Review Paper Antileishmanial activity of Annona species (Annonaceae) Heliton Patrick Cordovil Brígido1 · Juliana Correa‑Barbosa1 · João Victor da Silva‑Silva2 · Erica Vanessa Souza Costa1 · Sandro Percário3 · Maria Fâni Dolabela1 Received: 27 April 2020 / Accepted: 13 August 2020 / Published online: 18 August 2020 © Springer Nature Switzerland AG 2020 Abstract Annona species are widely used in traditional medicine against leishmaniasis. In vitro studies have confrmed their antileishmanial activity. Objective: review the antileishmanial activity of Annona species. Results: This article provides a review Annona species activity against leishmaniasis, in which it suggests that extracts of A. mucosa were active against promastigotes and amastigotes of L. amazonensis. Moreover, extracts of A. crassifora were active only against promastig- otes of L. donovani, whereas the extract, alkaloid fraction and liriodenine of A. foetida were active against promastigotes of L. braziliensis and L. guyanensis. Liriodenine was also very active against L. amazonensis. Furthermore, extracts and fractions from stems of A. muricata were active against Leishmania sp. This activity may be related to the presence of acetogenins, since fractionation contributed to increase activity. The fractionation of A. purpurea extract contributed to antileishmanial activity, and resulted in a fraction with high selectivity. Such activity may be related to alkaloids or acetogenins. Conclusions: In this review article it is suggested that Annona species are promising as leishmanicide and this activity may be related to acetogenins and alkaloids. Keywords Annona · Leishmaniasis · Alkaloid and acetogenin 1 Introduction The search for alternative therapies is very important, and medicinal plants are a source of bioactive molecules [4]. Leishmaniasis is caused by parasites belonging to the Annona species are used in traditional medicine to treat Trypanosomatidae family and Leishmania genus. There leishmaniasis. In vitro, antileishmanial studies of extracts are three main forms of leishmaniasis—visceral, cutaneous validated the popular use [5–7]. Some studies about and mucocutaneous [1]. Most cases of cutaneous leish- antileishmanial activity of Annona attribute its activity to maniasis occur in Afghanistan, Algeria, Brazil, Colombia, alkaloids [8, 9] and acetogenins [10]. Islamic Republic of Iran, Pakistan, Peru, Saudi Arabia and Several alkaloids were active against Leishmania, Syrian Arab Republic [1]. among these are coronaridine (Fig. 1a), 18-methoxycoro- Leishmaniasis treatment is performed with pentavalent naridine (Fig. 1b) [11], O-methylarmepavine (Fig. 1c) [10], antimonials (sodium stibogluconate and meglumine anti- liriodenine (Fig. 1d) [12]. Moreover, acetogenins annonaci- moniate), amphotericin B and pentamidine. However, the none (Fig. 1e) and corossolone (Fig. 1f) were also promis- use of these agents is questionable due to the variabil- ing as leishmanicide [10]. ity in their efcacy among Leishmania species, high cost, Previous studies on species of the genus Annona pre- need for parenteral administration, and high toxicity [2, 3]. sent biological investigations on promastigote and amas- tigote forms of Leishmania, for example, from seeds of A. * Maria Fâni Dolabela, [email protected] | 1Pharmaceutical Science Post-Graduation Program, Federal University of Pará, Belém, PA, Brazil. 2Laboratory of Immunomodulation and Protozoology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. 3Oxidative Stress Research Laboratory, Institute of Biological Sciences, Federal University of Pará, Belém, PA, Brazil. SN Applied Sciences (2020) 2:1524 | https://doi.org/10.1007/s42452-020-03340-7 Vol.:(0123456789) Review Paper SN Applied Sciences (2020) 2:1524 | https://doi.org/10.1007/s42452-020-03340-7 Fig. 1 Compounds isolated from species of Annona. Legend: (a) Coronaridine, (b) 18-Methoxycoronaridine, (c) O-methylarmepavine, (d) Liriodenine, (e) Corossolone, (f) Annonacinone squamosa a trihydroxylated acetogenin with two tetrahy- DATABASE = 1760), using as criterion articles with titles drofuran rings and α, β-unsaturated lactonic ring of 37 car- that ft the theme, summary compatible with this study bon atoms endowed with antihelmintic and antiprotozoal proposal, and the exclusion of duplicate occurrences. Four properties was isolated. This substance showed leishmani- articles from CAPES and twelve from PUBMED were elimi- cidal action against promastigotes and amastigotes of L. nated due to duplication. Regarding GOOGLE SCHOLAR chagasi [10]. The volatile oil of A. foetida was active against DATABASE, most of the eliminated articles had inap- promastigotes of four diferent species of Leishmania, hav- propriate title or duplication (1757). When the title and ing been more active in L. guyanensis (IC50: 4.1 μg/mL) [9]. abstract were analyzed, 14 papers were included. Figure 2 The alkaloids fraction from leaves of A. coriacea revealed shows the screening identifcation procedure included for activity against promastigotes of L. chagasi, with an IC 50 analysis. of 41.6 μg/mL. In amastigote forms, they caused death to Two reviewers selected, independently, studies based 27.2% of the parasites, at a concentration of 20 μg/mL [8]. on their title and abstract, those considered potentially The alkaloid fraction of A. foetida, showed activity against relevant were obtained for complete analysis. Any discrep- the promastigotes of L. braziliensis and L. guyanensis [12]. ancies were solved by consensus and a third reviewer was In this context, to validate the popular use on leishma- consulted to ensure compliance with the inclusion criteria. niasis, the analysis of several studies of Annona species At the end, 13 articles were selected for discussion and was performed, focused on their antileishmanial activity. inclusion in this analysis (Fig. 2). 2 Materials and methods A survey was performed with the selection of scien- tifc articles available at CAPES, PUBMED and GOOGLE SCHOLAR DATABASE; the year of publication was not limited. The search was carried out in January 2020 and only articles in Portuguese, English and Spanish, which presented leishmanicidal activity (inhibitory concentra- tion 50%—IC50) were considered. The following exclusion criteria were adopted: articles in other languages, those that did not address the proposed theme, in duplicate, and articles that could not be accessed in full. For the search, descriptors related to the theme were used in an associated way: Leishmania and Annona. The preliminary result included 1796 papers for screen- ing (CAPES = 21, PUBMED = 15 and GOOGLE SCHOLAR Fig. 2 Flowchart of article eligibility Vol:.(1234567890) SN Applied Sciences (2020) 2:1524 | https://doi.org/10.1007/s42452-020-03340-7 Review Paper Regarding data analysis, it was done in two stages: in macrophages (CC50: 19.11 ± 1.06 µg/mL) and low selectiv- the frst, a table with the following data was used: plant ity in L. guyanensis (SI: 0.34; Table 1) [15]. material, type of extract, fractions and isolated substances, Diferent extracts obtained from Annona mucosa were IC50 and the cytotoxic concentration (CC50). The results are tested on L. donovani, L. amazonensis, and L. braziliensis. summarized in tables and anti-Leishmania activity was Most of the extracts showed activity against promas- assessed using the following criteria: IC50 ≤ 100 μg/mL tigotes of L. amazonensis (PH8, IC 50: 9.3–46.5 µg/mL), active, IC50 between 101 and 200 μg/mL moderately active although it was not observed signifcant reduction in the and IC50 ≥ 200 μg/mL inactive [13]. Cytotoxicity results rate of macrophages infection by amastigotes (30%). When were assessed by the following criteria: CC50 ≤ 100 μg/mL cytotoxicity and anti-promastigote activity are related, a cytotoxic, CC50 between 101 and 500 μg/mL moderately low selectivity index is observed (SI: 0.9–6; Table 1) [15]. cytotoxic, and CC50 ≥ 500 μg/mL non-cytotoxic [13]. From Annona mucosa, the alkaloids oxoaporphine, atherospermidina and liriodenine were isolated. Liriode- nine was active against promastigotes of L. amazonensis 3 Results (IC50: 1.43 ± 0.58 µg/mL) and amastigotes forms of L. ama- zonensis [15]. High selectivity was observed (SI: 13.36), In order to identify whether Annona extracts presented especially for liriodenine (SI: 13.37; Table 1). antileishmanial activity, an extensive literature review was The anti-promastigote activity of A. muricata was exten- done, and the results are highlighted in Table 1. Studies sively evaluated, yielding inactive (hexane and metha- about antileishmanial activity for these species are scarce, nol extracts from pericarp: IC50 > 1000 µg/mL), moder- with only their anti-promastigote activity being evaluated ately active (hexane and methanol extracts from leaves: (Table 1). IC50 > 100 µg/mL), and active extracts (hexane and meth- The ethanol extracts obtained from root barks, anol extracts from stem and ethyl acetate extracts from stem barks, and stem wood of A. crassifora were active pericarp, leaves, and stem: IC50 ≤ 100 µg/mL). Fractionation against promastigotes of L. donovani (IC50: 3.7 ± 0.3 µg/ of A. muricata extracts led to the isolation of acetogenins, mL, 12.4 ± 0.3 µg/mL, and 8.3 ± 0.8 µg/mL, respectively; which were more active than the extracts against promas- Table 1) [14]. The total alkaloids obtained from the etha- tigotes (Table 1) [10, 16]. nol extract of A. crassifora leaves were active against L. Scoparone, corossolone, and annonacinone isolated