme has been suggested as a promising target for the design of trypanocidal agents [207]. The knowledge of these metabolic pathways is important for the rational design and synthesis of candidates for the treatment of Chagas disease, but unfortunately, literature data regarding the interaction of natural products and these targets are scarce. Within the reviewed period, 14 manuscripts reported different targets such as TryR, glyceraldehyde-3-phosphate dehydrogenase

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(GAPDH), cysteine proteinase, DNA synthesis, arginine kinase, trans-sialidase, and NADH oxidase. Particularly, those related to the inhibition of GAPDH were the most represented. On the basis of the essential role in the life cycle of the parasite, GAPDH has been considered an attractive target for it possesses important structural differences with the homologue protein of the mammalian host [144]. Many natural compounds and derivatives have been evaluated against this target, all of them belonging to the phenolic group (flavonoids, coumarins, and anacardic acids) [67,101,112, 127,144,187,195]. Among these, 3-piperonylcoumarins were designed as inhibitors of T. cruzi GAPDH based on the structure of other natural products (chalepin). Leite et al. and de Marchi et al. found that the most active synthesized derivatives from chalepin contained heterocyclic rings at position 6, making this class of substances one of the most promising with GAPDH inhibitory activity [67]. Within the flavonoids tested (flavones, isoflavones, chalcones), highly oxygenated flavones appear to possess the structural requirements to cause inhibition of the trypanosomal GAPDH [112,187]. A great number of trypanocidal drugs are TryR inhibitors. TryR is a NADPH-dependent oxidoreductase which plays an essential role in the parasites’ defenses against various reactive oxygen species (H2O2, O2, and OH) and it has been tested as an attractive target for drug design [208]. de Oliveira et al. and Hamilton et al. have reported the activity of alkaloids, lignans, and their synthetic analogues as TryR inhibitors [71,94]. Another molecular strategy is the inhibition of cruzipain, the major cysteine proteinase from T. cruzi. A protein isolated from a saline extract of Bauhinia bauhinioides has been reported to be an inhibitor of this enzyme [70]. Other reports dealing with the inhibition of the enzymes trans-sialidase, NADH oxidase, and arginine kinase and DNA synthesis inhibition can be found in the period reviewed [24,85,143,175]. Electron microscopy has proven to be a reliable and useful tool to study morphological alterations and target organelles in the investigation of new drugs for Chagas disease. Su¨lsen et al. have reported the ultrastructural alterations caused by the STL psilostachyin in T. cruzi epimastigotes. This compound induced cytoplasmic vacuolization, a slight increase in multivesicular bodies and mitochondrial swelling accompanied by a visible deformity of the kinetoplast [180]. Within the reviewed period, several other manuscripts referring to the study of T. cruzi morphological changes induced by active natural products were found [43,58,103,117,161–163]. Secondary metabolites are biosynthesized in order to exert some biological effect for a certain purpose within the plant. These compounds can be equally potent in other settings. The preparation of natural product analogues, which are themselves not naturally occurring, may allow tailoring and enhancing drug-like properties (bioactivity, pharmacokinetics, solubility, among others) of the medicines provided by nature [209]. Once a lead molecule has been identified, lead optimization follows. At this point, proprietary rights play l

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an important role in the pharmaceutical industry (unlike natural products, their derivatives can be patented as new chemical entities not present in nature). In our search, alkaloid, quinone, and flavonoid analogues have been found [21,33,38,40,66,67,69,71,72,74,81,94,111,134,144,146,166]. In the first stages of a drug discovery process of novel trypanocidal compounds (in vitro studies), criteria for considering either an extract or a pure compound as “active” or “inactive” have been found to be very variable within the selected references. There are no widely accepted criteria of IC50 limit values for considering a promising extract or compound. Gertsch has commented the low level of self-criticism (evaluation) in the interpretation of molecular pharmacological data in the ethnopharmacological area [204]. There are different opinions about which concentrations are substantial to meaningful effects. In this regard, Pink et al. have set different criteria for considering antiparasitic hits, lead, and candidate molecules [210]. An IC50 < 1 mg/ml and a 10-fold selectivity index (SI) is recommended by these authors as a cutoff value for in vitro activity of pure compounds. Osorio et al., in a screening performed on Annonaceae Colombian plants, have established the following criteria for extracts: highly active IC50 < 10 mg/ml, active 10 < IC50 < 50 mg/ml, moderately active 50 < IC50 < 100 mg/ml, and inactive IC50 > 100 mg/ml [141]. Romanha et al. have recommended testing concentrations of 1 mg/ml for pure compounds and 10 mg/ml for extracts in comparison with benznidazole (IC50 ¼ 3.8 mM) [2]. Thus, compounds displaying a trypanocidal effect similar or greater than that of benznidazole will move on to the next phase of screening. Upon reviewing patents related to the claim of natural compounds as antitrypanosomal agents, few were found [206]. Three of them were related to alkaloids such as a series of 3,3-dimethyl-8-oxoisoquinoline derivatives from natural naphthyl isoquinoline and tetrahydroisoquinoline derivatives [211,212]. The alkaloid canthin-6-one has been disclosed for the treatment of Chagas disease, being more effective than benznidazole in both chronic and acute mouse models [213]. A sulfonate derivative of the 1-phenyl-2-aminoethyl naphthalene showed selectivity with an IC50 value within the micromolar range [214]. A patent claimed that the lignans, cubebin and methylpluviatolide, isolated from Zanthoxylum naranjillo or Piper cubeba, and the semisynthetic derivatives of cubebin, especially dibenzylbutyrolactonic lignans, were useful for the treatment and prophylaxis of Chagas disease [215]. During a workshop held in Rio de Janeiro, Brazil, in 2008, organized by Fiocruz, Me´decines sans Frontie`rs, and WHO/TDR (among other organizations), a protocol was accorded where minimum standardized procedures to advance leading compounds to clinical trials were outlined. The recommendations included the use of parasite forms relevant to human infection (trypomastigotes and amastigotes) in the in vitro assays; screening for cytotoxicity in mammalian cell culture linkages for the determination of SI with an established cutoff value of <50; toxicity assays prior to in vivo studies; and in vivo

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studies in different steps, considering parasitemia reduction in the acute phase, cure in this same phase, and cure using other T. cruzi strains resistant to benznidazole [2]. These recommendations should be kept in mind by researchers working with natural products when the aim is to find a new lead drug feasible to be incorporated to the market so as to give a solution to the millions of people suffering from Chagas disease.

CONCLUDING REMARKS This review has focused on the research carried out on plants as sources of new trypanocidal drugs, over the period 2000–2010. The results shown herein demonstrate that bioprospection is important and that plants are still a good source since several secondary metabolites have great potential as new lead structures. The major drawback is that, even though, at early stages of research, many compounds might show promising activity against T. cruzi, only a few standardized protocols are available and a minimum set of criteria are required to guarantee reliable results. As shown above, only three species have been selected based upon their ethnomedical uses to treat Chagas disease, possibly due to the absence of external symptoms and the lack of recognition by general population as a specific disease. Instead, a good strategy may be the selection based on chemotaxonomic criteria. The most representative plant family for which trypanocidal activity has been reported, in the period studied, is the Asteraceae followed by the Fabaceae, Rutaceae, Annonaceae, and Lamiaceae. Among these, the Asteraceae, Lamiaceae, Rutaceae, and also the Ancistrocladaceae have given good hits. Although the analysis presented in this review demonstrates that there are plenty of classes of compounds with trypanocidal activity, only terpenoids (diterpenoids, sesquiterpenoids), alkaloids, and lignanes are the most promising ones in the search for new lead molecules with trypanocidal activity. Unfortunately, most extracts and isolated compounds regarded as active have rather low potency. The semisynthetic approach of several natural compounds has generated structurally diverse analogues with improved properties as evidenced by the patents shown herein. A wide range of therapeutic targets are currently under investigation. Among them, cysteine proteinase inhibitors and ergosterol biosynthesis inhibitors are currently in the pipeline. However, such bioassays for compounds of plant origin are scarce or still lacking. Moreover, although these compounds could not serve as drugs or templates, they can lead to a better understanding of specific targets. The majority of the compounds have been screened only in in vitro assays. Only five works have been done employing in vivo bioassays. Standardization of in vivo tests, both in acute and in chronic phase models, is of crucial importance.

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As for the early steps of a drug discovery process, from the finding of an active plant extract up to preclinical studies, some premises should be followed to ensure a sustainable pipeline for innovative products. Extracts from plants with an IC50 < 10 mg/ml should be further investigated for the isolation of active principles. Only, in vitro active compounds against the infective forms of the parasite (trypomastigotes and amastigotes) should be studied. Compounds with IC50 < 1 mg/ml and SI between 10 and 50 should be followed up. In vivo studies should be carried out on the most promising compounds. The preparation of analogues with better activity should be considered in the study, in order to encourage pharmaceutical industry to continue with the next stages of the development so as to bring a drug into the market. Although a large number of articles about new trypanocidal compounds have been published in the period, no new drug has come into clinical trials yet. This point needs a critical assessment in order to make the drug discovery process shorter and more effective.

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