In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

Abstract

In the present study, a quassinoid, neosergeolide, isolated from the roots and stems of Picrolemma sprucei (Simaroubaceae), the indole alkaloids ellipticine and aspidocarpine, isolated from the bark of Aspidosperma vargasii and A. desmanthum (Apocynaceae), respectively, and 4-nerolidylcatechol, isolated from the roots of Pothomorphe peltata (Piperaceae), all presented significant in vitro inhibition (more active than quinine and chloroquine) of the multi-drug resistant K1 strain of Plasmodium falciparum. Neosergeolide presented activity in the nanomolar range. This is the first report on the antimalarial activity of these known, natural compounds. This is also the first report on the isolation of aspidocarpine from A. desmanthum. These compounds are good candidates for pre-clinical tests as novel lead structures with the aim of finding new antimalarial prototypes and lend support to the traditional use of the plants from which these compounds are derived.Key words: neosergeolide -ellipticine -aspidocarpine -4-nerolidylcatechol -Pothomorphe peltata -Picrolemma spruceiAspidosperma spp.Malaria is the main cause of economic loss and high morbidity in the world today and continues to be endemic to tropical regions such as the Amazon. In the Brazilian Amazon, 1.6 million positive plates (thick smears) in a total of 8 million diagnostic tests for malaria were registered from January 2004 to February 2007 (Ministério da Saúde, Sivep-Malaria 2007). The lack of an effective vaccine and the increasing expansion of strains of Plasmodium falciparum presenting resistance towards commonly used, low-cost antimalarials make control of this disease difficult (Olliaro & Bloland 2001, Wellens & Plowe 2001, Vieira et al. 2001, Gonzales et al. 2003, Alecrim et al. 2006. As a result, the World Health Organization (WHO 1978(WHO , 1995 has been promoting research on natural product based drugs for treatment of disease and many plant species have been evaluated for antimalarial activity (Weniger et al. 2004). In these studies, emphasis has been on the discovery of lead compounds for drug development (Gundidza & Chinyanganya 1999). The rational search for active substances in medicinal plants is a very promising and cost-effective strategy for antimalarial drug discovery. This approach benefits from the accumulated knowledge of the curing capacity of plants possessed by inhabitants of malaria endemic regions and permits the extensive evaluation of natural products derived from these sources (Campbell et al. 1997, 1998, Brandão et al. 1992, 1997, Krettli et al. 2001, Andrade-Neto et al. 2004a.This triage of useful and effective plants is at the heart of traditional medicinal knowledge and is an extremely important source of therapeutic compounds in use today. Important semi-synthetic, low-cost, highly effective antimalarial drugs such as the quinolines (chloroquine, mefloquine, primaquine, etc.) and artemisinin derivatives (sodium artesunate, arteether, artemether, etc.) owe their initial discovery to the isolation and structural identi...

In vitro susceptibility of Plasmodium falciparum Welch field isolates to infusions prepared from Artemisia annua L. cultivated in the Brazilian Amazon

“…The stabilisation of geographically specific populations of P. falciparum in continuous culture permits the evaluation of the actual susceptibility profiles to drugs and to natural products of the parasites that are in circulation in the human (and insect) populations in a given region (Andrade-Neto et al 2007). In the present study, it was possible to stabilise, in continuous culture, nine (16%) of 55 field isolates of P. falciparum.…”

“…Patients presenting clinical symptoms related to severe malaria were invited to be enrolled in this study after confirmation of P. falciparum mono infection by thick smear diagnosis and their signing of an informed consent form (FMT-HVD Ethics in Research Commission 1838). Parasites were maintained in continuous culture using the method of Träger and Jensen (1976) with modifications, as described in Andrade-Neto et al (2007), using type A + human erythrocytes in RPMI-1640 medium (Sigma-Aldrich, St. Louis, MO, USA) supplemented with 10% A + human plasma (donated by blood banks). Cultures were maintained under an environment of 5% O 2 , 5% CO 2 and 90% N 2 and incubated at 37ºC.…”

“…The commercial drug standards chloroquine diphosphate salt (Sigma-Aldrich, Steinheim, Westphalia, Germany), quinine sulphate salt (Sigma-Aldrich, Steinheim, Westphalia, Germany) and artemisinin (Sigma-Aldrich, Steinheim, Westphalia, Germany) were also tested in the concentration ranges of 2.5 × 10 3 -3.4, 5.0 × 10 2 -0.70 and 1.0 × 10 2 -6.4 × 10 -3 ng/mL, respectively. The microtest was performed according to the method of Rieckmann et al (1978) with modifications as described in Andrade-Neto et al (2007). Briefly, the wells of a 96-well test plate were loaded with 180 μL of a parasitised red blood cell suspension in culture medium containing predominantly young trophozoites (ring forms), a 3% haematocrit and 1.5% initial parasitaemia.…”

LC-ESI-MS determination of quassinoids isobrucein B and neosergeolide in Picrolemma sprucei stem infusions

“…Ultrapure water, obtained from a Milli-Q Plus System (Millipore, Bedford, MA, USA), was used in all analyses. 1 and 2 were isolated from P. sprucei as described previously 11,19 and used as reference standards. Their identity and purity were established based on 1D and 2D NMR, IR, HR-ESI-TOF-MS, HPLC-DAD and LC-ESI-MS analyses and comparison to literature data.…”

Anti-Plasmodial Phytochemical Agents - The Effective Alternative for Drug-Resistant Plasmodial Control

“…There are a number of reports during the last few years mentioning several plant extracts possessing significant antimalarial activity and several active phytocompounds have also been initiated. de Andrade-Neto et al [36] reported quassinoid, neosergeolide isolated from the roots and stems of Picrolemma spruce (Simaroubaceae), the indole alkaloids ellipticine and aspidocarpine, isolated from the bark of Aspidosperma vargasii and Aspidosperma desmanthum (Apocynaceae), respectively and 4-nerolidylcatechol, isolated from the roots of Pothomorphe peltata (Piperaceae), have significant in vitro inhibition (more active than quinine and chloroquine) of the multi-drug resistant K1 strain of Plasmodium falciparum. Johns et al [37] isolated antimalarial compounds such as N-Nitrosoxylopine, Roemerolidine and Duguevalline from the extract of the bark of Annona squamosa.…”