Review article

Potential of the flora of Peru emphasizing in the Asteraceae family against Trypanosoma cruzi

Potencial de la flora del Perú enfatizando en la familia Asteraceae contra Trypanosoma cruzi

0000-0001-5769-8209Guillermo E. Delgado-Paredes^{1  2  *}  , 0000-0002-3518-1847Paulo R. Delgado-Rojas³  , 0000-0003-3525-6711Consuelo Rojas-Idrogo^{1  2} 

¹Universidad Nacional Pedro Ruiz Gallo, Vicerrectorado de Investigación, Instituto de Biotecnología. Lambayeque, Perú.

²Universidad Nacional Pedro Ruiz Gallo, Facultad de Ciencias Biológicas, Ciudad Universitaria. Lambayeque, Perú.

³Universidad Particular San Martin de Porres, Facultad de Medicina Humana. Chiclayo, Perú.

ABSTRACT

Introduction:

American trypanosomiasis or Chagas diseases, caused by Trypanosoma cruzi and Human African trypanosomiasis, caused by Trypanosoma brucei, are two neglected tropical, endemic and fatal disease, that affect 20 million people and cause 95,000 deaths per year in tropical and subtropical areas of the world.

Objective:

The objective of this review was to show the potential of the flora of Peru, emphasizing the Asteraceae family, against Trypanosoma cruzi, comparing it with American genera and species studied in various countries.

Methods:

A review of scientific articles on the subject was carried out, especially taken from the Scopus, SciELO, ScienceDirect, Medline and PubMed databases of American plant species, covering a period of twelve years (2010 to 2022).

Results:

A wide list of genera and species of the Asteraceae family and the flora of Peru with great potential in the treatment of trypanosomiasis is presented. Most of these species belong to the families Asteraceae, Piperaceae, Annonaceae, and Lauraceae. In the Asteraceae family, 48 genera and 76 species with trypanocidal activity were recorded, corresponding to 29 genera and 57 species for the flora of Peru. In these 29 genera, 174 endemic species potentially useful in the treatment of T. cruzi have been reported.

Conclusions:

The flora of Peru has around 22,000 species. Some of these genera and species are found in the flora of various American countries and have been tested in the treatment of Chagas disease, so the flora of Peru offers new opportunities in its treatment.

Key words: Chagas disease; crude extracts; medicinal plants; secondary metabolites; trypanosomiasis

RESUMEN

Introducción:

La tripanosomiasis americana o enfermedad de Chagas, causada por la Trypanosoma cruzi y la tripanosomiasis africana humana, causada por la Trypanosoma brucei, son dos enfermedades tropicales desatendidas, endémicas y fatales, que afectan a 20 millones de personas y causan 95 000 muertes por año en áreas tropicales y subtropicales del mundo.

Objetivos:

El objetivo de esta revisión fue mostrar el potencial de la flora del Perú, enfatizar en la familia Asteraceae contra la Trypanosoma cruzi y compararlos con géneros y especies americanas estudiadas en diversos países.

Métodos:

Se realizó una revisión de artículos científicos sobre el tema de especies vegetales americanas, especialmente tomados de la base de datos Scopus, SciELO, ScienceDirect, Medline and PubMed; se abarcó un período de 12 años (2010 a 2022).

Resultados:

Se presenta una amplia relación de géneros y especies de la familia Asteraceae y de la flora del Perú con gran potencial en el tratamiento de la tripanosomiasis. La mayoría de estas especies pertenecen a las familias Asteraceae, Piperaceae, Annonaceae y Lauraceae. En la familia Asteraceae se registraron 48 géneros y 76 especies con actividad tripanocida; correspondieron 29 géneros y 57 especies para la flora del Perú. Asimismo, en estos 29 géneros se han reportado 174 especies endémicas potencialmente útiles en el tratamiento de la T. cruzi.

Conclusiones:

La flora del Perú tiene alrededor de 22 000 especies. Algunos de estos géneros y especies se encuentran en la flora de varios países americanos y han sido ensayados en el tratamiento de la enfermedad de Chagas, por lo que la flora del Perú ofrece nuevas oportunidades en su tratamiento.

Palabras-clave: enfermedad de Chagas; extractos crudos; plantas medicinales; metabolitos secundarios; tripanosomiasis

Introduction

Trypanosomiasis is a tropical disease caused by Trypanosoma spp., a protozoan of the Trypanosomatid family. The human diseases caused by trypanosomatids are leishmaniasis (Leishmania spp.), Human African trypanosomiasis or sleeping sickness (Trypanosoma brucei) and American trypanosomiasis or Chagas disease (Trypanosoma cruzi). These diseases are originally transmitted by contact with infected blood-sucking insects (reduviid insects), blood transfusion, vertical transfer from mother to fetus, organ and tissue transplantation, oral ingestion in sylvatic/rural environments, contact with infected conjunctiva or oral mucosa, sharing of contaminated syringes and laboratory accidents.^1,2) Trypanosomiasis is part of a group of 17 parasitic infections that also includes dengue, rabies, trachoma, human African trypanosomiasis (sleeping sickness), leishmaniasis, leprosy, Buruli ulcer, echinococcosis, lymphatic filariasis, onchocerciasis, schistosomiasis, dracunculiasis (Guinea worm disease), foodborne trematodiases, taeniasis/cysticercosis, soil-transmitted helminth infection, and yaws.³ Fortunately, there are many efforts by various actors in the control and treatment of these diseases known as neglected tropical diseases (NTDs).^4,5).

Chagas disease is considered as a major public health problem in Latin America, estimating the approximately 10 millon people are infected and 100 millon are at risk worlwide, mainly due to migration of the population.⁶ Likewise, it was also reported that between six and seven million people are affected by this infection;⁷ however, recently trypanosomatids have been reported to affect about 20 million people in the world's poorest countries, leading to 95,000 deaths per year, and their incidence is often associated with “malnutrition, weak immune system, low quality housing, and population migration”.⁸

In Peru, the pioneer researcher on Chagas disease was the doctor Edmundo Escomel (1880-1959), who reported the presence of Triatoma infestans in Arequipa and thus described the first human case of the disease in Peru.⁹ However, studies carried out in Peru on the trypanocidal activity of native plants are few. In a study carried out by Peruvian researchers using the essential oils of ten plant species, mostly introduced, only EO of Cymbopogon citratus (DC.) Stapf (Poaceae) and Aloysia triphylla Paláu (Verbenaceae) inhibited the growth of T. cruzi epimastigote form.¹⁰ In another study carried out by Spanish scientists on eight species from the Peruvian Amazon, only Cedrela odorata L. (Myrtaceae) and Aristolochia pilosa Kunth (Aristolochiaceae) were the most active against T. cruzi, followed by Tabebuia serratifolia (Handroanthus serratifolius (Vahl) S.O. Grose (Bignoniaceae), Tradescantia zebrina Heynh. ex Bosse (Commelinaceae) and Zamia ulei Dammer (Zamiaceae).¹¹ Added to these is the study on the trypanocidal activity of Piper solmsianum C. DC. (Piperaceae) on epimastigote and trypomastigote forms of T. cruzi.¹²

The objective of this review was to show the potential of the Peruvian flora, emphasizing the Asteraceae family, against Trypanosoma cruzi, comparing it with American genera and species studied in various countries, based on ethnobotanical utility and complemented by phytochemical and pharmacological studies.

Methods

The methodology included a literature review of articles regarding the use of crude extracts and pure substances, obtained from American flowering plant species, in the treatment of Trypanosoma cruzi. No language restriction was made, although the vast majority of the articles consulted were in English and very rarely in Spanish. This literature review covered most of the studies conducted in the last twelve years (2010 to 2022). Exceptionally, studies carried out in years prior to 2010 were included, when they were carried out on highly promising plant species and on the treatment of Trypanosoma brucei, when T. cruzi was also included. In most cases Scopus database was use as well as SciELO, Science Direct, Medline and PubMed. The following keywords were used in the search, mainly word combinations: Trypanosoma cruzi, Chagas Disease, secondary metabolites, plant species, chemical composition. These keywords were the filter used in the search and selection of the articles.

The order of presentation of the plant families is based on the evolutionary position proposed by APG IV¹³ and Christenhusz and Byng,¹⁴ from the most primitive to the most evolved, with the exception of the families indicated in the regional flora and miscellaneous families. The comparisons with the species of the flora of Peru were made based on two important studies: Catalogue of the Flowering Plants and Gymnosperms of Peru¹⁵ and “Diez años de Adiciones a la Flora del Perú: 1993-2003”.¹⁶

Results

Current chemotherapy against Chagas disease

The chemotherapeutic treatment is the main therapy traditionally used to control of numerous parasitic infections like Chagas disease. However, the current treatment and drugs available are scarce, highly toxic, costy, lengthy, and often ineffective, with several secondary effects, requiring hospitalization some times.^17,18,19,20

The two main drugs used for the treatment of Chagas disease since the end of 60’ decade have been Lampit® (Nifurtimox) and Rochagan® (Benznidazole). In addition, Fungizone® (Amphoterecin B) is other drug that can be used as a second line treatment using nano-drug delivery systems. Recently, the trial of several drugs in the treatment against Chagas disease such as Biosynth® (Albaconazole); Milteforan® (Edelfosine); Rimidin® (Fenarimol); Sigma-Aldrich® (Ilmofosine); Nizoral® (Ketoconazole); Milteforan® (Miltefosine); Sigma-Aldrich® (Benznidazole nanoformulated), among others, has been reported; however, the results are under evaluation and are not definitive.^21,22 An extensive literature review on new drugs used in the treatment of Human African Trypanosomiasis has been recently published by Dickie et al²³⁾ and De Koning.²⁴

The current pharmacological treatment for Chagas disease is using nifurtimox and benznidazole, but unfortunately these drugs are relatively toxic for adult patients and require prolonged administration. On the other hand, many scientists in the world have oriented their research towards the search for plant species with potential utility in the treatment of several diseases,²⁵ as in this case trypanosomiasis. Two significant reviews in this regard have been reported by research groups in Rio de Janeiro¹⁸ and Minas Gerais,²⁶ both located in Brazil, where the disease was discovered.

Families of American and Peruvian plant species used against T. cruzi

The results on families, genera and species of American plants with emphasis on species of the flora of Peru and families listed evolutionarily, are summarized in table 1. This list includes 34 families, 122 genera and 115 species, including American species in general, species reported for the flora of Peru and species of specific regional flora. In the Asteraceae family, 48 genera and 76 species with trypanocidal activity were recorded, corresponding to 29 genera and 57 species for the flora of Peru. In these 29 genera, 174 endemic species potentially useful in the treatment of T. cruzi have been reported, highlighting the genera Pentacalia (21), Verbesina (21), Baccharis (20), Vernonia (20) and Mikania (18).

In total, 112 articles published between 2010 and 2022 were reviewed. Figure 1 shows the number of scientific publications per year.

Source: Own elaboration.

Fig. 1 - Scientific articles, published between the years 2010 to 2022, on the activity of various secondary metabolites isolated from numerous plant species, against Trypanosoma cruzi. 

The families considered in the study are the following:

1. Winteraceae: One on the most primitive family among basal angiosperms. Crude extracts from stem bark of Drimys brasilienses Miers, shrub or small tree collected in Umuarama, Campos do Jordão, São Paulo (SP)-Brazil, and its main derivative, the sesquiterpene polygodial, were tested against trypomastigotes of T. cruzi, but only polygodial showed high parasite selectivity with IC₅₀ = 2.0 μg/mL.²⁷

2. Piperaceae: Among the basal angiosperm highlights the Piperaceae family. Leaves extract of Piper regnelli (Miq.) C. DC. var. pallescens (C. DC.) Yunck., collected on the campus of the State University of Maringá in Paraná-Brazil, showing that the neolignan eupomatenoid-5 exhibited activity against trypomastigotes (IC₅₀ = 40.5 μM).²⁸ Essential oil (EO) from leaves of Piper aduncum L., collected in Medicinal Plants Garden of the Universidade Federal de Lavras, Minas Gerais-Brazil, with its main constituent linalool and nerolidol, was effective against trypomastigotes (IC₅₀ = 2.8 μg/mL) and metacyclic (IC₅₀ = 12.1 μg/mL) trypomastigotes, as well as amastigotes (IC₅₀ = 9 μg/mL), during 24 h.² Likewise, stem extracts (IC₅₀ = 50 μg/mL) from adult plants of Piper solmsianum C. DC., collected in the Núcleo de Picinguaba, Ubatuba, SP-Brazil, showed inhibitory activity against epimastigotes and 6-8 monts-old in vitro plants (IC₅₀ = 50 μg/mL) and grandisin (IC₅₀ = 25 μg/mL) against trypomastigotes.¹²

3. In leaves extract from Piper malacophyllum (C. Presl.) C. DC., collected in Parque Estadual Intervales (Sisbio 15780-2), SP-Brazil, were isolated one alkenylphenol, gibbilimbol B, showing activity against trypomastigotes with IC₅₀ = 17 µg/mL.²⁹ Others lignans such as the dibenzylbutyrolactone (-)-cubebin and (-)-hinokinin showed a significant parasitemia reduction in animals treated with oral administration of these compounds.³⁰⁾ Likewise, a new furofuran lignan, (1S,3aS,4S,6aS)-1-(3',4'-dimethoxyphenyl)-4-3'',4''methylendioxyphenyl) hexahydrofuro[3,4-c] furan, isolated from leaves of Piper jericoense Trel. & Yunck., collected in Puerto Triunfo, Antioquia, Colombia, were active against epimastigotes, amastigotes and trypomastigotes.³¹

4. Aristolochiaceae: In leaves extract from Aristolochia cymbifera Mart. & Zucc., collected from The Instituto Plantarum de Estudos da Flora, SP-Brazil, the dibenzylbutyrolactone lignan Kusunokinin with significant activity against amastigotes (IC₅₀ = 17 µM) and trypomastigotes (IC₅₀ = 51 µM), and copalic acid (ENT labdane diterpene) (IC₅₀ = 39.5 µM), were the most active compounds.³²

5. Annonaceae: In the volatile oil extracted from leaves of Annona crassiflora Mart., collected in Horto Florestal Andrade Silva in Avaré, SP-Brazil, with the major constituents α-amorphene (43.6%) and E-caryophyllene (17.7%), showed the highest activity against trypomastigotes (IC₅₀ = 5.31 μg/mL), nine folds higher than benznidazoles and more active than those of the other Annona species.³³ In the EO of the leaves from Annona coriacea Mart., collected in the Estação Ecológica of the Instituto Florestal of SP, at Águas de Santa Bárbara, Brazil, bicyclogermacrene was its major compound (39.8%), showing activity against trypomastigotes.³⁴

6. Lauraceae: Neolignans licarin A isolated from the green fruits of Nectandra glabrescens Benth., and burchellin isolated from Ocotea cymbarum Kunth, collected in northeastern Brazil (Belém-Pará), were tested against epimastigotes, showing growth inhibition in 45% with licarin A and 20% with burchellin with an IC₅₀/96 h of 462.7 and 756 μM, respectively.³⁵

7. In leaves of Nectandra oppositifolia Nees & Mart., collected in Artur Nogueira city, SP-Brazil, licarin A was isolated and displayed activity against trypomastigotes, where the derivative of licarin A, 2-allyl, showed the highest activity against trypomastigotes (IC₅₀ = 5.0 μM) and the heterocyclic derivative displayed IC₅₀ = 0.5 μM. Others different simplified structures of licarin A as vanillin and its acetyl derivative displayed activity against amastigotes (IC₅₀ = 5.5 and 5.6 μM, respectively).³⁶ In another study conducted on leaves extract from N. oppositifolia, collected at Artur Nogueira city, SP-Brazil, the flavonoids kaempferol, and kaempferol-3-O-α-(3,4-di-E-p-coumaroyl)-rhamnopyranoside were effective against trypomastigotes with IC₅₀ = 32.0 and 6.7 μM, respectively.³⁷ In leaves and twigs extracts from N. oppositifolia, ethyl protocatechuate (IC₅₀ = 18.1 μM), and its respective n-propyl, n-butyl, n-pentyl, and n-hexyl esters exhibited IC₅₀ values (20.4 to 11.7 μM) against amastigotes.³⁸ In n-hexane leaves extract from Nectandra leucantha Nees & Mart., a tree native to the tropical Atlantic Forest area of Cubatão city, SP-Brazil, four related neolignans showed trypanocidal activity (IC₅₀ = 15.2-86.5 μM),³⁹ as well as its dehydrodieugenol derivatives.⁴⁰ In Nectandra megapotamica (Spreng.) Mez, leaves extract the compound machilin G was the most active against trypomastigotes (IC₅₀ = 2.2 μM).⁴¹

8. In Aniba Amazonian species, Aniba panurensis (Meisn.) Mez, A. parviflora (Meisn.) Mez and A. rosaedora Ducke were isolated and identified three styrylpyrones, a pyridine alkaloid and two kavalactones; however, only A. panurensis extracts showed in vitro activities against T. cruzi. ⁴²

9. Calophyllaceae: Mammea A/BA (93.6%) and the mixture of coumarins (mammea A/BA + A/BB + A/BD) (86:10:1%), isolated from Calophyllum brasiliense Cambess, collected in Tropical Rain Forest, Tathuicapan de Juárez, Veracruz-Mexico, showed high trypanocidal activity than the current drug benznidazole of three Mexican strains of T. cruzi.⁴³ Likewise, Mammea A/BA showed LC₅₀ = 85.8 and 36.9 μM for epimastigotes and trypomastigotes, respectively, inducing apoptotic cell death of T. cruzi.⁴⁴ Mammea A/AA was obtained from the fruit peels of Mammea Americana,⁴⁵ commonly known as “mamey”, an edible fruit with a very pleasant taste and smell.

10. Salicaceae: In leaves extract from Casearia sylvestris Sw., collected from Atlantic Forest area in SP-Brazil, four active clerodane diterpenes (casearins A, B, G, and J) were isolated, observing activity against trypamastigotes (IC₅₀ = 0.53 to 2.77 µg/mL).⁴⁶ The sesquiterpene (-)- T-Cadinol, isolated from leaves extract showed activity against trypomastigotes and amastigotes with IC₅₀ = 18 and 15 µM, respectively.⁴⁷

11. Euphorbiaceae: Aqueous extract obtained from the roots of Croton heliotropiifolius Kunth was evaluated for its in vitro antiparasitic activity against T. cruzi showing a weak antiparasitic effect.⁴⁸

12. Vochysiaceae: Fractions from the leaves extract of Qualea grandiflora Mart., collected in the Brazilian Cerrado, were evaluated against T. cruzi observing that three fractions had a moderate activity (>100 μg/mL).⁴⁹

13. Myrtaceae: Fruits extracts of Eugenia uniflora L., collected in the municipality of Crato, Ceará-Brazil, showed anti-T. cruzi activity against epimastigotes (IC₅₀ = 62.76 mg/mL).⁵⁰

14. Sapindaceae: Chromatographical fractions from dried fruit resin and also pure compounds of Sapindus Saponaria, collected in Medellin-Colombia, were evaluated against T. cruzi, observing that caused low viability on amastigotes (1A: 6.21% and 2A: 9.86%).⁵¹

15. Rutaceae: Leaves extracts of Zanthoxyllum chiloperone var. angustifolium Engl., collected in Pirebebuy, Cordillera, Paraguay, were evaluated against trypomastigotes and amastigotes, observing that canthin-6-one and 5-methoxy-canthin-6-one, showed activity against trypomastigotes and amastigotes (IC₅₀ = 15.1 μM).⁵²

16. Malvaceae: In stem barks of Luehea ochrophylla Mart., native to Central and South American, it was observed that HEX, DCM and EtOH extracts and fractions exhibited activity against amastigotes and trypomastigotes, with IC₅₀ = 30.0, 25.6 and 28.1 µg/mL, respectively, and the isolated compounds were friedelin, β-friedelinol, lupeol, and others.⁵³

17. Solanaceae: The antiprotozoal activity of the terpenes dehydroabietic acid, dehyroabietinol, oleanolic acid and 34 synthetic derivatives, isolated from the aerial parts of Fabiana imbricata Ruiz & Pav., native to dry mountain slopes in Chile and Argentina, were evaluated against epimastigotes noting that the activity of the compounds was moderate (IC₅₀ = 43 to > 256 μg/mL).⁵⁴

18. Verbenaceae: Aerial parts of five species of Lippia, L. alba (Mill.) N.E.Br. ex Britton & P. Wilson, L. citriodora (L'Hér.) Kuntze, L. micromera Schauer., L. origanoides Kunth and L. dulcis Trev., collected in different places of Colombia as Armenia, Boyacá, Bucaramanga, and others places, were tested against T. cruzi, observing that EO of L. alba exhibited the highest activity against epimastigotes (IC₅₀ = 5.5 μg/mL) and amastigotes (12.2 μg/mL), while thymol (IC₅₀ = 3.2 μg/mL) and S-carvone (IC₅₀ = 6.1 μg/mL) were active on amastigotes.⁵⁵⁾ EO with monoterpenes and sesquiterpenes of L. sidoides Cham. and L. origanoides, were the most potent trypanocidal activity against trypomastigotes and amastigotes, respectively.⁵⁶ Likewise, EO of L. sidoides and L. origanoides, collected from Medicinal and Aromatic Plants of the Federal University of Piaui, Teresina-Brazil, showed that, in epimastigotes and trypomastigotes, induced a significant reduction in the percentage of macrophages infected.⁵⁷

19. Lamiaceae: Essential oils of Rhaphiodon echinus (Nees & Mart.) Schauer., no was active against the epimastigotes.⁵⁸

20. Asteraceae: This family is rich in species used in the treatment of T. cruzi, having initially reported 222 genera with 14 endemics for the flora of Peru, as well as 1,432 species with 729 endemics.¹⁵ To this was added later 230 new species in 29 new genera and others already reported.¹⁶⁾

In aerial parts from Achillea ptarmica L., collected from the Institute of Pharmaceutical Biology and Phytochemistry, Münster-Germany, the isolated alkamides, pellitorine and 8,9-Z-dehydropellitorine, showed activity against amastigotes.⁵⁹ Twenty-seven species of Asteraceae, collected in several countries, showed activity, and between these species, deoxymikanolide isolated from Mikania micrantha Kunth, and (+)-15-hydroxy-labd-7-en-17-al isolated from Aristiguietia glutinosa (Lam.) R.M. King & H. Rob. showed in vivo activity against T. cruzi.⁶⁰

In aerial parts of Stevia satureiifolia (Lam.) Sch. Bip. ex Klotzsch, collected in province of Entre Ríos-Argentina, the flavonoids eupatorine and 5-desmethylsinensetin showed activity against epimastigotes and trypomastigotes with IC₅₀ = 0.2 and 0.4 µg/mL, and 61.8 and 75.1 µg/mL, respectively.⁶¹ The sesquiterpene lactones eupatoriopicrin, estafietin, eupahakonenin B and minimolide, isolated from Argentinean Asteraceae species, Stevia maimarensis (Hieron.) Cabrera, S. alpina Griseb., S. gilliesii Hook. & Arn. and Mikania minima (Baker) B.L. Rob., respectively, were active against epimastigotes, resulting eupatoriopicrin the most active compound (IC₅₀ = 2.3 µg/mL).⁶² The action mode of the sesquiterpene lactones eupatoriopicrin and estafietin, isolated from S. alpina and S. maimarensis, respectively, it can be considered a promising alternative for the treatment of Chagas’ disease.⁶³ In addition, four sesquiterpenes lactones derivatives synthesized from estafietin, isolated from S. alpina, showed activity againstT. cruzi, and epoxyestafietin was the most active compound against trypomastigotes (IC₅₀ = 18.7 µg/mL) and amastigotes (IC₅₀=2.0 µg/mL).⁶⁴ Grandiflorenic acid, one of the main kaurene diterpenes, isolated from different parts of Sphagneticola trilobata (L.) Pruski, affected the viability of T. cruzi with IC₅₀ = 24.6 nM.⁶⁵

The sesquiterpenes lactones, cynaropicrin and psilostachyin A, isolated from Cynara scolymus L. and Ambrosia tenuifolia Spreng., respectively, showed activity against trypomastigotes and amastigotes.⁶⁶ In A. tenuifolia was also studied the activity of psilostachyins (psilostachyins A and C) as trypanocidal compounds.⁶⁷ In Tessaria absinthioides (Hook. & Arn.) DC and Flourensia oolepis S.F. Blake derivatives compounds obtained from tessaric acid and ilicic acid were the most active against T. cruzi with IC₅₀ = 9.3 and 8.8 µM, respectively.⁶⁸ The extract from aerial parts of Ageratum fastigiatum (Gardner) R.M. King & H. Rob. showed activity against T. cruzi, while the phytochemical screening revealed the presence of coumarins (ayapin), terpenes/sterols, and flavonoids.⁶⁹ In Parthenium hysterophorus L., Decachaeta incompta (DC.) R.M. King & H. Rob. and Vernonia liatroides DC., the sesquiterpenes lactone ambrosin was most effective (IC₅₀ = 67.1 µM) than incomptine B (IC₅₀ = 123.7 µM) and glaucolide E (IC₅₀ = 215.1 µM) and all of these were more potent than the drugs benznidazole and nifurtimox.⁷⁰

Several species of the Baccharis genus have been evaluated for their trypanocidal potential. The flavonoids naringenin and sakuranetin isolated from the dried leaves of B. retusa DC., collected from Campos do Jordão, SP-Brazil, showed activity against trypomastigotes (IC₅₀ = 20.17 µg/mL).⁷¹ In previous studies this species showed potential activity against trypomastigotes (IC₅₀ = 20.39 µg/mL).⁷² In new studies conducted on extract from the aerial parts of B. retusa, also collected from Campos do Jordão, were isolated and characterized three actives related diterpenes: ent-15β-senecioyl-oxy-kaur-16-en-19-oic (1), ent-kaur-16-en-19-oic (2) and ent-16-oxo-17-nor-kauran-19-oic (3) acids, compounds that were effective against trypomastigotes with IC₅₀=3.8 (1), 75.3 (2) and 44.2 µM (3), respectively.⁷³⁾ In extract of the aerial parts of B. uncinella DC., collected from Campos do Jordão, were identified the cinnamic acid derivatives [caffeic acid (1)] and two flavones [(hispidulin (3) and pectolinaringenin (4)] and a mixture of three chlorogenic acids (5), observing that compounds 4, 3 and 1 showed the highest activity against trypomastigotes (IC₅₀ = 52, 81 and 56 µg/mL, respectively), while compound 5 showed IC₅₀ = 61 µg/mL.⁷⁴ In oils of inflorescence of B. spicata (Lam.) Baill. and B. punctulata DC., β-Pinene, limone, and spathulenol oxide were detected in both species, but only (-)-alismol in B. punctulata, inhibits the growth of epimastigotes (IC₅₀ between 2.15 and 12.49 µg/mL).⁷⁵ Likewise, in extract from aerial parts of B. sphenophylla Dusén ex Malme, three diterpenes were evaluated, observing that ent-kaurenoic and 15β -tiglinoyloxy-ent-kaurenoic acids showed activity against trypomastigotes.⁷⁶ In this same species, the extract from aerial parts displayed activity against amastigotes, where the compounds 7α-hydroxy-ent-abieta-8(14),13(15)-dien-16,12β-olide and hexacosyl p-coumarate showed effectiveness with IC₅₀ = 21.3 and 16.9 µM, respectively.⁷⁷

Parthenoloide, isolated from leaves of Tanacetum vulgare L., collected in Irenice Silva Medicinal Plants Garden of the University of Maringá, Brazil, and evaluated for the synergistic effects with benznidazole against epimastigotes and trypomastigotes, showed a strong activity with IC₅₀ = 1.6 to 0.07 µg/mL, reducing 23-fold the concentration of benznidazole.⁷⁸ In aerial parts of T. parthenium (L.) Sch.Bip., collected from Laboratório Botânico Flores & Ervas, Piracicaba, SP-Brazil, guaianolide was effective against epimastigotes (IC₅₀ = 18.1 µM) and amastigotes (IC₅₀ = 66.6 µM) of T. cruzi. ⁽⁷⁹ Alcoholic leaves extract of Castanedia santamartensis R.M. King & H. Rob. displayed activity against T. cruzi, with kaurenoic acid as the major component.⁸⁰ Extracts from Helichrysum italicum (Roth) G. Don and Crithmum maritimum L. (Apiaceae), were evaluated against amastigotes observing that the extract (falcarindiol, as one major compound) and the fraction 1 from flowers of C. maritimum were the most active (EC₅₀ = 0.47 µg/mL).⁸¹

In extract leaves from Calea uniflora Less., collected from Imbituba, Santa Catarina-Brazil, ethyl caffeate and the mixture of butein and orobol demonstrated trypanocidal effect against amastigotes with IC₅₀ = 18.27 and 26.53 µM, respectively.⁸² Likewise, were also identified and evaluated four germacranolide-type sesquiterpene lactones; nevertheless, none of the isolated compounds showed trypanocidal effect.⁸³ In extract leaves of C. pinnatifida (R. Br.) Less., collected in “Costa da Lagoa”, Florianópolis-Brazil, a new furanoheliangolide sesquiterpene lactone named 11,13-dihydroxy-calaxin showing activity against trypomastigotes (IC₅₀ = 5.27 µM).⁸⁴ Dewaxed extract of Urolepis hecatantha (DC.) R.M. King & H. Rob. showed activity against epimastigotes (IC₅₀ = 7 µg/mL) and the sesquiterpene lactones eucannabinolide and santhemoidin C were active on T. cruzi.⁸⁵

Other Asteraceae species of the genera Gochnatia, Vernonia, Pentacalia, Aldama and Mikania have also shown trypanocidal potential. Extract, fractions, and compounds of Gochnatia pulchra Cabrera, an Asteraceae present from Mexico to Argentina, showed moderate activity against promastigotes of L. amazonensis, specifically apigenin;⁸⁶ therefore, this species is potentially useful against T. cruzi. The natural product lupeol, ten lupeol derivatives 2-11 and five new esters derivatives 7-11, isolated from aerial parts (leaves and flowers) of Vernonia scorpioides (Lam.) Pers., showed activity against T. cruzi, especially the derivative 6 (IC₅₀=12.48 µg/mL).⁸⁷ EO from leaves, flowers and roots of V. brasiliana (L.) Druce, collected in Monte Alegre de Minas, Minas Gerais-Brazil, showed activity against T. cruzi with IC₅₀=72, 88 and 70 µg/mL, respectively.⁸⁸ Fourteen plant extracts and seventeen sesquiterpene lactones from the South American tribe Vernonieae (Asteraceae) were evaluated against T. cruzi, observing the best results with leaves and flowers rinse extracts from Vernonanthura nebularum Cabrera (H. Rob.) and Elephantopus mollis Kunth (IC₅₀ values < 2 µg/mL).⁸⁹

The bioactive compound, jacaranone, isolated from the leaves of Pentacalia desiderabilis (Vell.) Cuatrec., collected in Campos do Jordão, SP-Brazil, showed activity against trypomastigotes (IC₅₀ = 13.0 µg/mL).⁹⁰ The ent-3-α-hydroxy-kaur-16-en-18-ol, three new diterpenes, namely, ent-7-oxo-pimara-8,15-diene-18-ol, ent-2S,4S-2-19-epoxy-pimara-8(3),15-diene-7β-ol and ent-7-oxo-pimara-8,15-diene-3β-ol, and sesquiterpene lactones budlein A, isolated from leaves extract of Aldama discolor (Baker) E.E. Schill. & Panero, endemic from the Brazilian “Cerrado” (Sacramento, Minas Gerais-Brazil), showed in vitro activity against amastigotes.⁹¹ In Artemisia copa Phil. were observed and identified several phenolic acids and flavonoids with activity against T. cruzi (LD₅₀ = 131.8 µg/mL).⁹² In leaves extract from Inula viscosa [Dittrichia viscosa (L.) Greuther] the sesquiterpene lactones 8-epi-xanthatin-1β,5β-epoxide and inuloxin A (IC₅₀ values between 4.99 and 14.26 µM) showed more activity against epimastigotes.⁹³

The organic and aqueous extracts of aerial parts from four Argentinean Mikania species, M. micrantha Kunth, M. parodii Cabrera, M. periplocifolia Hook. & Arn. and M. cordifolia (L. f.) Willd., collected in Entre Ríos-Argentina, showed activity against epimastigotes at 10 µg/mL ⁽⁹⁴ In species of this same genus, three sesquiterpene lactones, mikanolide, deoxymikanolide and dihydromikanolide, isolated of M. variifolia Hieron and M. micrantha, collected in Entre Rios and Tucumán-Argentina, respectively, were active against epimastigotes (IC₅₀ = 0.7, 0.08 and 2.5 µg/mL, respectively), trypomastigotes (IC₅₀ = 2.1, 1.5 and 0.3 µg/mL, respectively) and amastigotes (IC₅₀ = 4.5, 6.3 and 8.5 𝜇g/mL, respectively).⁹⁵ Likewise, in these species, collected in Entre Rios and Tucumán-Argentina, respectively, deoxymikanolide was evaluated for its in vitro activity on epimastigotes and in vivo activity on an infected mouse model, observing a depolarization of the mitochondrial membrane.⁹⁶ In Helianthus tuberosus L. the novel sesquiterpene lactone furanoheliangolide showed a much lower level of bioactivity against T. cruzi. ⁽⁹⁷

Ambrosia is another important genus of the Asteraceae family with several species with trypanocidal potential, which in the last 15 years has been exhaustively studied by Dr. VP Sülsen's group in Argentina. Psilostachyin, a natural sesquiterpene lactone, isolated from A. tenuifolia Spreng., was evaluated on the growth, proliferation and viability of epimastigotes, observing that the effect on parasite growth was irreversible (> 1.0 µg/mL concentration).⁹⁸ Psilostachyin C, isolated from A. scabra Hook. & Arn., was in vitro evaluated against epimastogotes, trypomastigotes and amastigotes, observing an IC₅₀=0.6, 3.5 and 0.9 μg/mL, respectively, and in in vivo assay, also exerted an inhibitory effect against T. cruzi with significative reduction of parasitemia.⁹⁹ In A. elatior L. only the sesquiterpene lactone cumanin and in A. scabra the sesquiterpene lactones, cumanin and cordilin were active against epimastigotes and trypomastigotes with IC₅₀ = 12 and 26 µM, respectively.¹⁰⁰ Both species, A. elatior and A. scabra were collected in Buenos Aires-Argentina. Psilostachyin and psilostachyin C, isolated from A. tenuifolia and A. scabra, respectively, were evaluated for their interaction with hemin, observing that both sesquiterpene lactones induced parasite death by apoptosis, and the increase in the generation of reactive oxygen species (ROS) in epimastigotes.¹⁰¹

In Smallanthus sonchifolius (Poepp.) H. Rob., native from the Andean of South America, collected in Tucuman-Argentina, the germacranolide-type sesquiterpene lactones, enhydrin (1), uvedalin (2), and polymatin B (3), showed activity against epimastigotes with IC₅₀ = 0.84, 1.09, and 4.90 𝜇M, respectively, and the compounds 1 and 2 showed IC₅₀=33.4 and 25.0𝜇M, respectively, against trypomastigotes.⁶⁾ These same compounds, isolated from S. sonchifolius, collected in the Centro Universitario “Horco Molle”, University of Tucumán-Argentina, were also evaluated on T. cruzi, observing that the three compounds exhibited activity on epimastigotes (IC₅₀ = 0.35-0.60 µg/mL).¹⁰² An inseparable mixture of two new trixikingolides from Trixis vauthieri DC. showed activity (IC₅₀ = 0.053 µM) against trypomastigotes and amastigotes, 70 times more potent than benznidazole.¹⁰³

Extract of aerial parts of Aristeguietia glutinosa, collected in “Pangor” plateau, Quito-Ecuador, showed activity against epimastigotes (IC₅₀ = 19.6 µg/mL) while los diterpenoids, (+)-15-hydroxy-labd-7-en-17-al (1) and (+)-13,14,15,16-tetranor-labd-7-en-17,12-olide (2), were more active with IC₅₀=3.0 and 15.6 µg/mL, respectively.¹⁰⁴ Likewise, showed activity against trypomastigotes and the secondary metabolites 1 and 2 were the most active components with 91±4% and 54±7% of lysis, respectively.¹⁰⁵ EO from Phania matricarioides (Spreng.) Griseb., with lavandulyl acetate (40.1%) as the major component, displayed activity against T. cruzi (IC₅₀=2.2 µg/mL).¹⁰⁶

On the other hand, thirty-six terpenes were isolated from Asteraceae plants from arid lands and evaluated against T. cruzi showing a sensitivity of 33% of active compounds.¹⁰⁷⁾ Likewise, extracts from 13 Argentinean Asteraceae species were evaluated against epimastigotes, showing that DCM extracts of Aspilia silphioides (Hook. & Arn.) Benth. & Hook. f., Viguiera tuberosa Griseb., Verbesina subcordata DC., Gimnocoronis spilanthoides (D. Don ex Hook. & Arn.) DC., Gaillardia megapotamica (Spreng.) Baker, Thelesperma megapotamicum (Spreng.) Herter and Zexmenia buphtalmiflora (Lorentz) Arisa showed trypanocidal activity (inhibitions higher than 60% at 10 µg/mL), and the MeOH extracts of Helenium radiatum (Less.) Seckt. and G. megapotamica (inhibitions of 70.1 and 77.7%, respectively, at 10 µg/mL).¹⁰⁸

Table 1 - List of American families and species, including Peruvian species and species of regional floras, used in tests on trypanocidal activity, emphasizing the genera of Peruvian species 

N. ^o	Peruvian families	American Species Tested	Genera of Peruvian Species
1	Winteraceae [1] 1	Drimys brasilienses	Drimys 1
2	Piperaceae [3] 811(528)	Peperomia pseudopereskiifolia, Piper aduncum, P. jacquemontianum, P. jericoense, P. lacunosum, P. malacophyllum, P. regnellii var. pallescens, P. solmsianum, P. tecnoiifolium, P. tuberculatum	Peperomia (381/226) Piper (429/302)
3	Aristolochiaceae [1] 40(16)	Aristolochia cymbifera	Aristolochia (40/16)
4	Annonaceae [23] 193(41)	Annona crassiflora, A. coriaceae	Annona (19/4)
5	Siparunaceae (= Monimiaceae) [2] 55(14)	Siparuna sessiflora	Siparuna (40/10)
6	Lauraceae [15] 197(49)	Aniba panurensis, A. parviflora, A. rosaedera, Nectandra leucantha, N. megapotamica, N. oppositifolia, Ocotea cymbarum	Aniba 16 Nectandra (29/5) Ocotea (62/22)
7	Arecaceae [33] 145(19)	Syagrus coronata	Syagrus (2/1)
8	Poaceae [150(1)] 719(112)	Cymbopogon citratus	Cymbopogon 1
9	Berberidaceae [1] 32(18)	Berberis microphylla	Berberis (32/8)
10	Fabaceae [138(1)] 971(280)	Haematoxylum brasiletto, Vatairea macrocarpa	Vatairea 3
11	Rosaceae [24] 120(12)	Kageneckia oblonga	Kageneckia 1
12	Connaraceae [3] 17(4)	Connarus suberosus	Connarus (7/2)
13	Calophyllaceae = Clusiaceae	Calophyllum brasiliense, Mammea americana	Calophyllum 2 Mammea 1
14	Clusiaceae [21] 124(28)	Clusia studartiana, Rheedia longifolia	Clusia (40/11) Rheedia 3
15	Malpighiaceae [19] 134(26)	Malpighia glabra	Malpighia 3
16	Salicaceae [2] 4 = Flacourtiaceae [18] 63(8)	Casearia sylvestris	Casearia (19/3)
17	Euphorbiaceae [57] 305(88)	Croton heliotropiifolius	Croton (49/31)
18	Vochysiaceae [4] 31(2)	Qualea grandiflora	Qualea (9/2)
19	Myrtaceae [20] 160(52)	Blepharocalyx salicifolius, Eugenia brejoensis, E. uniflora, Psidium laruotteanum	Blepharocalyx 1 Eugenia (51/20) Psidium (8/3)
20	Melastomataceae [42] 637(230)	Monochaetum myrtoideum	Monochaetum (4/1)
21	Anacardiaceae [12] 32(6)	Schinus mole	Schinus 4
22	Rutaceae [25(1)] 67(10)	Ruta graveolens, Zanthoxylum chiloperone var. angustifolium	Ruta 2, Zanthoxylum (17/4)
23	Meliaceae [10] 69(4)	Trichilia havanensis	Trichilia (27/2)
24	Sapindaceae [20(1)] 180(43)	Sapindus saponaria	Sapindus 1
25	Malvaceae [35] 256(82)	Luehea ochrophylla	-
26	Primulaceae [4] (Myrsinaceae) [9] 72(23)	Myrsine guianensis	Myrsine (22/13)
27	Clethraceae	Clethra fimbriata	Clethra (11/3)
28	Boraginaceae [16] 131(36)	Bourreria huanita	-
29	Solanaceae [42] 538(162)	Acnistus arborescens, Aureliana fasciculata var. fasciculata, Fabiana imbricata	Acnistus 1 Fabiana 1
30	Bignoniaceae [47] 166(13)	Crescentia cujete, Handroanthus impetiginosus	Crescentia 2 Handroanthus 12
31	Lamiaceae [20] 190(71)	Hyptis pectinata, Hypenia salzmanni, Marrubium vulgare, Rhaphiodon echinus	Hyptis (27/2) Marrubium 1
32	Verbenaceae [23] 200(44)	Lippia alba, L. citriodora L. dulcis, L. macrophylla, L. micromera, L. origanoides, L. sidoides	Lippia (12/4)
33	Asteraceae [222(14)] 1432(729)	Achillea ptarmica Acmellea bellidioides Ageratina vacciniaefolia Ageratum conyzoides A. fastigiatum Aldama discolor (syn. Viguiera discolor) Ambrosia elatior A. scabra A. tenuifolia Anacyclus pyrethrum Anthemis nobilis A. auriculata Aristeguietia glutinosa Artemisia annua A. campestris A. copa A. herba-alba Aspilia silphioides Baccharis dracunculifolia B. punctulata B. retusa B. sphenophylla, B. spicata B. uncinella Calea pinnatifida C. uniflora Calyptocarpus biaristatus Castanedia santamarcensis Cynara scolymus Decachaeta incompta, Elephantopus mollis, Flourensia oolepis Gaillardia megapotamica, Gochnatia pulcra Gymnocoronis spilanthoides Helenium radiatum Helianthus tuberosus Helichrysum italicum Hyalis argentea Inula viscosa Mikania braziliensis M. micrantha M. parodii M. periplocifolia M. variifolia Parthenium hysterophorus, Pentacalia desiderabilis Phania matricarioides Pluchea carolinensis Podanthus ovatifolius Porophyllum ruderale Smallanthus sonchifolius Sphagneticola trilobata Stevia alpina S. gilliesii S. maimarensis S. satureifolia S. satureiifolia var. satureiifolia Tanacetum vulgare T. parthenium T. sombolii Tessaria absinthioides Thelesperma megapotamicum Tithonia diversifolia Trixis vauthieri Urolepis hecatantha Verbesina subcordata Vernonanthura nebularum Vernonia brasiliana V. liatroides V. plantaginoides V. polyanthes V. scorpioides Viguiera anchusaefolia V. tuberosa Zexmenia buphtalmiflora	Achillea 1 Ageratina (40/24) Ageratum 2 Ambrosia (6/2) Aristeguieta (11/9) Artemisia 2 Baccharis (70/20) Calea (6/1) Elephantopus 2 Flourensia (5/5) Gochnatia (4/3), Gymnocoronis 1, Helenium 1 Helianthus 1 Helichrysum 1 Mikania (82/18) Pentacalia (30/21) Pluchea (4/2) Porophyllum (1) Schkuhria (2) Smallanthus (7/1) Stevia (24/15) Tanacetum 3 Tessaria 1 Trixis 6(2) Verbesina 41(21) Vernonia (39/20) Viguiera 37(10)
34	Apiaceae [29(1)] 88(26)	Crithmum maritimum	-

Legend: [X(X)]; X(X) = [Number of genera (Endemic genera)] Number of species (Endemic species); Genus (X/X) = Genus (Number of species/Endemic species). The underlined genera are American, but have not been reported for the flora of Peru.

Source: Taken from Brako & Zarucchi.¹⁵

Trypanocidal activity of regional flora species

Plant species evaluations have also been carried out in regional floras of Central and South American, El Salvador, Colombia, Brazilian Cerrado and Brazilian Caatinga, Chile and Mexico, being distributed in very specific ecological environments. These species belonged to the families Boraginaceae (1), Melastomataceae (1) and Solanaceae (1), from Central and South American region.¹⁰⁹ Meliaceae (1) and Piperaceae (3) from Salvadoran flora.¹¹⁰ Bignoniaceae (1), Clusiaceae (2), Malpighiaceae (1), Piperaceae (2) and Solanaceae (1), from Brazilian biodiversity.¹¹¹ Connaraceae (1), Fabaceae (1), Myrtaceae (2) and Primulaceae (1), from Brazilian Cerrado.¹¹² Asteraceae (1), Clethraceae (1) and Siparunaceae (1), from Colombian flora.¹¹³ Asteraceae (1), Bignoniaceae (1) and Rutaceae (1), from Minas Gerais.¹¹⁴ Asteraceae (1), Berberidaceae (1), Rosaceae (1) and Winteraceae (1), from Central Chile (Maule Region).¹¹⁵ Anacardiaceae (1), Fabaceae (1), Lamiaceae (1) and Poaceae (1), from Nuevo León-Mexico.¹¹⁶ Likewise, Arecaceae (1), Lamiaceae (2), Myrtaceae (1) y Verbenaceae (1), from Brazilian Caatinga.¹¹⁷

Figures 2 and 3 shows the percentage of number of species per family, and number of genera and species among the most representative families, respectively, in 34 families of phanerogams and families of regional floras, tested against T. cruzi.

Source: Own elaboration.

Fig. 2 - Percentage of number of species per family in 34 families of American phanerogams, including Peruvian species, indicated in table 1 and supplemented with species from regional floras, tested against T. cruzi., other families 23. 

Source: Own elaboration.

Fig. 3 - Number of genera and species in 34 families of American phanerogams, including Peruvian species, indicated in table 1 and supplemented with species from regional floras, tested against T. cruzi. 

Peruvian plants species

A recent report on Biodiversity in Peru revealed that the vascular flora in Peru is made up of 19,147 species, of which 7,590 are endemic.¹¹⁸ On this significant number of plant species, although there are some important ethnobotanical studies in traditional medicine,^119,120 there are few studies that relate them to phytochemistry and biological activity. The coronavirus pandemic, however, has sparked interest in using Peruvian plant species in the home treatment of this disease ^121,122,123

There is a very significant number of families, genera and species reported for the Flora of Peru (table 1) used in other countries, in the treatment of trypanosomiasis. This is the case of the Piperaceae family with 381 species of Peperomia and 429 species of Piper and a high degree of endemism (226 and 302 species, respectively). Another notable example corresponds to the families Annonaceae (Annona with 19 species), Siparunaceae (Siparuna with 40 species) and Lauraceae (Nectandra and Ocotea with 29 and 62 species, respectively). However, the Asteraceae family with 82, 70 and 41, species of the Mikania, Baccharis and Verbesina genera, respectively, are the ones that exhibit the greatest potential. In recent years, 230 new species of Asteraceae have been added to the flora of Peru, as well as 29 new genera.¹⁶

A special mention corresponds to the species Sapindus saponaria, a species from the seasonally dry tropical forest of northern Peru⁵¹⁾ and Mammea americana, a delicious native fruit tree, also from the north coast of Peru,^43,44 have been shown to have an important source of secondary metabolites in the treatment of trypanosomiasis.

For all this, the plant species that constitute the Flora of Peru is an unlimited source of secondary metabolites, potentially useful in the treatment of trypanosomiasis in Peru, America and the world.

Conclusions

The growing resistance of pathogens to conventional drugs, the side effects of these drugs in long-term treatments and the effect of Climate Change, which can induce mutations that increase the aggressiveness of pathogens, lead to exploring other sources of drugs. A primary source of these drugs are extracts obtained from plants. As mentioned in this study, extracts and isolated compounds from numerous genera and species of the Asteraceae family have shown promise in the treatment of Chagas disease. These compounds were mostly isolated from essential oils and belong to the group of sequiterpene lactones. In this scenario, the plant species of the Peruvian flora, especially those that make up the Asteraceae family, constitute a promising research source available to national and foreign researchers.

Acknowledgments

The authors thank Alain Monsalve for the English corrections and Jorge Fupuy and Pilar Bazán for the elaboration of the figures.

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Received: December 13, 2022; Accepted: November 10, 2023

^*Corresponding autor: [e-mail]

The authors declare that there is no conflict of interest.