Antimalarial Natural Products Research Articles

Antimalarial efficacy, cytotoxicity, and genotoxicity of methanolic stem bark extract from Hintonia latiflora in a Plasmodium yoelii yoelii lethal murine malaria model

Traditional medicines have been used to treat malaria for thousands of years and are the source of artemisinin and quinine derivatives. With the increasing levels of drug resistance, the high cost of artemisisnin-based combination therapies, and fake antimalarials drugs, traditional medicine have become an important and sustainable source of malaria treatment. For the benefit of those who use traditional medicine to treat malaria, there is an urgent need to study the efficacy and toxicity of herbal remedies. Hintonia latiflora stem bark infusions are use in Mexican traditional medicine to treat malaria, diabetes, and gastrointestinal diseases. Its efficacy in the treatment of complicated malaria and its ability to generate DNA damage to the host is not fully evaluated. In our search for antimalarial natural products, in the present study, we tested the efficacy of H. latiflora stem bark methanolic extract (HlMeOHe) in CD1 male mice infected with lethal Plasmodium yoelii yoelii and its in vivo cytotoxicity and genotoxicity. To assess the antimalarial activity, the extract was evaluated in a 4-day test scheme in oral doses of 1,200, 600, and 300 mg/kg prior acute toxicity test; oral chloroquine (15 mg/kg) was used as positive control. The ability of 1,200 mg/kg of HlMeOHe to induce cytotoxicity and DNA damage in the peripheral blood of mice was assessed using a fluorochrome-mediated viability test and the micronucleus (MN) assay; N-ethyl-N-nitrosourea (ENU) was used as a positive control. HlMeOHe median acute toxicity (LD₅₀) was 2,783.71 mg/kg and LD10 was 1,293.76 mg/kg (taken as the highest work dose). Plasmodium yoelii yoelii-infected mice in the untreated control group died between 6 and 7 days post-infection (PI) with parasitemia over 70%. Even though mice treated with 600 and 300 mg/kg showed a chemosuppression percentage of total parasitemia of 99.23 and 23.66, respectively, animals in both groups died 6 to 7 days PI with parasitemia over 45%. A 4-day dosage of 1,200 mg/kg of the extract showed, in the P. yoelii yoelii-infected mice, a 100% chemosuppression of total parasitemia on 5 days PI and a 23 days survival time with a mean parasitemia of 23.6% at the date of death. Only mice treated with chloroquine survived until the end of the experiment. Cell viability was not affected. The average number of micronuclei in the treated mice increased significantly (P < 0.05) to 4.8 MN when compared with the untreated control group (0.9 MN). The results obtained in this study showed that the infection outcome of P. yoelii yoelii-infected mice is affected by HlMeOHe. Although a concentration of 1,200 mg/kg of HlMeOHe is suitable to use in the treatment of malaria fever, slowed down the parasite replication, retarded the patency time, and increased the infected P. yoelii yoelii mice survival time, its chemical composition should be studied in detail in order to reduce its genotoxic potential.

Total synthesis of thiaplakortone a: derivatives as metabolically stable leads for the treatment of malaria.

Thiaplakortone A (3a), an antimalarial natural product, was prepared by an operationally simple and scalable synthesis. In our efforts to deliver a lead compound with improved potency, metabolic stability, and selectivity, the synthesis was diverted to access a series of analogues. Compounds 3a-d showed nanomolar activity against the chloroquine-sensitive (3D7) Plasmodium falciparum line and were more active against the chloroquine- and mefloquine-resistant (Dd2) P. falciparum line. All compounds are "Rule-of-5" compliant, and we show that metabolic stability can be enhanced via modification at either the primary or pyrrole nitrogen. These promising results lay the foundation for the development of this structurally unprecedented natural product.

Biomimetic Total Syntheses of Borreverine and Flinderole Alkaloids

Dimeric indole alkaloids represent a structurally unique class of natural products having interesting biological activities. Recently, we reported the first total synthesis of flinderoles B and C, structurally unique and potent antimalarial natural products. Central to the design of the approach and by virtue of a one-pot, acid-catalyzed dimerization reaction, the route also provided total synthesis of the borreverine class of natural products. This full account details the progress of efforts that culminated in the protecting-group-free, six-step total synthesis of all of the flindersia alkaloids: dimethylisoborreverine, isoborreverine, flinderoles A-C, and their analogues. A biomimetic approach featuring a scalable and catalytic formal [3 + 2] cycloaddition and Diels-Alder reaction is outlined in detail. On the basis of the experimental observations, a detailed mechanism has been proposed for the dimerization of tertiary alcohol 28.

Pharmacokinetics, Metabolism, and in Vivo Efficacy of the Antimalarial Natural Product Bromophycolide A

A suite of pharmacokinetic and pharmacological studies show that bromophycolide A (1), an inhibitor of drug-sensitive and drug-resistant Plasmodium falciparum, displays a typical small molecule profile with low toxicity and good bioavailability. Despite susceptibility to liver metabolism and a short in vivo half-life, 1 significantly decreased parasitemia in a malaria mouse model. Combining these data with prior SAR analyses, we demonstrate the potential for future development of 1 and its bioactive ester analogs.

Amazonian plant natural products: perspectives for discovery of new antimalarial drug leads.

Plasmodium falciparum and P. vivax malaria parasites are now resistant, or showing signs of resistance, to most drugs used in therapy. Novel chemical entities that exhibit new mechanisms of antiplasmodial action are needed. New antimalarials that block transmission of Plasmodium spp. from humans to Anopheles mosquito vectors are key to malaria eradication efforts. Although P. vivax causes a considerable number of malaria cases, its importance has for long been neglected. Vivax malaria can cause severe manifestations and death; hence there is a need for P. vivax-directed research. Plants used in traditional medicine, namely Artemisia annua and Cinchona spp. are the sources of the antimalarial natural products artemisinin and quinine, respectively. Based on these compounds, semi-synthetic artemisinin-derivatives and synthetic quinoline antimalarials have been developed and are the most important drugs in the current therapeutic arsenal for combating malaria. In the Amazon region, where P. vivax predominates, there is a local tradition of using plant-derived preparations to treat malaria. Here, we review the current P. falciparum and P. vivax drug-sensitivity assays, focusing on challenges and perspectives of drug discovery for P. vivax, including tests against hypnozoites. We also present the latest findings of our group and others on the antiplasmodial and antimalarial chemical components from Amazonian plants that may be potential drug leads against malaria.

Recent Developments in Antimalarial Natural Products Isolated from Medicinal Plants

Malaria is an infectious disease causing almost one million deaths each year. There is an urgent need for discovery of new antimalarial compounds. Natural products have been the single most productive source of leads for the development of drugs, because of their great variety of chemical structures. This review covers studies on antimalarial natural products isolated from plants, published from January 2010 until April 2012. A total of 171 structures comprising alkaloids, terpenoids, phenolics and other metabolites are listed in this review, including information on their antiplasmodial and cytotoxic activity.

Pd-Catalyzed Imine Cyclization: Synthesis of Antimalarial Natural Products Aplidiopsamine A, Marinoquinoline A, and Their Potential Hybrid NCLite-M1

Palladium-catalyzed cyclization of imines has been developed to construct the extremely rare 3H-pyrrolo[2,3-c]quinoline ring system for diversity oriented first total synthesis of antimalarial marine natural product Aplidiopsamine A as well as synthesis of Marinoquinoline A and potential natural product hybrid NCLite-M1.

Antimalarial natural products from traditional chinese medicinal herbs

Malaria is a disease caused by parasites of the genus Plasmodium. The latest statistics show that malaria kills in excess of 1 million people and causes over 600,000 cases of acute illness per year. Historically, natural products have played a major role in the treatment of malaria. For centuries the Chinese medicinal plant, Artemisia annua has been used as an antimalarial herbal remedy. Subsequent chemical investigation of A. annua has led to the discovery of the antimalarial drug, artemisinin. Over 300 medicinal herbs are commonly used as antimalarial remedies in China. In this study, 100 herbals extracts were investigated for their antimalarial activity; 72 extracts showed >50% inhibition, while 54 samples showed >90% inhibition against a chloroquine-sensitive Plasmodium falciparum line (3D7). Chemical investigation of the active extract from Picrorhiza kurroa has yielded 2 new and 9 known natural products. This presentation will discuss the activity profiles of the 100 medicinal herb extracts and the isolation and structure elucidation of several antimalarial natural products.

Antimalarial natural products from Picrorhiza scrophulariiflora

As part of a program aimed at identifying antimalarial natural products, we screened traditional Chinese herbs that are alleged to have antimalarial activity and are used in primary health care. This study used selected herb extracts in a biological assay against Plasmodium falciparum. The crude CH2Cl2 and MeOH extract of the rhizome Picrohiza scrophulariiflora Pennell shows high potency and has been investigated in detail employing the same bioassay to guide the isolation. Chemical investigation of the activity fractions of P. scrophulariiflora have lead to the isolation of 12 natural products, two of them are novel compounds. The structures of the 12 compounds have been fully characterized based on their NMR and MS spectroscopic data. The evaluation of their antimalarial activity is currently underway.

Discovery of anticancer drugs from antimalarial natural products: a MEDLINE literature review

Nature-derived antimalarials might have anticancer potential, yet no systematic reviews exist on the topic. We screened MEDLINE using an automated algorithm in a high-volume search for antimalarial agents recognized by the WHO and natural antimalarials from knowledge-resource texts and databases for reported evidence of anticancer activity. Results are reported by source (plants, fungi, marine organisms and bacteria) and anticancer mechanism. In total, 14 out of 15 nature-derived antimalarials (93%) referenced by WHO as well as 146 of 235 antimalarial natural species (62%) from our defined MEDLINE search were reported as having anticancer activity. Therefore, antimalarial natural products might provide a fertile and much needed lead in anticancer drug discovery.

Synthesis and Evaluation of 1‐Amino‐6‐halo‐β‐carbolines as Antimalarial and Antiprion Agents

Malaria is one of the world's most devastating parasitic diseases, causing almost one million deaths each year. Growing resistance to classical antimalarial drugs, such as chloroquine, necessitates the discovery of new therapeutic agents for successful control of this global disease. Here, we report the synthesis of some 6-halo-β-carbolines as analogues of the potent antimalarial natural product, manzamine A, retaining its heteroaromatic core whilst providing compounds with much improved synthetic accessibility. Two compounds displayed superior activity to chloroquine itself against a resistant Plasmodium falciparum strain, identifying them as promising leads for future development. Furthermore, in line with previous reports of similarities in antimalarial and antiprion effects of aminoaryl-based antimalarial agents, the 1-amino-β-carboline libraries were also found to possess significant bioactivity against a prion-infected cell line.

High content live cell imaging for the discovery of new antimalarial marine natural products

BackgroundThe human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, Plasmodium falciparum.MethodsA high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown in vitro in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope.ResultsImage analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts.ConclusionCollectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials.

Antimalarial natural products: a review.

Malaria is an infectious disease commonplace in tropical countries. For many years, major antimalarial drugs consisted of natural products, but since 1930s these drugs have been largely replaced with a series of synthetic drugs. This article tries to briefly indicate that some plants which previously were used to treat malaria, as a result of deficiencies of synthetic drugs, have revived into useful products once more. It also attempts to describe some tests which can be used to evaluate plant extracts for antimalarial activity. By referring to some recent literatures, data were collected about plants used for the treatment of malaria, evaluation of plant extracts for antimalarial activity, modes of action of natural antimalarial agents, and recent research on antimalarial plants in Iran and other countries. There is an urgent need for the development of new treatments for malaria. Many countries have a vast precedence in the use of medicinal plants and the required knowledge spans many centuries. Although malaria is controlled in Iran, some researchers tend to study malaria and related subjects. In vitro biological tests for the detection of antimalarial activities in plant extracts are currently available. It is vital that the efficacy and safety of traditional medicines be validated and their active constituents be identified in order to establish reliable quality control measures.

Triterpenes from Minquartia guianensis (Olacaceae) and in vitro antimalarial activity

Minquartia guianensis, popularly known as acariquara, was phytochemically investigated. The following triterpenes were isolated from the dichloromethane extract of leaves: lupen-3-one (1), taraxer-3-one (2) and oleanolic acid (3). The dichloromethane extract of branches yielded the triterpene 3β-methoxy-lup-20(29)-ene (4). The chemical structures were characterized by NMR data. Plant extracts, substance 3, squalene (5) and taraxerol (6), (5 and 6 previously isolated), were evaluated by in vitro assay against chloroquine resistant Plasmodium falciparum. The dichloromethane extract of leaves and the three triterpenes assayed have shown partial activity. Thus, these results demonstrated that new potential antimalarial natural products can be found even in partially active extracts.

Synthesis and evaluation of a novel series of indoloisoquinolines as small molecule anti-malarial leads

A group of novel synthetic indoloisoquinolines was prepared and its potential as a novel series of small-molecule anti-malarial leads was assessed. The structure–activity relationship on variation of three distinct regions of chemical space was investigated. A lead compound was generated with an activity close to that observed for a known anti-malarial natural product, dihydrousambarensine, that shares the indoloisoquinoline template structure.

Over-expression of HMG-CoA reductase and amorpha-4,11-diene synthase genes in Artemisia annua L. and its influence on artemisinin content

Artemisinin, an endoperoxide sesquiterpene lactone, is a novel antimalarial natural product isolated from Artemisia annua L. plants. The low concentrations (0.01-1.1%) of this compound in A. annua L. plants is, however, a major constraint for commercialization of artemisinin-based combination therapies (ACTs) recommended by WHO for treating malaria caused by multidrug-resistant P. falciparum sp. In this context, in vivo yield improvement programs were undertaken by us. In the present study, HMG-Co A reductase gene (hmgr) from Catharanthus roseus (L) G. Don and amorpha-4,11-diene synthase (ads) gene from A. annua L. were over-expressed in A. annua L. plants to study their effects on artemisinin yields. The transgenic lines developed from putative transgenic regenerants were evaluated for integration and copy number of the transgenes using hptII gene probe, as it was a part of the expression cassette. The transgenic lines showed positive bands of hptII gene on Southern blots confirming the integration of transgenes. Some of the transgenic lines had single copy of the transgenes, while others had multiple copies. The expressions of hmgr and ads at the transcriptional level were also confirmed in each transgenic line employing RT-PCR assays. The HPLC analyses showed that the artemisinin contents were significantly increased in these transgenics. One of the transgenic lines, TR4, was found to contain 7.65-fold higher (1.73 mg/gDW) artemisinin than the non-transgenic plant (W). The increased artemisinin levels were found to be correlated with HMG-Co A reductase and amorpha-4,11-diene synthase enzymatic activities in the biochemical analyses.

Concise Photochemical Synthesis of the Antimalarial Indole Alkaloid Decursivine

A four-step synthesis of the extracyclic, antimalarial indole natural product decursivine is described starting from commercial piperonyl bromide and serotonin (see scheme). A photoinitiated reaction cascade involving indole radical cation formation, rearrangement, radical recombination, rearomatization, elimination, and diastereoselective auto-acid-catalyzed closure of the dihydrofuran ring combine in a single step to conclude this remarkably efficient synthesis.

Formal Total Synthesis of (–)‐Raphidecursinol B

AbstractAn efficient enantioselective formal total synthesis of antimalarial natural product (–)‐raphidecursinol B along with its all stereoisomers is described from commercially available 3,4,5‐trimethoxybenzaldehyde using the Sharpless asymmetric dihydroxylation, regioselective α‐tosylation, epoxide opening and Mitsunobu reaction as the key reaction steps.

Hypervalent iodine(III)-mediated tandem oxidative reactions: application for the synthesis of bioactive polyspirocyclohexa-2,5-dienones

In 2002, we reported the first total syntheses of potent antimalarial natural products, the aculeatins, employing the concept of tandem oxidative reactions mediated by hypervalent iodine(III) reagent to access to polyspirocyclohexa-2,5-dienone cores in very concise manner. Efforts in this field have allowed to identify cyclohexa-2,5-dienone group as a new potent class of pharmacophoric group for treating malaria disease. This article sums up recent contributions devoted to the synthesis of complex and diverse polycyclic structures using the concept of tandem oxidative activations, with p-phenol as co-reactant. More recently, we have explored a variant of the new tandem oxidative reactions that employs a catalytic amount of 4-iodotoluene in the presence of mCPBA as the stoichiometric oxidant (Kita’s procedure).

Plant-derived antimalarial agents: new leads and efficient phythomedicines. Part I. Alkaloids

Malaria remains one of the most serious world health problem and the major cause of mortality and morbidity in the endemic regions. Brazil is among the 30 high-burden countries and most of the cases occur in the Legal Amazonian Region. New chemotherapeutical agents are needed for the treatment of malaria. Many plant species are used in traditional medicines of malarious countries and a relatively few number of these have been investigated for evaluation of their antimalarial effect. Still lower is the number of those that have had the active natural compounds isolated and the toxicity determined. This area is, then, of great research interest. discovery project of antimalarial natural products from plants traditionally used to treat malaria must include in vitro and in vivo assays as well as bioguided isolation of active compounds. The final products would be antimalarial chemical entities, potential new drugs or templates for new drugs development, and/or standardized antimalarial extracts which are required for pre-clinical and clinical studies when the aim is the development of effective and safe phythomedicines. This review discusses these two approaches, presents briefly the screening methodologies for evaluation of antimalarial activity and focuses the activity of alkaloids belonging to different structural classes as well as its importance as new antimalarial drugs or leads and chemical markers for phytomedicines.