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Essential Oils from Neotropical Piper Species and Their Biological Activities

The Piper genus is the most representative of the Piperaceae reaching around 2000 species distributed in the pantropical region. In the Neotropics, its species are represented by herbs, shrubs, and lianas, which are used in traditional medicine to prepare teas and infusions. Its essential oils (EOs) present high yield and are chemically constituted by complex mixtures or the predominance of main volatile constituents. The chemical composition of Piper EOs displays interspecific or intraspecific variations, according to the site of collection or seasonality. The main volatile compounds identified in Piper EOs are monoterpenes hydrocarbons, oxygenated monoterpenoids, sesquiterpene hydrocarbons, oxygenated sesquiterpenoids and large amounts of phenylpropanoids. In this review, we are reporting the biological potential of Piper EOs from the Neotropical region. There are many reports of Piper EOs as antimicrobial agents (fungi and bacteria), antiprotozoal (Leishmania spp., Plasmodium spp., and Trypanosoma spp.), acetylcholinesterase inhibitor, antinociceptive, anti-inflammatory and cytotoxic activity against different tumor cells lines (breast, leukemia, melanoma, gastric, among others). These studies can contribute to the rational and economic exploration of Piper species, once they have been identified as potent natural and alternative sources to treat human diseases.


Introduction
The genus Piper L. has approximately 2000 species distributed in the pantropical region, in the Neotropics occurring from northern Mexico to Chile and Argentina. The Andean slopes, Central American lowlands and Central Amazonia have been considered as centers of high species richness for the genus [1,2]. Piper belongs to Piperaceae, classified in the order Piperales, Magnoliids clade included in angiosperm basal group [3]. Phylogenetic studies have confirmed the monophyly of the group with eight subgenera recognized in the Neotropics: Enckea, Macrostachys, Ottonia, Peltobryon, Piper, Pothomorphe, Radula and Schilleria [4].

Antiprotozoal Activity
Parasitic protozoal diseases are the major economic and public health problems in the world causing high rates of human morbidity and mortality in developing countries [32]. The prevalence of these diseases is higher in the tropics, where a significant number of deaths are attributed to leishmaniasis, malaria, and trypanosomiasis [66]. Piper species have been reported as good sources of antiparasitic compounds [67].

Anticholinesterase Potential
Acetylcholinesterase (AChE) is an enzyme involved in the termination of impulse transmission by quick hydrolysis of the neurotransmitter acetylcholine (ACh). The AChE potential of drugs is inhibition of this enzyme from breaking down ACh, increasing the level and duration of the neurotransmitter activity [76]. For this reason, studies aiming to discover compounds with anticholinesterase potential are relevant. However, there have been few investigations with this focus in Neotropical regions. The EOs from aerial parts of Piper species from the Brazilian Amazon displayed a high activity when evaluated by bioautographic method. All samples had a detection limit (DL) value of 0.01 ng, about one hundred times more effective than the standard physostigmine (DL = 1.0 ng). P. hispidum and P. anonifolium oils were mainly composed of sesquiterpenoids, such as selin-11-en-4α-ol, β-selinene, α-selinene, β-caryophyllene, and α-humulene [61]. In contrast, EOs from the aerial parts of P. callosum and P. marginatum were mainly composed of phenylpropanoids, such as safrole and 3,4-methylenedioxypropiophenone (propiopiperone) [62]. Although there are limited data on AChE activity of Piper essential oils from the Neotropics, a significant amount of research has been performed on Old World Piper essential oils [77][78][79][80][81].

Anti-Inflammatory and Antinociceptive Effects
Although a considerable number of analgesic and anti-inflammatory drugs are available for the treatment of pain and inflammation, there is a continuous search for new compounds, due to the fact that some current drugs lead to adverse reactions and have low efficacy [82]. Plants used in folk medicine, including essential oils, have been shown to be promising new sources of anti-inflammatory and antinociceptive drugs [83][84][85][86][87].

Composition-Bioactivity Correlation
A multivariate statistical analysis was carried out in order to discern any relationship between chemical profiles and biological activities for Piper essential oils (described in Appendix A). The total percentage of compound classes (monoterpene hydrocarbons (MH), oxygenated monoterpenoids (OM), sesquiterpene hydrocarbons (SH), oxygenated sesquiterpenoids (OS) and phenylpropanoids (PP) to each oil was extracted from original citation (Table A1). These data were used as variables (see Appendix C). The values were normalized and submitted to Principal Component Analysis (PCA) using the Minitab software (free 390 version, Minitab Inc., State College, PA, USA).
The antimicrobial activity (fungicidal and bactericidal) displayed a correlation to all compound classes identified in Piper species. However, the cytotoxic activity is related to higher amounts of sesquiterpene hydrocarbons (0-94.9%), monoterpene hydrocarbons (0-83.7%). The antiprotozoal activity is related to Piper oils with low concentrations of monoterpene hydrocarbons (<29.9%) and high concentrations of oxygenated monoterpenoids (0-50.3%), sesquiterpene hydrocarbons (3.3-76.0%) and oxygenated sesquiterpenoids (0-86.2%). For this activity, only the P. auritum oil, which was rich in phenylpropanoids (88.5%), showed activity against Leishmania spp. Piper oils described as rich in phenylpropanoids and sesquiterpenes hydrocarbons displayed high insecticidal and acaricidal activities. In addition, the amounts of phenylpropanoids and sesquiterpenoids (hydrocarbons and oxygenated) are related to acetylcholinesterase inhibition. The anti-inflammatory effects were mostly observed in Piper oils rich in sesquiterpene hydrocarbons (16.2-62.6%) while antinociceptive effects cover oils that showed monoterpene hydrocarbons (16.6-65.0%) as main compounds. The essential oil composition and biological activity correlations are summarized in Figure A5 and Table 1.

Conclusions
The Piper genus has shown great biodiversity in the Neotropics, and essential oils from Piper species have likewise demonstrated abundant chemical diversity. The chemical diversity of Piper essential oils has led to a myriad of traditional medicinal uses as well as numerous biological activities. The promise of Piper essential oils to treat human diseases, infections, and suffering has already been realized, and the future exploration of this genus shows much promise). The expectation that Piper's essential oils can be used to treat diseases, infections and human suffering is already a reality, and the future economical exploration of some species of this genus seems to us as very promising.
Author Contributions: All authors contributed to surveying the literature, preparation and editing of the manuscript.

Conflicts of Interest:
The authors declare no conflict of interest.