Plants from South America: A Systematic Review of Their Antiplasmodial and Antimalarial Activities Based on Ethnopharmacological Use

Isabela Penna Ceravolo; Rita de Cássia Cardoso Arcas; Antoniana Ursine Krettli

doi:10.37871/jbres1972

ISSN: 2766-2276

Medicine Group. 2024 August 10;5(8):921-948. doi: 10.37871/jbres1972.

Subject area(s)

Pharmacology

| | |

Review Article

Plants from South America: A Systematic Review of Their Antiplasmodial and Antimalarial Activities Based on Ethnopharmacological Use

Isabela Penna Ceravolo^*, Rita de Cássia Cardoso Arcas^# and Antoniana Ursine Krettli^#

René Rachou Institute, FIOCRUZ-MG, Augusto de Lima Avenue 1715, Belo Horizonte, MG, 30.190-002
^#These authors are contributed equally

*Corresponding authors: Isabela Penna Ceravolo, René Rachou Institute, FIOCRUZ-MG, Augusto de Lima Avenue 1715, Belo Horizonte, MG, 30.190-002, Brazil E-mail:

Received: 29 July 2024 | Accepted: 09 August 2024 | Published: 10 August 2024

How to cite this article: Ceravolo IP, Arcas RCC, Krettli AU. Plants from South America: A Systematic Review of Their Antiplasmodial and Antimalarial Activities Based on Ethnopharmacological Use. J Biomed Res Environ Sci. 2024 Aug 10; 5(8): 921-948. doi: 10.37871/jbres1951, Article ID: jbres1757

Keywords

Malaria
Antimalarial
Ethnopharmacology
South America
Traditional knowledge
Medicinal plants

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Abstract

Malaria remains one of the most important diseases in the world, being lethal to 610 thousand individuals annually. The widespread resistance of P. falciparum to antimalarials emphasizes the urgent need for new therapies, as treatment remains the primary strategy to control the disease. Although combinations of synthetic drugs are used in treatment, medicinal plants are often utilized in folk medicine as a complement and/or alternative to treat human malaria, especially in poor endemic areas. This systematic review evaluates the antiplasmodial and/or antimalarial activities, as well as the ethnopharmacological use of plant species by traditional communities from South America, through a search in the PubMed Central and Science Direct databases. Among 346 articles selected using the keywords “Malaria”, “Plants”, “Traditional”, “Knowledge”, “Antimalarial” and “Amazon”, 27 were considered eligible. Plant species with no activities were used to a new search on Google, PubMed, and Science Direct. Of the 389 species or genera from 88 botanical families evaluated, most studies were conducted in Peru, with leaves being the primary plant part used for treatment and/or prevention. Out of the analyzed species, excluding 30 mentioned only by genus, 185 had their extracts, fractions, or pure substances assessed, and only nine species had both in vitro and in vivoactivity. Among the 174 species cited by traditional communities evaluated, with no data for activity, 66 presented results when a new literature search was performed. The Chayahuita ethnicity was the community providing more traditional knowledge about malaria treatment. Most plant species mentioned in the articles indicated for treatment and/or prevention of malaria have not yet been evaluated for antiplasmodial and antimalarial activities. Collecting ethnopharmacology information of plants is important, since their use for malaria treatment significantly increases the chances of finding a plant to be used as antimalarial substitutes.

Introduction

Malaria is a global health problem with an estimated 249 million cases in 85 endemic countries, with 610,000 deaths reported in 2022, the majority occurring in Africa among children aged under five years [1]. Different measures are essential for malaria control, but drug treatment remains the main control strategy, and the most important tool to prevent morbidity and death from the disease.

Drug chemotherapy has a strong historical link to the use of traditional plant infusions in various cultures. Research based on such knowledge has yielded the two most important drugs used in malaria treatment: the alkaloid quinine, present in the Cinchona species, and artemisinin, from Artemisia annua [2]. These discoveries were both based on traditional use and ethnomedicine [3-5]. Currently, Artemisinin-based Combination Therapies (ACTs) are recommended by the World Health Organization (WHO) as the first and second-line treatment for uncomplicated P. falciparum malaria, as well as for chloroquine-resistant P. vivax malaria [6]. However, resistance to ACT has already been described in Southeast Asia and in some regions of Africa [7]. Additionally, due to the high cost of antimalarials, especially ACTs, the poor populations in Africa continue to use herbal medicines for the treatment of malaria [8] and in countries like Brazil [9], China [10,11], India [12], and Papua [13].

According to the WHO, traditional and complementary medicine is used by at least 80% of the global population [14]. However, it is estimated that less than 10% of the approximately 250,000 plants used in folk medicine have had their pharmacological activities studied [15]. Natural substances have long served as sources of therapeutic drugs and provide important leads against various pharmacological targets [16]. About one-third of the best-selling drugs in the world are either natural products or their derivatives [17].

In Brazil, 131,224 cases of malaria were notified in 2022, with 99% of transmission occurring in the Amazon region. Of these, 15.8% were caused by P. falciparum or mixed infection, and the remaining cases attributed to P. vivax and other parasitic species [18]. Although synthetic drug combinations form the basis for malaria treatment in Brazil, in the Amazon region, where malaria is endemic, the use of medicinal plants against fever and/or malaria is common [19,20].

The search for new compounds derived from plants remains an excellent strategy for drug development. Considering that the Amazon has one of the richest and most diverse biodiversities, plus the necessity of discovering new drugs due to the reports of resistance to ACTs [21], the present study reviews the literature on antiplasmodial and antimalarial activities of plants from South America and their ethnopharmacological use for the treatment and prevention of malaria, based on a bibliographic survey using PubMed and Science Direct databases, with the aim of finding new antimalarials that could help control the emergence of drug-resistant parasites.

Materials and Methods

To conduct this study, a bibliographic survey in the PubMed and Science Direct databases was initially carried out on September 25, 2023, in the health-related databases PubMed Central® and Science Direct® using the keywords “Malaria”; “Plants”; “Traditional”; “Knowledge”; “Anti-malarial”; “Amazon”. The relevant literature was examined on the antiplasmodial and/or antimalarial activities of plants demonstrated in bioassays or reported in traditional use. No filter was applied regarding the years of publications, but all articles searched were in English.

The articles listed in the search from the two databases were obtained through a selection process, where only publications undertaken in South America were selected and considered potentially eligible. If information about the country was not included in the title, the abstracts or the full text of each article were evaluated. Articles were excluded when focused on: (i) historical aspects; (ii) qualitative studies; (iii) subjects unrelated to malaria and/or medicinal plants; (iv) citation of data from other authors as to prevent duplication of data; (v) reviews; (vi) book chapters, conference abstracts, glossaries and symposium papers; (vii) plants used as repellents or with activity against the vector; and (viii) tests conducted on exoerythrocytic forms.

The search conducted resulted in 346 articles, with 190 found in PubMed and 156 in Science Direct (Figure 1). Of the articles listed in PubMed, six were excluded because they were duplicates of those found in Science Direct. After removing the duplicates, the total was 340 articles, with 184 from PubMed and 156 from Science Direct. Of these, 168 from PubMed and 136 from Science Direct were excluded because they did not meet the minimum criteria established, resulting in 36 full text articles evaluated. However, as nine of these articles presented data from other authors, or addressed historical aspects or the vector, they were also removed.

When considering articles from both databases, a total of 27 complete articles met the established minimum requirements, and their data on antiplasmodial and antimalarial activities were annotated in a spreadsheet. The steps through which eligible articles were selected from the two databases are shown in figure 1.

From the selection of 27 eligible articles the following information was annotated for each plant: reference; link; country; scientific and popular names of the plant; botanical family; part of the plant used; whether the traditional knowledge was cited; method used to obtain data (interview or experimental); medicinal use of the plant; results of cytotoxicity in vitro and in vivo; toxicity data in vivoand whether pure substances had been isolated and tested. All the information collected were summarized and arranged in an Excel spreadsheet. The tables were organized in alphabetical order of families and species. When the same plant species was studied by more than one author, it was cited only once.

The criterion adopted to determine plant activity in vitro was based on literature articles. Only species that inhibited 50% of parasite growth (IC₅₀) at a value ≤ 10 µg/mL were considered active [22-24]. For the evaluation of in vivoactivity, the plants had to reduce parasitemia by ≥ 30% [25-35]. After surveying plant species that presented antiplasmodial and/or antimalarial activities in the eligible articles, the species with no data were used for a new search on the Google platform, PubMed and Science Direct databases using “the name of the plant species researched” and the keywords “malaria” or “Plasmodium”.

Results

In the first analysis of the eligible articles, a survey of the botanical classification, the plant parts used, their ethnomedical uses, and location/origin were carried out, as shown in table 1.

Table 1: Botanical classification, ethnomedical use, and location of plants from South America cited by the authors.
Botanic family	Plant species	Plant parts used	Traditional use	Countries	Reference
Acanthaceae	Hygrophila guianensis	Aerial parts	Others	Colombia	[41]
	Justicia appendiculata	Whole plant	Malaria	Peru	[40]
	Ruellia ruiziana	Leaves	Others	Peru	[3]
	Sanchezia oblonga	Leaves	Others	Peru	[3]
Adiantaceae	Pityrogramma calomelanos	Leaves	Others	Peru	[3]
Amaranthaceae	Alternanthera braziliana	Leaves, NS	Malaria	Peru	[38]
	Chenopodium ambrosioides	Aerial parts	Malaria	Peru	[36]
	Iresine diffusa	Whole plant	Malaria	Peru	[3] (a); [40] (b)
Amaryllidaceae	Allium sativum	Roots	Malaria	Bolivia, Peru	[37] (a); [38] (b)
Anacardiaceae	Anacardium occidentale	Bark, Leaves, NS	Malaria	Peru (2), Brazil	[38] (a); [36] (b); [47] (c)
	Campnosperma panamense	Leaves	Others	Colombia	[41]
	Mangifera indica	Bark, NS	Malaria	Brazil, Peru, Bolivia	[20] (a); [38] (b); [37] (c)
	Spondias mombin	Leaves, NS	Malaria	Peru	[38]
	Tapirira guianensis	Bark	Malaria	Bolivia	[37]
Annonaceae	Guatteria amplifolia	Aerial parts	Others	Colombia	[41]
	Rollinia mucosa	Leaves	Others	Peru	[3]
	Xylopia amazonica	Leaves, Branches	Malaria	Brazil	[47]
Apiaceae	Coriandrum sativum	NS	Malaria	Peru	[38]
	Daucus montanus	Roots	Others	Peru	[3]
	Eryngium foetidum	Whole plant, NS	Malaria	Peru (2), French Guiana	[38] (a); [39] (b); [36] (c)
Apocynaceae	Aspidosperma megalocarpon	Bark, roots, seeds	Malaria	Colombia, Bolivia	[41] (a); [37] (b)
	Aspidosperma nitidum	Wood bark, leaves, branches, NS	Malaria	Peru, Brazil	[38] (a); [27] (b)
	Aspidosperma rigidum	Bark	Malaria	Brazil	[20]
	Aspidosperma pyrifolium	Stalk, roots, Leaves	Others	Brazil	[48]
	Aspidosperma vargasii	Bark	Malaria	Brazil	[49]
	Geissospermum laeve	Inner bark	Malaria	French Guiana	[39]
	Geissospermum reticulatum	Bark	Malaria	Bolivia	[37]
	Himatanthus articulatus	Bark, Stalk	Malaria	Brazil	[50]
	Himatanthus sucuuba	Whole plant, exudate	Malaria	Peru (2), Bolivia	[36] (a); [40] (b); [37] (c )
	Tabernaemontana linkii	Bark, leaves, roots	Malaria	Bolivia	[37]
	Tabernaemontana obliqua	Leaves	Others	Colombia	[41]
	Tabernaemontana sananho	Bark	Others	Peru	[3]
Araceae	Anthurium croatii	Stalk	Others	Peru	[3]
	Anthurium dombeyanum	Whole plant	Malaria	Peru	[40]
	Anthurium ernestii	Leaves, roots	Others	Peru	[3]
	Dieffenbachia sp.	Stalk	Others	Peru	[36]
	Dieffenbachia seguine	Aerial parts	Others	Peru	[43]
	Dieffenbachia williamsii	Stalk	Others	Peru	[3]
	Dracontium spruceanum	Tuber	Others	Peru	[43]
	Homalomena picturata	Rhizome	Others	Peru	[36]
	Monstera lechleriana	Stalk	Others	Peru	[36]
	Philodendron ernestii	Stalk	Others	Peru	[3]
	Philodendron plowmanii	Whole plant	Malaria	Peru	[40]
	Xanthosoma poeppigii	Stalk	Others	Peru	[36]
	Xanthosoma sagittifolium	Tuber	Others	Peru	[36]
Arecaceae	Cocos nucifera	Fruit water, NS	Malaria	Peru (2)	[38] (a); [36] (b)
	Desmoncus mitis	Leaves	Fever	Peru	[36]
	Euterpe oleraceae	Roots, pulp	Malaria	Brazil (2), French Guiana	[20] (a); [39] (b); [51] (c)
	Euterpe precatoria	Roots	Malaria	Peru	[38]
	Iriartea deltoidea	Whole plant	Malaria	Peru (2)	[43] (a); [40] (b)
	Oenocarpus bataua	NS	Malaria	Peru	[38]
	Socratea exorrhiza	Roots	Others	Peru	[36]
Aristolochiaceae	Aristolochia stahelii	Stalk	Malaria	French Guiana	[39]
	Aristolochia trilobata	Leaves	Malaria	French Guiana	[39]
Aspleniaceae	Asplenium spp.	Whole plant	Malaria	Peru	[40]
Asteraceae	Artemisia spp.	Leaves	Malaria	French Guiana	[39]
	Ayapana lanceolata	Leaves	Malaria	Peru	[38]
	Ayapana triplinervis	Aerial parts, leaves	Malaria	French Guiana, Peru	[39] (a); [36] (b)
	Bidens spp.	Whole plant	Malaria	Peru	[40]
	Bidens cynapiifolia	Leaves	Others	Peru	[36]
	Calea montana	Leaves	Others	Peru	[3]
	Chaptalia nutans	Whole plant	Malaria	Peru	[40]
	Clibadium sylvestre	Whole plant	Malaria	Peru	[40]
	Elephantopus mollis	Leaves	Fever	Peru	[36]
	Gymnanthemum amygdalinum	Leaves	Malaria	Brazil, French Guiana	[20] (a); [39] (b)
	Hebeclinum macrophyllum	Whole plant	Malaria	Peru	[40]
	Mikania guaco	Leaves	Malaria	French Guiana	[39]
	Munnozia hastifolia	Whole plant	Malaria	Peru (2)	[3] (a); [40] (b)
	Tagetes erecta	Whole plant	Malaria	Peru (3)	[38] (a); [36] (b); [40] (c)
	Tessaria integrifolia	Leaves	Fever	Peru	[43]
	Trixis divaricata	Whole plant	Malaria	Peru	[40]
	Vernonanthura patens	Leaves	Others	Peru	[3]
Begoniaceae	Begonia glabra	Leaves	Others	Peru	[3]
	Begonia parviflora	Leaves	Malaria	Peru	[3]
Bignoniaceae	Arrabidaea platyphylla	Roots	Malaria	Bolivia	[37]
	Ceratophytum tetragonolobum	Whole plant	Malaria	Bolivia	[37]
	Crescentia cujete	Leaves	Malaria	Peru	[38]
	Handroanthus impetiginosus	Bark	Malaria	Peru	[43]
	Handroanthus serratifolius	Bark	Malaria	Peru	[43]
	Jacaranda caucana	Leaves	Others	Colombia	[41]
	Jacaranda copaia	Whole plant	Malaria	Peru (2)	[3] (a); [40] (b)
	Mansoa alliacea	Whole plant, NS	Malaria	Peru (4)	[38] (a); [3] (b); [36] (c); [40] (d)
	Mussatia hyacinthina	Bark	Others	Peru	[36]
	Tynanthus panurensis	Bark, sap	Others	Peru	[36]
Bixaceae	Bixa orellana	Leaves, roots, exudate, seeds	Malaria	Peru (2), Bolivia	[38] (a); [36] (b); [37] (c)
Bombacaceae	Ceiba pentandra	NS	Malaria	Peru	[38]
	Huberodendron patinoi	Bark	Others	Colombia	[41]
Burseraceae	Tetragastris panamensis	Bark	Others	Peru	[3]
	Protium amplum	Fruits	Others	Colombia	[41]
	Protium puncculatum	Branches, leaves	Malaria	Brazil	[52]
Capparaceae	Capparis coimbrana	Bark	Malaria	Bolivia	[37]
	Capparis osmantha	Bark	Others	Peru	[36]
Cardiopteridaceae	Citronella spp. (cf. melliodora or incanum)	Tuber	Malaria	Peru	[36]
Caricaceae	Carica papaya	Leaves, stalk, roots, flowers, fruits	Malaria	Peru (3), French Guiana	[38] (a); [39] (b); [3] (c); [36] (d)
Cecropiaceae	Cecropia latiloba	Leaves	Others	Peru	[3]
Celastraceae	Maytenus spp.	Bark, roots	Malaria	Peru	[36]
	Maytenus krukovii	Bark, roots	Malaria	Peru	[36]
	Maytenus macrocarpa	Bark, NS	Malaria	Peru (2)	[38] (a); [43] (b)
Chloranthaceae	Hedyosmum lechleri	Leaves	Others	Peru	[3]
Clusiaceae	Clusia hammeliana	Leaves	Others	Peru	[3]
	Clusia trochiformis	Leaves	Others	Peru	[3]
	Marila laxiflora	Leaves	Others	Colombia	[41]
Combretaceae	Buchenavia viridiflora	Branches, leaves	Others	Brazil	[53]
	Terminalia spp.	Whole plant	Malaria	Peru	[40]
Commelinaceae	Tripogandra serrulata	Leaves	Others	Peru	[3]
Convolvulaceae	Ipomoea batatas	Tuber, whole plant	Malaria	Peru, Bolivia	[36] (a); [37] (b)
	Operculina hamiltonii	Tuber	Malaria	Brazil	[20]
Costaceae	Costus spp.	Whole plant	Malaria	Peru	[40]
	Costus spp.	Whole plant	Malaria	Peru	[40]
	Costus arabicus	Stalk	Malaria	Peru	[38]
	Costus curvibracteatus	Stalk, leaves	Fever	Peru	[43]
	Costus guanaiensis	Stalk	Fever	Peru	[36]
	Costus scaber	Stalk	Fever	Peru	[36]
Cucurbitaceae	Citrullus lanatus	Seeds	Malaria	Brazil	[20]
	Gurania lobata	Leaves	Others	Peru	[3]
	Luffa operculata	Fruits	Malaria	Brazil	[20]
	Momordica charantia	Whole plant	Malaria	Peru, Brazil	[40] (a); [42] (b)
Cyclanthaceae	Cyclanthus bipartitus	Whole plant	Malaria	Peru	[40]
	Carludovica palmata	Whole plant	Malaria	Peru	[40]
Cyperaceae	Cyperus spp.	Whole plant, seeds	Malaria	Bolivia	[37]
Dilleniaceae	Curatella americana	Bark	Malaria	Bolivia	[37]
Elaeocarpaceae	Sloanea schomburgki	Bark	Malaria	Peru	[43]
Ericaceae	Satyria panurensis	Leaves	Others	Peru	[3]
Euphorbiaceae	Acalypha macrostachya	Leaves	Others	Peru	[3]
	Acalypha mapirensis	Aerial parts	Others	Peru	[3]
	Alchornea castaneifolia	Leaves	Fever	Peru	[43]
	Alchornea triplinervia	Bark	Malaria	Peru (2)	[43] (a); [38] (b)
	Caryodendron orinocense	Leaves	Others	Peru	[36]
	Croton spp.	Leaves, whole plant	Malaria	Bolivia	[37]
	Croton cajucara	Bark	Malaria	Brazil	[20]
	Croton cajucara (white variety) WV)	Bark, leaves	Malaria	Brazil	[47]
	Croton cajucara (red variety) RV)	Bark, leaves	Malaria	Brazil	[47]
	Croton lechleri	Latex	Malaria	Peru	[36]
	Croton sacaquinha	Bark	Malaria	Brazil	[20]
	Euphorbia heterophylla	Leaves	Others	Peru	[3]
	Hevea braziliensis	Leaves, bark, exudate	Malaria	Bolivia	[37]
	Hevea guianensis	Bark	Malaria	Peru	[43]
	Hura crepitans	Latex, bark	Others	Peru	[36]
	Jatropha curcas	Leaves, latex	Malaria	Peru, Bolivia	[36] (a); [37] (b)
	Jatropha gossypifolia	Leaves	Malaria	Peru	[38]
	Manihot esculenta	Leaves	Others	Peru	[36]
	Phyllanthus amarus	Whole plant	Malaria	French Guiana	[39]
	Phyllanthus niruri	Whole plant	Malaria	Peru (2)	[38] (a); [40] (b)
	Ricinus communis	Whole plant	Malaria	Peru	[40]
Fabaceae	Abrus arboreus	Bark	Malaria	Peru	[43]
	Acrocarpus fraxinifolius	Bark	Others	Peru	[3]
	Albizia niopoides	Bark	Fever	Peru	[43]
	Amburana cearensis	Bark, Leaves	Malaria	Bolivia	[37]
	Bauhinia spp.	Stalk	Malaria	Peru	[36]
	Bauhinia herrerae	Leaves	Fever	Peru	[43]
	Campsiandra angustifolia	Bark, NS	Malaria	Peru (2)	[43] (a); [38] (b)
	Copaifera paupera	Bark	Others	Peru	[43]
	Dalbergia riedelii	Bark	Malaria	Brazil	[20]
	Derris floribunda	Bark, Leaves	Malaria	Brazil	[47]
	Desmodium spp.	Whole plant	Malaria	Peru	[40]
	Desmodium adscendens	Whole plant	Others	Peru	[3]
	Erythrina poeppigiana	Bark	Others	Peru	[36]
	Hymenaea courbaril	Bark, seeds, NS	Malaria	Peru, Bolivia	[38] (a); [37] (b)
	Inga spp.	Whole plant	Malaria	Peru	[40]
	Inga sertulifera	Bark	Malaria	Peru	[43]
	Libidibia ferrea	Fruits	Malaria	Brazil	[54]
	Machaerium acutifolium	Roots	Malaria	Bolivia	[37]
	Machaerium ferox	Stalk	Malaria	Brazil	[20]
	Myroxylon balsamum	Bark	Malaria	Peru	[36]
	Ormosia costulata	Bark, leaves	Malaria	Peru	[43]
	Ormosia nobilis	Bark, seeds	Malaria	Bolivia	[37]
	Parkia nitida	Bark, seeds	Malaria	Brazil	[47]
	Senna alata	Roots	Malaria	French Guiana	[39]
	Senna hirsuta	Aerial parts	Malaria	Peru	[36]
	Senna reticulata	Leaves, roots, NS	Malaria	Peru	[38]
	Senna ruiziana	Leaves	Others	Peru	[3]
	Swartzia simplex	Bark	Malaria	Peru	[43]
	Tachigali polyphylla	Bark	Fever	Peru	[43]
Flacourtiaceae	Banara guianensis	Leaves	Malaria	French Guiana	[39]
Gentianaceae	Chelonanthus alatus	Aerial parts	Malaria	Peru	[43]
	Coutoubea spicata	Whole plant	Malaria	French Guiana	[39]
	Deianira erubescens	Roots, leaves	Malaria	Brazil	[26]
	Irlbachia alata	Leaves	Malaria	Peru	[3]
Gesneriaceae	Columnea guttata	Leaves	Others	Peru	[3]
	Corytoplectus speciosus	Whole plant	Malaria	Peru	[40]
	Gloxinia sylvatica	Leaves	Others	Peru	[3]
Haemodoraceae	Xiphidium caeruleum	Stalk	Others	Peru	[3]
Humiriaceae	Endopleura uchi	Bark	Malaria	Brazil	[20]
Hypericaceae	Vismia spp.	Stalk	Others	Peru	[3]
	Vismia baccifera	Bark	Others	Peru	[3]
	Vismia macrophylla	Leaves, seeds, bark, stem, exudate	Malaria	Bolivia	[37]
	Vismia pozuzoensis	Leaves	Others	Peru	[3]
Icacinaceae	Leretia cordata	Roots	Malaria	Peru	[36]
Lamiaceae	Cornutia spp.	Leaves	Malaria	Peru	[36]
	Hyptis lacustris	Leaves	Others	Peru	[3]
	Hyptis pectinata	Leaves	Malaria	French Guiana	[39]
	Leonotis nepetifolia	Leaves	Malaria	French Guiana	[39]
	Liabum eriocaulon	Leaves	Fever	Peru	[3]
	Marsypianthes chamaedrys	Aerial parts	Fever	Peru	[36]
	Ocimum basilicum	Whole plant	Malaria	Peru	[40]
	Ocimum campechianum	Leaves	Malaria	French Guiana	[39]
	Plectranthus barbatus	Leaves	Malaria	French Guiana	[39]
Lauraceae	Cinnamomum verum	Leaves	Malaria	Brazil	[20]
	Nectandra cuspidata	Bark	Others	Peru	[3]
	Persea americana	Leaves, NS	Malaria	Peru	[38]
	Persea peruviana	Bark	Others	Peru	[3]
Lecythidaceae	Bertholletia excelsa	Fruit peel, bark	Malaria	Brazil	[20]
	Couroupita guianensis	Roots, flowers, Fruits	Malaria	Peru (2)	[38] (a); [36] (b)
	Grias newberthii	Bark, NS	Malaria	Peru (2)	[38] (a); [43] (b)
	Gustavia angustifolia	Bark	Fever	Peru	[43]
Linaceae	Roucheria columbiana	Bark	Malaria	Peru	[43]
Loganiaceae	Strychnos pseudoquina	Bark	Malaria	Brazil	[26]
	Potalia resinifera	Leaves, roots, NS	Malaria	Peru	[38]
Loranthaceae	Phoradendron crassifolium	Leaves	Others	Peru	[3]
Malpighiaceae	Banisteriopsis caapi	NS	Malaria	Peru	[38]
	Stigmaphyllon sinuatum	Leaves	Malaria	Brazil	[47]
Malvaceae	Abelmoschus moschatus	Seeds, leaves	Fever	Peru	[36]
	Eriotheca spp.	Bark	Malaria	Bolivia	[37]
	Malachra alceifolia	Leaves	Malaria	Peru (2)	[38] (a); [36] (b)
	Pseudobombax septenatum	Leaves	Malaria	Bolivia	[37]
	Quararibea guianensis	Bark	Malaria	Brazil	[20]
	Sabdariffa rubra	Leaves	Malaria	Peru	[36]
	Scleronema micranthum	Branches, leaves	Malaria	Brazil	[52]
	Theobroma speciosum	Leaves, fruits, flowers	Malaria	Bolivia	[37]
Melastomataceae	Clidemia hirta	NS	Malaria	Peru	[38]
	Clidemia bullosa	Leaves, branches	Malaria	Brazil	[47]
	Miconia albicans	Not mentioned	Malaria	Bolivia	[37]
	Miconia nervosa	Bark, leaves	Malaria	Brazil	[47]
Meliaceae	Carapa guianensis	Seeds	Malaria	Brazil	[20]
	Cedrela fissilis	Leaves, bark	Malaria	Bolivia	[37]
	Cedrela odorata	Bark, stalk, NS	Malaria	Brazil; Peru (2)	[20] (a); [43] (b); [55] (c)
	Guarea guidonia	Bark, seeds	Malaria	Peru, Colombia	[43] (a); [41] (b)
	Guarea polymera	Leaves, bark	Others	Colombia	[41]
Menispermaceae	Abuta curarea	Stalk	Malaria	Peru	[36]
	Abuta rufescens	NS	Malaria	Peru	[38]
	Curarea toxicofera	Branches	Malaria	Colombia	[56]
	Tinospora crispa	Stalk	Malaria	French Guiana	[39]
Moracaceae	Brosimun rubescens	NS	Malaria	Peru	[38]
Moraceae	Clarisia biflora	Bark	Others	Peru	[43]
	Clarisia racemosa	Bark	Others	Peru	[43]
	Ficus spp.	Bark, exudate, stem	Malaria	Bolivia	[37]
	Ficus insipida	Bark, raiz	Malaria	Peru (2)	[43] (a); [38] (b)
	Ficus mathewsii	Bark, exudate, stem	Malaria	Bolivia	[37]
	Parahancornia fasciculata	Latex	Malaria	Brazil	[20]
	Pseudolmedia laevis	Leaves	Others	Peru	[3]
Myristicaceae	Otoba novogranatensis	Leaves, fruits	Did not mention	Colombia	[41]
	Otoba parviflora	Bark	Others	Colombia	[41]
	Virola spp.	Bark	Others	Peru	[3]
	Virola calophylla	Bark	Malaria	Peru	[43]
	Virola surinamensis	Bark	Others	Peru	[43]
Myrtaceae	Campomanesia aromatica	Leaves	Malaria	French Guiana	[39]
	Myrciaria dubia	Leaves, NS	Malaria	Peru	[38]
	Psidium acutangulum	Branches, leaves, fruits	Malaria	French Guiana	[57]
	Psidium guajava	Bark, leaves	Malaria	Bolivia, Peru	[37] (a); [38] (b)
Nyctaginaceae	Neea spp.	Whole plant	Malaria	Peru	[40]
Olacaceae	Minquartia guianensis	Bark, NS	Malaria	Peru (3)	[38] (a); [36] (b); [43] (c)
Oxalidaceae	Oxalis boliviana	Leaves	Others	Peru	[3]
Passifloraceae	Passiflora quadrangularis	Leaves	Malaria	Peru	[43]
Pedaliaceae	Sesamum indicum	Seeds	Malaria	Brazil	[20]
Phytolaccaceae	Petiveria alliacea	Leaves	Malaria	Peru (2), French Guiana	[38] (a); [39] (b); [36] (c)
	Phytolacca rivinoides	Fruits	Others	Peru	[3]
Piperaceae	Peperomia distachya	Leaves	Others	Peru	[3]
	Piper spp.	Leaves	Fever	Peru	[3]
	Piper spp.	Whole plant	Malaria	Peru	[40]
	Piper acutilimbum	Leaves, stalk	Malaria	Peru	[10]
	Piper aduncum	Whole plant	Malaria	Peru (3)	[3] (a); [36] (b); [40] (c)
	Piper armatum	Leaves, stalk, aerial parts	Malaria	Peru	[58]
	Piper braziliense	Leaves, stalk, aerial parts	Malaria	Peru	[58]
	Piper bullatum	Leaves, stalk, aerial parts	Malaria	Peru	[58]
	Piper callosum	Leaves, stalk	Fever	Peru	[10]
	Piper calvescentinerve	Leaves, stalk, aerial parts	Malaria	Peru	[58]
	Piper casapiense	Leaves, stalk, aerial parts	Malaria	Peru (2)	[10] (a); [58] (b)
	Piper cordatomentosa	Leaves, stalk, Aerial parts	Malaria	Peru	[58]
	Piper coruscans	Leaves, stalk, Aerial parts	Others	Peru (2)	[10] (a); [43] (b)
	Piper crassinervium	Whole plant	Malaria	Peru (2)	[3] (a); [58] (b)
	Piper dennisii	Leaves	Others	Peru	[3]
	Piper divaricatum	Leaves, stalk, Aerial parts	Malaria	Peru	[58]
	Piper dumosum	Leaves, stalk	Malaria	Peru	[10]
	Piper glabribaccum	Leaves, stalk, aerial parts	Malaria	Peru	[58]
	Piper gratum	Leaves, stalk	Fever	Peru	[10]
	Piper guianense	Leaves, stalk	Malaria	Peru	[10]
	Piper heterophyllum	Leaves, stalk, aerial parts	Malaria	Peru	[58]
	Piper jalapense	Leaves, stalk	Fever	Peru	[10]
	Piper laevilimbum	Leaves, stalk	Malaria	Peru	[10]
	Piper lanceolatum	Leaves, stalk	Fever	Peru	[10]
	Piper lehmannianum	Leaves, stalk	Malaria	Peru	[10]
	Piper lineatum	Leaves, stalk	Others	Peru	[10]
	Piper longestylosum	Whole plant	Malaria	Peru	[40]
	Piper marginatum	Leaves	Malaria	French Guiana	[39]
	Piper nudilimbum	Leaves, stalk	Others	Peru	[10]
	Piper oblongum	Leaves, stalk, aerial parts	Malaria	Peru	[58]
	Piper obtusilimbum	Leaves, stalk	Malaria	Peru	[10]
	Piper peltatum	Leaves	Malaria	Peru	[38]
	Piper politaereum	Leaves	Others	Peru	[3]
	Piper pseudoarboreum	Leaves, stalk, aerial parts	Malaria	Peru (2)	[10] (a); [58] (b)
	Piper reticulatum	Leaves, stalk, aerial parts	Malaria	Peru	[58]
	Piper sancti-felici	Leaves, stalk, aerial parts	Malaria	Peru	[58]
	Piper stellipilum	Leaves, stalk, aerial parts	Malaria	Peru	[58]
	Piper strigosum	Leaves, stalk, aerial parts	Malaria	Peru (2)	[10] (a); [58] (b)
	Piper tenuistylum	Leaves, stalk	Malaria	Peru	[10]
	Piper tridentipilum	Leaves, stalk	Malaria	Peru	[10]
	Piper trigonum	Leaves, stalk, aerial parts	Malaria	Peru	[58]
	Piper umbellatum	Leaves	Others	Peru	[3]
	Piper verruculosum	Leaves, stalk, aerial parts	Malaria	Peru	[58]
	Piper xanthostachyum	Leaves, stalk, aerial parts	Malaria	Peru	[58]
	Pleiostachyopiper nudilimbum	Leaves, stalk	Malaria	Peru	[10]
Poaceae	Andropogon leucostachyus	Aerial parts	Malaria	Brazil	[47]
	Cymbopogon citratus	Leaves, NS	Malaria	Peru (2), French Guiana, Bolivia	[38] (a); [39] (b); [36] (c); [37] (d)
	Saccharum officinarum	Stalk	Malaria	Peru	[38]
Polygonaceae	Triplaris americana	Leaves, seeds, bark	Malaria	Bolivia	[37]
	Triplaris poeppigiana	Bark	Malaria	Peru	[36]
	Triplaris weigeltiana	Bark	Others	Peru	[43]
Proteaceae	Oreocallis grandiflora	Leaves	Others	Peru	[3]
Pteridaceae	Duroia hirsuta	Leaves	Malaria	Peru	[36]
Rhamnaceae	Ampelozizyphus amazonicus	Bark	Malaria	Brazil	[20]
Rubiaceae	Calycophyllum multiflorum	Bark	Others	Peru	[43]
	Capirona decorticans	Bark	Malaria	Peru	[43]
	Cephaelis tomentosa	Bark	Fever	Peru	[43]
	Coffea arabica	Leaves	Malaria	Peru	[38]
	Coutarea hexandra	Whole plant	Malaria	Bolivia	[37]
	Hamelia patens	Whole plant	Malaria	Peru (2)	[3] (a); [40] (b)
	Isertia hypoleuca	Bark	Malaria	Peru	[43]
	Ladenbergia oblongifolia	Leaves	Malaria	Peru	[43]
	Psychotria poeppigiana	Leaves, bark	Malaria	Peru (2)	[3] (a); [40] (b)
	Remijia ferruginea	Bark	Malaria	Brazil	[26]
	Uncaria guianensis	Bark, Stalk, NS	Malaria	Brazil; Peru (2)	[20] (a); [38] (b); [36] (c)
	Warszewiczia coccinea	Bark	Others	Peru	[3]
Rutaceae	Citrus sp. (lemon)	Roots, Leaves	Malaria	French Guiana	[39]
	Citrus sp. (orange)	Leaves	Malaria	French Guiana	[39]
	Citrus aurantiifolia	Leaves, fruits, seeds, roots, bark	Malaria	Peru, Bolivia	[36] (a); [37] (b)
	Citrus limetta	Roots	Malaria	Bolivia	[37]
	Citrus limon	Roots, NS	Malaria	Peru	[38]
	Citrus medica	Leaves	Malaria	Peru	[38]
	Citrus paradisi	Roots, fruits, bark, leaves, NS	Malaria	Peru, Bolivia	[38] (a); [37] (b)
	Esenbeckia febrifuga	Stalk	Malaria	Brazil	[59]
	Ruta graveolens	Aerial parts	Malaria	Brazil	[20]
	Swinglea glutinosa	Bark	Malaria	Colombia	[41]
	Zanthoxylum djalma-batistae	Leaves, branches	Malaria	Brazil	[47]
	Zanthoxylum rhoifolium	Inner bark	Malaria	French Guiana	[39]
Sapindaceae	Paullinia cupana	Leaves, fruits, branches	Malaria	Brazil	[47]
Sapotaceae	Ecclinusa ramiflora	Leaves	Malaria	Peru	[36]
	Pouteria caimito	Leaves	Malaria	Peru	[38]
	Pouteria guianensis	Bark, leaves, roots	Malaria	Peru	[43]
	Prieurella prieurii	Bark	Malaria	Peru	[43]
Scrophulariaceae	Conobea scoparioides	Leaves	Others	Colombia	[41]
	Scoparia dulcis	Leaves, NS	Malaria	Peru	[38]
Selaginellaceae	Selaginella conduplicata	Leaves	Fever	Peru	[3]
Simaroubaceae	Picrolemma huberi	Stem bark	Malaria	Colombia	[60]
	Picrolemma pseudocoffea	Stalk, leaves, roots	Malaria	French Guiana	[39]
	Quassia amara	Leaves	Malaria	French Guiana	[39]
	Simaba cedron	Bark	Malaria	Brazil	[20]
	Simarouba amara	Bark, fruit, leaves	Malaria	Peru, Bolivia	[43] (a); [37] (b)
Siparunaceae	Siparuna aspera	Bark, leaves	Fever	Peru (2)	[36] (a); [3] (b)
	Siparuna guianensis	Bark, leaves	Malaria	Peru, Bolivia, French Guiana	[36] (a); [37] (b); [39] (c)
	Siparuna radiata	Leaves	Fever	Peru	[3]
Solanaceae	Brunfelsia grandiflora	Roots, whole plant	Malaria	Peru (2)	[38] (a); [40] (b)
	Cestrum sp.	Leaves	Malaria	Peru	[36]
	Cestrum hediondinum	Whole plant	Malaria	Peru	[40] (b)
	Cestrum megalophyllum	Leaves	Malaria	Peru	[38]
	Cestrum racemosum	Leaves	Malaria	Peru	[3]
	Cyphomandra sp.	Leaves	Malaria	Peru	[36]
	Cyphomandra pendula	Not mentioned	Malaria	Peru	[36]
	Nicotiana tabacum	Whole plant	Malaria	Peru	[40]
	Physalis angulata	Aerial parts, leaves, NS	Malaria	Peru (2)	[38] (a); [36] (b)
	Solanum betaceum	Bark	Malaria	Bolivia	[37]
	Solanum leucocarpon	Leaves	Malaria	French Guiana	[39]
	Solanum peruvianum	Aerial parts	Others	Peru	[3]
Thelypteridaceae	Thelypteris spp.	Leaves	Malaria	Peru	[36]
Tliaceae	Apeiba tibourbou	Bark	Others	Peru	[43]
	Heliocarpus americanus	Bark	Malaria	Peru	[3]
Trigoniaceae	Trigonia killipii	Bark	Malaria	Bolivia	[37]
Urticaceae	Laportea aestuan	Roots, leaves, stalk	Malaria	Peru	[38]
	Urera baccifera	Whole plant	Malaria	Peru (2), Bolivia	[3] (a); [40] (b); [37] (c)
	Urera capitata	Whole plant	Malaria	Peru	[40]
	Urera laciniata	Whole plant	Malaria	Peru	[40]
Verbenaceae	Lantana spp.	Leaves	Malaria	Peru	[3]
	Lantana camara	Leaves	Malaria	French Guiana	[39]
	Lantana cujabensis	Leaves, bark, flower	Malaria	Bolivia	[37]
	Lantana trifolia	Bark	Malaria	Bolivia	[37]
	Lippia alba	Whole plant	Malaria	French Guiana, Peru	[39] (a); [40] (b)
	Phyla spp.	Whole plant	Malaria	Peru	[40]
	Stachytarpheta cayennensis	Leaves, aerial parts	Malaria	Peru (3), Bolivia	[36] (a); [43] (b); [37] (c) [3] (d)
	Stachytarpheta straminea	Leaves	Malaria	Peru	[38]
	Verbena spp.	Whole plant	Others	Peru	[40]
	Verbena littoralis	Aerial parts, leaves	Malaria	Peru (2)	[3] (a); [38] (b)
Violaceae	Rinoreocarpus ulei	Bark	Malaria	Bolivia	[37]
Viscaceae	Phthirusa robusta	Leaves	Others	Peru	[3]
	Phthirusa stelis	Leaves	Others	Peru	[3]
Zingiberaceae	Alpinia nutans	Leaves	Malaria	Peru	[38]
	Curcuma longa	Roots, rhizome	Malaria	Peru (2), French Guiana	[38] (a); [36] (b); [39] (c)
	Hedychium coronarium	Rhizome	Others	Peru	[3]
	Renealmia alpinia	Rhizome	Others	Peru	[3]
	Renealmia thyrsoidea	Rhizome	Others	Peru	[3]
	Zingiber officinale	Rhizome, leaves	Fever	Peru	[36]
NS = non specified; plants parts that these were not specified by the authors. Numbers cited in parentheses refer to the number of plant studies conducted in each country by the respective author. **The letters in parentheses refer to the identification of the authors who were responsible for the studies also mentioned in tables 2-4.

As shown in table 1, 88 botanical families and 389 plants were cited in the 27 articles analyzed. Of these, 30 had only the genus mentioned, so only 359 plant species were listed in tables 2-4. The botanical family that presented the largest number of specimens was Piperaceae (n = 45), followed by the families Fabaceae (n = 29), Euphorbiaceae (n = 21), and Asteraceae (n = 17). Among the ethnopharmacological uses cited by traditional medicine, plants to prevent or treat malaria were the most cited (n = 271; 69.7%). The indication for fever not related to malaria represented 6.2% (n = 93), while 23.9% (n = 93) were for other purposes, including symptoms such as headache, diarrhea, flu, chills, feeling cold, anemia, stomach pain, body pain, rheumatism, bronchitis, infected wounds, ulcers, among others, and 0.2% (n = 1) did not have their use mentioned (Figure 2A).

The plant part mostly used were leaves (n = 183; 34.1%), followed by barks (n = 107; 19.9%), stalks (n = 60; 11.2%), whole plants (n = 52; 9.7%), aerial parts (n = 34; 6.3%), and roots (n = 31; 5.8%). The other parts used (n = 74; 13.8%) included seeds, fruits, branches, exudate, rhizomes, flowers, stems, latex, tuber, sap, inner barks, pulps, stem barks, and fruit peels (Figure 2B).

Regarding the location where the plants were studied, the majority of the 474 citations of plant species were in Peru (68.8%), followed by Brazil (11%), Bolivia (9.7%), French Guiana (7.2%), and Colombia (3.4%). Some plant species/genera were cited by more than one author (Figure 2C).

The next step was to identify whether the plants cited in the studies had antiplasmodial and antimalarial activities described, and/or the cytotoxicity assessed, as shown in table 2.

Among the extracts or fractions from 359 plant species studied (Tables 2-4), 185 had the antiplasmodial and/or antimalarial activities evaluated (Tables 2,3). However, pure substances were isolated only in a few of them (n = 5). A total of 180 species were tested in vitro against blood forms of P. falciparum, 12 were tested in a murine experimental model of P. berghei and nine were tested in vitro and in vivo. Of all these evaluated species, 51 showed anti-P. falciparum activity in vitro and nine species against P. berghei in mice. Six species were active In vitro and In vivo (Andropogon leucostachyus, Aspidosperma nitidum, Aspidosperma pyrifolium, Curarea toxicofera, Psidium acutangulum and Xylopia amazonica). Among the active samples tested in vitro, 34 had their cytotoxicity assessed; thus, the selectivity index could be determined. None of the plant species had its acute toxicity in vivoevaluated (Tables 2,3).

Table 2: Antiplasmodial and antimalarial activities, cytotoxicity, and selectivity index of plants from South America.
Plant species	*P. falciparum* strains, In vitro IC₅₀ values (µg/mL),a*	Cytoxicity (µg/mL) and/or Selectivity indexa	In vivotest (tested dose and % parasitemia reduction)
Abrus arboreus	3D7: > 10	NT	NT
Abuta rufescens	FCR-3: 5.9	NT	NT
Acalypha macrostachya	FCR-3: 24.7	NT	NT
Acrocarpus fraxinifolius	FCR- 3: 49.8	NT	NT
Albizia niopoides	3D7: > 10	NT	NT
Alchornea castaneifolia	3D7: > 10	NT	NT
Alchornea triplinervia	3D7: 0.38; with filtration 3D7: 0.62; W2: 0.72 (a)	CC₅₀: 100.0	NT
Alternanthera brasiliana	FCR-3: > 10	NT	NT
Ampelozizyphus amazonicus	W2: Aq: > 50	NT	NT
Anacardium occidentale	W2: bark CHCl₃: 36.6; K1 EtOH > 50; Aq > 50; leaves CHCl₃ W2 43.9; K1 EtOH > 50; W2 Aq 45.0 (c)	CC₅₀ Macrophages: bark CHCl₃, leaf CHCl₃ and Aq: > 200/SI = bark CHCl₃: > 5.5/ leaf CHCl₃: > 4.6/ Aq: > 4.4	NT
Andropogon leucostachyus	K1: CHCl₃: > 50/ W2 Aq: 45.4/ MeOH: 7.1	CC₅₀ Macrophages: > 200; SI = Aq: > 4.4 / MeOH: > 28.2	250 mg/kg, aerial parts: Day 5: 71% suppression/ Day 7: 48% suppression.
Anthurium ernestii	FCR-3: Leaves 22.9; roots 27.0	NT	NT
Apeiba tibourbou	3D7: > 10	NT	NT
Aspidosperma megalocarpon	F32: MeOH: 25; D2: MeOH: 8 (a)	CC₅₀ U-937: 0.4. SI F32: 0.02/ SI D2: 0.05	NT
Aspidosperma nitidum	P. falciparum W2: Bark: EtOH: 4.6-7/ MeOH-A: 8.3-10.7/ MeOH-B: 6.6-10/ MeOH-C: 10.8-12.4/ Fractions from MeOH-C: Fraction FO III: 1.6-2.3/ Fraction FO IV: 3.3-4.8/ Precipitate: 5.5-7.6/ Leaves: EtOH: 22-25.3/ Acetonic: ≥ 50 /Aq: ≥ 50/ Branches extracts: EtOH: ≥ 50/Aq: ≥50 (b)	CC₅₀: EtOH: BGM: ≥ 2000, HepG2: 654; MeOH-A: BGM: 964, HepG2: 255; MeOH-B: BGM ≥ 2000, HepG2 ≥ 1000; MeOH-C: BGM 427, HepG2 600; Fractions from MeOH-C - Fraction FO III: BGM 301; HepG2: 62; Fraction FO IV: BGM 89, HepG2 169; Precipitate: BGM ≥2000, HepG2 1,103; Leaves extracts: EtOH, acetonic and Aq: BGM ≥ 2000, HepG2 ≥ 1000; Branches extracts: EtOH: BGM ≥ 2000, HepG2 280; Aq: BGM ≥ 2000, HepG2 ≥ 1000/ SI: Bark extracts EtOH: BGM: 286-435/HepG2: 83-126/ MeOH-A: BGM: 116-90/HepG2: 31-24 /MeOH-B: BGM: 200-303/HepG2:100-152/MeOH-C: BGM: 34-40/ HepG2:48-56 /Fractions from MeOH-C: Fraction FO III: BGM: 188-70/HepG2: 39-30 /Fraction FO IV: BGM: 30-19/HepG2: 51-35 /Precipitate: BGM: 364-263/HepG2: 201-145/ Leaves extracts EtOH: BGM: 91-79/HepG2: 29-25 /Acetonic and Aq: Inactive/ Branches extracts EtOH and Aq: Inactive.	Wood bark MeOH 100 mg/Kg 67%; Fraction FO III 50-100 mg/Kg: 66-48%; Fraction FO IV: 50-100: 65-54%; Precipitate: 50-100 mg/Kg 57-53% (b)
Aspidosperma pyrifolium	W2: Stem bark extracts: 3.0/ Stem: 17.0 /Root bark: 14.0/ Roots: 18.0 /Leaves: 12.0/ Stem bark fractions: ETOAC: 9.0 /Aq: 20.0/ Stem fractions: ETOAC: 6.0 /Alkaloid-rich: 5.0 /Aq: ≥ 50 /BUT: ≥ 40/ Aq: 27.0	CC₅₀: BGM: 287- ≥ 1000/ HepG2: 316 - ≥ 1000/ PBMC: 145 - ≥ 1000/ SI: Stem bark: HepG2: 137/ BGM e PBMC: 333; Aq: HepG2: 32/ BGM e PBMC: 50/ ETOAC: HepG2: 54/ BGM: 111/ PBMC: 48/ Stem: HepG2: 24/ BGM: 59/ PBMC: 24/ ETOAC: HepG2: 53/ BGM: 167/ PBMC: 26/ Alkaloid-rich: HepG2: 84/ BGM: 200/ PBMC: 29/ Root bark: HepG2: 29/ BGM and PBMC: 21/ Root: HepG2: 23/ BGM: 56/ PBMC: 22/ Leaves: HepG2:41/ BGM: 37/ PBMC: 46	Extracts: Root bark: Day 5: 79%/ Day 10: 29% /Root: Day 5:75%/ Day 10: 52%/Leaves: Day 5: 23%/Day 10: 40% / Fractions: Aqueous: Day 5: 93% /Day 10: 57%/ ETOAC: Day 5: 0% /Day 10: 34%/ Alkaloid-rich: Day 5: 79%/Day 10: 57%
Aspidosperma rigidum	W2: EtOH: 6.0; DCM: 2.5; BUT: 2.5; Aq: 10.2	NT	NT
Ayapana lanceolata	FCR-3: 8.2	NT	NT
Bauhinia herrerae	3D7: > 10	NT	NT
Begonia glabra	FCR-3: 22.1	NT	NT
Bertholletia excelsa	W2: EtOH fruit peel = 4.5; EtOH bark = 2.0; Sap = 7.5	NT	NT
Buchenavia viridiflora	3D7 e Dd2: Lignin branch: 14.08; Lignin leaves: 3D7: 350.20	Jurkat: IC₅₀: Lignin branch: 21.37; SI: 1.33/ MCF-7: IC₅₀: 12.63; SI: 1.14/ DU145: IC₅₀: 37.56; SI: 0.80/ T47D: IC₅₀: 25.46; SI: 1.12/ HepG2: IC₅₀: > 100; SI: < 0.28/ Lignin leaves: Jurkat: IC₅₀: 25.76; SI: 0.03/MCF-7: IC₅₀:24.88; SI: 0.91/DU145: IC₅₀: 41.65; SI: 0.54/ T47D: IC₅₀: 47.74; SI: 0.47/ HepG2:IC₅₀: > 100; SI: < 0.22	NT
Calea montana	3D7: > 10	NT	NT
Calycophyllum multiflorum	3D7: > 10	NT	NT
Campnosperma panamense	F32: DCM: 3/ MeOH: 15; D2: DCM: 35/ MeOH: 5	CC₅₀ U-937: DCM: 172.5/ MeOH: 653.5/ SI F32: DCM: 5,6/ MeOH: 43,6. SI D2: DCM: 0,5/ MeOH: 130.7	NT
Campsiandra angustifolia	3D7: > 10 (a); FCR-3: 8,8 (b)	NT	NT
Capirona decorticans	3D7: > 10	NT	NT
Carapa guianensis	W2: Oil > 50	NT	NT
Carica papaya	FCR-3: 19.8 (c)	NT	NT
Cecropia latiloba	FCR-3: 45.2	NT	NT
Cedrela odorata	3D7: > 10 (b)	NT	NT
Cephaelis tomentosa	3D7: > 10	NT	NT
Cestrum megalophyllum	FCR-3: > 10	NT	NT
Chelonanthus alatus	3D7: > 10	NT	NT
Citrus limon	FCR-3: F 4.9; R > 10	NT	NT
Citrus paradisi	FCR-3: F = 4.0, Leaf: > 10, Roots: > 10, Stem: >10	NT	NT
Clarisia biflora	3D7: > 10	NT	NT
Clarisia racemosa	3D7: > 10	NT	NT
Clidemia bullosa	K1: Leaf: CHCl₃: >50/ MeOH: >50/ K1 Aq: 26.2. Branch: CHCl₃: 13.5/ Aq: 21.2/ K1 MeOH: > 50	CC₅₀ Macrophages: > 200/ SI: Leaf Aq > 7.6/ Branch CHCl₃ > 14.8	NT
Clusia trochiformis	FCR-3: 30.4	NT	NT
Conobea scoparioides	F32: > 50; D2: > 50	CC₅₀ U-937: 63.4	NT
Copaifera paupera	3D7: > 10	NT	NT
Coriandrum sativum	FCR-3: > 10	NT	NT
Costus curvibracteatus	3D7: stem: > 10, leaves: 1.39. Polyamide filtered: W2: 1.16. C6H12: 42.43/ DCM: 40.15/ ETOAC: 30.14/ 1-BUT: 46.18/ Aq: 3.02	CC₅₀: C6H12 > 100/SI: 2.36/ DCM: 13.75/ SI: 0.34/ ETOAC: > 100/ SI: >3.32/ 1-BUT > 100/ SI: >2.17/ Aq: 17.78/ SI: 5.89	NT
Couroupita guianensis	FCR-3: > 10 (a)	NT	NT
Croton cajucara (red variety-RV)	W2: Bark: CHCl₃ 32.2/ EtOH K1 > 50/ Aq > 50/ Leaf: CHCl₃: W2 6.4/ EtOH: 13.3/ K1 Aq: >50	CC₅₀ Macrophages: bark: > 200; Leaf: 40.6 and > 200/ Bark: SI: CHCl₃: > 6.2/ Leaf: SI: CHCl₃: 6.3/ EtOH: > 15.0	250 mg/kg. Leaf: CHCl₃: 19% day 5/ 0% day 7
Croton cajucara (white variety-WV)	W2: bark CHCl₃: 29.1/ EtOH: 17.2/ K1 Aq: > 50/ Leaf CHCl₃: W2 11.3/ EtOH: 16.3/ K1 Aq: > 50	CC₅₀ Macrophages: Bark: 43.1 and 127; Leaf > 200/ Bark: SI: CHCl₃: 1.5 EtOH: 7.4/ Leaf: SI: CHCl₃: > 17.7 EtOH: > 12.3	NT
Curarea toxicofera	FCR-3: 7.3	NT	350 mg/ kg: ≈ 49%/ 1.020 mg/kg: ≈ 69%/ 200 mg/kg: ≈ 11%
Cymbopogon citratus	FCR-3: > 10	NT	NT
Daucus montanus	FCR-3: 28.6	NT	NT
Deianira erubescens	NT	NT	Leaves 1.000 and 500 mg/Kg 0%; roots 1.000 mg/kg: 0%; 500 mg/Kg 18%
Derris floribunda	K1: Bark: CHCl₃ > 50 / Aq > 50/ MeOH >50/ Leaf: CHCl₃ W2 47.4/ K1 Aq 27.5/ MeOH > 50	CC₅₀ Macrophages: > 200/ Leaf: SI CHCl₃: > 4.2	NT
Dieffenbachia seguine	3D7: aerial parts: 0.7. Polyamide filtered: W2: 0.01	CC₅₀: 62.2	NT
Dracontium spruceanum	3D7: > 10	NT	NT
	W2: Aq: > 50	NT	NT
Eryngium foetidum	FCR-3: > 10 (a)	NT	NT
Esenbeckia febrifuga	W2: 15.5; 3D7: 21.0	NT	NT
Euterpe oleraceae	W2: EtOH > 50 (a); 20,0 mg/L gallic acid equivalent (GAE) 1 e 3 inativo/ 10mg/L (GAE) DNA content HB3 76.5% and Dd2 65.1%/ 20mg/L (GAE) DNA content HB3 65.8%, Dd2 61.7% (c)	The 1, 2, and 3 fractions did not negatively influence viability of RAW264 (c)	Polyphenolic açaí pulp fractions, 20 mg/kg: 86.8 % inhibition at day 5, 89.4% at day 6, 77.5% at day 7, 42.5% at day 8 (c)
Euterpe precatoria	FCR-3: > 10	NT	NT
Ficus insipida	3D7: > 10	NT	NT
Gloxinia sylvatica	FCR-3: 22.9	NT	NT
Grias newberthii	FCR-3: > 10 (a); 3D7: 0.04; Polyamide filtered: 3D7: 0.03; W2: 0.03. 3D7: Fractionation: C6H12: 39.82; DCM > 100/ ETOAC: 0.58; 1-BUT: 56.35; Aq > 100 (b)	CC₅₀: 100.0 HUVEC cells: C6H12: CC₅₀: >100/ SI: > 2.51/ DCM: CC₅₀: > 100/ SI: > 1/ ETOAC: CC₅₀: 12.40 / SI 21.38/ 1-BUT: CC₅₀: 50.83 / SI: 0.9/ Aq: CC₅₀:18.51 / SI: 0.19 (b)	NT
Guarea guidonia	3D7: > 10 (a); F32: 10; D2: 10 (b)	CC₅₀ U-937: 28.8/ SI F32 and D2: 2.9 (b)	NT
Guarea polymera	F32: > 50 D2: > 50	CC₅₀ U-937: 6.1	NT
Guatteria amplifolia	F32: MeOH: 1.9; D2: MeOH: 1.5	CC₅₀ U-937: 75.7. SI (F32): 39.8. SI (D2): 50.5	NT
Gurania lobata	FCR-3: 23.5	NT	NT
Gustavia angustifolia	3D7: > 10	NT	NT
Handroanthus impetiginosus	3D7: > 10	NT	NT
Handroanthus serratifolius	3D7: > 10	NT	NT
Hedychium coronarium	FCR-3: 26.3	NT	NT
Hedyosmum lechleri	FCR-3: 25.7	NT	NT
Hevea guianensis	3D7: 7.41; Polyamide filtered: 3D7: 0.08/ W2: 4.94	CC₅₀: 88.8	NT
Himatanthus articulatus	W2: Three fractions the lyophilized ethanol extract from H. articulatus stem barks: DCM: 22.9; ETOAC (plumieride) and the MeOH fractions were inactive	H. articulatus showed low cytotoxicity to HepG2 cells in the concentrations used (CC₅₀ > 1000 μg/mL)	MeOH: reduced parasitaemia by 35.4% at a dose of 200 mg/kg
Huberodendron patinoi	F32: MeOH: 3.0; D2: MeOH: 18.0	CC₅₀ U-937: 501. SI F32: 167.0 / SI D2: 27.8	NT
Hygrophila guianensis	F32: > 50; D2: > 50	CC₅₀ U-937: 101.8	NT
Inga sertulifera	3D7: > 0	NT	NT
Iriartea deltoidea	3D7: > 10 (a)	NT	NT
Isertia hypoleuca	3D7: > 10	NT	NT
Jacaranda caucana	F32: MeOH: 14 / D2: MeOH: 4.6	CC₅₀ U-937: 281.7. SI F32: 20.1 / SI D2: 61.2	NT
Jacaranda copaia	FCR-3: 8.1 (a)	NT	NT
Ladenbergia oblongifolia	3D7: > 10	NT	NT
Libidibia ferrea	W2: HA: 11.10	CC₅₀ human cell line WI-26-VA-4 > 100/ SI: 9.0	NT
Machaerium ferox	W2: EtOH: 20	NT	NT
Malachra alceifolia	FCR-3: > 10 (a)	NT	NT
Mangifera indica	W2: EtOH > 50 (a)	NT	NT
Mansoa alliacea	FCR-3: > 10 (a); 24.5 (b)	NT	NT
Marila laxiflora	F32: DCM: 20; D2: DCM: 28	CC₅₀ U-937: 203.1 / SI: F32: 10.2/ SI D2: 7.3	NT
Maytenus macrocarpa	3D7: 1.49. Polyamide filtered: 3D7: 0.02 / W2: 0.02	CC₅₀ HUVEC cells: 44.1	NT
Miconia nervosa	W2: Bark: CHCl₃ 13.3/ K1 Aq > 50/ MeOH > 50/ Leaf: CHCl₃ W2 12.4/ Aq 10.2/ MeOH 9.9.	CC₅₀ Macrophages: Bark: 46.6; Leaf: 70.6, > 200 and 95.9/ SI CHCl₃ bark: 3,5 / SI Leaf: CHCl₃: 5,7/ SI Aq: > 19,6/ SI MeOH: 9,7	NT
Minquartia guianensis	FCR-3: 4.2 (a); 3D7: >10 (c)	NT	NT
Munnozia hastifolia	FCR-3: 26.3 (a)	NT	NT
Myrciaria dubia	FCR-3: > 10	NT	NT
Operculina hamiltonii	W2: Aq: > 50	NT	NT
Ormosia costulata	3D7: > 10	NT	NT
Otoba novogranatensis	F32: leaves: > 50; D2: > 50 and 26. F32: 20; Fruits: F32: > 50; D2: > 50	CC₅₀ U-937: leaves DCM: 27.6; MeOH: 76.6; fruits DCM: 28.5; MeOH: 38.1; SI leaves: F32: 28.4; D2: 21.9	NT
Otoba parviflora	F32: > 50; D2: > 50	CC₅₀ U-937: 233.7	NT
Oxalis boliviana	FCR-3: 34.9	NT	NT
Parkia nitida	K1: Bark: CHCl₃ > 50/ Aq > 50/ MeOH > 50/ Leaf: CHCl₃ >50/ Aq > 50 / MeOH > 50	NT	NT
Passiflora quadrangularis	3D7: > 10	NT	NT
Paullinia cupana	K1: Leaf: CHCl₃ > 50/ Aq > 50/ MeOH > 50/ W2 Fruit: CHCl₃ 19.3/ K1 Aq > 50/ MeOH >50/ Branch: CHCl₃ W2 19.3/ K1 Aq > 50/ MeOH > 50	CC₅₀ Macrophages: Fruit: > 200, Branch: 62.9/ Fruit CHCl₃ SI: > 10.4/ Branch CHCl₃ SI: 3.3	NT
Peperomia distachya	FCR-3: 22.1	NT	NT
Persea americana	FCR-3: > 10	NT	NT
Petiveria alliacea	FCR-3: > 10 (a)	NT	NT
Philodendron ernestii	FCR-3: 28.5	NT	NT
Phthirusa robusta	FCR-3: 23.9	NT	NT
Physalis angulata	FCR-3: 4.6 (b)	NT	NT
Phytolacca rivinoides	FCR-3: 26.4	NT	NT
Piper acutilimbum	3D7: HEX: 33.29; DCM: 26.89; Aq: 33.18. W2: HEX: > 100; DCM: 49.08; Aq: 41.84	CC₅₀ HUVEC: HEX: 19.11; DCM: 18.1; Aq: 54.44/ SI 3D7: HEX: 0.57/ DCM: 0.67/ Aq: 1.64	NT
Piper aduncum	FCR-3: 9.6 (a); P. falciparum (Ghana): 1.3 (d)	NT (a); MRC-5 cells: EO inhibited cell growth, with an IC₅₀ value of 5,1 µg/mL (d)	NT
Piper armatum	3D7: HEX: > 100/ DCM: > 100/ MeOH: > 100	CC₅₀ HUVEC: HEX > 100; DCM: 55.31; MeOH: 35.86; SI: HEX: ≤ 1/ DCM: 0.55/ MeOH: 0.36	NT
Piper brasiliense	3D7: HEX: > 100, DCM: 20.19	CC₅₀ HUVEC: HEX > 100; DCM: 20.19; SI: HEX: ≤ 1/ DCM: 1.00	NT
Piper bullatum	3D7: HEX: > 100/ DCM: >100/ MeOH: >100	CC₅₀ HUVEC: H >100; DCM: 43.79; MeOH: 25.09/ SI: HEX: ≤ 1/ DCM: 0.44/ MeOH: 0.25	NT
Piper callosum	3D7: MeOH = 24.49; HEX = 25.31; DCM = 8.77. W2: MeOH: 26.13; HEX: 22.74; DCM: 12.86	CC₅₀ HUVEC: MeOH: > 100, HEX: > 100, DCM: 46,45/ SI 3D7: MeOH: 4.08; HEX: 3,95 e DCM: 5,30.	NT
Piper calvescentinerve	3D7: HEX: > 100/ DCM: > 100/ MeOH: > 100	CC₅₀ HUVEC: HEX > 100; DCM: 38.83; MeOH: 38.55; SI: HEX: ≤ 1/ DCM: 0.39/ MeOH: 0.39	NT
Piper casapiense	3D7: EtOH: 12.27. W2: > 100. DCM: 9.4; W2 > 100 (a); 3D7 > 100 HEX, DCM and MeOH (b)	CC₅₀ HUVEC: EtOH: 24.26, DCM: 50.93/ 3D7 SI: EtOH: 1.98/ DCM: 5.42 (a)/ HUVEC CC₅₀: H > 100; DCM: 45.31; MeOH: 30.48; SI HEX: ≤ 1; SI DCM: 0.45; SI MeOH: 0.30 (b)	NT
Piper cordatomentosa	3D7: HEX, DCM and MeOH > 100	CC₅₀ HUVEC: HEX > 100; DCM: 58.32; MeOH: 61.50/ SI: HEX: ≤ 1/ DCM: 0.58/ MeOH: 0.62	NT
Piper coruscans	3D7: EtOH: 1.36; Aq: 41.27/ W2: EtOH: 2.33; Aq: > 100 (a); 3D7: 1.36. Polyamide filtered: W2: 2.33 (b)	CC₅₀ HUVEC: EtOH: 43.60; Aq: 3.09/ SI: EtOH: 32.06; Aq: 0.07 (a)/ Cytotoxicity (% of living cells): 43.6 (b)	NT
Piper crassinervium	FCR-3: 33.5 (a); MeOH > 100; HEX = 5.66; DCM = 7.41 (b)	NT (a); CC₅₀ HUVEC: MeOH: 15.28/ HEX: 3.51/ DCM: > 100; SI H: 0.62; DCM: 13.50; MeOH: 0.15 (b)	NT
Piper dennisii	FCR-3: 21.4	NT	NT
Piper divaricatum	3D7: HEX and DCM: >100	CC₅₀ HUVEC: HEX: 30.04; DCM: > 100; 3D7: SI: HEX: 0.30/ DCM: ≤1	NT
Piper dumosum	3D7: HA: 9.74; W2: 29.28	CC₅₀ HUVEC: 18.77; SI 3D7: 1.93	NT
Piper glabribaccum	3D7: HEX, DCM and MeOH > 100	CC₅₀ HUVEC: HEX > 100; DCM: 35.62; MeOH: 84.72; SI: HEX: ≤ 1/ DCM: 0.36/ MeOH: 0.85	NT
Piper gratum	3D7: HEX :12.82; W2: 48.69/ DCM: 3D7: 8.64; W2: 49.93	CC₅₀ HUVEC: HEX: 38.03; DCM: 55.47. SI 3D7 HEX: 2.97; SI 3D7 DCM: 6.42	NT
Piper guianense	HA: 3D7: 27.04; W2: > 100	CC₅₀ HUVEC: 53.25/ SI: 1.97	NT
Piper heterophyllum	3D7: HEX and DCM > 100	CC₅₀ HUVEC: HEX: 81.67; DCM: 17.14; SI: HEX: 0.82/ DCM: 0.17	NT
Piper jalapense	3D7: HEX = 26.67; DCM = 10.34. W2: HEX: 25.48; DCM: 12.3	CC₅₀ HUVEC: HEX >100, SI: 3.75. DCM CC₅₀: HUVEC: 49.91, SI: 4.83	NT
Piper laevilimbum	3D7: HEX: 10.43; DCM: 6.94; Aq: 2.3. W2: HEX: 22.57; DCM: > 100; Aq: > 100	CC₅₀ HUVEC: HEX: 32.69; DCM: 24.8; Aq: > 100. SI HEX: 3.13; DCM: 3,57; Aq: 43.48	NT
Piper lanceolatum	3D7: MeOH = 25.26; EtOH = 11.42; HEX = 27.59; DCM = 18.63; MeOH = 22.2. W2: MeOH: 22.38; EtOH: 13.63; HEX: 25.29; DCM: 12.83; MeOH: > 100.	CC₅₀ HUVEC: MeOH: > 100, EtOH: 58.06, HEX: 23.88, DCM: 52.55, MeOH: 43.41/ SI 3D7: MeOH: 3.96/ EtOH: 5.08/ HEX: 0.87/ DCM: 2.82/ MeOH: 1.96	NT
Piper lineatum	3D7: DCM: 2.81. W2: DCM: 43.21	CC₅₀ HUVEC: 16.08/ SI DCM: 5.72	NT
Piper nudilimbum	3D7: HA: 22.31; W2: 34.87	CC₅₀ HUVEC: 53.19/ SI 3D7: HA: 2.38	NT
Piper oblongum	3D7: HEX, DCM and MeOH > 100	CC₅₀ HUVEC: HEX: 48.32; DCM: 26.23; MeOH: 21.43; SI: HEX: 0.48/ DCM: 0.26/MeOH: 0.21	NT
Piper obtusilimbum	3D7: HA: 23.89; W2: 26.37	CC₅₀ HUVEC: 26.58/ SI 3D7: HA: 1.11	NT
Piper pseudoarboreum	3D7: HEX:11.23; DCM: 5.7; MeOH: 6.81; W2: HEX: 18.27; DCM: 4.81; MeOH: 8.95 (a); 3D7: HEX, DCM and MeOH: > 100 (b)	CC₅₀ HUVEC: HEX: 58.77; DCM: 6.35; MeOH: 52.00/ SI 3D7: HEX: 5.23/DCM: 1.11/MeOH: 7.64 (a); HUVEC CC₅₀: HEX: 61.94; DCM: 40.21; MeOH: 25.49; SI 3D7: HEX: 0.62/ DCM: 0.40/ MeOH: 0.25 (b)	NT
Piper reticulatum	3D7: HEX, DCM and MeOH > 100	CC₅₀ HUVEC: HEX, DCM and MeOH: > 100; SI: HEX, DCM and MeOH ≤ 1	NT
Piper sancti-felicis	3D7: HEX, DCM and Aq > 100	CC₅₀ HUVEC: HEX: > 100; DCM: 49.40; Aq: 72.22; SI: HEX: ≤ 1 / DCM: 0.49/ Aq: 0.72	NT
Piper stellipilum	3D7: MeOH: 8.22; HEX > 100; DCM: 13.44	CC₅₀ HUVEC: HEX: >100; DCM: 18.05; MeOH: 25.03; SI HEX ≤1 / SI DCM = 1,34 / SI MeOH = 3,04	NT
Piper strigosum	3D7: HEX: 24.58; DCM: 11.74; MeOH: 8.85; W2: HEX: 40.1; DCM: 29.99; MeOH: 53.81 (a); IC₅₀ > 100 (HEX, DCM and MeOH extracts) (b)	CC₅₀ HUVEC: HEX: 26.72; DCM: 58.77; MeOH: 59.83/ SI 3D7: HEX: 1.09/DCM: 5.0/MeOH: 6.76 (a); CC₅₀ HUVEC: HEX > 100; DCM: 41.66; MeOH: 51.22; SI 3D7: HEX: ≤ 1/ DCM: 0.42/ MeOH: 0.51 (b)	NT
Piper tenuistylum	3D7: EtOH: 11.07; W2: 21.69	CC₅₀ HUVEC: 17.26/ SI 3D7: EtOH: 1.56	NT
Piper tridentipilum	3D7: EtOH: 22.28; W2: >100	CC₅₀ HUVEC: 23.96/ SI 3D7: EtOH: 1.08	NT
Piper trigonum	3D7: HEX, DCM and MeOH > 100	CC₅₀ HUVEC: HEX: > 100; DCM: 30.51; MeOH > 100; SI: HEX: ≤ 1/ DCM: 0.31/ MeOH: ≤ 1	NT
Piper umbellatum	FCR-3: 19.2	NT	NT
Piper verruculosum	3D7: HEX, DCM and MeOH > 100	CC₅₀ HUVEC: HEX, DCM and MeOH: > 100; SI: HEX, DCM and MeOH ≤ 1	NT
Piper xanthostachyum	3D7: HEX > 100; DCM: 6.33; HA > 100	CC₅₀ HUVEC: HEX > 100; DCM: 6.18; HA: 49.84; SI: HEX: ≤ 1/ DCM: 0.98/ HA: 0.50	NT
Pityrogramma calomelanos	FCR-3: 49.9	NT	NT
Potalia resinifera	FCR-3: (B) 6.2; (L) > 10; (R) 8.3	NT	NT
Pouteria guianensis	3D7: > 10	NT	NT
Prieurella prieurii	3D7: > 10	NT	NT
Protium amplum	F32: DCM: 32; D2: DCM: 50	CC₅₀ U-937: 56.8 /SI F32: 1.8/ D2: 1.1	NT
Protium puncticulatum	3D7 and Dd2: Low inhibition values: < 20% and < 5%	CC₅₀: Macrophage J774 branches: 34.20; leaves: 36.51/ Fibroblast (V79): branches: 94.56; leaves: 96.45/ Vero Cell: branches: 95.0; leaves: 97.0/ HepG2 branches and leaves: > 100	NT
Pseudolmedia laevis	FCR-3: 22.3	NT	NT
Psidium acutangulum	FcB1: 3.3; NF54: 10.3; 7G8: 19.0	Reduction at a concentration of 50 mg/mL. TNFα (18%), IL-1β (58%), IL-6 (32%), IL-8 (21%). The decoction was non-cytotoxic against L6 cells, RAW cells and PBMC: > 100 mg/mL.	Decoction of P. acutangulum aerial parts: 350 mg/Kg/day 39.7%
Remijia ferruginea	NT	NT	Bark 1.000 mg/Kg 48%; 500 mg/Kg 34 %
Renealmia alpinia	FCR-3: 10	NT	NT
Renealmia thyrsoidea	FCR-3: 6.8	NT	NT
Rollinia mucosa	FCR-3: 12.8	NT	NT
Roucheria columbiana	3D7: > 10	NT	NT
Ruellia ruiziana	FCR-3: 33.7	NT	NT
Sanchezia oblonga	FCR-3: 26.8	NT	NT
Scleronema micranthum	3D7 and Dd2: Low inhibition values: < 20 % and < 5%	CC₅₀: Macrophage J774 branches: 34.20; leaves: 36.51/ Fibroblast (V79): branches: 94.56; leaves: 96.45/ Vero Cell: branches: 95.0; leaves: 97.0/HepG2 branches and leaves: > 100	NT
Scoparia dulcis	FCR-3: 6.6	NT	NT
Senna reticulata	FCR-3: > 10	NT	NT
Senna ruiziana	FCR-3: 25.4	NT	NT
Simaba cedron	W2: 1.6	NT	NT
Simarouba amara	3D7: > 10 (a)	NT	NT
Siparuna aspera	FCR-3: 6.4 (b)	NT	NT
Siparuna radiata	FCR-3: 21.7	NT	NT
Sloanea schomburgki	3D7: 1.52. Filtrated on polyamide: 3D7: 0.36/ W2: 0.7	CC₅₀: 90.3. SI 3D7: 59,4/ SI 3D7 filtrated 250.8/ SI W2: 129	NT
Solanum peruvianum	FCR-3: 26.9	NT	NT
Stachytarpheta cayennensis	3D7: >10 (b)	NT	NT
Stigmaphyllon sinuatum	K1: CHCl₃ > 50/ EtOH > 50/ Aq > 50	NT	NT
Strychnos pseudoquina	NT	NT	Bark 1.000 mg/Kg 10%; 500 mg/Kg 0%
Swartzia simplex	3D7: 0.12/ filtrated on polyamide 3D7: 0.07/ W2: 0.77	CC₅₀: 100	NA
Tabernaemontana obliqua	F32: MeOH: 25/ D2: MeOH: 40	CC₅₀ U-937: 231.6/ SI F32: 9.3 / SI D2: 5.8	NA
Tachigali polyphylla	3D7: 0.04. Filtrated on polyamide: 3D7: 2.51/ W2: 2.66	CC₅₀: 86.1. SI 3D7: 2.152/ SI 3D7 filtrado: 34.3 / SI W2: 32.3	NT
Tessaria integrifolia	3D7: > 10	NT	NT
Triplaris weigeltiana	3D7: > 10	NT	NT
Uncaria guianensis	W2: Aq: > 50 (a)	NT	NT
Verbena littoralis	FCR-3: 23.5 (a); > 10 (b)	NT	NT
Vernonanthura patens	FCR-3: 38.7	NT	NT
Virola calophylla	3D7: > 10	NT	NT
Virola surinamensis	3D7: > 10	NT	NT
Vismia pozuzoensis	3D7: 22.9	NT	NT
Xylopia amazonica	W2: CHCl₃ 7.3/ Aq 10.5/ EtOH > 50/ CHCl₃ 19.5/ Aq > 50/ EtOH 9.8	CC₅₀ macrophages: Leaf: 33.9, > 200; branch: 29.2 and 6.9/ leaves SI CHCl₃: 4,6/ SI Aq: > 19.0/ branches SI CHCl₃: 1.5/ SI EtOH: 0.7	Leaf: CHCl₃ 250 mg/Kg/day: 52% day 5, and 11% day 7
Zanthoxylum djalma-batistae	W2: CHCl₃ 40.2/ Aq 15.6/ MeOH >50/ CHCl₃ 17.4/ Aq 32.5/ MeOH 21.8	CC₅₀ macrophages: leaf > 200; branch: 24.7 and > 200/ leaves SI CHCl₃: > 5 / Aq: > 12.8/ Branches CHCl₃: 1.4/ Aq: > 6.2/ EtOH: > 9.2	NT
NT = not tested. aLetters mentioned in the plant parts column were not specified by the authors. Plant extracts or fractions: Aq = Aqueous; BUT = Butanol; CHCl₃ = Chloroform; DCM = Dichloromethane; EtOH = Ethanol; ETOAC = Ethyl acetate; FO = Organic Fraction; HA = Hydroalcoholic; HEX = Hexane; MeOH = Methanol. IC₅₀ = Concentration required to Inhibit 50% of parasite growth. Strains or clones of P. falciparum: 3D7, F32, D2, Dd2, HB3, FcB1, NF54, 7G8, W2 and Ghana. CC₅₀ = value corresponding to the cytotoxicity to 50% of the cells. Cell lines: HepG2, BGM, Jurkat, MCF-7, DU145, T47D, U-937, MRC-5, L6 cells, J774, V79, Vero, HUVEC and Peripheral Blood Mononuclear Cells (PBMC). SI = Selectivity Index, that correspond to the ratio of the concentration toxic to host cells to the concentration that inhibits parasite growth. The letters in parentheses refer to the authors who were responsible for the studies and are mentioned in table 1.

Table 3: Pure substances described in plants from South America with their antiplasmodial and/or antimalarial activities evaluated.
Compounds	Plant Species	P. falciparum strain and in vitro IC₅₀ value (µg/mL)*	Reference
Brazniditumine	Aspidosperma nitidum	W2, inactive (data not shown)	[27]

Ellipticine	Aspidosperma vargasii	K1: 0.19; 3D7: 0.085	[49]
Olivacine		K1: 0.35; 3D7: 0.29
9-bromoellipticine + 7,9-dibromoellipticine		K1: 0.30; 3D7: 0.20
7,8,9-tribromoellipticine		NT
9-nitroellipticine		K1: 0.20; 3D7: NT
7-nitroellipticine		K1: 3.9; 3D7: 4.9
2-methyl-1,2,3,4-tetrahydroellipticine		K1: 1.1; 3D7: 3.5

Flindersiamine 3	Esenbeckia febrifuga	3D7: 72.5/ W2: 95.0	[59]
Skimmiamine 5		3D7: 43.0/ W2: 19.5
g-Fagarine 6		3D7: 25.0/ W2: 36.0
Alkaloid 7		3D7 e W2 >100
Rutaevine 8		3D7 e W2 > 100

Plumieride	Himatanthus articulatus	Inactive	[50]

Huberine	Picrolemma huberi	FCR-3, inactive	[60]
1-Hydroxy-canthin-6-one		FCR-3, inactive
Canthin-6-one		FCR-3, inactive
IC₅₀ = Concentration of the sample required to inhibit 50% of parasite growth. Strains or clones of P. falciparum: W2, K1, 3D7 and FCR-3. NT = Not Tested.

Table 4: Plants from South America used in traditional medicine with no data of antiplasmodial or antimalarial activities described in the eligible articles.
Plant Species	Ethnopharmacological uses	Reference in literature
Abelmoschus moschatus	Chayahuita	Not found
Abuta curarea	Chayahuita	[56]
Acalypha mapirensis	Yanesha communities	Not found
Allium sativum	Chácobo (a); Indigenous and Mestizo Amazonian groups (b)	[61]
Alpinia nutans	Indigenous and Mestizo Amazonian groups	Not found
Amburana cearensis	Chácobo	[62]
Anthurium croatii	Yanesha communities	Not found
Anthurium dombeyanum	Asháninka	Not found
Aristolochia stahelii	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	Not found
Aristolochia trilobata	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	Not found
Arrabidaea platyphylla	Chácobo	Not found
Ayapana triplinervis	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups (a); Chayahuita (b)	Not found
Banara guianensis	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	Not found
Banisteriopsis caapi	Indigenous and Mestizo Amazonian groups	[63]
Begonia parviflora	Yanesha communities	Not found
Bidens cynapiifolia	Chayahuita	Not found
Bixa orellana	Indigenous and Mestizo Amazonian groups (a); Chayahuita (b); Chácobo (c)	[64]
Brosimun rubescens	Indigenous and Mestizo Amazonian groups	[65]
Brunfelsia grandiflora	Indigenous and Mestizo Amazonian groups (a); Asháninka (b)	Not found
Calea montana	Yanesha communities	Not found
Campomanesia aromatica	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	Not found
Capparis coimbrana	Chácobo	Not found
Capparis osmantha	Chayahuita	Not found
Carludovica palmata	Asháninka	Not found
Caryodendron orinocense	Chayahuita	Not found
Cedrela fissilis	Chácobo	Not found
Ceiba pentandra	Indigenous and Mestizo Amazonian groups	[66]
Ceratophytum tetragonolobum	Chácobo	Not found
Cestrum hediondinum	Asháninka	Not found
Cestrum racemosum	Yanesha communities	Not found
Chaptalia nutans	Asháninka	Not found
Chenopodium ambrosioides	Chayahuita	[67]
Cinnamomum verum	Quilombola community	[68]
Citrullus lanatus	Quilombola community	[69]
Citrus aurantiifolia	Chayahuita (a)/ Chácobo (b)	Not found
Citrus limetta	Chácobo	[70]
Citrus medica	Indigenous and Mestizo Amazonian groups	Not found
Clibadium sylvestre	Asháninka	Not found
Clidemia hirta	Indigenous and Mestizo Amazonian groups	[47]
Clusia hammeliana	Yanesha communities	Not found
Cocos nucifera	Indigenous and Mestizo Amazonian groups (a); Chayahuita (b)	[71]
Coffea arabica	Indigenous and Mestizo Amazonian groups	[72]
Columnea guttata	Yanesha communities	Not found
Corytoplectus speciosus	Asháninka	Not found
Costus arabicus	Indigenous and Mestizo Amazonian groups	[73]
Costus guanaiensis	Chayahuita	Not found
Costus scaber	Chayahuita	Not found
Coutarea hexandra	Chácobo	Not found
Coutoubea spicata	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	Not found
Crescentia cujete	Indigenous and Mestizo Amazonian groups	[74]
Croton cajucara	Quilombola community	[75]
Croton lechleri	Chayahuita	[76]
Croton sacaquinha	Quilombola community	[77]
Curatella americana	Chácobo	Not found
Curcuma longa	Indigenous and Mestizo Amazonian groups (a); Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups (b); Chayahuita (c)	[78]
Cyclanthus bipartitus	Asháninka	Not found
Cyphomandra pendula	Chayahuita	Not found
Dalbergia riedelii	Quilombola community	Not found
Desmodium adscendens	Yanesha communities	Not found
Desmoncus mitis	Chayahuita	Not found
Dieffenbachia williamsii	Yanesha communities	Not found
Duroia hirsuta	Chayahuita	Not found
Ecclinusa ramiflora	Chayahuita	Not found
Elephantopus mollis	Chayahuita	[79]
Erythrina poeppigiana	Chayahuita	[80]
Euphorbia heterophylla	Yanesha communities	[81]
Ficus mathewsii	Chácobo	Not found
Geissospermum laeve	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	[82]
Geissospermum reticulatum	Chácobo	Not found
Gymnanthemum amygdalinum	Quilombola community (a); Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups (b)	[83]
Hamelia patens	Yanesha communities	Not found
Hebeclinum macrophyllum	Asháninka	Not found
Heliocarpus americanus	Yanesha communities	[82]
Hevea brasiliensis	Chácobo	Not found
Himatanthus sucuuba	Chayahuita (a); Asháninka (b); Quilombola community (c)	[84]
Homalomena picturata	Chayahuita	Not found
Hura crepitans	Chayahuita	[85]
Hymenaea courbaril	Indigenous and Mestizo Amazonian groups (a); Chácobo (b)	Not found
Hyptis lacustris	Yanesha communities	Not found
Hyptis pectinata	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	[86]
Ipomoea batatas	Chayahuita (a); Chácobo (b)	Not found
Iresine diffusa	Yanesha communities	Not found
Irlbachia alata	Yanesha communities	Not found
Jatropha curcas	Chayahuita (a); Chácobo (b)	[87]
Jatropha gossypifolia	Indigenous and Mestizo Amazonian groups	[88]
Justicia appendiculata	Asháninka	Not found
Lantana camara	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	[81]
Lantana cujabensis	Chácobo	[89]
Lantana trifolia	Chácobo	[90]
Laportea aestuan	Indigenous and Mestizo Amazonian groups	Not found
Leonotis nepetifolia	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	[81]
Leretia cordata	Chayahuita	Not found
Liabum eriocaulon	Yanesha communities	Not found
Lippia alba	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups (a); Asháninka (b)	[91]
Luffa operculata	Quilombola community	Not found
Machaerium acutifolium	Chácobo	Not found
Manihot esculenta	Chayahuita	Not found
Marsypianthes chamaedrys	Chayahuita	Not found
Maytenus krukovii	Chayahuita	Not found
Miconia albicans	Chácobo	Not found
Mikania guaco	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	Not found
Momordica charantia	Asháninka (a); traditional communities (b)	[82]
Monstera lechleriana	Chayahuita	Not found
Mussatia hyacinthina	Chayahuita	Not found
Myroxylon balsamum	Chayahuita	Not found
Nectandra cuspidata	Yanesha communities	[82]
Nicotiana tabacum	Asháninka	[92]
Ocimum basilicum	Asháninka	[93]
Ocimum campechianum	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	Not found
Oenocarpus bataua	Indigenous and Mestizo Amazonian groups	Not found
Oreocallis grandiflora	Yanesha communities	Not found
Ormosia nobilis	Chácobo	Not found
Parahancornia fasciculata	Quilombola community	[94]
Persea peruviana	Yanesha communities	Not found
Philodendron plowmanii	Asháninka	Not found
Phoradendron crassifolium	Yanesha communities	Not found
Phthirusa stelis	Yanesha communities	Not found
Phyllanthus amarus	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	[95]
Phyllanthus niruri	Indigenous and mestizo amazonian groups (a); Asháninka (b)	[96]
Picrolemma pseudocoffea	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	[97]
Piper lehmannianum	Shawi and mestizos	Not found
Piper longestylosum	Asháninka	Not found
Piper marginatum	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	[98]
Piper peltatum	Indigenous and mestizo Amazonian groups	[82]
Piper politaereum	Yanesha communities	Not found
Plectranthus barbatus	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	[73]
Pleiostachyopiper nudilimbum	Shawi and mestizos	Not found
Pouteria caimito	Indigenous and mestizo amazonian groups	[99]
Pseudobombax septenatum	Chácobo	[100]
Psychotria poeppigiana	Yanesha communities	[101]
Psidium guajava	Indigenous and mestizo amazonian groups (a); Chácobo (b)	[102]
Quararibea guianensis	Quilombola community	Not found
Quassia amara	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	[103]
Ricinus communis	Asháninka	[81]
Rinoreocarpus ulei	Chácobo	Not found
Ruta graveolens	Quilombola community	Not found
Sabdariffa rubra	Chayahuita	Not found
Saccharum officinarum	Indigenous and Mestizo Amazonian groups	[104]
Satiria panurensis	Yanesha communities	Not found
Selaginella conduplicata	Yanesha communities	Not found
Senna alata	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	[105]
Senna hirsuta	Chayahuita	[106]
Sesamum indicum	Quilombola community	[107]
Siparuna guianensis	Chayahuita (a); Chácobo (b); Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups (c)	[108]
Socratea exorrhiza	Chayahuita	[85]
Solanum betaceum	Chácobo	Not found
Solanum leucocarpon	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	Not found
Spondias mombin	Indigenous and Mestizo Amazonian groups	Not found
Stachytarpheta straminea	Indigenous and Mestizo Amazonian groups	Not found
Swinglea glutinosa	Afro-Colombian communities	[109]
Tabernaemontana linkii	Chácobo	Not found
Tabernaemontana sananho	Yanesha communities	Not found
Tagetes erecta	Indigenous and mestizo amazonian groups (a); Chayahuita (b); Asháninka (c)	[110]
Tapirira guianensis	Chácobo	[55]
Tetragastris panamensis	Yanesha communities	Not found
Theobroma speciosum	Chácobo	Not found
Tinospora crispa	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	[111]
Trigonia killipii	Chácobo	Not found
Triplaris americana	Chácobo	[82]
Triplaris poeppigiana	Chayahuita	Not found
Tripogandra serrulata	Yanesha communities	Not found
Trixis divaricata	Asháninka	Not found
Tynanthus panurensis	Chayahuita	Not found
Urera baccifera	Yanesha communities	Not found
Urera capitata	Asháninka	Not found
Urera laciniata	Asháninka	Not found
Vismia baccifera	Yanesha communities	Not found
Vismia macrophylla	Chácobo	Not found
Warszewiczia coccinea	Yanesha communities	Not found
Xanthosoma poeppigii	Chayahuita	Not found
Xanthosoma sagittifolium	Chayahuita	Not found
Xiphidium caeruleum	Yanesha communities	Not found
Zanthoxylum rhoifolium	Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups	[112]
Zingiber officinale	Chayahuita	[113]
*The letters in parentheses refer to the authors who cited the study populations, as shown in table 1.

Regarding the isolation and testing of pure substances, five plant species had their antiplasmodial and/or antimalarial activity evaluated: Aspidosperma nitidum, Aspidosperma vargasii, Esenbeckia febrifuga, Himatanthus articulates, and Picrolemma huberi (Table 3).

Among the 359 species found in the 27 articles, 174 that had been mentioned by 198 traditional communities lacked data on antiplasmodial and antimalarial activities. Considering this, a new search was conducted on the Google platform, PubMed, and Science Direct databases, and only 66 presented data on activity. The remaining 108 plant species have not yet had their activity evaluated in laboratory assays (Table 4).

Among the citations of the plant species by traditional communities, Chayahuita [36], an ethnic group from the Peruvian Amazon, was the most frequent (21.2%), followed by Chácobo (16.7%) [37], Yanesha (16.2%) [3], Indigenous and Mestizo Amazonian groups (13.1%) [38], Crioulo, Palikur, Galibi, Brazilian, Hmong and European groups (12.6%) [39], and Asháninka (11.6%) [40]. The other five communities were responsible for less than 10% of all citations [10,20,41-43].

Discussion

Human malaria remains one of the world's most significant parasitic diseases. It causes intense morbidity being lethal for over 600,000 people yearly. The emergence of P. falciparum resistance to available antimalarials, including artemisinin derivatives, and of P. vivax to chloroquine, highlights the urgent need for new therapies. Given that drug treatment remains the primary strategy to control the disease, the development of novel and effective antimalarial drugs is essential to combat this global health challenge.

Approximately 35% of medicines originate directly or indirectly from natural products, and about 25% of them from plants, proving to be an important resource for global pharmaceutical companies working on the development of new drugs [17]. Studies that analyze bioactive compounds from plants are therefore of great relevance for the discovery and development of new medicines for malaria and other diseases. This review evaluates the antiplasmodial and antimalarial activities, as well as the ethnopharmacology use of 389 plants from South America. The leaves were the plant part most frequently used probably because plants are ingested in the form of tea [40].

The ethnomedicinal indication of plants against malaria and fever represents 75.9% of all those mentioned. This is particularly interesting, since there is a greater chance of finding a plant with good activity when traditional knowledge is used. In contrast, the probability is around 1% to discover such activity through random selection of plant species [44].

As described in the present review, Peru was the country where most plants studies were carried out, followed distantly by Brazil and Bolivia. All three countries have the Amazon rainforest within their territories which offers a vast array of plant species with potential medicinal properties. The difference in the quantity of studies among them is likely to be a result of excessive bureaucracy and the high amount of investment necessary to develop qualified research. These challenges potentially hinder research efforts and limit the exploration of the full potential of the region’s biodiversity. Addressing these barriers is crucial to promoting further research and exploring the potential of plants found in the Amazon rainforest in the development of new therapies.

Among the 359 plant species evaluated, 185 had extracts and fractions evaluated in vitro and/or in vivoassays. Only six species were active in vitro and in vivo(Andropogon leucostachyus, Aspidosperma nitidum, Aspidosperma pyrifolium, Curarea toxicofera, Psidium acutangulum and Xylopia amazonica) which represents a low number of species compared to those that were tested in vitro. However, pure substances were rarely described. In addition, a larger number of plant species mentioned in the eligible articles have not yet had their antiplasmodial and/or antimalarial activity evaluated, thus encouraging the search for potential antimalarials among these species.

Among the active species evaluated in vitro, not all had their cytotoxicity assessed, which is a minimum requirement to determine the selectivity index of a given sample. Assessing cytotoxicity is critical for understand the safety profile of potential antimalarial compounds. This helps to determine whether the plant species selectively targets the parasite while being harmless to the host cells, ensuring a more comprehensive evaluation of their pharmacological properties.

By assessing acute toxicity early, researchers can mitigate human risks and ensure that only compounds with favorable safety profiles progress to further stages of development [45]. However, none of the plant species in the analyzed articles had their acute toxicity tested, which is different from what has been observed before in other studies [2]. Incorporating acute toxicity tests in preclinical studies of potential antimalarial compounds is essential to ensure the safety and efficacy of future treatments.

In most countries, combinations of antimalarials are used to treat malaria, although plants are often used as popular medicine in poor and endemic areas for treatment and as prophylaxis of this disease. Indeed, it is estimated that less than 10% of plant species have been studied for their pharmacological properties [46]. Therefore, using traditional knowledge can be an excellent strategy to search for new medicines, saving many steps in the investigation of new therapeutic options to combat malaria.

Acknowledgment

We are deeply thankful to Dr. Milena Botelho Pereira Soares for her English review.

Conflicts of interest

The authors declare no conflict of interest.

Author contributions

IPC conceived and led the study, wrote the text, designed the figures, helped to construct the tables; RCCA performed the bibliographic survey of the articles and prepared the tables; AK helped in the English correction and gave suggestions for improving the final work.

Funding

This work was supported by funds from the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG, N°APQ-01861-18), by the Instituto René Rachou, Fundação Oswaldo Cruz, Brazil, and for the author CNPq fellowship.