378 Reviews Aspidosperma Species as Sources of Antimalarials. Part III. A Review of Traditional Use and Antimalarial Activity* Authors Renata Cristina de Paula1**, Maria Fâni Dolabela2**, Alaíde Braga de Oliveira 1** Affiliations 1 Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil 2 Departamento de Farmácia, ICS, Universidade Federal do Pará, Belém, PA, Brazil Key words Abstract and/or alkaloids evaluated, with good results, for l" Aspidosperma spp. ! in vitro and/or in vivo antimalarial activity. Indole l" Apocynaceae Several plant species belonging to the genus Aspi- alkaloids are typical constituents of Aspidosperma l" malaria dosperma are traditionally used in Brazil and oth- species. However, only 20 out of more than 200 l" Plasmodium falciparum er Meso- and South American countries for the known indole alkaloids isolated from this genus l" antimalarial activity treatment of malaria and fevers. These traditional have been assayed for antimalarial activity. These uses were motivation for this review. A literature data support the potential of Aspidosperma spe- survey completed for this review has identified cies as sources of antimalarials and the impor- scientific bibliographical references to the use of tance of research aimed at validating their use in 24 Aspidosperma species to treat malaria/fevers the treatment of human malaria. and to 19 species that have had their extracts Introduction first antimalarial drug introduced in chemother- ! apy and remained the only clinical weapon until Natural products and malaria the 1940s, when chloroquine, a synthetic 4-ami- Malaria remains one of the most prevalent infec- noquinoline, became available. Efficient and inex- tious diseases worldwide and is, therefore, a glob- pensive, chloroquine was widely used until the al health problem despite substantial efforts to 1960s, when resistance to the drug by P. falcipa- control the disease over the past few decades. Ap- rum became widespread in the malaria-endemic proximately 3.3 billion people are at risk, and 250 countries, causing a strong increase in mortality million cases each year were reported in the peri- rates. The antimalarial drugs in current use are ar- received August 18, 2013 od 2006–2008, primarily in Africa [1]. In the temisinin, the active compound from Artemisia revised January 10, 2014 accepted January 11, 2014 Americas, malaria transmission occurs in 21 annua L. (Asteraceae), a traditional plant used for countries. P. vivax caused 77% of all cases reported millennia in China, and its semisynthetic deriva- Bibliography in 2008, but P. falciparum was responsible for al- tives artemether, artesunate, and arteether [5]. DOI http://dx.doi.org/ most 100% of all cases in Haiti and the Dominican Artemisinins are currently the most effective This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 10.1055/s-0034-1368168 Published online March 3, 2014 Republic [1]. Brazil reported the highest number drugs for antimalarial chemotherapy and have Planta Med 2014; 80: 378–386 of malaria cases (603 532) in the region in 2005, been globally adopted for the treatment of P. falci- © Georg Thieme Verlag KG primarily in the Brazilian Legal Amazon Region, parum malaria. The most recently introduced Stuttgart · New York · where 10–15% of the population is at risk. Brazil antimalarial drug is atovaquone, a synthetic ISSN 0032‑0943 was among the 30 highest-burden countries for naphthoquinone based on lapachol. Lapachol, a Correspondence malaria [2]. However, a decrease of approximately prenylnaphtoquinone, was first isolated from Ta- Alaíde Braga de Oliveira 25% in the number of reported cases has been re- bebuia impetiginosa (Mart. ex DC.) Standl. (synon. Departamento de Produtos Farmacêuticos corded since 2006 [3,4]. T. avellanedeae Lor. ex Griseb.), a South American Faculdade de Farmácia Historically, plants have had a remarkable role in representative of the Bignoniaceae [6]. Universidade Federal de Minas therapeutics and were the principal source of The emergence of P. falciparum strains resistant to Gerais Av. Antônio Carlos, 6.627 drugs until the 19th century. Quinine, isolated in artemisinin and its derivatives would cause a re- 31270–901 Belo Horizonte, MG 1820, from Cinchona species (Rubiaceae), was the surgence of human malaria to high levels in many Brazil Phone: + 553134096950 Fax:+553134415575 * For Part I see [48], for Part II see [36]. Part of RCP Doctor- ** All authors contributed equally to this article. [email protected] ate Thesis at PPGCF, UFMG, Belo Horizonte, MG, Brazil. de Paula RC et al. Aspidosperma Species as… Planta Med 2014; 80: 378–386 Reviews 379 countries. For this reason, R&D on new antimalarial drugs is ur- Traditional use in treating malaria gent. Plants continue to represent a valuable source of drugs. A Data obtained by searching for Aspidosperma species with re- review of all small molecules that have been approved as phar- ported traditional uses as antimalarials and/or febrifuges as well maceutical agents within the 25-year period from 1/1981 to 6/ as those species that have been experimentally evaluated for 2006 has demonstrated that approximately 50% of these mole- antimalarial activity are shown in l" Table 1. The table includes cules originated from natural products [7]. Investigations that be- the accepted taxonomic nomenclature, synonyms, and occur- gin by screening plants used in traditional medicines are particu- rence, according to Koch and collaborators [20], LEFB [24], Loren- larly valuable. In the past decade, a substantial number of publi- zi (1992) [15], TROPICOS® Specimen Data Base [25], and The Plant cations have focused on the screening of either extracts or natu- List [26]. The reported uses for treating malaria/fevers are based ral products for antimalarial activity [8]. However, as we have on the scientific literature. Medicinal uses described on commer- noted previously, very few highly active antimalarial natural cial Internet sites, as well as uses other than for malaria and/or products have been evaluated for cytotoxicity and in in vivo as- fevers, have not been included. Reported antimalarial activity says. This lack of previous study limits the potential of these may refer to in vitro assays with different Plasmodium species,in products as bases for the development of new antimalarial drugs vivo assays in different animals with different Plasmodium spe- [5,9]. The relevance of these results should not, however, be cies, or clinical assays in humans. Details of these findings are underestimated. Active naturally occurring antimalarial com- shown in l" Table 2. pounds might be useful as bases for semisynthetic derivatives, Our literature survey has identified 24 Aspidosperma species as agents for direct use if their structures are too complex for an (l" Table 1) used to treat malaria/fevers, representing approxi- economically and/or technologically viable total synthesis, or as mately 50% of the representatives of this taxon [24]. In addition templates for the total synthesis of structurally related com- to these 24 species, l" Table 1 includes two other species, A. cylin- pounds [5]. Moreover, bioactive natural products from medicinal drocapon and A. macrocarpon, for which no reports have been plants might be useful as biological markers in the development found on their use to treat malaria/fever but that have been eval- of efficient and safe phytomedicines [5,9], a new approach of uated for antimalarial activity [27,28]. growing interest that would provide malaria-endemic countries The “Dicionário das plantas úteis do Brasil e das exóticas cultiva- with good-quality herbal medicines of low cost, that would be lo- das” (Dictionary of useful plants from Brazil and of the exotics cally and sustainably produced [8]. High-tech methods are avail- cultivated), by Pio-Corrêa (1874–1934) [17], was our first source able to standardize phytopreparations [10,11], and new molecu- of information on the antimalarial use of plants belonging to the lar biological assays can serve to screen extracts and plant con- genus Aspidosperma. More than 50 Aspidosperma species are stituents as well as to evaluate their pharmacological profiles, listed within this six-volume collection, with taxonomic data elucidate the synergistic effects of the constituents of an extract and vernacular names. Most of the applications described there and, thus, gain a better understanding of the various mechanisms are as sources of timber, whereas only three species, A. discolor, underlying their pharmacological effects [11–14]. A. polyneuron,andA. gomezianum, are identified as plants used Several Aspidosperma species have a history of medicinal uses, to treat malaria and/or fevers. including the treatment of human malaria and/or fevers in Brazil The botanical names shown for the 26 Aspidosperma species in as well as in other Meso- and South American countries [15–19]. l" Table 1 are those originally reported in the literature. However, The present review reports the results of a literature survey on it should be emphasized that these are not the presently accepted Aspidosperma species traditionally used to treat malaria and/or names in certain cases. This is the situation for A. marcgravianum fevers as well as data on those previously evaluated for antima- Woodson (A. marckgravianum), which is not presently an ac- larial activity. cepted name [24] but a synonym of A. excelsum Benth. together with A. nitidum Benth. ex Müll. Arg., according to Koch and col- laborators [20] and LEFB [24], but is described as a synonym for The Genus Aspidosperma A. excelsum only by the The Plant List [26]. In the same source ! [26], however, A. nitidum Benth. ex Müll. Arg. is an accepted Taxonomy and geographic distribution name, with A. acquaticum Ducke as a synonym. Another contra- The genus Aspidosperma Mart. & Zucc. belongs to the family diction is found for A. album (Vahl) Benoist ex Pichon and A. des- Apocynaceae, one of the ten largest angiosperm families [20]. manthum Benth. ex Müll. Arg., cited as accepted names for dis- The Apocynaceae s.l.