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Treating leishmaniasis in Amazonia: a review of ethnomedicinal concepts and pharmaco-chemical analysis of traditional treatments to inspire modern phytotherapies.

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Guillaume Odonne¹*, Emeline Houël², Geneviève Bourdy³, Didier Stien⁴

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¹: Laboratoire Ecologie, Evolution, Interactions des Systèmes Amazoniens (LEEISA), CNRS, Université de Guyane, IFREMER, 97300 Cayenne, France

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²: CNRS, UMR EcoFoG, AgroParisTech, Cirad, INRA, Université des Antilles, Université de Guyane, 97300 Cayenne, France.

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³: UMR 152 Pharma Dev, Université de Toulouse, IRD, UPS, France.

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⁴: Sorbonne Universités, UPMC Univ Paris 06, CNRS, Laboratoire de Biodiversité et Biotechnologies Microbiennes (LBBM), Observatoire Océanologique, Banyuls-sur-Mer, France

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Corresponding author: guillaume.odonne@gmail.com

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*: Corresponding author: guillaume.odonne@gmail.com

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Phone: +(594)594010008

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**Abstract:**

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**Ethnopharmacological relevance:**

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Cutaneous and mucocutaneous leishmaniasis are neglected tropical diseases that occur in all intertropical regions of the world. Amazonian populations have developed an abundant knowledge of the disease and its remedies. Therefore, we undertook to review traditional antileishmanial plants in Amazonia and have developed new tools to analyze this somewhat dispersed information.

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**Material and Methods:**

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A literature review of traditional remedies for cutaneous/mucocutaneous leishmaniasis in the Amazon was conducted and the data obtained was used to calculate distribution indexes designed to highlight the most relevant uses in Amazonia. The cultural distribution index represents the distribution rate of a given taxon among different cultural groups and was calculated as the ratio of the number of groups using the taxon to the total number of groups cited. The geographical

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distribution index allowed us to quantify spatial distribution of a taxon's uses in Amazonia and was
calculated geometrically by measuring the average distance between the points where uses have
been reported and the barycenter of those points. The general distribution index was defined as an
arithmetic combination of the previous two and provides information on both cultural and spatial
criteria.

## Results:

475 use reports, concerning 291 botanical species belonging to 83 families have been gathered depicted from 29 sources. Uses concern 34 cultural groups. While the use of some taxa appears to be Pan-Amazonian, some others are clearly restricted to small geographical regions. Particular attention has been paid to the recipes and beliefs surrounding treatments. Topical application of the remedies dominated the other means of administration and this deserves particular attention as the main treatments against Neotropical leishmaniasis are painful systemic injections. The data set was analyzed using the previously defined distribution indexes and the most relevant taxa were further discussed from a phytochemical and pharmacological point of view.

## Conclusions:

The Amazonian biodiversity and cultural heritage host a fantastic amount of data whose systematic investigation should allow a better large-scale understanding of the dynamics of traditional therapies and the consequent discovery of therapeutic solutions for neglected diseases. Distribution indices are indeed powerful tools for emphasizing the most relevant treatments against a given disease and should be very useful in the meta-analysis of other regional pharmacopeia. This focus on renowned remedies that have not yet benefitted from extended laboratory studies, could stimulate future research on new treatments of natural origin for leishmaniasis.

Keywords: Ethnomedecine, medicinal plants, distribution indices, interculturality, leishmaniasis, traditional medicine, Amazonia

# 1. Introduction

For years, ethnopharmacologists and ethnobotanists have tried to develop quantitative methods of understanding the use of biodiversity in traditional health systems, from field data collection to analysis. Quantitative analysis is mainly used in two ways; the first consisting of quantifying the importance of plant taxa among human groups, particularly by reaching a consensus amongst data from various informants (Alexiades & Sheldon, 1996; Hoffmann and Gallaher, 2007; Tardio & Pardo-
de-Santayana, 2008) and the second is understanding the complex relationship between peoples and their surrounding plant diversity (Bennett & Husby, 2008; Moerman, 1979; 2005; Moerman & Estabrook, 2003; Weckerle et al., 2011; 2012). Although the methods developed to establish plant use values, cultural importance indices or consensus analysis have led to the development of useful tools for ethnobotanical studies dealing with multiple use categories, these indices may also specifically refer to a single plant use, especially medicinal use (Heinrich et al., 1998; Moerman, 2007). The meta-analytic approach has also been considered to show that the selection of useful taxa is based on a logical process more than on a random selection, representing local biodiversity. In particular, Leonti et al. (2013) applied it in an evolutionary perspective to traditional uses and chemical data at pharmacopoeia level. However, from Milliken (1997) collecting information on antimalarial plants at Roraima scale, to Molander et al., (2012), focusing on snakebites and comparing anti-venom uses worldwide, works centered on single diseases are not so numerous.

Among them, Andrade-Cetto et al. (2006) developed for example a Disease-Consensus Index (DCI) for specifically analyzing ethnopharmacological field data from a Yucatec Mayan community and selecting useful plant species to treat type 2 diabetes. Eventually, other types of indices, such as those illustrated by Willcox et al. (2011) with the development of an evaluation score including both ethnobotanical and pharmacological data, were designed to prioritize antimalarial traditional remedies for further pharmacological and possibly clinical investigations. In general, strengthening the use of these methods to forge consensus, systematically review information and select plant species for further evaluation is one of the major challenges for ethnopharmacology in the forthcoming years (Heinrich et al., 2009; Leonti, 2011).

The need for intercultural comparisons of plant uses and more particularly medicinal ones, as previously emphasized by Heinrich et al. (1998), is continually growing in order to understand the intimate relationship between people and plants. However, this has been poorly addressed apart from Scarpa (2009) who summarized 573 ethnobotanical data from various bibliographical sources concerning wild food plants used by 10 indigenous groups of the Gran Chaco or the remarkable work of Camara-Leret et al. (2014) to understand the complexity of regional knowledge sharing of the geographical qualification and quantification of patterns of medicinal use, allowing comparisons between numerous cultural groups. In our group, we undertook to understand and quantify the use of medicinal plants against a single disease in a large geographical area. Owing to our previous experience, we decided to focus our study on leishmaniasis in Amazonia.

Plant knowledge in Amazonia is a highly dynamic field and intercultural exchanges are numerous, even if lightly documented (Milliken & Albert, 1996; Milliken, 1997; Camara-Leret et al., 2014). As an example, Lewis & Elvin-Lewis (1991) precisely describe how a remedy against snakebite prepared
from *Pentagonia gigantifolia* Ducke quickly transferred from the Candoshi to the Achuar in the Peruvian Amazon. These transfers are meaningful and we assume that a geographical and ethnomedical overview of the practices related to a given disease will help to precisely understand many aspects of this disease and its treatments and particularly its anthropologic rationales.

Moreover, over the last few years, our team has studied traditional antimicrobials of natural origin in many parts of Amazonia, from Peru to French Guiana. These studies have led to hundreds of new records of traditional uses (Bourdy et al., 1998; 2000; 2004; Vigneron et al., 2005; Estevez et al. 2007; Valadeau et al., 2009; 2010; Odonne et al. 2013), a better understanding of Amazonian medicines both on ethnomedical (Vigneron et al., 2005; Valadeau et al, 2010; Odonne et al., 2011a; 2013) and pharmacological bases (Bertani et al., 2005; Estevez et al, 2007; Houël et al., 2009; Odonne et al., 2009) and to the discovery of dozens of active molecules, some of them new to science (Bertani et al., 2006; Castillo et al., 2007; Portet et al., 2007; Cachet et al., 2009; 2012; Acebey et al., 2010; Cabanillas et al., 2012; Odonne et al., 2011b). In addition, this extensive work also led to the gathering of a rich bibliography concerning natural medicines in Amazonia and to critical insight on the globalization of Amazonian cultures.

Leishmaniasis are vector borne diseases, caused by several species belonging to the *Leishmania* genus, among which 15 species are human pathogens in the Americas and are transmitted by phlebotomine sand flies belonging to the *Lutzomyia* genus (PAHO, 2016). They are considered neglected tropical diseases (Hotez et al., 2008) and occur in the neotropics in three main forms: a cutaneous, a mucocutaneous and a visceral form (WHO, 2016). This disease complex, even if rarely fatal, is responsible for severe conditions. In Amazonia, 3 *Leishmania* species are prevailing: *Leishmania amazonensis*, *L. braziliensis* and *L. guyanensis*, along with a handful of less common species (Dedet, 1999). Not all species are present everywhere and, in our opinion, their spatial distribution might be an important clue to understand the regional specificity of traditional remedies. Briefly, *L. amazonensis* is present in Bolivia, Colombia, Brazil, Ecuador, French Guiana, Peru and Venezuela and leads to the less serious clinical forms. *L. braziliensis* is the most widespread, occurring in the same countries as *L. amazonensis*, but responsible for more cases. This species is known to cause both cutaneous and mucocutaneous forms and is thus considered to be more detrimental. Lastly, *L. guyanensis* is responsible for non-severe cutaneous forms. It is mainly present on the Guiana shield (North of Brazil, French Guiana, Suriname, Guyana and Venezuela) (Dedet, 1999). It is likely that *Leishmania* have been present in South America since the pre-Columbian era, as suggested by historical (Altamirano-Enciso et al., 2003), anatomical and histological evidence (Tuon et al., 2008). It has been suggested that the facial deformations observed on pre-Inca ceramics (Chimu, Moche) were representations of the invalidating mucocutaneous forms (Weiss, 1943;
Altamirano-Enciso et al., 2003). These artistic representations illustrate the relevance of the ethnopharmacological approach in the field of leishmaniasis, more particularly concerning cutaneous and mucocutaneous forms, which has already been widely discussed in Odonne et al. (2011a).
Briefly, they are generally well recognized diseases by local populations, with a high overlapping of local and biomedical definitions.

Based on ethnological and ecological considerations, Amazonia includes the Amazon basin, the Orinoco basin, the Guiana shield and the North of the Brazilian shield (Mato Grosso) (Erikson, 2001).
It is constituted of a patchwork of environments, from altitude cloud forests to mangroves, including lowland inundated forests (varzea) and savannahs. Politically, it is divided into nine countries: Bolivia, Brazil, Columbia, Ecuador, French Guiana, Guyana, Peru, Suriname and Venezuela (figure 1). Cultural groups present in this geographical area are numerous. For example, in 2001 Erikson counted more than 60 Amerindian groups in Peru, around 30 in Bolivia and more than 200 in Brazil. Amazonian inhabitants are commonly classified into 3 groups: Amerindian (or native South Americans), Maroons (i.e. people from African origin, escaped from slavery in the 18th century: Aluku, N'djuka, Saramaka...) and Mixed groups (Creoles, Mestizos, Caboclos and the rural populations of lowland Amazonia in general). Whereas the last groups mix European, Amerindian and African descents, they still have very singular cultures. In general, these different origins also notably influence the ethnopharmacopeias (van Andel et al., 2012; Vossen et al., 2014; Torres-Avilez et al., 2015). The patchwork of environments mentioned above might thus be compared to the patchwork of cultures and in both cases, they share constant factors. From the ecological point of view, a few hundred species among the more or less 16 000 tree species of the Amazon are widespread throughout the area and account for more than half of the individuals encountered (Ter Steege et al., 2013). Also numerous species are shared in the home gardens from the Amazon delta to the Andean slopes, supported by a long history of plant exchanges throughout the region (Clement et al., 2015). On the other hand, from the socio-cultural point of view, there is a common base in remedies used (see Schultes & Raffauf (1990) or Duke & Vasquez (1994) for overviews and overlapping of ethnopharmacopeias) or in general cultural concepts (see for example Erikson (2001) or Levi-Strauss (1964)).

Antileishmanial traditional phytoremedies are numerous and of frequent use, notably in Amazonia.
For many of them, pharmacological evidence of bioactivity no longer needs to be proven (Akendengue et al., 1999; Davies & Kedzierski, 2005; Fournet & Munoz, 2002; Ioset, 2008; Kaiser et al., 2003; Mishra et al., 2009; Rocha et al., 2005). However, although many traditional remedies are effectively shared by thousands of people across Amazonia (Cámara-leret et al., 2014; Roersch,
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2010), the precise reason for each use, whether it be emic or etic efficacy, is not always understood by researchers.

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Cultural considerations may indeed be underpinning diffusion process. According to a study realized in four Basque regions (Menendez-Baceta et al., 2015), cultural factors such as language, cultural meaning of plants, cultural identity or social network may indeed account for the structuration of local ethnofloras, even if some preparations were also highlighted to be widely used among the different regions of the study area. In the latter case, it can be hypothesized that ecological availability and chemical composition of the plants may explain the persistence of these widely spread remedies. This is consistent with the work of Moerman (2007), who studied information on 219 Native American groups and concluded that a consensus of use between different cultural groups tends to correlate with pharmacological activity. In fact, Saslis-Lagoudakis et al. (2012) proposed after analyzing phylogenetic patterns of representative floras that the: "*use of the same or related plants by people from different regions and cultures provides indirect evidence for bioactivity, if the similarities in medicinal floras are the result of independent discoveries rather than cultural transmissions*". This competition between cultural transmission and clinical objectivity has been studied by Tanaka et al. (2009), calculating through modelisation that the most active remedies are not always the most widespread. Nevertheless, his modeling lacks the geographical dimension. Eventually, assuming that on a large scale, the "cultural bias" might be less important than the pharmacological activity is controversial.

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Cultural distribution in Amazonia is an intermediate between a cultural continuum and a mosaic. The novelty of our proposition is to question if cultural exchanges necessarily balance biological activity, in a comparison involving more than 30 cultural groups. Quantifying the geographical distribution of a plant's use for a specific disease had never been realized and our objectives are double. On the one hand, the mechanisms underlying medicinal plant selection by local people are still poorly understood and such a study might help to define patterns of use at a regional scale, a first step before further investigation of this complex mix of culture, ecology and pharmacology. On the other hand, we aim to propose a practical tool to help pharmacologists and phytochemists in the selection of plants to be explored for antileishmanial nature-based solutions. Agreeing here again with Leonti (2011) when he argues that phytochemical/pharmacological exploration of ethnopharmacopeias is often done "*indiscriminately and overoptimistically*"; we suppose that having an inside view will lead to better detection of the pharmacological potential of a given species, allowing better assessment between the emic and etic perceptions of efficacy of antileishmanial remedies.

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## 2. Material and methods

### 2.1 Literature review

Bibliographic sources dealing with Amazonian ethnobotany were carefully revised between 2006 and 2014. We consulted books and journals from best sellers to old documents in libraries, as well as Ph. D. or Master's theses available on the web or in Peruvian, French and Brazilian libraries. Scopus, Google Scholar, Pubmed, Science Direct and SciELO databases were consulted using as many keywords related to Amazonian ethnobotany and leishmaniasis as possible. Unfortunately, many sources were useless for this study because our main criterion was a reliable correlation of described symptoms with cases of leishmaniasis. Classification in medicinal ethnobotany is a recurrent problem (Gruca et al., 2014; Staub et al., 2015) and clustering is often based on subjective organ or symptom defined criteria. Thus, many sources describing imprecise use-categories such as "wounds" or "dermatological affections" were rejected. Botanical names were updated according to APG3 nomenclature according to the Missouri botanical garden (Tropicos, 2016).

### 2.2 Setting up of distribution indices

To measure distribution of the antileishmanial use of each species on both a cultural and geographical level, three indices were defined: a geographical distribution index, a cultural distribution index and, lastly, a general distribution index combining both previously defined indices. Ecologists already model species diversity on a spatial scale, but their tools and the way they use them, are too complex for researchers that are not very close to statistical ecology. Here, we tried to set the simplest and most user-friendly index possible. To calculate these indices, a Use Record UR was defined as a combination of one species, used in one cultural group, cited in one reference. The same species used in the same group but cited by 2 references are then considered as 2 URs (although only occurring very few times).

#### 2.2.1 Geographical distribution index ($I_g$)

The geographical distribution index ($I_g$) aims to measure, for each species, the extent of the spatial distribution of its antileishmanial use reports. Each use report for a given species was located on a map of Amazonia (considered as an orthonormal system) in order to obtain a scatter plot. A pair of coordinates $(x_i, y_i)$ was attributed to each locality by placing the mouse cursor on the map with the Gimp 2.0 software. The coordinates $(x_b, y_b)$ of the barycenter of the scatter plot were calculated using Excel software. We measured the distance ($D_i$, without units) between each locality and the barycenter: $D_i = \sqrt{(x_i - x_b)^2 + (y_i - y_b)^2}$, and calculated the average of the distances $D_i$ (a$D_i$). The maximal theoretical distance ($D_{max}$) that can be observed between a dot and a barycenter is calculated as half of the distance between the two most distant use-reports for any plant species (the
Embera in Colombia and the rural population of Maranhão in Brazil) and is 512.7. Then we calculated the ratio Dᵢ/Dₘₐₓ in order to obtain a value ranging between 0 and 1, normalized by dividing by the maximal value of Dᵢ obtained (Dᵢₘₐₓ): Ig = (Dᵢ÷Dₘₐₓ) / Dᵢₘₐₓ. The closer to 0 the Ig value for a given species is, the more the use reports are restricted to a small area in Amazonia. The closer to 1 the Ig value is, the more the use reports are widespread over the region.

## 2.2.2 Cultural distribution index (I<sub>c</sub>)

The cultural distribution index (I<sub>c</sub>) aims to measure, for a given species, the ratio of cultural groups using that species as antileishmanial. Assuming that two use reports in two different groups was more significant than two use reports in only one group, we decided to count not the total number of use reports but the total number of groups using a plant species. Then, this number is divided by the maximum number of Amazonian groups using a same species (i.e. 10 groups, for *Spondias mombin*, *Anacardiaceae*). The value obtained ranges from 0 to 1 with 0 corresponding to a species with no use-reports and 1 corresponding to the species with the highest number of groups using it.

For some large groups, such as the Peruvian Mestizos cited by Kvist et al. (2006), only one group was counted in the I<sub>c</sub> calculation despite the 4 different places of study but the geographical localization was selected depending on the sub-group using the most the plant species.

## 2.2.3 General distribution index (I<sub>d</sub>)

The general distribution index (I<sub>d</sub>) is calculated as following for a given species, as the mean of the two former indices: I<sub>d</sub> = (I<sub>c</sub>+I<sub>g</sub>)/2

# 3. Results

## 3.1 Inventory of cultural groups and geographic distribution

Twenty-nine references have been selected after analysis and revision of the bibliography (table 1, also including anthropological references). They document leishmaniasis knowledge and therapeutic practices of 34 cultural groups (table 1). The groups are localized on figure 1. One of these groups, the H'mong present in French Guiana since the 1970's, arrived from Laos and are thus of recent Asiatic origin. The Teribe from Panama and the rural population of San Jose in Costa-Rica are not considered in the calculation of the indexes (as they are far from Amazonia) but as their remedies and perceptions are very similar to Amazonian ones, they were only included in the discussion.

Insert Table 1 synthesis of the results/groups

<table><thead><tr><td>ID</td><td>Cultural group</td><td>Country</td><td>local name</td><td>Use reports</td><td>References (ethno. & bota.)</td></tr></thead></table>
<table><tr><td>1</td><td>Aluku</td><td>French Guiana</td><td>azo</td><td>21</td><td>Agelas, 1999</td></tr><tr><td>2</td><td>Arawak</td><td>Guyana</td><td></td><td>34</td><td>Van Andel, 2000</td></tr><tr><td>3</td><td>Bora</td><td>Peru</td><td></td><td>1</td><td>Denevan &amp; Padoch, 1988</td></tr><tr><td>4</td><td>Brazilian</td><td>French Guiana</td><td></td><td>10</td><td>Agelas, 1999; Odonne et al., 2011a</td></tr><tr><td>5</td><td>Campa-Ashaninca</td><td>Peru</td><td></td><td>3</td><td>Reynel et al., 1990</td></tr><tr><td>6</td><td>Carib</td><td>Guyana</td><td></td><td>11</td><td>Van Andel, 2000</td></tr><tr><td>7</td><td>Chayahuita</td><td>Peru</td><td>ta'ta',<br/>huayani</td><td>60</td><td>Kvist et al., 2006; Estevez et al., 2007;<br/>Odonne et al., 2009</td></tr><tr><td>8</td><td>Chimane</td><td>Bolivia</td><td></td><td>4</td><td>Fournet et al., 1994a; Fournet et al.,<br/>1994b</td></tr><tr><td>9</td><td>Chinese</td><td>French Guiana</td><td></td><td>1</td><td>Agelas, 1999</td></tr><tr><td>10</td><td>Cocama</td><td>Peru</td><td></td><td>13</td><td>Kvist et al., 2006</td></tr><tr><td>11</td><td>costlanders</td><td>Guyana</td><td></td><td>9</td><td>Van Andel, 2000</td></tr><tr><td>12</td><td>Créoles</td><td>French Guiana</td><td>pian bois</td><td>56</td><td>Agelas, 1999; Grenand et al., 2004</td></tr><tr><td>13</td><td>Embera</td><td>Colombia</td><td>aidá</td><td>4</td><td>Morales, 1995</td></tr><tr><td>14</td><td>H'mong</td><td>French Guiana</td><td>txhab qawj</td><td>1</td><td>Agelas, 1999</td></tr><tr><td>15</td><td>Kali'na</td><td>French Guiana</td><td>aleko</td><td>11</td><td>Agelas, 1999</td></tr><tr><td>16</td><td>Karipuna</td><td>French Guiana</td><td></td><td>2</td><td>Agelas, 1999</td></tr><tr><td>17</td><td>Kechua</td><td>Bolivia</td><td></td><td>5</td><td>Fournet et al., 1994b</td></tr><tr><td>18</td><td>Matsigenka</td><td>Peru</td><td>tsirivaito</td><td>1</td><td>Shepard, 1999</td></tr><tr><td>19</td><td>N'djuka</td><td>French Guiana</td><td>busi yasi</td><td></td><td>Agelas, 1999</td></tr><tr><td>20</td><td>Palikur</td><td>French Guiana</td><td>yatuwe,<br/>yatuwa</td><td>25</td><td>Agelas, 1999; Grenand et al., 2004;<br/>Odonne et al., 2011a</td></tr><tr><td>21</td><td>Quichua (Napo)</td><td>Peru</td><td></td><td>1</td><td>Benett &amp; Prance, 2000</td></tr><tr><td>22</td><td>rural pop.</td><td>Bolivia</td><td>espundia</td><td>5</td><td>Fournet et al., 1994b</td></tr><tr><td>23</td><td>rural pop.</td><td>Brazil</td><td>lésh, boba,<br/>ferida brava</td><td>17</td><td>França et al., 1996; Moreira et al., 2002</td></tr><tr><td>24</td><td>rural pop.</td><td>Colombia</td><td>bejuco, yatevi</td><td></td><td>Isaza et al., 1999</td></tr><tr><td>25</td><td>rural pop.</td><td>Costa Rica</td><td>papalomoyo</td><td>12</td><td>Dobles-Ulloa &amp; Perriard, 1994</td></tr><tr><td>26</td><td>rural pop.</td><td>Ecuador</td><td>sarna brava,<br/>charra brava,<br/>marca de<br/>Santo<br/>Domingo, la<br/>colombiana</td><td>34</td><td>Weigel et al., 1994</td></tr></table>
<table><caption>**Table 1: Synthesis of the results by group.** The 473 URs (different from the 470 counted in the article) are due to 3 redundant use reports (same plant/same group/different source)</caption><tr><td>27</td><td>rural pop.<br>(Mestizo)</td><td>Peru</td><td>uta</td><td>38</td><td>Weiss, 1943; Hermoso et al., 2003; Kvist<br>et al., 2006; Castillo et al., 2007;<br>González-Coloma et al., 2012</td></tr><tr><td>28</td><td>Saramaka</td><td>French Guiana</td><td>busi yasi</td><td>8</td><td>Sauvain, 1989; Agelas, 1999</td></tr><tr><td>29</td><td>Shipibo-Konibo</td><td>Peru</td><td></td><td>7</td><td>Tournon, 2006</td></tr><tr><td>30</td><td>Tacana</td><td>Bolivia</td><td></td><td>11</td><td>Bourdy, 1998; Bourdy et al., 2000</td></tr><tr><td>31</td><td>Teko</td><td>French Guiana</td><td>kalasapa</td><td>10</td><td>Odonne et al. 2011a</td></tr><tr><td>32</td><td>Teribe</td><td>Panama</td><td></td><td>4</td><td>Gupta et al., 2005</td></tr><tr><td>33</td><td>Ticuna</td><td>Peru</td><td></td><td>4</td><td>Kvist et al., 2006</td></tr><tr><td>34</td><td>Warao</td><td>Guyana</td><td></td><td>5</td><td>Van Andel, 2000</td></tr><tr><td>35</td><td>Wayãpi</td><td>French Guiana</td><td>kalasapau</td><td>33</td><td>Grenand et al., 2004</td></tr><tr><td>36</td><td>Yanesha</td><td>Peru</td><td>mareñets</td><td>12</td><td>Valadeau et al., 2009</td></tr></table>

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Insert figure 1 (Distribution map of groups cited in the study)

<figure><img src="image_1.png" /><figcaption>**Figure 1: Repartition map of the groups cited in the study (in orange, extra-Amazonian groups).**</figcaption></figure>

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## 3.2 Designation and emic etiology of leishmaniasis across Amazonia

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In spite of the evidence of *Leishmania* presence in South America since ancient times, only few documents describe leishmaniasis and their causes from an emic perspective. In **table 1** the names of

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265 leishmaniasis in different Amazonian cultures are summarized.

266 Among the Matsigenka (Peru) two forms of leishmaniasis (*tsirivaito*) are recognized (Shepard, 2004).
267 They are strictly cutaneous and two insects are perceived as responsible. In one case a pathogenic
268 agent is thought to be transmitted by the pulsating glow of the lightning bug (*Lampyridae* order) and
269 in the other, the gnawing pincers of the click beetle (*Elateridae* order) is involved. Even if these
270 insects are different from the biomedical vector, it is interesting to see how close these etiologies are
271 to the biomedical one. In rural communities of the Choco region (Columbia), cutaneous leishmaniasis
272 is called *bejuco* and *yatevi* (Isaza et al., 1999). Two etiologies prevail in local perception: disease may
273 come either from a worm (*guzano*) living in mud or under tree leaves or from a liana (*bejuco*). A
274 mosquito transmitting the disease is finally evoked at a lower frequency. Still in the Choco but in
275 Embera groups, cutaneous ulcers linked to leishmaniasis (*aidá*) were brought to earth by the mythical
276 twins *Tutruika* and *Karagabi* (Morales, 1995). One can be affected by the disease after a social
277 transgression and particularly during female puberty and periods of mourning. In addition, *aidá*
278 appears here as a social sanction. In Costa-Rica (geographically far from our study area, but culturally
279 close enough to be discussed here) Dobles-Ulloa & Perriard (1994) have collected information about
280 knowledge and practices in the rural area of San Jose. They highlight a good knowledge of the disease
281 called *papalomoyo* and its variations: *papalomoyo seco, llorando, con hijitos*; respectively dry, crying
282 (wet), or with children (disseminated). These names may refer to the different clinical forms
283 (granulomatous, ulcerate or diffuse). This study also highlights the knowledge of the population
284 regarding the biomedical etiology, including the role of a fly vector. Still, the nature of the agent
285 transmitted is vague and it is sometimes said that the vector only transmits a poison picked up from a
286 poisonous animal (snake, toad). In Brazilian rural communities from Maranhão, Moreira et al. (2002)
287 report a good knowledge of the disease, even if the etiology is poorly known. It is named *lésh, boba,*
288 or *ferida brava*. Among the Yanesha (Peru), cutaneous leishmaniasis is called *mareñets* (Valadeau et
289 al., 2009). It is a spirit from the non visible world, pictured as a short legged man, carrying a heavy
290 bag, biting men or women, in order to make them die and live after their death a matrimonial union.
291 Also, Alexiades (1999) reports from the Ese-eja that leishmaniasis is caused by the spirit (the *eshawa*)
292 of a small undetermined fish.

293 We have previously shown that the Chayahuita (Peru) have a good knowledge of the disease and
294 consider *ta'ta* (cutaneous leishmaniasis) to be mainly transmitted by a leach, or to a lesser extent by
295 a mosquito (Odonne et al., 2009). The watery aspect of the disease is of a cultural importance. The
296 Teko and the Wayãpi from French Guiana also know leishmaniasis very well (*kalasapa* and *kalasapau*
297 respectively) and insects (everything but sandflies) are said to be the vector. The sign associated to
298 the *kalasapau* is the growth rate of the ulcer (Odonne et al., 2011a).
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From all of these perceptions of leishmaniasis, 3 classes of etiologies arise: the transgression of social rules, the action (physical or symbolic) of an animal or a spirit and contact with a plant. The first class is very representative of Amazonian Amerindian logic (Grenand & Grenand, 1981) and it is likely that this etiology was probably more represented before the arrival of Europeans. Some aspects deriving from the biomedical definition seem to be at least partially integrated into traditional concepts, mainly in non-Amerindians populations, in a form of cultural hybridization.

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### 3.3. Medicinal attitudes among Amazonian cultures

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As everywhere, disease is part of general systems of thought that structure knowledge. Here we aim to link the emic perception of leishmaniasis to the nature of the remedies. For the Chayahuita, the watery aspect of the disease, as previously mentioned, is seen as important. Thus, the consumption of chilies and salt is prohibited due to the nasal and ocular discharge associated with chili eating and to the hydrophilic properties of salt. The leishmaniasis is a cutaneous ulcer and the depth of the wounds is a sign of seriousness. Chayahuita avoid eating the meat from animals that dig (armadillos or tortoises for example) because the wound would enlarge immediately. This must be related to Shepard's statement (Shepard, 2004): "(...) illnesses are treated by ingesting or applying plants with strong, noxious sensory properties (bitter, astringent, pungent, caustic, and sour). Such properties are manifestations of the plant's soul (osure), a holistic healing force that infuses (okitsitingakero) the herbal decoction and the body of the patient. Pathogenic agents react to noxious properties much like humans, suffering pain and discomfort, retreating, and at high enough doses, perishing". Amongst the Yanesha, the skin ulcer is considered to be a sure indication of the attraction of Mareñets for someone. Part of the cure is based upon the necessity for the person to refrain any expression of pain or feeling of discomfort when treated with medicinal plants poultices applied topically, as it could be interpreted as the manifestation of a pain resulting from the separation with this spirit. In the contrary, it is said that the treatment will not be efficient (Valadeau et al., 2009).

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Amongst the Wayãpi Amerindians, the most important character of the disease is the speed of ulcer's growth. Thus, the selected plants are of two kinds: fast growing species, often encountered in second growth vegetation and species whose bark scars quickly after cutting. Alexiades (1999), discussing cutaneous ulcers of the Ese-eja, relates a symbolic association concerning the disease and its treatment: "Certain types of chihi, skin ulcers, are believed to be caused by (the eshawa of) minute fish who 'eat' away the flesh of their human hosts. The effect of certain plants applied over chihi is likened to that of fish poisons: indeed, shaka [Tephrosia sinapou (Buc'hoz) A. Chevalier, Fabaceae] is used both as a fish poison and as a cure for a number of skin infections". It appears clearly from the last examples that the way the disease is perceived induces different therapeutic consequences, both in the practices and in the choice of the plant remedies and particularly towards painful plants.
Nonetheless, it is almost impossible not to discuss one of the most widespread aspects, although not linked with medicinal plants. The title of Ramdas (2012) article: "*Cruel disease, cruel medicine...*" is evocative and perfectly reflects what has been observed throughout Amazonia. Household products (e.g. bleach), non-biomedical chemicals (e.g. battery acid, fuel), veterinary insecticides for example, are in common use in Colombia, Ecuador and Suriname (Isaza et al., 1999; Ramdas, 2012; Velez et al., 2001; Weigel & Armijos, 2001; Weigel et al., 1994). These practices have also been observed by the authors in French Guiana, Bolivia and Peru. Even if Ramdas (2012) claims that low income, remoteness and low levels of education might explain the use of these types of products, she also highlights a gender ideology, where masculinity is associated with toughness and courage, particularly amongst the Maroons that represent half of her sample. The use of many irritant plants throughout Amazonia should be related to this behavior.

## 3.4. Analysis of botanical traditional remedies

### 3.4.1 Galenic

Amongst the 475 URs of Table 1, precision concerning the method of application are only presented 211 times. Thus, 93.8 % (198/211) of the URs are strictly external and 6.1 % (7/211) strictly internal. Mixed applications occur for only 2.8 % (6/211). As far as external use is concerned, topical application (89.4 %; 177/198) is by far the most common, followed by washes (5.6 %; 10/198), washes and topical application together (4.5 %; 9/198) and fumigation (1.0 %; 2/198). In Odonne et al. (2013) we observed in the general Chayahuita pharmacopoeia, a balance between internal and external treatments. Lacking a global database of Amazonian remedies, and as these results seemed to be representative of Amazonian phytotherapy, we used them to compare practices concerning all diseases in general to leishmaniasis in particular. Here, the difference observed (Chi², 1 df, p<0.00001) clearly illustrates that the topical form is favoured for cutaneous leishmaniasis. This form of application is interesting when compared to its marginal status in chemotherapy (Blum et al., 2012). In fact, external administration is rarely employed in biomedicine and one of the major recommendations inspired by traditional use might be to reconsider it.

### 3.3.2 Plant parts

Out of 475 plants, our database only includes 359 URs with detailed plant parts (75.6 %). By order of decreasing importance, chlorophyllous parts (leaves, meristems and aerial parts of herbaceous taxa) occur for 33.1 % (119/359) of use reports, barks for 29 % (104/359), exudates (latex, resins and saps) for 17.8 % (64/359), roots and underground organs for 11.1 % (40/359), fruits and seeds for 9.5 % (34/359) and wood and stems for 4.5 % (16/359, total over 100 % due to multiple uses). The distribution of plant parts used against leishmaniasis versus all types of diseases (from Odonne et al.,
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2013) is once again clearly independent (Chi², 5 df, p<0.001), which we assume to be influenced by the nature of the disease treated, at least at least at an Amazonian scale.

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### 3.3.3 Families, genera most used

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Amongst the 83 plant families in table 1, the most cited are respectively Fabaceae (63 URs)

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Euphorbiaceae (38 URs), Solanaceae (26 URs), Araceae (23 URs), Anacardiaceae (22 URs), Asteraceae

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and Bignoniaceae (20 URs), Hypericaceae (18 URs), Rutaceae (16 URs) and Apocynaceae, Meliaceae and Rubiaceae (13 URs). Concerning the 201 genera cited, the most frequent are *Inga* (Fabaceae, 19

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URs), *Vismia* (Hypericaceae, 18 URs), *Citrus* (Rutaceae, 13 URs), *Piper* (Piperaceae, 11 URs), *Jatropha*

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(Euphorbiaceae, 10 URs), *Spondias* (Anacardiaceae, 10 URs), *Manihot* (Euphorbiaceae, 8 URs),

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*Anacardium* (Anacardiaceae, 7 URs), *Carapa* (Meliaceae, 7 URs) and *Solanum* (Solanaceae, 7 URs).

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Many of these families and genera are notably known to produce bioactive secondary metabolites (Zhu et al., 2011) and it would thus be interesting to search for a phylogenetic signal. However, we lack both a global Amazonian phylogeny, and to define the interesting chemical patterns to be correlated to these traditional uses.

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### 3.3.4 Ecology of species used

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Are cultivated plants more used than wild plants and does this depend on the population's degree of proximity to the forest? Furthermore, are introduced plants more commonly used than local ones?

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These are some of the questions that need to be answered. At first glance, with 218 species (324 URs) of strictly wild plants, 48 species (107 URs) of strictly cultivated plants and 25 species (44 URs) of both wild and cultivated plants, wild plants appear to be highly valued as antileishmanials.

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Although cultivated plants might be more easily accessed in daily use, the clear tendency to select wild plants is interesting and their ecological status, be they weeds or mature forest plants, would have been a valuable variable to explore (Stepp & Moerman, 2001), but difficult to implement in this study.

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Following the work of Bennet & Prance (2000), occasionally completed by general botanical bibliography and localizations given by GBIF.org (GBIF, 2016), we propose a rough "Amazonian native vs Amazonian exotic plants dichotomy". Plants with debatable status are few and do not significantly affect the analysis. Native plants account for 256 species (88%; 411 URs) whilst exotics account for 35 species (64 URs). In addition, results are very different in this field although Molares & Ladio (2009) observed a less contrasted proportion, with 39% of exotic species generally used as medicinal by the Mapuche in south American Patagonia which is similar to the 55% native vs. 45% exotics observed in Bahia state (Brazil) by de Santana et al. (2016), in the Atlantic Brazilian forest Alencar et al. (2014) observed a neat dominance of native plants (13 spp. vs 3 spp.) used for wound healing, the closest

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indication we found to antileishmanials. Pedrollo et al. (2016) observed a similar proportion of 80% of native plants used in a wide array of indications among riverine communities along the Rio Negro (Amazonian Brasil). In our opinion, as exotic plants are mainly cultivated (as food crops or as ornamentals) or weeds, they are more prone to be found around houses. A global reflection associating ecology (wild, cultivated, weeds) to geography is necessary and still needs to be undertaken in order to disentangle medicinal flora use patterns throughout Amazonia. Nevertheless, this predominant use of native species might be of interest to help define conservation policy in the region.

The present study also highlights the profound influence of humans on Amazonia. Pre-Columbian evidence of Amerindian-mediated floristic modifications are now numerous (Clement et al., 2015; Lins et al., 2015; Shepard & Ramirez, 2011), but this review shows that this could extend to present day and to less salient taxa. Medicinal use of many non-Amazonian cultivated plants, as well as of some exotic weeds, such as *Plantago major*, for example, is a good illustration.

### 3.4 Classification by distribution indexes

We restricted the calculation of the distribution indices to the plants with at least 3 URs (31 spp., table 2)

### Insert table 2: Distribution indices for the most used plants.

<table><thead><tr><td>Scientific name</td><td>I<sub>g</sub></td><td>I<sub>c</sub></td><td>I<sub>d</sub></td><td>Agr.</td><td>Or.</td></tr></thead><tbody><tr><td>Spondias mombin L.</td><td>0,73</td><td>1</td><td>0,86</td><td>W/C</td><td>Na</td></tr><tr><td>Nicotiana tabacum L.</td><td>1</td><td>0,5</td><td>0,75</td><td>C</td><td>Na</td></tr><tr><td>Citrus aurantifolia (Christm.) Swingle</td><td>0,84</td><td>0,6</td><td>0,72</td><td>C</td><td>Ex</td></tr><tr><td>Jatropha curcas L.</td><td>0,66</td><td>0,7</td><td>0,68</td><td>C</td><td>Ex</td></tr><tr><td>Musa x paradisiaca L.</td><td>0,79</td><td>0,5</td><td>0,65</td><td>C</td><td>Ex</td></tr><tr><td>Carica papaya L.</td><td>0,84</td><td>0,4</td><td>0,62</td><td>C</td><td>Na</td></tr><tr><td>Anacardium occidentale L.</td><td>0,52</td><td>0,7</td><td>0,61</td><td>C</td><td>Na</td></tr><tr><td>Chelonanthus alatus (Aubl.) Pulle</td><td>0,72</td><td>0,5</td><td>0,61</td><td>W</td><td>Na</td></tr><tr><td>Manihot esculenta Crantz</td><td>0,40</td><td>0,8</td><td>0,60</td><td>C</td><td>Na</td></tr><tr><td>Plantago major L.</td><td>0,89</td><td>0,3</td><td>0,60</td><td>W/C</td><td>Ex</td></tr><tr><td>Cedrela odorata L.</td><td>0,63</td><td>0,5</td><td>0,57</td><td>W</td><td>Na</td></tr><tr><td>Citrus limon (L.) Burm. F.</td><td>0,78</td><td>0,3</td><td>0,54</td><td>C</td><td>Ex</td></tr><tr><td>Jacaranda copaia (Aubl.) D. Don</td><td>0,74</td><td>0,3</td><td>0,52</td><td>W</td><td>Na</td></tr><tr><td>Bixa orellana L.</td><td>0,63</td><td>0,4</td><td>0,51</td><td>C</td><td>Na</td></tr><tr><td>Carapa guianensis Aubl.</td><td>0,22</td><td>0,7</td><td>0,46</td><td>W</td><td>Na</td></tr></tbody></table>
<table><caption>**Table 2: Distribution indices for the most used plants.**</caption><tr><td>Mangifera indica L.</td><td>0,61</td><td>0,3</td><td>0,46</td><td>C</td><td>Ex</td></tr><tr><td>Scoparia dulcis L.</td><td>0,50</td><td>0,4</td><td>0,45</td><td>W</td><td>Na</td></tr><tr><td>Brunfelsia grandiflora D. Don</td><td>0,24</td><td>0,6</td><td>0,42</td><td>W</td><td>Na</td></tr><tr><td>Jatropha gossypifolia L.</td><td>0,50</td><td>0,3</td><td>0,40</td><td>C</td><td>Ex</td></tr><tr><td>Inga alba (Sw.) Willd.</td><td>0,07</td><td>0,7</td><td>0,39</td><td>W</td><td>Na</td></tr><tr><td>Hura crepitans L.</td><td>0,26</td><td>0,5</td><td>0,38</td><td>W</td><td>Na</td></tr><tr><td>Vismia guianensis (Aubl.) Pers.</td><td>0,21</td><td>0,4</td><td>0,31</td><td>W</td><td>Na</td></tr><tr><td>Senna alata (L.) Roxb.</td><td>0,15</td><td>0,4</td><td>0,28</td><td>W</td><td>Na</td></tr><tr><td>Croton lechleri Muell. Arg.</td><td>0,20</td><td>0,3</td><td>0,25</td><td>W</td><td>Na</td></tr><tr><td>Aloe vera (L.) Burm. F.</td><td>0,19</td><td>0,3</td><td>0,24</td><td>C</td><td>Ex</td></tr><tr><td>Curarea tecunarum Barneby & Krukoff</td><td>0,08</td><td>0,3</td><td>0,19</td><td>W</td><td>Na</td></tr><tr><td>Calycophyllum spruceanum (Benth.) Hook. f. ex K. Schum.</td><td>0,08</td><td>0,3</td><td>0,19</td><td>W</td><td>Na</td></tr><tr><td>Momordica charantia L.</td><td>0,05</td><td>0,3</td><td>0,18</td><td>W/C</td><td>Ex</td></tr><tr><td>Chromolaena odorata (L.) King & Robinson</td><td>0,05</td><td>0,3</td><td>0,18</td><td>W</td><td>Na</td></tr><tr><td>Gossypium barbadense L.</td><td>0,05</td><td>0,3</td><td>0,18</td><td>C</td><td>Na</td></tr><tr><td>Pentaclethra macroloba (Willd.) Kuntze</td><td>0,05</td><td>0,3</td><td>0,17</td><td>W</td><td>Na</td></tr></table>

Agr.: agricultural status; W: wild; C: cultivated. Or.: origin of the species; Na.: native from Amazonia; Ex.: exotic.

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417 3.4.1 Taxa with the highest distribution values

418 In this subchapter, we aim to briefly discuss how these patterns might testify to different aspects of ethnobotanical use and how they can be used both to select interesting candidates for further evaluation, or to understand use patterns in Amazonian societies, bridging ethnology and pharmacology. **Figure 2** is a graphical representation of the species depending on their $I_g$ and $I_c$, allowing clusters to be visually determined. These clusters are not representative of any mathematical formula, but might reflect some different patterns.

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424 Insert figure 2: graphical representation of the species depending on their $I_g$ and $I_c$
<figure><img src="image_2.png" /><figcaption>Figure 2: Graphical representation of the species depending on their I<sub>d</sub> and I<sub>c</sub></figcaption></figure>

### 3.4.1.1. High I<sub>d</sub>

A high I<sub>d</sub> probably means that a plant is widely used, testifying to a compromise between availability (the first 7 plants are cultivated), cultural relevance, and pharmacological success. Disentangling cultural and pharmacological aspects is a complex issue and the persistency of a use despite a moderate activity has been addressed by Tanaka et al. in 2009 in a convincing way. Traditional phytochemical analyses, derived from bio-guided fractionation, might fail in the study of these plants, but an integrated approach, notably implementing *in vivo* assays, has a greater chance of success. In this cluster of species, the first 5 are *Spondias mombin*, *Nicotiana tabacum*, *Citrus aurantifolia*, *Jatropha curcas* and *Musa x paradisiaca*. Interestingly, they are all cultivated and widespread in Amazonia, *C. aurantifolia* and *M. x paradisiaca* were both introduced during the colonial era. In this case the low activity/high availability compromise is a path that needs to be explored.

### 3.4.1.2 Medium to low I<sub>c</sub>, high I<sub>g</sub> (green)

A low I<sub>c</sub> means fewer groups using the plant, but a high I<sub>g</sub> means a wide distribution range. Due to the fact that all of these plants are common throughout Amazonia, we could hypothesise that species in this cluster arose by convergence of practices rather than by cultural dissemination. In this case, pharmacological activity would probably be easier to detect. This cluster seems thus the most
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interesting for pharmacological development. Interestingly, wild plants such as *Chelonanthus alatus*,
*Plantago major* or *Jacaranda copaia* are more numerous in this cluster.

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3.4.1.3 High I<sub>c</sub>, low I<sub>g</sub> (yellow)

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Three plants belong to this cluster: *Inga alba*, *Carapa guianensis* and *Brunfelsia grandiflora*. They reflect highly localised and therefore highly locally shared uses. The first two species are actually very widespread, but the third one, although present in all the Amazon, is much more frequent in the Western part of the area. From our sources, *C. guianensis* is used throughout the Guiana shield (French Guiana, Guyana) while *I. alba* is only used in French Guiana. Conversely, *B. grandiflora* is only used in Peru. Two types of hypotheses might there be formulated: a cultural one, with a highly culture-dependent perception of these plants, where neighbouring groups, more prone to sharing cosmological concepts, also share plants. This might be the case for *C. guianensis*, which provides *Andiroba* oil, the main preventive/protective oil used throughout the Guiana shield. The other hypothesis relies on biologic variability: these patterns might either reflect chemical variations between eastern or western chemotypes, or a different pathosphere, i.e. different species or sub-species of *Leishmania* with different responses to allelochemicals, appearing as a kind of regional pharmacological match between plants used and parasites. As the Guiana shield is mainly affected by *Leishmania guianensis*, this hypothesis potentially explains the uses of *I. alba* or *C. guianensis* in this area. Lastly, the case of *B. grandiflora* is certainly explained by its restricted distribution, nevertheless making it an interesting candidate for evaluation.

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3.4.2 Phytochemical and pharmacological review

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A bibliographical survey was undertaken for the 10 species with the highest I<sub>g</sub>. Major metabolites are presented hereafter, along with some activities of extracts and pure molecules when available. The review was limited to the plant part used as recorded in **table 3 in supplementary data**. We concentrated on antileishmanial activities, and antitrypanosomal activities were treated as they are closely related to Leishmaniasis. Antibacterial activities are also reported due to frequent co-infections, the reduction of a bacterial co-infection leads to a perceived improvement by traditional societies. Antifungal activities are also reported due to the taxonomic proximity between yeasts and *Leishmania*, leading to a therapeutic translation where antifungals achieve good results against *Leishmania* (Houël et al., 2015). Lastly, due to the intramacrophagic location of the parasites, inflammatory processes subtending the pathogenesis and immunity in general, are key targets in leishmaniasis healing (Alexander & Russel, 1992; Sher & Coffman, 1992; Soong et al., 1997; Matte & Olivier, 2002).

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1. *Spondias mombin* (leaves and bark)
To our knowledge, few data are available concerning *S. mombin* leaves and bark chemistry. This

species is characterized by the presence of flavonol-3-O-glycosides, with quercetin-3-O-rutinoside

being identified as the major phenolic compound in a methanolic leaf extract (Pereira et al., 2015).

Quercetin, isoquercetin, ellagic acid and chlorogenic acid were also identified in hydromethanolic or

hydroethanolic leaves extracts (Cabral et al., 2016; da Silva et al., 2012), and ellagitannins (geraniin

and galoilgeraniin) and phenolic acids (6-alkenyl-salicylic acids) from *S. mombin* leaves and stems

hydroethanolic extract (figure 3) (Corthout et al., 1991; Corthout et al., 1994). Moreover, 3β-olean-

12-en-3-yl (9Z)-hexadec-9-enoate was isolated from methanolic leaf extract (Fred-Jaiyesimi et al.,

2009).

Using carrageenan-induced peritonitis model in mice, a significant anti-inflammatory effect was

demonstrated for hydroethanolic leaf extract at 300 and 500 mg/kg, by inhibiting leukocyte

migration to the peritoneal cavity and without cytotoxicity in vitro on 3T3 fibroblast cells. The same

activity was observed for ellagic acid and chlorogenic acid pure compounds at doses of 2.5, 5 and 10

mg/kg (Cabral et al., 2016). Similar results concerning anti-inflammatory activity have also been

obtained by Nworu et al. (2011) on methanolic leaf extract, which reduced the production of LPS-

induces TNF-α and NO in a dose-dependent manner and inhibited carrageenan-induced paw edema

at doses of 100, 200, and 400 mg/kg per os.

A moderate antibacterial activity was demonstrated for a hydromethanolic leaf extract, with MIC

values of 125 µg/ml against *Serratia marcescens*, *Proteus mirabilis* and *Enterobacter cloacae* (da Silva

et al., 2012). Phenolic acids isolated from leaves and stems also exhibited strong antibacterial activity

(MIC in the 3-25 µg/ml range) against *Bacillus cereus*, *Streptococcus pyogenes* and *Mycobacterium*

fortuitum* (Corthout et al., 1994). Anticandidal activity was demonstrated for a crude methanolic

extract of *S. mombin* bark and leaves (Okwuosa et al., 2012).

No antileishmanial activity was detected for *S. mombin* ethanolic bark extract on *L. major*

promastigotes (Kvist et al., 2006) or *L. amazonensis* axenic amastigotes (Estevez et al., 2007). Bark

aqueous decoction was also inactive on *L. guyanensis*, *L. major* and *L. donovani* promastigotes as well

as on *L. donovani* amastigotes, with IC₅₀ > 500 µg/ml in all cases (Mans et al., 2016). *S. mombin* bark

extracts were also inactive against *L. infantum* but exhibited strong antitrypanosomal activity (IC₅₀ in

the 2.3-12.2 µg/ml range) against *T. brucei brucei* (Traore et al., 2014). Interestingly, two fractions

obtained from a methanolic extract of *S. mombin* leaves and consistent with galloylquinic acids, were

inactive against *L. chagasi* promastigotes (IC₅₀ > 200 µg/ml) but exhibited IC₅₀ of 0.6 and 17.1 µg/ml

respectively against the amastigote stage. A third fraction, presenting chemical characteristics of

galloyl-glucose, exhibited an IC₅₀ of 0.3 µg/ml against *L. chagasi* amastigotes (Accioly et al., 2012).
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Eventually, biological evaluation of *S. mombin* extract did not display any cicatrizant activity (Villegas et al., 1997).

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<figure><img src="image_3.png" /></figure>

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**Figure 3:** Anti-inflammatory and antibacterial compounds isolated from *S. mombin* leaves and stems

2. *Nicotiana tabacum* (leaves).

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Besides the well-known alkaloid nicotine and other alkaloidic compounds (nornicotine, anabasine, anatabine) (Saitoh et al., 1985), *N. tabacum* leaves contain various classes of compounds: isoindolin-1-ones (Yang et al., 2016), isocoumarins (Wang et al., 2016), isoflavones and other flavonoids such as kaempferol and derivatives, quercetin and derivatives, taxifolin or moraclacone A (Li et al., 2015; Chen et al., 2013), lignans and lignan derivatives (Chen et al., 2012; Hu et al., 2012), phenylpropanoids (Leng et al., 2014) and sesquiterpenes (figures 4a & 4b) (Shang et al., 2016; Shen et al., 2016). Leaf cuticular wax of *Nicotiana* sp., in particular *Nicotiana tabacum*, contains cembranoid diterpens (Baraka et al., 2011).

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No data seems available for antileishmanial or antitrypanasomal activities, nor for anti-inflammatory or immunomodulatory effects of *N. tabacum* extracts.

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No conclusive results were obtained concerning antibacterial activity of *N. tabacum* extracts (Kalayou et al., 2012).
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<figure><img src="image_4.png" /><figcaption>**Figure 4a:** Recently isolated constituents of *N. tabacum* leaves</figcaption></figure>

<figure><img src="image_5.png" /></figure>

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532 **Figure 4b:** Recently isolated constituents of *N. tabacum* leaves

533 3. *Citrus aurantifolia* (fruit, bark)
Numerous flavonoids such as isorhamnetin derivatives, luteolin and luteolin derivatives, apigenin and
apigenin derivatives, narigin, rutin, quercetin and quercetin derivatives, kaempferol, nobiletin,
hesperidin and eriocitrin were identified from methanol and ethyl acetate extracts of peel and juices
of *C. aurantifolia* (Brito et al., 2014; Costa et al., 2014; Loizzo et al., 2012). Coumarins and
furocoumarins, such as bergamotin, 5-geranyloxypsoralen or 5,7-dimethoxycoumarin were also
identified in *C. aurantifolia* peel and juice (figure 5) (Costa et al., 2014; Sandoval-Montemayor et al.,
2012). Limonoids (limonexic acid, isolimonexic acid, and limonin) are present in *C. aurantifolia* juice
(Patil et al., 2009). *C. aurantifolia* fruits are also characterized by the presence of essential oil, the
major compound being limonene, alongside with α-terpineol, γ-terpinene, β-pinene, neral, geranial
and coumarins (Amorim et al., 2016; Craske et al., 2005).

No evaluation of antileishmanial properties of *C. aurantifolia* was found in literature. Weak activity
has been measured for *C. limon* root extract against *L. major* promastigotes and *C. paradisi* root
extract was shown as inactive against *L. major* promastigotes (Kvist et al., 2006). Interestingly
however, limonene and derivatives show activity *in vitro* against *L. braziliensis* promastigotes
(Graebin et al., 2010) and pure limonene applied topically led to a significant reduction of lesion sizes
and a notable decrease in the parasite burden in *L. amazonensis*-infected mice (Arruda et al., 2009).

Immunomodulatory properties of concentrated lime juice extract were demonstrated on PHA
activated human mononuclear cells (Gharagozloo & Ghaderi, 2001). Anti-inflammatory properties
were also demonstrated, measuring the effect of *C. aurantifolia* essential oil on inflammation models
in mice. Inhibition of cytokines and NO production was also observed for the essential oil and pure
limonene. However, *C. aurantifolia* induced myelotoxicity in mice, which could be due to the
presence of citral (Amorim et al., 2016).

As far as antimicrobial activity was concerned, 5,8-dimethoxypsoralen, 5-geranyloxypsoralen,
palmitic acid, linoleic acid, oleic acid, 4-hexen-3-one and citral, isolated or identified from a hexane
extract of *C. aurantifolia* peels, were active against *Mycobacterium tuberculosis*, with MIC values in
the 25-100 µg/ml range (Sandoval-Montemayor et al., 2012). Antibacterial activity against the same
microorganism has also been demonstrated for a hexane peel extract (Camacho-Corona et al., 2008).
Methanolic extract of *C. aurantifolia* fruit also exhibited antimicrobial activity against various Gram-
negative and Gram-positive micro-organisms (Melendez & Capriles, 2006).
<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /><figcaption>**Figure 5:** Antibacterial furanocoumarins isolated from *C. aurantifolia* peel extract</figcaption></figure>

4. *Jatropha curcas* (latex, leaves, bark, fruit, roots)

*Jatropha curcas* phytochemistry has been extensively studied and constituents isolated from various organs were specifically reviewed by Zhang et al. (2009). Diterpenes and diterpenoids represent an important class of compounds isolated from diverse *J. curcas* plant parts, e.g. jatrophalactone, jatrophalone and jatrophadiketone (Liu et al., 2012) curcusones A, B and spirocurcasone (Chianese et al., 2011; Li et al., 2014) isolated from roots, jatrophodione from aerial parts methanolic extract (Xu et al., 2011), or jatrocurcadiones A and B from twig ethanolic extract (Bao et al., 2015). Most of these compounds have been tested for cytotoxic activity (Li et al., 2014; Liu et al., 2012; Xu et al., 2011).

Lignans and coumarins are also a representative class of *J. curcas* compounds (Zhang et al., 2009). In particular, the lignans jatrophasins A, C and D were isolated from dried seed ethanolic extract (Li et al., 2014). Lignans, such as curcaslignan A-D, are also present in aerial plant parts (Xu et al., 2012).

Phytosterols are mostly found in leaves (e.g. campsterol, stigmasterol and β-sitosterol) (Ribeiro et al., 2012), whereas seeds are characterized by the presence of phorbol esters (*Jatropha* factors C1-C6) (Haas et al., 2002). Cyclic peptides (curacycline A and B) were isolated from *J. curcas* latex, alongside with the protease curcain (Auvin et al., 1997; Van den Berg et al., 1995; Nath & Dutta 1991).

An aqueous decoction of *J. curcas* root bark was tested for antiprotozoal activity against *Trypanosoma b. brucei*, *T. cruzi*, *Leishmania infantum*. An $IC_{50}$ of 30.3 µg/ml was measured against *T. b. brucei*, but the extract was shown to be inactive in the other bioassays (Musuyu Muganza et al., 2012). Interestingly, jatrogrossidione isolated from *J. grossidentata* roots, and jatrophone isolated from *J. isabellii* roots exhibited notable antileishmanial activities *in vitro* against *L. braziliensis*, *L. amazonensis* and *L. chagasi* (promastigote forms, and amastigote forms infecting macrophages).

Jatrophone, also identified in *J. gossypifolia*, was also active *in vivo* against *L. amazonensis*, but exhibited significant toxicity (Schmeda-Hirschmann et al., 1996).

Noticeable anti-inflammatory activity of *J. curcas* acetone leaf extract was measured using nitric oxide (NO) production measurement and 12-lipoxygenase (LOX) inhibitory bioassay. The extract had a significant effect on LOX inhibition at 100 µg/ml, and inhibited 92.7 to 85.0 % of NO production at
concentrations ranging from 50 to 6.25 µg/ml in a dose-dependant manner (Dzoyem & Eloff, 2015). A strong inhibition of NO production was also demonstrated for a root extract, which however also showed high cytotoxicity. According to the authors, the anti-inflammatory activity of the root extract could be due to the presence of hexadecanoic acid methyl ester, octadecanoic acid methyl ester and octadecanoic acid (Othman et al., 2015). *Jatropha curcas* root powder applied topically in paste form in distilled water significantly reduced ear inflammation in mice at the dose of 1.0 mg per ear and this anti-inflammatory activity was also observed for the methanol extract in various induced oedema models (Mujumdar & Misar, 2004). *J. curcas* crude latex (Villegas et al., 1997) and bark extract (Shetty et al., 2006) exhibited significant wound healing activity *in vivo*. Lastly, curacycline A was shown to exhibit anti-inflammatory properties by inhibiting the classical pathway complement activity and human T-cell proliferation in a moderate dose-dependant manner (Van den Berg et al., 1995).

Antimicrobial activity of *J. curcas* leaf methanolic extract was also studied against various strains of fungi and bacteria (Villaseñor & Cariño, 2011). Palmarumycins CP1, JC1 and JC2, three deoxypreussomerins isolated from *J. curcas* stems, were active against *Staphylococcus aureus* (Ravindranath et al., 2004).

<figure><img src="image_8.png" /><figcaption>**Figure 6:** Antimicrobial compounds (palmarumycins) isolated from *Jatropha curcas* stems and antileishmanial compounds (jatrogrossidione and jatrophone) isolated from *J. grossidentata* and *J. isabellii* roots</figcaption></figure>

5. *Musa x paradisiaca* (leaves, fruit peels)
612 Tannins and steroids of a methanolic extract obtained from *M. paradisiaca* leaves were identified
613 using colorimetric and spectroscopic detection (Accioly et al., 2012). Fruit peel methanol extracts led
614 to the isolation of the acyl steryl glycosides sitoindoside-I, sitoindoside-II, sitoindoside-III and
615 sitoindoside-IV, and of the glycoside sitosterol gentobioside and sitosterol *myo*-inosityl-β-D-
616 glucoside. Some of these compounds were responsible for the anti-ulcerogenic activity of the
617 extracts (Ghosal, 1985; Ghosal & Saini, 1984).

618 Similar compounds, i.e., triterpenes and sterols isolated from *M. paradisiaca* fruit peels, were tested
619 for antileishmanial activity against *L. infantum chagasi* promastigotes and amastigotes. 31-
620 Norcyclolaudenone, 24-methylene-cicloartanol and a mixture of β-sitosterol and stigmasterol
621 exhibited activities similar to pentamidine against promastigotes, with EC₅₀ values of 39.3, 14.3 and
622 16.5 µg/ml, respectively, and cycloeucalenone, 24-methylene-cicloartanol, and the mixture of β-
623 sitosterol and stigmasterol (figure 7) exhibited statistically similar activity to amphotericin B against
624 amastigotes, yet with large confidence intervals (Silva et al., 2014).

625

<figure><img src="image_9.png" /></figure>

626

<caption>627 **Figure 7:** Leishmanicidal triterpenes and steroids isolated from *Musa x paradisiaca*</caption>

628 In addition, five compounds were isolated from a methanol extract of the fruits of *Musa x*
629 *paradisiaca*: hydroxyanigorufone, rel-(3S,4aR,10bR)-8-hydroxy-3-(4-hydroxyphenyl)-9-methoxy-
630 4a,5,6,10b-tetrahydro-3H-naphtho[2,1-b]pyran, 1,2-dihydro-1,2,3-trihydroxy-9-(4-
631 methoxyphenyl)phenalene, 2-(4-hydroxyphenyl)naphthalic anhydride and 1,7-bis(4-
632 hydroxyphenyl)hepta-4(E),6(E)-dien-3-one (figure 8) (Jang et al., 2002). Previously, two phenalenone
633 phytoalexins, irenolone and emenolone, had also been isolated from an ethyl acetate extract of
634 *Musa x paradisiaca* leaves and green fruits treated with kanamycin as inducer (figure 8) (Luis et al.,
1993). It is of notable interest that antifungal phenyl-phenalenone phytoalexins (anigorufone as well as precursors and derivatives, particularly 2-methoxy-9-phenyl-phenalen-1-one, **figure 8**) isolated from *M. acuminata* plants submitted to fungal stress exhibited moderate leishmanicidal activities against *L. infantum* axenic amastigotes (LC₅₀ in the 10.5-23.9 µg/ml range) and *L. donovani* promastigotes (LC₅₀ in the 10.3-68.7 µg/ml range) (Luque-Ortega et al., 2004).

<figure><img src="image_10.png" /><figcaption>**Figure 8:** Compounds isolated from fruits and leaves of *Musa x paradisiaca*, alongside two antileishmanial phytoalexins (anigorufone and 2-methoxy-9-phenyl-phenalen-1-one) isolated from *Musa acuminata*.</figcaption></figure>

Moreover, fractions obtained from a methanolic extract of *M. x paradisiaca* leaves were subjected to antileishmanial activity evaluation against *L. chagasi* promastigotes and amastigotes. Two of them exhibited IC₅₀ values < 2 µg/ml against promastigotes. Against the amastigote stage, their respective IC₅₀ were of 14.2 and 16.5 µg/ml. In terms of chemical composition, the data concerning these fractions indicated the presence of condensed tannins (Accioly et al., 2012).
650 Anti-inflammatory properties of *M. x paradisiaca* extracts were also evaluated. A decoction of fresh
651 leaves topically applied on *Croton* oil-induced ear oedema in mice significantly reduced the lesion
652 (Brito Alvarez et al., 2014). Likewise, stem juice methanol extract at a dose of 200 and 400 mg/kg
653 orally exhibited significant anti-inflammatory activity in a dose-dependent manner in various oedema
654 models in rats (Biswas et al., 2012). Interestingly, wound healing activity was also demonstrated for
655 *M. sapientum* var. *paradisiaca* aqueous and methanolic extracts at 100 mg/kg in rats, decreasing
656 wound area, scar area and lipid peroxidation in particular (Agarwal et al., 2009).

657 An alcoholic extract of *M. x paradisiaca* stems tested for antimicrobial activity did not inhibit the
658 growth of various pathogens (*Staphylococcus aureus*, *Salmonella paratyphi*, *Shigella dysenteriae*,
659 *Escherichia coli*, *Bacillus subtilis*, *Candida albicans*) (Ahmad & Beg, 2004), whereas organic leaves
660 extracts, and ethanolic and water fruit peel extracts, exhibited moderate antibacterial and antifungal
661 activity respectively with agar diffusion method (Karuppiah & Mustaffa, 2013; Okechukwu, 2012).
662 6. *Carica papaya* (latex, fruit)

663 A characteristic of *C. papaya* is the abundant presence of latex in several organs, including leaves and
664 stems. This latex is known to contain four main cysteine endopeptidases: papain, chymopapain, glycil
665 endopeptidase and caricain, alongside with minor enzymatic constituents (Azarkan et al., 2003;
666 Brocklehurst et al., 1985). The presence of lipids in the lipophilic fraction of *C. papaya* latex was also
667 investigated and revealed the presence of polar lipids composed of free fatty acids, sterols and
668 triterpenic alcohols. Among fatty acids oleic acid and linoleic acid (Barouh et al., 2010) were
669 specifically identified. Phytochemical studies were also conducted on leaves, for example on
670 methanolic leaf extract (Canini et al., 2007) and chromatographic analyses revealed the presence of
671 numerous classes of compounds: alkaloids represented by carpaine, the major alkaloid of *C. papaya*
672 leaves, phenolic compounds including tocopherol, ascorbic acid, caffeic acid, coumarin and
673 derivatives, flavonoids (kaempferol, quercetin and derivatives) and aminoacids.

674 Carpain has demonstrated moderate *in vitro* activity against *Trypanosoma brucei rhodesiense*
675 trypomastigotes and *T. cruzi* amastigotes (IC₅₀ of 12.7 and 16.3 µM) but was inactive against
676 *Leishmania donovani* amastigotes (IC₅₀ > 200 µM) (Julianti et al., 2014), and it was recently
677 demonstrated that pure caffeic acid and quercetin (figure 9) exhibited interesting antileishmanial
678 activities against various stages of *L. amazonensis* (promastigotes, amastigotes, infected
679 macrophages) (Montrieux et al. 2014).

680 The medicinal properties of *Carica papaya* L. (Caricaceae) were reviewed by Mbosso Teinkela et al.
681 (2016). Notably, significant anti-inflammatory activity of an ethanolic extract of air-dried leaves was
682 demonstrated *in vivo* using carrageenan induced paw oedema model in rats as well as formaldehyde
683 arthritis model (Owoyele et al., 2008). Anti-inflammatory activity was also demonstrated *in vitro* for an ethanol fresh aerial parts extract which, in a dose dependent manner, inhibited the TNF-α production induced by LPS or IPP by immature dendritic cells (Sagnia et al., 2014). However, it should be noted that papaya latex is commonly used to induce oedema in inflammation models (Gupta et al., 1992).

688 As far as wound healing is concerned, papaya latex prepared in gel form was shown to be effective in the treatment of burns in a mouse model (Gurung & Skalko-Basnet, 2009).

690 Lastly, antimicrobial activity of the methanol extract of *C. papaya* latex was studied against various bacteria and pathogenous fungi (*Enterococcus faecalis*, *Staphylococcus aureus*, *S. saprophyticus*, *S. epidermididis*, *Escherichia coli*, *Klebsiella pneumonia*, *Salmonella typhimurium*, *Candida albicans*, and *Trichophyton rubrum*). The extract exhibited weak antimicrobial activity, with MIC values from 125 to 500 µg/mL (Mbosso Teinkela et al., 2016). Fungistatic effect of the latex against *Candida albicans* was also demonstrated and attributed by the authors to the presence of cysteine proteases present in the latex and causing cell wall degradation (Giordani et al., 1996). To our knowledge, no evaluation of antileishmanial activity of *C. papaya* latex or leaves has been performed to date.

<figure><img src="image_11.png" /><figcaption>Carpaine</figcaption></figure>

<figure><img src="image_12.png" /><figcaption>Quercetin</figcaption></figure>

<figure><img src="image_13.png" /><figcaption>Caffeic acid</figcaption></figure>

698

<caption>699 **Figure 9:** Antiparasitic compounds isolated from *Carica papaya* leaves</caption>

700

701 *7. Anacardium occidentale* (leaves, bark)

702 Several parts of this tree native to North-East Brazil are used in traditional medicine, particularly against leishmaniasis. Bark contains a yellowish resin containing a polysaccharide named bassorin (Oliver-Beyer, 1986). Anacardic acids, aromatic phenols such as cardol, anacardol and ginkgol, tanins, flavones and sigmast-4-en-3-one (figure 10a & b) were also isolated from the bark (Huok, 2014; Sankara Subramanian et al., 1969; Roth & Lindorf, 2002; Alexander-Lindo et al., 2007). Essential oils were identified from leaves containing as major compounds mostly sesquiterpenes (among which β-phellandrene, germacrene B and D, *trans*-α-bergamotene, α- and β-copaene, (E)-caryophyllene) and
some monoterpenes (limonene, methyl-chavicol, and linalool) (Kossouoh et al., 2006; Montanari et al., 2012). A high content of phenolic compounds was also measured in leaves, including the presence of cyanidin and peonidin alongside β-carotene and lutein, (Konan and Bacchi, 2007; Kongkachuichai et al., 2015). The biflavonoid agasthisflavone was also isolated (Konan et al., 2012).

A. occidentale stem bark methanolic extract was shown to be inactive against L. amazonensis and L. chagasi promastigotes (Braga et al., 2007).

Significant anti-inflammatory activity was observed *in vivo* (carrageenan induced rat paw oedema) for crude leaf ethanolic extract and a butanone fraction (Patil et al., 2003). *In vivo* and *in vitro* anti-inflammatory effects were also observed for bark extracts (Olajide et al., 2009; Olajide et al., 2013; Mota et al., 1985).

Weak antifungal activity was observed for this extract against *Cryptococcus neoformans* (Braga et al., 2007). Antimicrobial activity was also demonstrated *in vitro*, particularly against *Staphylococcus aureus*, *Bacillus stearothermophilus* and *Shigella dysenteriae* (Akinpelu, 2001).

Cytotoxicity and toxicity of pure compounds or leaf extracts was also studied (Konan et al., 2007; Konan et al., 2012).

724

<figure><img src="image_14.png" /></figure>

725

Figure 10a: Carotenoid and flavonoid compounds identified in *Anacardium occidentale* leaves and bark.

727
<figure><img src="image_15.png" /><figcaption>**Figure 10b:** Phenolic and sterol compounds identified in *Anacardium occidentale* leaves and bark.</figcaption></figure>

729

730

731

732

### 8. Chelonanthus alatus (whole plant)

733

734

735

736

737

This herbaceous plant from the Gentianaceae family is characterized by the presence of secoiridoids, which are acknowledged as chemotaxonomic markers of this botanical family. Sweroside, vogeloside and chelonanthoside were isolated from leaves of *C. alatus* (Sanchez et al., 2012; Shiobara et al., 1994) (Figure 11). Phenolic compounds and flavonoids were also described in the leaves (Lizcano et al., 2010), as well as bisphosphocholine irlbacholine (Bierer et al., 1995).

738

739

An ethanolic leaf extract exhibited moderate activity (Cl<sub>50</sub> 37,4 µg/ml) on *L. amazonensis* axenic amastigotes (Valadeau et al., 2009).

740

741

742

743

744

Interestingly, irlbacholine, isolated from *C. alatus* roots showed a strong antifungal activity against *Candida albicans*, *Cryptococcus neoformans* and *Aspergillus fumigatus* (Lu et al., 1999). Notably, it can be considered as a dimer of miltefosine, also demonstrated as antifungal (Lu et al., 1999) but more particularly used as a promising antileishmanial compound in the neotropics (Soto et al., 2004; Croft et al., 2006).

745

746

Sweroside demonstrated antibacterial (Dinda et al., 2007) and wound healing properties *in vitro* (Oztürk et al., 2006).
<figure><img src="image_16.png" /><figcaption>**Figure 11:** Secoiridoids and bisphosphocholine irlbacholine isolated from *Chelonanthus alatus*.</figcaption></figure>

### 9. Manihot esculenta (leaves, roots)

Chemicals studies concerning *Manihot esculenta* (Euphorbiaceae) reveal the presence of two major classes of compounds: lipids and glycosides. Notably, phospholipids, glycolipids, free sterols and triacylglycerol were isolated from fresh roots, representing 0.25% of roots fresh weight (Lalaguna & Agudo, 1988). Cyanogenic glycosides are known to accumulate in all parts of *M. esculenta*, the two major compounds being linamarin which accounts for around 90% of the total glycosides, and lotaustralin (Burns et al., 2012; Du et al., 1995) (Figure 12). These compounds were, for example, isolated from an ethanolic extract of the fresh root cortex, alongside other cyanogenic and non-cyanogenic glycosides, and were also identified in a methanolic extract of fresh leaves (Prawat et al., 1995). The presence of flavonoids, including rutin, correlated to the antioxidant effect of an aqueous extract of young leaves (Tsumbu et al., 2012). Two flavonoid glycosides, kaempferol-3-O-rutinoside and quercetin-3-O-rutinoside, were also isolated from leaves (Prawat et al., 1995). Terpenoids such as the two acid triterpenes esculentoic acid A and B, alongside with taraxerol, 3-epi-taraxerol, β-amyrin, taraxerone, lupenone, β-amyrinone and sigmasterol, were identified from an ethyl acetate extract of aerial parts (leaves, stems and twigs) in the context of the search for novel anticancer compounds (Chaturvedula et al., 2003). Other terpenoids were also isolated from stems (Zeng et al., 2015; Pan et al., 2015; Li et al., 2011).
To our knowledge, no evaluation of this species' biological activity against *Leishmania* has been undertaken.

Based on the use of *M. esculenta* in traditional African medicine against inflammation and pain, the anti-inflammatory and analgesic effects of an aqueous leaf extract were evaluated *in vivo*, and the results obtained were significant in carrageenan-induced paw oedema in rats as well as against xylene-induced ear oedema in mice models (Adeyemi et al., 2008). Taraxerol is also known as an anti-inflammatory compound (Yao et al., 2013).

Antibacterial activity was also demonstrated *in vitro* for the chloroform leaf extract against *Listeria monocytogenes*, *Vibrio cholerae*, *Shigella flexneri* and *Salmonella typhi* and for the ethanol leaf extracts against *Pseudomonas aeruginosa*, *Corynebacterium diphtheria* and *Vibrio cholerae* (Zakaria et al., 2006). β-Amyrin has been reported as antibacterial (Abdel-Raouf et al., 2015).

<figure><img src="image_17.png" /><figcaption>Linamarin</figcaption></figure>

<figure><img src="image_18.png" /><figcaption>Lotaustralin</figcaption></figure>

**Figure 12:** Major cyanogenic glycosides isolated from roots and leaves of *Manihot esculenta*.

### 10. *Plantago major* (leaves)

Chemical constituents and biological activities of *Plantago major* are well described and have been extensively reviewed by Samuelsen (2000). Numerous chemical compounds from various classes have been isolated from leaves, such as polysaccharides presenting anti-inflammatory and immunostimulatory properties *in vitro* and *in vivo* (Hetland et al., 2000; Samuelsen et al. 1995; Samuelsen et al., 1998). Leaves also contain fatty acids and are characterized by the presence of leaf wax rich in triterpenic acids, notably oleanolic acid and ursolic acid, which are also anti-inflammatory (Samuelsen, 2000). Caffeic acid derivatives, including plantamajoside and acteoside were also isolated from *P. major*. Plantamajoside has anti-inflammatory, inhibitory of lipoxygenases, antioxidant and antibacterial activities amongst others. Acteoside is a known antioxidant, antibacterial and immunosuppressant (Jimenez & Riguera, 1994; Ravn and Brimer, 1988; Samuelsen, 2000). Flavonoids are well represented in *P. major* extracts. Plantaginin, scutellarein, baicalein and
794 hispidulin are antioxidant compounds and the last three compounds have been described as anti-inflammatory and antiallergic (Bellik et al., 2013; Clavin et al., 2007; Toyoda et al., 1997; Wang et al., 1995). Finally, iridoid glycosides represent the last major class of compounds isolated from *P. major*. 796 These include aucubin, particularly known for its topical anti-inflammatory properties in vivo (Recio 1998). Structures of the major biologically active compounds isolated from *P. major* are 798 represented in figure 13. 799

800 To our knowledge, no *in vivo* or *in vitro* evaluation of *P. major* extract on *Leishmania* has been 801 performed.

802 Biological activities of crude leaf extracts are nonetheless numerous. Anti-inflammatory properties 803 have been demonstrated in vivo (Samuelsen, 2000). In addition, the influence of *P. major* leaf 804 methanol extract on NO and TNF-α production by rat peritoneal macrophages has been studied by 805 Gomez-Flores et al. (2000) and strong immunoenhancing properties have been highlighted. Anti- 806 inflammatory properties and enhancement of innate antioxidant activity of *P. major* extracts were 807 also shown in the case of liver injury caused by acetaminophen (Hussan et al., 2015). Wound healing 808 properties of water and ethanol-based leaf extract have been demonstrated in the case of oral 809 epithelial cells in a scratch assay (Zubair et al., 2012) using an ex-vivo porcine wound-healing model 810 (Zubair et al., 2016).

811 Lastly, *P. major* extracts presented antibacterial and antifungal activities. The 50% aqueous ethanol 812 extract was active against *Staphylococcus aureus*, *Bacillus subtilis*, *Shigella dysenteriae* and 813 *Escherichia coli* and the methanol extract was effective against *Fusarium tricuictum*, *Saccharomyces 814 cerevisiae*, *Microsporum gypseum* and *Candida albicans* (Samuelsen, 2000).

<figure><img src="image_19.png" /><figcaption>Ursolic acid</figcaption></figure>

<figure><img src="image_20.png" /><figcaption>Oleanolic acid</figcaption></figure>

<figure><img src="image_21.png" /><figcaption>Aucubin ($R = Glc$)</figcaption></figure>

<figure><img src="image_22.png" /><figcaption>R= Glc Plantamajoside</figcaption></figure>

<figure><img src="image_23.png" /><figcaption>Baicalein
Hispidulin
Plantaginin
Scutellarein</figcaption></figure>
<caption>**Figure 13:** Examples of biologically active compounds isolated from *Plantago major*</caption>

**3. Conclusion**

This review of Amazonian people's perceptions of cutaneous leishmaniasis and its treatments shows that many practices are shared throughout the region although questions regarding the selection of plants are raised. Nevertheless, this type of review of traditional antileishmanials in Amazonia is indubitably biased. Firstly, in terms of bibliography, as it is clear that ethnobotanical publications are not equally available for all countries: French Guiana accounts for 178 URs, while Brazil only accounts for 17. This probably reflects a combination of field accessibility (both logistic and administrative), of the dynamics of both local and international research, and of the publication strategies of public researchers in the countries. On this basis, the use of the most current statistical tests is impossible, as the basic sampling needs to be balanced. Nevertheless, this work has enabled us to highlight some patterns of use: plants are still used throughout the region and the compromise between clinical efficiency, resource availability, and cultural relevance of the remedy plays an important role, leading to an over representation of cultivated species some of which are exotic to Amazonia.

One criticism that could be made of these indices is that they are compare uses taken at different times, in a synchronic study. However, it is impossible to overcome the problem of different dates. As local knowledge is dynamic, a diachronic approach would better fit to the study of ethnobotanical knowledge evolution, but is beyond the realms of the current state of research.

Analysing the botanical species level instead of the genus level is explained by the high variations of phytochemical patterns between species of a same genus, although traditional uses are sometimes more coherent at genus level. Nevertheless, a genus analysis can be provided if necessary. Examples of genera that suffer from this choice are *Piper* (Piperaceae) and *Vismia* (Hypericaceae). The first genus, including 11 URs, barely includes 2 URs for the two most highly cited species, *P. elongatum* and *P. marginatum*. The *Vismia* genus includes 18 URs while the most highly cited species, *V. guianensis*, includes 4 URs in the area.

In addition, the more localised the plant use is, the more difficult it is to discriminate a regional pharmacological match from cultural dissemination. In the case of *B. grandiflora*, with a high $I_c$ and a low $I_g$, its high level of activity on *L. major*, *L. guyanensis* and *L. panamensis* promastigotes was described (< 10 µg/mL for each) (Fuchino et al., 2008) and tips the balance in favour of pharmacological activity.

It might be easier to detect pharmacological potential in the Low $I_c$ high $I_g$ cluster as a convergence of use due to independent discoveries seems highly probable. In this category, *Chelonanthus alatus* is
849

astonishing as it produces a unique dimer of miltefosine, a synthetic molecule now being trialed

850

against cutaneous leishmaniasis in the Neotropics. This compound would need to be tested in order

851

to better evaluate its therapeutic potential.

852

An important factor is the high predominance of topical application of these remedies, with nearly

853

90 % of recipes collected being applied directly on the wound. Until now, the main antileishmanials

854

are given by injection. A topical formulation would be a revolution in the field and traditional

855

practices advocate for such a paradigm shift. A convergence has also been observed between the use

856

of irritating/burning plants and the use of household chemicals highlighted by Ramdas (2012).

857

Species such as *Jatropha curcas* or *Anacardium occidentale* could easily enter in this category.

858

Another lesson from this review is that very few of the traditional antileishmanial plants have

859

undergone *in vivo* assays. Promastigote tests are still the norm despite years of discussion for a

860

model closer to reality. It also appears that many of the high *I*<sub>d</sub> plants have anti-inflammatory

861

activities and sometimes anticandidal activities. The example of *Jatropha* should be cited as a

862

potential synergy: a protease (curcain) might ease the penetration of leishmanicidal diterpenes, all

863

supported by anti-inflammatory metabolites calming down the pro-inflammatory cytokine response

864

leading to tissue necrosis. Lastly, all these remarks support the need for more integration in

865

ethnopharmacology ... for antileishmanials as for everything else.

866

867

## 4. Acknowledgments

868

This work was supported by an "Investissement d'Avenir" grants managed by the Agence Nationale

869

de la Recherche (CEBA: ANR-10-LABX-25-01).

870

871

## 5. Bibliography

872

Abdel-Raouf, N., Al-Enazi, N. M., Al-Homaidan, A. A., Ibraheem, I. B. M., Al-Othman, M. R., Hatamleh,

873

A. A., 2015. Antibacterial β-amyrin isolated from *Laurencia microcladia*. Arabian Journal of

874

Chemistry, 8(1): 32-37.

875

Accioly, M. P., Bevilaqua, C. M. L., Rondon, F. C. M., de Morais, S. M., Machado, L. K. A., Almeida, C. A.,

876

de Andrade, H. F., Cardoso, R. P. A., 2012. Leishmanicidal activity *in vitro* of *Musa paradisiaca* L. and

877

*Spondias mombin* L. fractions. Veterinary Parasitology, 187(1-2): 79-84.

878

Acebey, L., Jullian, V., Sereno, D., Chevalley, S., Estevez, Y., Moulis, C., Beck, S., Valentin, A., Gimenez,

879

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