Potential Antimalarial Compounds Research Articles

Pharmacokinetic properties and metabolism of a new potent antimalarial N-alkylamidine compound, M64, and its corresponding bioprecursors

Antimalarial activities and pharmacokinetics of the bis-alkylamidine, M64, and its amidoxime, M64-AH, and O-methylsulfonate, M64-S-Me, derivatives were investigated. M64 and M64-S-Me had the most potent activity against the Plasmodium falciparum growth (IC 50 < 12 nM). The three compounds can clear the Plasmodium vinckei infection in mice (ED 50 < 10 mg/kg). A liquid chromatography–mass spectrometry method was validated to simultaneously quantify M64 and M64-AH in human and rat plasma. M64 is partially metabolized to M64-monoamidoxime and M64-monoacetamide by rat and mouse liver microsomes. The amidoxime M64-AH undergoes extensive metabolism forming M64, M64-monoacetamide, M64-diacetamide and M64-monoamidoxime. Strong interspecies differences were observed. The pharmacokinetic profiles of M64, M64-AH and M64-S-Me were studied in rat after intravenous and oral administrations. M64 is partially metabolized to M64-AH; while M64-S-Me is rapidly and totally converted to M64 and M64-AH. M64-AH is mostly oxidized to the inactive M64-diacetamine while its N-reduction to the efficient M64 is a minor metabolic pathway. Oral dose of M64-AH was well absorbed (38%) and converted to M64 and M64-diacetamide. This study generated substantial information about the properties of this class of antimalarial drugs. Other routes of synthesis will be explored to prevent oxidative transformation of the amidoxime and to favour the N-reduction.

Development of a New Generation of 4-Aminoquinoline Antimalarial Compounds Using Predictive Pharmacokinetic and Toxicology Models

Among the known antimalarial drugs, chloroquine (CQ) and other 4-aminoquinolines have shown high potency and good bioavailability. Yet complications associated with drug resistance necessitate the discovery of effective new antimalarial agents. ADMET prediction studies were employed to evaluate a library of new molecules based on the 4-aminoquinolone-related structure of CQ. Extensive in vitro screening and in vivo pharmacokinetic studies in mice helped to identify two lead molecules, 18 and 4, with promising in vitro therapeutic efficacy, improved ADMET properties, low risk for drug-drug interactions, and desirable pharmacokinetic profiles. Both 18 and 4 are highly potent antimalarial compounds, with IC(50) values of 5.6 and 17.3 nM, respectively, against the W2 (CQ-resistant) strain of Plasmodium falciparum (for CQ, IC(50) = 382 nM). When tested in mice, these compounds were found to have biological half-lives and plasma exposure values similar to or higher than those of CQ; they are therefore desirable candidates to pursue in future clinical trials.

PERFORMANCE OF ARTEMISIA ANNUA L. CULTIVARS IN DIFFERENT LOCATIONS IN ARGENTINA

Artemisinin, a sesquiterpene lactone endoperoxide isolated from the herb Artemisia annua L. (Asteraceae), is a highly potent antimalarial compound, which is efficient against multidrug-resistant strains of Plasmodium falciparum. The promotion of artemisinin-based combination therapies (ACTs) by the WHO during the past years lead to strong pressure on the world market of artemisinin. In order to assess the potential of this new culture in Argentina, the 'Artemis' cultivar was grown in 2007 and 2008 in four different locations. On one of the sites, 2 new hybrids were tested to assess their potential. The following parameters were recorded during the growing period: plant height, phenology, biomass production, percentage of dry leaves and artemisinin content. The results obtained with the cultivar 'Artemis' showed that the highest yield of biomass reached at the time of harvest was 2.5 t/ha dry leaves. At the harvesting stage, artemisinin contents ranged from 0.77% to 1.12% depending on the location. The two new hybrids tested showed a similar production of leaves, but a significantly higher level of artemisinin than those observed for 'Artemis'. Future trials are planned to optimise the cultivation of annual wormwood in Argentina.

Boromycin Derivatives: Synthesis and Antimalarial Activity in vitro and in vivo

Derivatives of boromycin, which has significant antimalarial properties both in vitro and in vivo, were examined for similar the efficacy against both drug-resistance strain and drug-sensitive strain of malaria and as a means to elucidate structure-activity relationships. More potent in vitro compounds tended to lose their properties in vivo when administered orally. Some novel 16-O-acyl derivatives were found to be more potent and selective antimalarial compounds compared to boromycin. Furthermore, alkyne-bearing 16-O-alkylacyl compounds retained reasonably good efficacy in vivo when given per os.

Optimized and convergent synthesis of potent anti-malarial aminoquinoline compounds: easy access to analogs

Optimized and convergent synthesis of potent anti-malarial aminoquinoline compounds: easy access to analogs

Bio-transformation of artemisinin using soil microbe: Direct C-acetoxylation of artemisinin at C-9 by Penicillium simplissimum

Potent antimalarial compound artemisinin, 1 was bio-transformed to C-9 acetoxy artemisinin, 2 using soil microbe Penicillium simplissimum along with C-9 hydroxy derivative 3. The products were characterized using high field NMR and MS-MS data. The absolute stereochemistry of the newly generated chiral centers has been ascertained by COSY and 1D NOESY experiments. This is the first Letter of direct C-acetoxylation of artemisinin using microbial strains.

Aggregated Enhanced Raman Scattering in Fe(III)PPIX Solutions: The Effects of Concentration and Chloroquine on Excitonic Interactions

Resonance Raman spectra of hematin and hemin solutions are reported for 413 and 514 nm excitation wavelengths. Enhancement of A1g modes (1569 and 1370 cm(-1)) and B1g modes (1124 and 755 cm(-1)) as a function of increased concentration are observed when irradiating with 514 nm laser excitation but not 413 nm. This can be rationalized by considering an excitonic coupling mechanism. As the concentration of hematin increases there is an increased probability of supramolecular interactions between iron(III) protoporphyrin IX (Fe(III)PPIX) units occurring. The Fe(III)PPIX concentration reaches a saturation point in solution and excitonic coupling reaches a maximum causing the enhancement profile to plateau when applying 514 nm excitation. In contrast, when using 413 nm excitation there were no changes in band intensity with increased concentration showing that excitonic coupling through supramolecular interactions for aggregated solutions is wavelength dependent. Electronic absorption spectra show that as the concentration of Fe(III)PPIX increases in solution the Soret band is slightly blue shifted and the Q-band significantly broadens supporting the excitonic hypothesis. Understanding the mechanism that accounts for the Raman photophysical behavior of hemes at high concentrations provided an indirect method to monitor antimalarial drug interactions. A second aim was to investigate chloroquine binding to Fe(III)PPIX-OH/H2O monomers, pi-pi dimers and micro-oxo dimers formed in highly concentrated solutions approaching those of the digestive vacuole of the P. falciparum malaria parasite using excitonic Raman enhancement. It was hypothesized that the Raman excitonic enhancement mechanism could be impeded in heme aggregated solutions by the addition of chloroquine. This would result in a reduction in heme bands associated with the A1g modes including nu4. Resonance Raman spectra recorded using 514 nm excitation show that chloroquine (CQ) acts as a molecular spacer and binds noncovalently through dispersion interactions giving rise to pi-pi interactions, between micro-oxo dimer units of Fe(III)PPIX as evinced by the decrease in intensity of nu4 in the Raman spectrum as a function of increasing CQ mole ratio. In comparison, electronic spectra show that CQ can bind to the unligated face of Fe(III)PPIX-OH/H2O monomers, potentially reducing the formation of pi-pi dimers. This study has important implications in determining the effectiveness of potential antimalarial compounds that are thought to exert their effectiveness by binding through supramolecular interactions to the unligated faces of Fe(III)PPIX-OH/H2O monomers and micro-oxo dimers.

Use of high-density tiling microarrays to identify mutations globally and elucidate mechanisms of drug resistance in Plasmodium falciparum

Using tiling microarrays, a mechanism by which Plasmodium falciparum parasites acquire resistance to the antimalarial fosmidomycin has been elucidated

Depsipeptides from Microorganisms: A New Class of Antimalarials

Depsipeptides are a large group of natural products produced by fungi, actinomycetes, cyanobacteria, higher plants and marine organisms. This family of compounds is known to exhibit a wide range of biological activities, and thanks to the progress of isolation techniques and the advances of methods for structure determination, the numbers of depsipeptides having both unique structures and attractive biological activities are increasing. Many of these compounds have shown a wide range of biological activities, and some are in clinical use or have entered human clinical trials as antibiotic or anticancer agents. However, only a handful of them have been evaluated for their antimalarial activity. This paper aims to review the recent advances in depsipeptides as potential antimalarial compounds.

Cloning, Expression, and Biochemical Characterization of Streptomyces rubellomurinus Genes Required for Biosynthesis of Antimalarial Compound FR900098

The antibiotics fosmidomycin and FR900098 are members of a unique class of phosphonic acid natural products that inhibit the nonmevalonate pathway for isoprenoid biosynthesis. Both are potent antibacterial and antimalarial compounds, but despite their efficacy, little is known regarding their biosynthesis. Here we report the identification of the Streptomyces rubellomurinus genes required for the biosynthesis of FR900098. Expression of these genes in Streptomyces lividans results in production of FR900098, demonstrating their role in synthesis of the antibiotic. Analysis of the putative gene products suggests that FR900098 is synthesized by metabolic reactions analogous to portions of the tricarboxylic acid cycle. These data greatly expand our knowledge of phosphonate biosynthesis and enable efforts to overproduce this highly useful therapeutic agent.

NEW ARTEMISIA ANNUA HYBRIDS WITH HIGH ARTEMISININ CONTENT

NEW ARTEMISIA ANNUA HYBRIDS WITH HIGH ARTEMISININ CONTENT

A Survey of Synthetic and Natural Phytotoxic Compounds and Phytoalexins as Potential Antimalarial Compounds

The apicomplexan parasites pathogens such as Plasmodium spp. possess an apicoplast, a plastid organelle similar to those of plants. The apicoplast has some essential plant-like metabolic pathways and processes, making these parasites susceptible to inhibitors of these functions. The main objective of this paper is to determine if phytotoxins with plastid target sites are more likely to be good antiplasmodial compounds than are those with other modes of action. The antiplasmodial activities of some compounds with established phytotoxic action were determined in vitro on a chloroquine (CQ) sensitive (D6, Sierra Leone) strain of Plasmodium falciparum. In this study, we provide in vitro activities of almost 50 such compounds, as well as a few phytoalexins against P. falciparum. Endothall, anisomycin, and cerulenin had sufficient antiplasmodial action to be considered as new lead antimalarial structures. Some derivatives of fusicoccin possessed markedly improved antiplasmodial action than the parent compound. Our results suggest that phytotoxins with plastid targets may not necessarily be better antiplasmodials than those that act at other molecular sites. The herbicides, phytotoxins and the phytoalexins reported here with significant antiplasmodial activity may be useful probes for identification of new antimalarial drug targets and may also be used as new lead structures for new antiplasmodial drug discovery.

Synthesis and biological evaluation of phenolic Mannich bases of benzaldehyde and (thio)semicarbazone derivatives against the cysteine protease falcipain-2 and a chloroquine resistant strain of Plasmodium falciparum

A targeted series of phenolic Mannich bases of benzaldehyde and (thio)semicarbazone derivatives were synthesized and evaluated in vitro against the malarial cysteine protease falcipain-2 and a chloroquine resistant strain (W2) of Plasmodium falciparum. A novel series of 4-aminoquinoline semicarbazones were the most effective inhibitors of falcipain-2 (most potent inhibitor had IC 50 = 0.63 μM) while a bisquinoline semicarbazone compound 8f was the most potent antimalarial compound with an IC 50 of 0.07 μM against W2. Compound 8f also weakly inhibited falcipain-2, with an IC 50 of 3.16 μM, although its principal antiparasitic activity did not appear to be due to inhibition of this enzyme.

In Silico Three Dimensional Pharmacophore Models to Aid the Discovery and Design of New Antimalarial Agents

Malaria is one of the most dangerous diseases affecting primarily poor people of tropical and subtropical regions of the world with a worldwide death toll of over 1.5 million a year coupled with increasing resistance to common antimalarial drugs, such as chloroquine and mefloquine, justifies WHOs appeal for search and delivery of novel antimalarial drugs as quick as possible. This review describes how by using in silico (computational) methods, specifically three-dimensional QSAR pharmacophores developed from known antimalarial compounds could be used as screening tools for identification of potential new candidates through search of virtual compound libraries. The review is based on two select examples of pharmacophore models published by us recently: the antimalarial indolo[2,1-b]quinazoline-6,12-diones (tryptanthrins) and the tricyclic antidepressants as chloroquine (CQ) resistance reversal agents. The model developed from the tryptanthrins was found to correlate well with this class of compounds and predictive for other known antimalarials of different chemical classes, such as quinolines, chalcones, rhodamine dyes, Pfmrk (malarial cyclin dependent kinase inhibitors), malarial FabH (KASIII) inhibitors, and plasmepsin inhibitors. Similarly, the CQ-resistance reversal model too is found to be fairly well correlated for the tricyclic antidepressants and predictive for a variety of other known CQ-resistance reversal agents. The pharmacophores allowed search and identification of potent antimalarial compounds from in-house databases and enabled custom designed synthesis of new potent analogues.

Antiplasmodial Activity and Acute Toxicity of N-alkyl and N-benzyl-1,10-Phenanthroline Derivatives in Mouse Malaria Model

Previous study on in vitro antiplasmodial activity of diaza phenanthrene analogs indicated that the 1,10-phenanthroline skeleton represents a potential antimalarial leader compound. Based on those skeletons, six derivatives of N-alkyl and N-benzyl-1,10-phenanthroline were synthesized and the in vitro antiplasmodial activities was evaluated. This paper reported the in vivo antiplasmodial activity study of the 1,10-phenanthroline derivatives performed by the classical 4-day suppressive test against Plasmodium berghei. Acute toxicity of each compound was determined after a single injection of the compound intraperitoneally in Swiss mice. The 50% effective dose (ED50) of the compound ranged from 2.08 to 50.93 mg/kg of body weight, and the therapeutic indices (TIs) ranged from 2.06 to 7.57 except (1)-N-benzyl-1,10-phenantrolinium iodide, which was 58.38. All of the 1,10-phenanthroline derivatives had in vivo antiplasmodial activity and (1)-N-benzyl-1,10-phenantrolinium iodide was the most potent.

Antimalarial compounds from Kniphofia foliosa roots

During the course of screening Ethiopian medicinal plants for their antimalarial properties, it was found that the dichloromethane extract of the roots of Kniphofia foliosa Hochst. (Asphodelaceae), which have long been used in the traditional medicine of Ethiopia for the treatment of abdominal cramps and wound healing, displayed strong in vitro antiplasmodial activity against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum with an ED50 value of 3.8 microg/mL and weak cytotoxic activity against KB cells with an ED50 value of 35.2 microg/mL. Five compounds were isolated from the roots and evaluated for their in vitro antimalarial activity. Among the compounds tested, 10-(chrysophanol-7'-yl)-10-(xi)-hydroxychrysopanol-9-anthrone and chryslandicin, showed a high inhibition of the growth of the malaria parasite, P. falciparum with ED50 values of 0.260 and 0.537 microg/mL, respectively, while the naphthalene derivative, 2-acetyl-1-hydroxy-8-methoxy-3-methylnaphthalene, exhibited a less significant antimalarial activity with an ED50 value of 15.4 microg/mL. To compare the effect on the parasite with toxicity to mammalian cells, the cytotoxic activities of the isolated compounds against the KB cell line were evaluated and 10-(chrysophanol-7'-yl)-10-(xi)-hydroxychrysopanol-9-anthrone and chryslandicin displayed very low toxicity with ED50 values of 104 and 90 microg/mL, respectively. This is the first report of the inhibition of the growth of P. falciparum by anthraquinone-anthrone dimers and establishes them as a new class of potential antimalarial compounds with very little host cell toxicity.

Stage-specific activity of potential antimalarial compounds measured in vitro by flow cytometry in comparison to optical microscopy and hypoxanthine uptake.

The evaluation of new antimalarial agents using older methods of monitoring sensitivity to antimalarial drugs are laborious and poorly suited to discriminate stage-specific activity. We used flow cytometry to study the effect of established antimalarial compounds, cysteine protease inhibitors, and a quinolone against asexual stages of Plasmodium falciparum. Cultured P. falciparum parasites were treated for 48 h with different drug concentrations and the parasitemia was determined by flow cytometry methods after DNA staining with propidium iodide. P. falciparum erythrocytic life cycle stages were readily distinguished by flow cytometry. Activities of established and new antimalarial compounds measured by flow cytometry were equivalent to results obtained with microscopy and metabolite uptake assays. The antimalarial activity of all compounds was higher against P. falciparum trophozoite stages. Advantages of flow cytometry analysis over traditional assays included higher throughput for data collection, insight into the stage-specificity of antimalarial activity avoiding use of radioactive isotopes.

Computational studies of new potential antimalarial compounds--stereoelectronic complementarity with the receptor.

One of the most important pharmacological mechanisms of antimalarial action is the inhibition of the aggregation of hematin into hemozoin. We present a group of new potential antimalarial molecules for which we have performed a DFT study of their stereoelectronic properties. Additionally, the same calculations were carried out for the two putative drug receptors involved in the referred activity, i.e., hematin mu-oxo dimer and hemozoin. A complementarity between the structural and electronic profiles of the planned molecules and the receptors can be observed. A docking study of the new compounds in relation to the two putative receptors is also presented, providing a correlation with the defined electrostatic complementarity.

Novel and Potent Anti-malarial Agents

Readily accessible, novel, and potent anti-malarial compounds have been developed. Optimization of the initial lead structure resulted in derivatives with IC 50 values from 7 to 35 nM against chloroquine-sensitive and 70–350 nM against chloroquine-resistant strains of Plasmodium falciparum.

ChemInform Abstract: Design, Synthesis, and Biological Evaluation of a Series of Simple and Novel Potential Antimalarial Compounds.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.