RESUMEN
Neglected tropical diseases caused by trypanosomatid parasites have devastating health and economic consequences, especially in tropical areas. New drugs or new combination therapies to fight these parasites are urgently needed. Venturicidin A, a macrolide extracted from Streptomyces, inhibits the ATP synthase complex of fungi and bacteria. However, its effect on trypanosomatids is not fully understood. In this study, we tested venturicidin A on a panel of trypanosomatid parasites using Alamar Blue assays and found it to be highly active against Trypanosoma brucei and Leishmania donovani, but much less so against Trypanosoma evansi. Using fluorescence microscopy, we observed a rapid loss of the mitochondrial membrane potential in T. brucei bloodstream forms upon venturicidin A treatment. Additionally, we report the loss of mitochondrial DNA in approximately 40%-50% of the treated parasites. We conclude that venturicidin A targets the ATP synthase of T. brucei, and we suggest that this macrolide could be a candidate for anti-trypanosomatid drug repurposing, drug combinations, or medicinal chemistry programs.
Asunto(s)
ADN de Cinetoplasto , Macrólidos , Potencial de la Membrana Mitocondrial , Trypanosoma brucei brucei , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma brucei brucei/genética , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Macrólidos/farmacología , ADN de Cinetoplasto/genética , ADN de Cinetoplasto/efectos de los fármacos , Tripanocidas/farmacología , Leishmania donovani/efectos de los fármacos , Leishmania donovani/genética , Animales , ADN Mitocondrial/genética , ADN Mitocondrial/efectos de los fármacosRESUMEN
Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC50 value of 0.5 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the <1 µM range. We have demonstrated that substituted 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidines present promising antitrypanosomal hit molecules with potential for further preclinical development.
Asunto(s)
Pirimidinas , Tripanocidas , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Relación Estructura-Actividad , Pruebas de Sensibilidad Parasitaria , Estructura Molecular , Trypanosoma brucei brucei/efectos de los fármacos , Humanos , Trypanosoma brucei rhodesiense/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Tripanosomiasis Africana/tratamiento farmacológicoRESUMEN
Folk medicine is widely used in Angola, even for human African trypanosomiasis (sleeping sickness) in spite of the fact that the reference treatment is available for free. Aiming to validate herbal remedies in use, we selected nine medicinal plants and assessed their antitrypanosomal activity. A total of 122 extracts were prepared using different plant parts and solvents. A total of 15 extracts from seven different plants exhibited in vitro activity (>70% at 20 µg/mL) against Trypanosoma brucei rhodesiense bloodstream forms. The dichloromethane extract of Nymphaea lotus (leaves and leaflets) and the ethanolic extract of Brasenia schreberi (leaves) had IC50 values ≤ 10 µg/mL. These two aquatic plants are of particular interest. They are being co-applied in the form of a decoction of leaves because they are considered by local healers as male and female of the same species, the ethnotaxon "longa dia simbi". Bioassay-guided fractionation led to the identification of eight active molecules: gallic acid (IC50 0.5 µg/mL), methyl gallate (IC50 1.1 µg/mL), 2,3,4,6-tetragalloyl-glucopyranoside, ethyl gallate (IC50 0.5 µg/mL), 1,2,3,4,6-pentagalloyl-ß-glucopyranoside (IC50 20 µg/mL), gossypetin-7-O-ß-glucopyranoside (IC50 5.5 µg/mL), and hypolaetin-7-O-glucoside (IC50 5.7 µg/mL) in B. schreberi, and 5-[(8Z,11Z,14Z)-heptadeca-8,11,14-trienyl] resorcinol (IC50 5.3 µg/mL) not described to date in N. lotus. Five of these active constituents were detected in the traditional preparation. This work provides the first evidence for the ethnomedicinal use of these plants in the management of sleeping sickness in Angola.
Asunto(s)
Antiprotozoarios , Nymphaea , Tripanosomiasis Africana , Humanos , Animales , Angola , Semillas , Antiprotozoarios/farmacología , Extractos Vegetales/farmacologíaRESUMEN
The transition between hosts is a challenge for digenetic parasites as it is unpredictable. For Trypanosoma brucei subspecies, which are disseminated by tsetse flies, adaptation to the new host requires differentiation of stumpy forms picked up from mammals to procyclic forms in the fly midgut. Here we show that the Alba-domain protein Alba3 is not essential for mammalian slender forms, nor is it required for differentiation of slender to stumpy forms in culture or in mice. It is crucial, however, for the development of T. brucei procyclic forms during the host transition. While steady state levels of mRNAs in differentiating cells are barely affected by the loss of Alba3, there are major repercussions for the proteome. Mechanistically, Alba3 aids differentiation by rapidly releasing stumpy forms from translational repression and stimulating polysome formation. In its absence, parasites fail to remodel their proteome appropriately, lack components of the mitochondrial respiratory chain and show reduced infection of tsetse. Interestingly, Alba3 and the closely related Alba4 are functionally redundant in slender forms, but Alba4 cannot compensate for the lack of Alba3 during differentiation from the stumpy to the procyclic form. We postulate that Alba-domain proteins play similar roles in regulating translation in other protozoan parasites, in particular during life-cycle and host transitions.
Asunto(s)
Proteoma/metabolismo , Proteínas Protozoarias/metabolismo , Trypanosoma brucei brucei/genética , Moscas Tse-Tse/parasitología , Adaptación Fisiológica , Animales , Ciclo Celular , Diferenciación Celular , Femenino , Técnicas de Inactivación de Genes , Estadios del Ciclo de Vida , Mamíferos , Ratones , Polirribosomas/metabolismo , Dominios Proteicos , Proteínas Protozoarias/genética , Trypanosoma brucei brucei/fisiologíaRESUMEN
A new dimeric naphthylisoquinoline alkaloid, jozibrevine D (4e), was isolated from the Central-African liana Ancistrocladus ileboensis. It is a Dioncophyllaceae-type metabolite, being R-configured at C-3 and lacking an oxygen function at C-6 in both isoquinoline moieties. The two identical monomers of jozibrevine D are symmetrically linked via the sterically constrained 3',3''-positions of the naphthalene units so that the central biaryl linkage is rotationally hindered and the alkaloid is, thus, C2-symmetric. With the two outer biaryl bonds being chiral, too, 4e possesses three consecutive stereogenic axes. The absolute stereostructure of the new compound was assigned by 1D and 2D NMR, ruthenium-mediated oxidative degradation, and electronic circular dichroism (ECD) spectroscopy. Jozibrevine D (4e) is the fifth discovered isomer in a series of six possible natural atropo-diastereomeric dimers. It shows potent, and selective, antiprotozoal activity against P. falciparum (IC50 = 0.14 µM), and it also exhibits good cytotoxic activities against drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells (IC50 = 11.47 µM) and their multidrug-resistant CEM/ADR5000 subline (IC50 = 16.61 µM).
Asunto(s)
Alcaloides , Antimaláricos , Antineoplásicos , Antiprotozoarios , Caryophyllales , Antiparasitarios/farmacología , Antimaláricos/química , Estructura Molecular , Alcaloides/química , Antiprotozoarios/farmacología , Antiprotozoarios/química , Caryophyllales/químicaRESUMEN
The 4-substituted 3-amino-1,2,5-oxadiazole 1 from the Malaria Box Project of the Medicines for Malaria Venture foundation shows very promising selectivity and in vitro activity against Plasmodium falciparum. Within the first series of new compounds, various 3-acylamino analogs were prepared. This paper now focuses on the investigation of the importance of the aromatic substituent in ring position 4. A number of new structure-activity relationships were elaborated, showing that antiplasmodial activity and selectivity strongly depend on the substitution pattern of the 4-phenyl moiety. In addition, physicochemical parameters relevant for drug development were calculated (logP and ligand efficiency) or determined experimentally (CYP3A4-inhibition and aqueous solubility). N-[4-(3-ethoxy-4-methoxyphenyl)-1,2,5-oxadiazol-3-yl]-3-methylbenzamide 51 showed high in vitro activity against the chloroquine-sensitive strain NF54 of P. falciparum (PfNF54 IC50 = 0.034 µM), resulting in a very promising selectivity index of 1526.
Asunto(s)
Antimaláricos , Malaria Falciparum , Malaria , Humanos , Antimaláricos/química , Malaria Falciparum/tratamiento farmacológico , Cloroquina/farmacología , Malaria/tratamiento farmacológico , Plasmodium falciparum , Relación Estructura-ActividadRESUMEN
The natural product aurachin D is a farnesylated quinolone alkaloid, which is known to possess activity against the causative agent of malaria, Plasmodium spp. In this study, we show that aurachin D inhibits other parasitic protozoa as well. While aurachin D had only a modest effect on Trypanosoma brucei rhodesiense, two other trypanosomatids, T. cruzi and Leishmania donovani, were killed at low micromolar and nanomolar concentrations, respectively, in an in vitro assay. The determined IC50 values of aurachin D were even lower than those of the reference drugs benznidazole and miltefosine. Due to these promising results, we set out to explore the impact of structural modifications on the bioactivity of this natural product. In order to generate aurachin D derivatives with varying substituents at the C-2, C-6 and C-7 position of the quinolone ring system, we resorted to whole-cell biotransformation using a recombinant Escherichia coli strain capable of aurachin-type prenylations. Quinolone precursor molecules featuring methyl, methoxy and halogen groups were fed to this E. coli strain, which converted the substrates into the desired analogs. None of the generated derivatives exhibited improved antiprotozoal properties in comparison to aurachin D. Obviously, the naturally occurring aurachin D features already a privileged structure, especially for the inhibition of the causative agent of visceral leishmaniasis.
Asunto(s)
Antiprotozoarios , Productos Biológicos , Enfermedad de Chagas , Leishmania donovani , Quinolonas , Trypanosoma cruzi , Humanos , Escherichia coli , Antiprotozoarios/farmacología , Antiprotozoarios/química , Biotransformación , Quinolonas/farmacología , Productos Biológicos/farmacología , Plasmodium falciparum , Pruebas de Sensibilidad ParasitariaRESUMEN
Thanks to its expertise in clinical research, epidemiology, infectious diseases, microbiology, parasitology, public health, translational research and tropical medicine, coupled with deeply rooted partnerships with institutions in low- and middle-income countries (LMICs), the Swiss Tropical and Public Health Institute (Swiss TPH) has been a key contributor in many drug research and development consortia involving academia, pharma and product development partnerships. Our know-how of the maintenance of parasites and their life-cycles in the laboratory, plus our strong ties to research centres and disease control programme managers in LMICs with access to field sites and laboratories, have enabled systems for drug efficacy testing in vitro and in vivo, clinical research, and modelling to support the experimental approaches. Thus, Swiss TPH has made fundamental contributions towards the development of new drugs - and the better use of old drugs - for neglected tropical diseases and infectious diseases of poverty, such as Buruli ulcer, Chagas disease, food-borne trematodiasis (e.g. clonorchiasis, fascioliasis and opisthorchiasis), human African trypanosomiasis, leishmaniasis, malaria, schistosomiasis, soil-transmitted helminthiasis and tuberculosis. In this article, we show case the success stories of molecules to which Swiss TPH has made a substantial contribution regarding their use as anti-infective compounds with the ultimate aim to improve people's health and well-being.
Asunto(s)
Úlcera de Buruli , Enfermedades Transmisibles , Medicina Tropical , Humanos , Salud Pública , Suiza , Enfermedades Transmisibles/tratamiento farmacológicoRESUMEN
We discovered tetrahydro-γ-carboline sulfonamides as a new antischistosomal chemotype. The aryl sulfonamide and tetrahydro-γ-carboline substructures were required for high antischistosomal activity. Increasing polarity improved solubility and metabolic stability but decreased antischistosomal activity. We identified two compounds with IC50 values <5 µM against ex vivo Schistosoma mansoni.
Asunto(s)
Carbolinas/farmacología , Schistosoma mansoni/efectos de los fármacos , Sulfonamidas/farmacología , Animales , Carbolinas/síntesis química , Carbolinas/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
Two new ircinianin-type sesterterpenoids, ircinianin lactone B and ircinianin lactone C (7 and 8), together with five known entities from the ircinianin compound family (1, 3-6) were isolated from the marine sponge Ircinia wistarii. Ircinianin lactones B and C (7 and 8) represent new ircinianin terpenoids with a modified oxidation pattern. Despite their labile nature, the structures could be established using a combination of spectroscopic data, including HRESIMS and 1D/2D NMR techniques, as well as computational chemistry and quantum-mechanical calculations. In a broad screening approach for biological activity, the class-defining compound ircinianin (1) showed moderate antiprotozoal activity against Plasmodium falciparum (IC50 25.4 µM) and Leishmania donovani (IC50 16.6 µM).
Asunto(s)
Poríferos , Sesterterpenos , Animales , Lactonas/química , Lactonas/farmacología , Estructura Molecular , Poríferos/química , Sesterterpenos/química , Sesterterpenos/farmacología , Terpenos/farmacologíaRESUMEN
Nitro-containing compounds are a well-known class of anti-infective agents, especially in the field of anti-parasitic drug discovery. HAT or sleeping sickness is a neglected tropical disease caused by a protozoan parasite, Trypanosoma brucei. Following the approval of fexinidazole as the first oral treatment for both stages of T. b. gambiense HAT, there is an increased interest in developing new nitro-containing compounds against parasitic diseases. In our previous projects, we synthesized several megazole derivatives that presented high activity against Leishmania major promastigotes. Here, we screened and evaluated their trypanocidal activity. Most of the compounds showed submicromolar IC50 against the BSF form of T. b. rhodesiense (STIB 900). To the best of our knowledge, compound 18c is one of the most potent nitro-containing agents reported against HAT in vitro. Compound 18g revealed an acceptable cure rate in the acute mouse model of HAT, accompanied with noteworthy in vitro activity against T. brucei, T. cruzi, and L. donovani. Taken together, these results suggest that these compounds are promising candidates to evaluate their pharmacokinetic and biological profiles in the future.
Asunto(s)
Antiprotozoarios , Enfermedad de Chagas , Tripanocidas , Trypanosoma brucei brucei , Tripanosomiasis Africana , Animales , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico , Ratones , Enfermedades Desatendidas/tratamiento farmacológico , Nitrocompuestos , Tiadiazoles , Tripanocidas/farmacología , Trypanosoma brucei rhodesiense , Tripanosomiasis Africana/tratamiento farmacológico , Tripanosomiasis Africana/parasitologíaRESUMEN
2,4-Diaminopyrimidines and (dialkylamino)azabicyclo-nonanes possess activity against protozoan parasites. A series of fused hybrids were synthesized and tested in vitro against pathogens of malaria tropica and sleeping sickness. The activities and selectivities of compounds strongly depended on the substitution pattern of both ring systems as well as on the position of the nitrogen atom in the bicycles. The most promising hybrids of 3-azabicyclo-nonane with 2-aminopyrimidine showed activity against P. falciparum NF54 in submicromolar concentration and high selectivity. A hybrid with pyrrolidino substitution of the 2-azabicyclo-nonane as well as of the pyrimidine moiety exhibited promising activity against the multiresistant K1 strain of P. falciparum. A couple of hybrids of 2-azabicyclo-nonanes with 2-(dialkylamino)pyrimidines possessed high activity against Trypanosoma brucei rhodesiense STIB900 and good selectivity.
Asunto(s)
Antiprotozoarios , Malaria Falciparum , Humanos , Plasmodium falciparum , Antiprotozoarios/farmacología , Trypanosoma brucei rhodesiense , Pirimidinas/farmacología , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
Quinones and quinols are secondary metabolites of higher plants that are associated with many biological activities. The oxidative dearomatization of phenols induced by hypervalent iodine(III) reagents has proven to be a very useful synthetic approach for the preparation of these compounds, which are also widely used in organic synthesis and medicinal chemistry. Starting from several substituted phenols and naphthols, a series of cyclohexadienone and naphthoquinone derivatives were synthesized using different hypervalent iodine(III) reagents and evaluated for their in vitro antiprotozoal activity. Antiprotozoal activity was assessed against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. Cytotoxicity of all compounds towards L6 cells was evaluated and the respective selectivity indices (SI) were calculated. We found that benzyl naphthoquinone 5c was the most active and selective molecule against T. brucei rhodesiense (IC50 = 0.08 µM, SI = 275). Furthermore, the antiprotozoal assays revealed no specific effects. In addition, some key physicochemical parameters of the synthesised compounds were calculated.
Asunto(s)
Antiprotozoarios , Yodo , Malaria Falciparum , Naftoquinonas , Antiprotozoarios/química , Antiprotozoarios/farmacología , Ciclohexenos , Humanos , Hidroquinonas/farmacología , Indicadores y Reactivos , Naftoles/farmacología , Naftoquinonas/farmacología , Estrés Oxidativo , Pruebas de Sensibilidad Parasitaria , Fenoles/farmacología , Plasmodium falciparum , Trypanosoma brucei rhodesienseRESUMEN
N-(Aminoalkyl)azabicyclo[3.2.2]nonanes possess antiplasmodial and antitrypanosomal activity. A series with terminal tetrazole or sulfonamido partial structure was prepared. The structures of all new compounds were confirmed by NMR and IR spectroscopy and by mass spectral data. A single crystal structure analysis enabled the distinction between isomers. The antiprotozoal activities were examined in vitro against strains of Plasmodium falciparum and Trypanosoma brucei rhodesiense (STIB 900). The most active sulfonamide and tetrazole derivates showed activities in the submicromolar range.
Asunto(s)
Antimaláricos , Antiprotozoarios , Alcanos , Antiprotozoarios/química , Antiprotozoarios/farmacología , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum , Sulfanilamida , Sulfonamidas/farmacología , Tetrazoles/farmacología , Trypanosoma brucei rhodesienseRESUMEN
Species of the genus Pleiocarpa are used in traditional medicine against fever and malaria. The present study focuses on the isolation and identification of bioactive compounds from P. bicarpellata extracts, and the evaluation of their antiprotozoal activity. Fractionation and isolation combined to LC-HRMS/MS-based dereplication provided 16 compounds: seven indole alkaloids, four indoline alkaloids, two secoiridoid glycosides, two iridoid glycosides, and one phenolic glucoside. One of the quaternary indole alkaloids (7) and one indoline alkaloid (15) have never been reported before. Their structures were elucidated by analysis of spectroscopic data, including 1D and 2D NMR experiments, UV, IR, and HRESIMS data. The absolute configurations were determined by comparison of the experimental and calculated ECD data. The extracts and isolated compounds were evaluated for their antiprotozoal activity towards Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum, as well as for their cytotoxicity against rat skeletal myoblast L6 cells. The dichloromethane/methanol (1:1) root extract showed strong activity against P. falciparum (IC50 value of 3.5 µg/mL). Among the compounds isolated, tubotaiwine (13) displayed the most significant antiplasmodial activity with an IC50 value of 8.5 µM and a selectivity index of 23.4. Therefore, P. bicarpallata extract can be considered as a source of indole alkaloids with antiplasmodial activity.
Asunto(s)
Antimaláricos , Antiprotozoarios , Apocynaceae , Leishmania donovani , Malaria Falciparum , Animales , Antiprotozoarios/química , Antiprotozoarios/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Plasmodium falciparum , Ratas , Trypanosoma brucei rhodesienseRESUMEN
Sphingofungins are fungal natural products known to inhibit the biosynthesis of sphingolipids which play pivotal roles in various cell functions. Here, we report a short and flexible synthetic approach towards the sphingofungin family. Key step of the synthesis was a decarboxylative cross-coupling reaction of chiral sulfinyl imines with a functionalized tartaric acid derivative, which yielded the core motif of sphingofungins carrying four consecutive stereocenters and a terminal double bond. Subsequent metathesis reaction allowed for the introduction of different side chains of choice resulting in a total of eight sphingofungins, including for the first time sphingofunginâ C (eight steps from commercially available protected tartaric acid with an overall yield of 6 %) and sphingofunginâ A (ten steps). All newly synthesized derivatives were tested for their antifungal, cell-proliferative and antiparasitic activity unraveling their structure-activity relations.
Asunto(s)
Aminoácidos , Ácidos Grasos InsaturadosRESUMEN
The development of reactions converting alkenes and alkynes into valuable building blocks remains one of the main goals of synthetic chemistry. Herein, we present the leveraging of highly electron-deficient iminium ions, rare and fleeting intermediates, into a general amine synthesis. This enables the preparation of amines bearing e.g. valuable α-trifluoromethyl moieties under mild conditions. This broad concept is highlighted by the late-stage amination of quinine into a biologically interesting new analogue.
Asunto(s)
Aminas , Electrones , Alquenos , AminaciónRESUMEN
The glidobactin-like natural products (GLNPs) glidobactinâ A and cepafunginâ I have been reported to be potent proteasome inhibitors and are regarded as promising candidates for anticancer drug development. Their biosynthetic gene cluster (BGC) plu1881-1877 is present in entomopathogenic Photorhabdus laumondii but silent under standard laboratory conditions. Here we show the largest subset of GLNPs, which are produced and identified after activation of the silent BGC in the native host and following heterologous expression of the BGC in Escherichia coli. Their chemical diversity results from a relaxed substrate specificity and flexible product release in the assembly line of GLNPs. Crystal structure analysis of the yeast proteasome in complex with new GLNPs suggests that the degree of unsaturation and the length of the aliphatic tail are critical for their bioactivity. The results in this study provide the basis to engineer the BGC for the generation of new GLNPs and to optimize these natural products resulting in potential drugs for cancer therapy.
Asunto(s)
Photorhabdus/genética , Inhibidores de Proteasoma/metabolismo , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Diseño de Fármacos , Escherichia coli/metabolismo , Familia de Multigenes/genética , Péptidos Cíclicos/biosíntesis , Péptidos Cíclicos/química , Photorhabdus/metabolismo , Inhibidores de Proteasoma/química , Relación Estructura-ActividadRESUMEN
Quinazolines have long been known to exert varied pharmacologic activities that make them suitable for use in treating hypertension, viral infections, tumors, and malaria. Since 2014, we have synthesized approximately 150 different 6,7-dimethoxyquinazoline-2,4-diamines and evaluated their antimalarial activity via structure-activity relationship studies. Here, we summarize the results and report the discovery of 6,7-dimethoxy-N4-(1-phenylethyl)-2-(pyrrolidin-1-yl)quinazolin-4-amine (20, SSJ-717), which exhibits high antimalarial activity as a promising antimalarial drug lead.
Asunto(s)
Antimaláricos/farmacología , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Femenino , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
Spirombandakamine A3 (7) is only the third known naphthylisoquinoline dimer with a spiro-fused novel molecular framework and the first such representative to possess a relative trans-configuration at the two chiral centers in both tetrahydroisoquinoline subunits. It was found in the leaves of a botanically as yet unidentified Congolese Ancistrocladus plant, which is morphologically closely related to the Central African taxon Ancistrocladus ealaensis. Likewise isolated were the new cyclombandakamines A8 (8) and A9 (9), which belong to another most recently discovered type of unusual oxygen-bridged naphthylisoquinoline dimers and two previously described "open-chain" analogues, mbandakamines C (10) and D (11). The full absolute stereostructures of these compounds were assigned by combining spectroscopic, chemical, and chiroptical methods. Preliminary biomimetic investigations indicated that both spirombandakamine- and cyclombandakamine-type dimers result from the oxidation of their open-chain mbandakamine-type congeners. The new dimeric alkaloids 7-9 displayed potent growth-inhibitory activity against Plasmodium falciparum, the protozoal pathogen causing malaria, and moderate effects on Trypanosoma brucei rhodesiense, the parasite responsible for African sleeping sickness.