Plants of the Araceae family for malaria and related diseases: a review / Plantas da família Araceae para a malária e doenças relacionadas: uma revisão

ABSTRACTIn the current work we performed a review of the Araceae family species traditionally used to treat malaria and its symptoms. The aim is to reveal the large number of antimalarial Araceae species used worldwide and their great unexplored potential as sources of antimalarial natural products. The SciFinder Scholar, Scielo, PubMed, ScienceDirect and Google books search engines were consulted. Forty-three records of 36 species and 23 genera of Araceae used for malaria and symptoms treatment were found. The neotropical genera Philodendron Schott and Anthurium Schott were the best represented for the use in the treatment of malaria, fevers, liver problems and headaches. Leaves and tubers were the most used parts and decoction was the most common preparation method. The extracts of Araceae species inhibit the in vitro growth of the human malaria parasite, the Plasmodium falciparum Welch, and significant median inhibitory concentrations (IC50) for extracts of guaimbê-sulcado (Rhaphidophora decursiva (Roxb.) Schott), aninga (Montrichardia linifera (Arruda) Schott), Culcasia lancifolia N.E. Br. and forest anchomanes (Anchomanes difformis (Blume) Engl.) have been reported demonstrating the antimalarial and cytotoxicity potential of the extracts and sub-fractions. In the only report about the antimalarial components of this family, the neolignan polysyphorin and the benzoperoxide rhaphidecurperoxin presented strong in vitro inhibition of the D6 and W2 strains of Plasmodiumfalciparum (IC50 = 368-540 ng/mL). No live study about antimalarial activity in animal models has been conducted on a species of Araceae. More bioguided chemical composition studies about the in vitro and also thein vivo antimalarial activity of the Araceae are needed in order to enhance the knowledge about the antimalarial potential of this family.

RESUMONo presente trabalho realizamos uma revisão das espécies da família Araceae usadas para tratar malária e seus sintomas. O objetivo foi revelar o grande número de espécies da família usadas no mundo, assim como seu potencial como fontes de produtos naturais antimaláricos. Foram consultadas as plataformas de busca SciFinder Scholar, Scielo, PubMed, ScienceDirect e Google books. Encontramos quarenta e três registros de 36 espécies e 23 generos de Aráceas usadas para tratar malária e seus sintomas. Os generos neotropicais Philodendron Schott e Anthurium Schott foram os melhor representados, úteis para o tratamento da malária, febres, problemas hepáticos e dores de cabeça. Folhas e tubérculos foram as partes mais utilizadas, enquanto a decocção foi o método de preparo mais comum. Os extratos de espécies de Araceae inibem o crescimento in vitro do parasito da malária humana, Plasmodium falciparum Welch, e concentrações inibitórias medianas (CI50) significativas foram relatadas para extratos de guaimbê-sulcado (Rhaphidophora decursiva (Roxb.) Schott), aninga (Montrichardia linifera (Arruda) Schott), Culcasia lancifoliaN.E. Br. e anchomanes do mato (Anchomanes difformis (Blume) Engl.), demonstrando o potencial antimalárico e citotóxico de extratos e subfrações. No único relato sobre os componentes antimaláricos dessa família, a neolignana polisiforina e o benzoperóxido rafidecurperoxina apresentaram forte inibição das cepas D6 e W2 de Plasmodiumfalciparum in vitro (CI50 = 368-540 ng/mL). Nenhum estudo sobre a atividade antimalárica in vivo em modelo animal foi realizado com espécies da família Araceae. Mais trabalhos biomonitorados pela composição química sobre a atividade antimalárica in vitro, assim como estudos in vivo, são necessários para aprofundar os conhecimentos sobre potencial antimalárico da familia.

Comparative in vitro and in vivo antimalarial activity of the indole alkaloids ellipticine, olivacine, cryptolepine and a synthetic cryptolepine analog.

Indole alkaloids ellipticine (1), cryptolepine triflate (2a), rationally designed 11-(4-piperidinamino)cryptolepine hydrogen dichloride (2b) and olivacine (3) (an isomer of 1) were evaluated in vitro against Plasmodium falciparum and in vivo in Plasmodium berghei-infected mice. 1-3 inhibited P. falciparum (IC50≤1.4 µM, order of activity: 2b>1>2a>3). In vitro toxicity to murine macrophages was evaluated and revealed selectivity indices (SI) of 10-12 for 2a and SI>2.8×10² for 1, 2b and 3. 1 administered orally at 50mg/kg/day was highly active against P. berghei (in vivo inhibition compared to untreated control (IVI)=100%, mean survival time (MST)>40 days, comparable activity to chloroquine control). 1 administered orally and subcutaneously was active at 10 mg/kg/day (IVI=70-77%; MST=27-29 days). 3 exhibited high oral activity at ≥50 mg/kg/day (IVI=90-97%, MST=23-27 days). Cryptolepine (2a) administered orally and subcutaneously exhibited moderate activity at 50mg/kg/day (IVI=43-63%, MST=24-25 days). At 50 mg/kg/day, 2b administered subcutaneously was lethal to infected mice (MST=3 days) and moderately active when administered orally (IVI=45-55%, MST=25 days). 1 and 3 are promising compounds for development of antimalarials.

The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases - part II.

Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen "Neglected Tropical Diseases" (NTDs) defined by the WHO. Furthermore, malaria (caused by various Plasmodium species) can be considered a neglected disease in certain countries and with regard to availability and affordability of the antimalarials. Living organisms, especially plants, provide an innumerable number of molecules with potential for the treatment of many serious diseases. The current review attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs. In part I, a general description of the diseases, the current state of therapy and need for new therapeuticals, assay methods and strategies applied in the search for new plant derived natural products against these diseases and an overview on natural products of terpenoid origin with antiprotozoal potential were given. The present part II compiles the current knowledge on natural products with antiprotozoal activity that are derived from the shikimate pathway (lignans, coumarins, caffeic acid derivatives), quinones of various structural classes, compounds formed via the polyketide pathways (flavonoids and related compounds, chromenes and related benzopyrans and benzofurans, xanthones, acetogenins from Annonaceae and polyacetylenes) as well as the diverse classes of alkaloids. In total, both parts compile the literature on almost 900 different plant-derived natural products and their activity data, taken from over 800 references. These data, as the result of enormous efforts of numerous research groups world-wide, illustrate that plant secondary metabolites represent an immensely rich source of chemical diversity with an extremely high potential to yield a wealth of lead structures towards new therapies for NTDs. Only a small percentage, however, of the roughly 200,000 plant species on earth have been studied chemically and only a small percentage of these plants or their constituents has been investigated for antiprotozoal activity. The repository of plant-derived natural products hence deserves to be investigated even more intensely than it has been up to present.

The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases - part I.

Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen "Neglected Tropical Diseases" (NTDs) defined as such by WHO due to the neglect of financial investment into research and development of new drugs by a large part of pharmaceutical industry and neglect of public awareness in high income countries. Another major tropical protozoan disease is malaria (caused by various Plasmodium species), which -although not mentioned currently by the WHO as a neglected disease- still represents a major problem, especially to people living under poor circumstances in tropical countries. Malaria causes by far the highest number of deaths of all protozoan infections and is often (as in this review) included in the NTDs. The mentioned diseases threaten many millions of lives world-wide and they are mostly associated with poor socioeconomic and hygienic environment. Existing therapies suffer from various shortcomings, namely, a high degree of toxicity and unwanted effects, lack of availability and/or problematic application under the life conditions of affected populations. Development of new, safe and affordable drugs is therefore an urgent need. Nature has provided an innumerable number of drugs for the treatment of many serious diseases. Among the natural sources for new bioactive chemicals, plants are still predominant. Their secondary metabolism yields an immeasurable wealth of chemical structures which has been and will continue to be a source of new drugs, directly in their native form and after optimization by synthetic medicinal chemistry. The current review, published in two parts, attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs.

Volatile Substances Produced by Fusarium oxysporum from Coffee Rhizosphere and Other Microbes affect Meloidogyne incognita and Arthrobotrys conoides.

Microorganisms produce volatile organic compounds (VOCs) which mediate interactions with other organisms and may be the basis for the development of new methods to control plant-parasitic nematodes that damage coffee plants. In the present work, 35 fungal isolates were isolated from coffee plant rhizosphere, Meloidogyne exigua eggs and egg masses. Most of the fungal isolates belonged to the genus Fusarium and presented in vitro antagonism classified as mutual exclusion and parasitism against the nematode-predator fungus Arthrobotrys conoides (isolated from coffee roots). These results and the stronger activity of VOCs against this fungus by 12 endophytic bacteria may account for the failure of A. conoides to reduce plant-parasitic nematodes in coffee fields. VOCs from 13 fungal isolates caused more than 40% immobility to Meloidogyne incognita second stage juveniles (J2), and those of three isolates (two Fusarium oxysporum isolates and an F. solani isolate) also led to 88-96% J2 mortality. M. incognita J2 infectivity decreased as a function of increased exposure time to F. oxysporum isolate 21 VOCs. Gas chromatography-mass spectrometry (GC-MS) analysis lead to the detection of 38 VOCs produced by F. oxysporum is. 21 culture. Only five were present in amounts above 1% of the total: dioctyl disulfide (it may also be 2-propyldecan-1-ol or 1-(2-hydroxyethoxy) tridecane); caryophyllene; 4-methyl-2,6-di-tert-butylphenol; and acoradiene. One of them was not identified. Volatiles toxic to nematodes make a difference among interacting microorganisms in coffee rhizosphere defining an additional attribute of a biocontrol agent against plant-parasitic nematodes.

The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases - part I

Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen "Neglected Tropical Diseases" (NTDs) defined as such by WHO due to the neglect of financial investment into research and development of new drugs by a large part of pharmaceutical industry and neglect of public awareness in high income countries. Another major tropical protozoan disease is malaria (caused by various Plasmodium species), which -although not mentioned currently by the WHO as a neglected disease- still represents a major problem, especially to people living under poor circumstances in tropical countries. Malaria causes by far the highest number of deaths of all protozoan infections and is often (as in this review) included in the NTDs. The mentioned diseases threaten many millions of lives world-wide and they are mostly associated with poor socioeconomic and hygienic environment. Existing therapies suffer from various shortcomings, namely, a high degree of toxicity and unwanted effects, lack of availability and/or problematic application under the life conditions of affected populations. Development of new, safe and affordable drugs is therefore an urgent need. Nature has provided an innumerable number of drugs for the treatment of many serious diseases. Among the natural sources for new bioactive chemicals, plants are still predominant. Their secondary metabolism yields an immeasurable wealth of chemical structures which has been and will continue to be a source of new drugs, directly in their native form and after optimization by synthetic medicinal chemistry. The current review, published in two parts, attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs.