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antiprotozoal polyacetylenes from the tanzanian medicinal plant cussonia zimmermannii.from the petroleum ether extract of the root bark of cussonia zimmermannii four polyacetylenes, 1- 4, were isolated, three of which ( 1- 3) were active against trypanosoma brucei rhodesiense, trypanosoma cruzi, plasmodium falciparum, and leishmania donovani.200717922552
synthesis and in vitro protozoocidal evaluation of novel diazabicyclic tropolone derivatives.the synthesis and in vitro antiparasitic activity of twenty-seven novel diazabicycles based on tropolone ethers is presented. the compounds can be readily prepared by means of a high-yielding hetero diels-alder reaction using simple and readily available starting materials. several of the new diazabicycles have in vitro activities against trypanosoma cruzi, leishmania donovani, trypanosoma brucei rhodesiense, and chloroquine-resistant plasmodium falciparum that are comparable or superior to thos ...200717924365
synthesis and in vitro antiprotozoal activity of bisbenzofuran cations.forty three cationic bisbenzofurans were synthesized either by interaction of o-hydroxyaldehydes with alpha-halogenated ketones followed by intramolecular ring closure or by a copper- or palladium-mediated heteroannulation of substituted o-iodophenols with terminal acetylenes. in vitro antiprotozoal activities of compounds 1-43 against trypanosoma brucei rhodesiense, plasmodium falciparum, and leishmania donovani and cytotoxicity against mammalian cells were influenced by the position and the ty ...200717948982
spatially and genetically distinct african trypanosome virulence variants defined by host interferon-gamma response.we describe 2 spatially distinct foci of human african trypanosomiasis in eastern uganda. the tororo and soroti foci of trypanosoma brucei rhodesiense infection were genetically distinct as characterized by 6 microsatellite and 1 minisatellite polymorphic markers and were characterized by differences in disease progression and host-immune response. in particular, infections with the tororo genotype exhibited an increased frequency of progression to and severity of the meningoencephalitic stage a ...200718008245
sleeping sickness--a re-emerging disease in the serengeti?sleeping sickness is a re-emerging disease in the serengeti ecosystem affecting both local people and tourists. here we report the results of a survey to assess the prevalence of trypanosomiasis in both domestic and wild animals from this area. five hundred and eighteen cattle samples were collected from 12 villages that bordered the serengeti national park and 220 samples from 15 different wild animal species were collected from within the park. pcr analysis, directed against the human serum re ...200717298919
african trypanosomes: intracellular trafficking of host defense molecules.trypanosoma brucei brucei is the causative agent of nagana in cattle and can infect a wide range of mammals but is unable to infect humans because it is susceptible to the innate cytotoxic activity of normal human serum. a minor subfraction of human high-density lipoprotein (hdl), containing apolipoprotein a-i (apoa1), apolipoprotein l-i (apol1) and haptoglobin-related protein (hpr) provides this innate protection against t. b. brucei infection. both hpr and apol1 are cytotoxic to t. b. brucei b ...200717300512
cpg oligodeoxynucleotide treatment enhances innate resistance and acquired immunity to african trypanosomes.relative resistance to african trypanosomiasis is based on the development of a type i cytokine response, which is partially dependent on innate immune responses generated through myd88 and toll-like receptor 9 (tlr9). therefore, we asked whether enhancement of the immune response by artificial stimulation with cpg oligodeoxynucleotide (odn), a tlr9 agonist, would result in enhanced protection against trypanosomes. in susceptible balb/c mice, relative resistance to infection was significantly en ...200717339353
artemisinins inhibit trypanosoma cruzi and trypanosoma brucei rhodesiense in vitro growth.artemisinin compounds inhibit in vitro growth of cultured trypanosoma cruzi and trypanosoma brucei rhodesiense at concentrations in the low micromolar range. artemisinin also inhibits calcium-dependent atpase activity in t. cruzi membranes, suggesting a mode of action via membrane pumps. artemisinins merit further investigation as chemotherapeutic options for these pathogens.200717339374
chemotherapeutic strategies against trypanosoma brucei: drug targets vs. drug targeting.trypanosoma brucei rhodesiense and t. b. gambiense are the causative agents of sleeping sickness, a fatal disease that affects 36 countries in sub-saharan africa. nevertheless, only a handful of clinically useful drugs are available. these drugs suffer from severe side-effects. the situation is further aggravated by the alarming incidence of treatment failures in several sleeping sickness foci, apparently indicating the occurrence of drug-resistant trypanosomes. because of these reasons, and sin ...200717346174
public-private partnership works to stamp out sleeping sickness in uganda. 200717392023
synthesis and in vitro antiprotozoal activities of dicationic 3,5-diphenylisoxazoles.3,5-bis(4-amidinophenyl)isoxazole (3)-an analogue of 2,5-bis(4-amidinophenyl)furan (furamidine) in which the central furan ring is replaced by isoxazole-and 42 novel analogues were prepared by two general synthetic pathways. the 43 isoxazole derivatives were assayed against trypanosoma brucei rhodesiense (t. brucei rhodesiense) stib900, plasmodium falciparum (p. falciparum) k1, and rat myoblast l6 cells (for cytotoxicity) in vitro. eleven compounds (3, 13, 16-18, 22, 26, 29, 31, 37, and 41) exhi ...200717439202
resolution of the species problem in african trypanosomes.there is a general assumption that eukaryote species are demarcated by morphological or genetic discontinuities. this stems from the idea that species are defined by the ability of individuals to mate and produce viable progeny. at the microscopic level, where organisms often proliferate more by asexual than sexual reproduction, this tidy classification system breaks down and species definition becomes messy and problematic. the dearth of morphological characters to distinguish microbial species ...200717451719
diphenyl furans and aza analogs: effects of structural modification on in vitro activity, dna binding, and accumulation and distribution in trypanosomes.human african trypanosomiasis is a devastating disease with only a few treatment options, including pentamidine. diamidine compounds such as pentamidine, db75, and db820 are potent antitrypanosomal compounds. previous investigations have shown that diamidines accumulate to high concentrations in trypanosomes. however, the mechanism of action of this class of compounds remains unknown. a long-hypothesized mechanism of action has been binding to dna and interference with dna-associated enzymes. th ...200717517831
bicyclo[2.2.2]octyl esters of dialkylamino acids as antiprotozoals.a couple of bicyclo[2.2.2]octyl esters of 2-dialkylaminoacetic acids were prepared. their antiplasmodial and antitrypanosomal activities against trypanosoma brucei rhodesiense (stib 900) and the k(1) strain of plasmodium falciparum (resistant to chloroquine and pyrimethamine) were determined using microplate assays. structure-activity relationships were discussed. the antiprotozoal activities were remarkably increased by insertion of a second basic centre. the selectivity indices of the most act ...200717544672
characterisation of the trypanosoma brucei rhodesiense isolates from tanzania using serum resistance associated gene as molecular marker.serum resistance associated (sra) gene has been found to confer resistance to the innate trypanolytic factor (tlf) found in normal human serum; thus allowing trypanosoma brucei brucei to survive exposure to normal human serum. this study was carried out to examine the presence of sra gene and identify the origin of t. b. rhodesiense isolates from three districts in tanzania, namely kibondo, kasulu and urambo. twenty-six t. b. rhodesiense isolates and two references t. b. rhodesiense isolates fro ...200717547097
the soluble variant surface glycoprotein of african trypanosomes is recognized by a macrophage scavenger receptor and induces i kappa b alpha degradation independently of traf6-mediated tlr signaling.the gpi residues of soluble variant surface glycoprotein (svsg) molecules released from the membrane of african trypanosomes during infection induce macrophage activation events. in this study, we demonstrate that the trypanosome svsg molecule binds to the membrane of murine raw 264.7 macrophages and activates the nf-kappab cascade independently of a tlr-mediated interaction. the binding of fluorochrome-labeled svsg molecules to macrophage membranes was saturable, was inhibited by the scavenger ...200717579076
melarsoprol- and pentamidine-resistant trypanosoma brucei rhodesiense populations and their cross-resistance.resistance to melarsoprol and pentamidine was induced in bloodstream-form trypanosoma brucei rhodesiense stib 900 in vitro, and drug sensitivity was determined for melarsoprol, pentamidine and furamidine. the resistant populations were also inoculated into immunosuppressed mice to verify infectivity and to monitor whether rodent passage selects for clones with altered drug sensitivity. after proliferation in the mouse, trypanosomes were isolated and their ic(50) values to the three drugs were de ...200717602691
targeting the polyamine biosynthetic enzymes: a promising approach to therapy of african sleeping sickness, chagas' disease, and leishmaniasis.trypanosomatids depend on spermidine for growth and survival. consequently, enzymes involved in spermidine synthesis and utilization, i.e. arginase, ornithine decarboxylase (odc), s-adenosylmethionine decarboxylase (adometdc), spermidine synthase, trypanothione synthetase (trys), and trypanothione reductase (tryr), are promising targets for drug development. the odc inhibitor alpha-difluoromethylornithine (dfmo) is about to become a first-line drug against human late-stage gambiense sleeping sic ...200717610127
human african trypanosomiasis: pharmacological re-engagement with a neglected disease.this review discusses the challenges of chemotherapy for human african trypanosomiasis (hat). the few drugs registered for use against the disease are unsatisfactory for a number of reasons. hat has two stages. in stage 1 the parasites proliferate in the haemolymphatic system. in stage 2 they invade the central nervous system and brain provoking progressive neurological dysfunction leading to symptoms that include the disrupted sleep wake patterns that give hat its more common name of sleeping s ...200717618313
in vitro antiprotozoal activities and cytotoxicity of some selected cameroonian medicinal plants.eight extracts from seven selected cameroonian medicinal plants, traditionally used to treat malaria and other protozoal diseases, were tested in vitro for their antiprotozoal activities against plasmodium falciparum k1 chloroquine-resistant strain, leishmania donovani, trypanosoma cruzi and trypanosoma brucei rhodesiense, protozoa responsible for malaria, visceral leishmaniasis, chagas disease and african trypanosomiasis, respectively. the most active extract against plasmodium falciparum k1 st ...200717141994
synthesis and antiparasitic evaluation of bis-2,5-[4-guanidinophenyl]thiophenes.a series of bis-2,5-[4-guanidinophenyl]thiophenes were prepared in a five step process starting from 2,5-bis[trimethylstannyl]thiophene. the compounds were evaluated in vitro against trypanosoma brucei rhodesiense (t. b. r.), plasmodium falciparum (p. f.), leshmania donovani (l. d.) and trypanasoma cruzi (t. c.), and in vivo against t. b. r. certain compounds show promising in vitro activity against t. b. r. and p. f. and have superior in vivo activity against t. b. r. to that of pentamidine and ...200717178177
a multiplex pcr that discriminates between trypanosoma brucei brucei and zoonotic t. b. rhodesiense.two subspecies of trypanosoma brucei s.l. co-exist within the animal populations of eastern africa; t. b. brucei a parasite which only infects livestock and wildlife and t. b. rhodesiense a zoonotic parasite which infects domestic livestock, wildlife, and which in humans, results in the disease known as human african trypanosomiasis (hat) or sleeping sickness. in order to assess the risk posed to humans from hat it is necessary to identify animals harbouring potentially human infective parasites ...200817643434
new bis(2-aminoimidazoline) and bisguanidine dna minor groove binders with potent in vivo antitrypanosomal and antiplasmodial activity.a series of 75 guanidine and 2-aminoimidazoline analogue molecules were assayed in vitro against trypanosoma brucei rhodesiense stib900 and plasmodium falciparum k1. the dicationic diphenyl compounds exhibited the best activities with ic 50 values against t. b. rhodesiense and p. falciparum in the nanomolar range. five compounds (7b, 9a, 9b, 10b, and 14b) cured 100% of treated mice upon ip administration at 20 mg/kg in the difficult to cure t. b. rhodesiense stib900 mouse model. overall, the com ...200818247550
loop-mediated isothermal amplification (lamp) method for rapid detection of trypanosoma brucei rhodesiense.loop-mediated isothermal amplification (lamp) of dna is a novel technique that rapidly amplifies target dna under isothermal conditions. in the present study, a lamp test was designed from the serum resistance-associated (sra) gene of trypanosoma brucei rhodesiense, the cause of the acute form of african sleeping sickness, and used to detect parasite dna from processed and heat-treated infected blood samples. the sra gene is specific to t. b. rhodesiense and has been shown to confer resistance t ...200818253475
eliminating human african trypanosomiasis: where do we stand and what comes next? 200818303943
infections with immunogenic trypanosomes reduce tsetse reproductive fitness: potential impact of different parasite strains on vector population structure.the parasite trypanosoma brucei rhodesiense and its insect vector glossina morsitans morsitans were used to evaluate the effect of parasite clearance (resistance) as well as the cost of midgut infections on tsetse host fitness. tsetse flies are viviparous and have a low reproductive capacity, giving birth to only 6-8 progeny during their lifetime. thus, small perturbations to their reproductive fitness can have a major impact on population densities. we measured the fecundity (number of larval p ...200818335067
synthesis of a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives bearing anti-trypanosomal and anti-leishmanial activity.taking advantage of the structural features of natural products showing anti-trypanosomatid activity, we designed and synthesized a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives. the library was obtained following a parallel approach and using readily available synthons. all the derivatives showed inhibitory activity toward either trypanosoma or leishmania species, with 8, 10, and 16 being the most active compounds against trypanosoma brucei rhodesiens ...200818353643
estimating the burden of rhodesiense sleeping sickness during an outbreak in serere, eastern uganda.zoonotic sleeping sickness, or hat (human african trypanosomiasis), caused by infection with trypanosoma brucei rhodesiense, is an under-reported and neglected tropical disease. previous assessments of the disease burden expressed as disability-adjusted life years (dalys) for this infection have not distinguished t.b. rhodesiense from infection with the related, but clinically distinct trypanosoma brucei gambiense form. t.b. rhodesiense occurs focally, and it is important to assess the burden at ...200818366755
novel bisbenzimidazoles with antileishmanial effectiveness.a small library of 2,2'-[(alpha,omega-alkanediylbis(oxyphenylene)]bis-1h-benzimidazoles has been prepared and screened in vitro against pneumocystis carinii, trypanosoma brucei rhodesiense, and leishmania donovani. among the six tested compounds two derivatives emerged as promising hits characterized by ic(50) values lower than that determined for pentamidine against l. donovani.200818367395
novel linear triaryl guanidines, n-substituted guanidines and potential prodrugs as antiprotozoal agents.a series of triaryl guanidines and n-substituted guanidines designed to target the minor groove of dna were synthesized and evaluated as antiprotozoal agents. selected carbamate prodrugs of these guanidines were assayed for their oral efficacy. the linear triaryl bis-guanidines 6a,b were prepared from their corresponding diamines 4a,b through the intermediate boc protected bis-guanidines 5a,b followed by acid catalyzed deprotection. the n-substituted guanidino analogues 9c-f were obtained in thr ...200818455271
synthesis and in vitro antiprotozoal activities of water-soluble, inexpensive 3,7-bis(dialkylamino)phenoxazin-5-ium derivatives.3,7-bis(dialkylamino)phenoxazinium salts were synthesized and evaluated for in vitro activities against plasmodium falciparum, trypanosoma cruzi, t. brucei rhodesiense, and leishmania donovani. notably, the compounds showed potent antiprotozoal activities, especially against p. falciparum and t. cruzi. the compounds with alkyl side chains less than three carbons in length possessed good activities with high selective indices.200818476684
novel azabicyclo[3.2.2]nonane derivatives and their activities against plasmodium falciparum k1 and trypanosoma brucei rhodesiense.new diaryl substituted 2-azabicyclo[3.2.2]nonane derivatives have been synthesized in order to investigate the influence of the aromatic substitution and of n substitution on the antiprotozoal activities of those compounds. following a manual method for the hansch approach, different 4-substituted aryl rings were systematically inserted, and moieties with varying basicity and polarity were attached to the ring nitrogen. all compounds were investigated for their activities against trypanosoma bru ...200818502136
high levels of genetic differentiation between ugandan glossina fuscipes fuscipes populations separated by lake kyoga.glossina fuscipes fuscipes is the major vector of human african trypanosomiasis, commonly referred to as sleeping sickness, in uganda. in western and eastern africa, the disease has distinct clinical manifestations and is caused by two different parasites: trypanosoma brucei rhodesiense and t. b. gambiense. uganda is exceptional in that it harbors both parasites, which are separated by a narrow 160-km belt. this separation is puzzling considering there are no restrictions on the movement of peop ...200818509474
synthesis of bicyclic amines and their activities against trypanosoma brucei rhodesiense and plasmodium falciparum k1.new alkenes, aziridines, and diamines were prepared from antiprotozoal 4-dialkylaminobicyclo[2.2.2]octan-2-imines to investigate the influence of several functional groups in position 2 of the ring skeleton on the antitrypanosomal and antiplasmodial activities. they were synthesized from 4-dialkylaminobicyclo[2.2.2]octan-2-imines and tested for their activities against trypanosoma b. rhodesiense and plasmodium falciparum k1 (resistant to chloroquine and pyrimethamine) using in vitro microplate a ...200818563349
genetic analysis of the human infective trypanosome trypanosoma brucei gambiense: chromosomal segregation, crossing over, and the construction of a genetic map.trypanosoma brucei is the causative agent of human sleeping sickness and animal trypanosomiasis in sub-saharan africa, and it has been subdivided into three subspecies: trypanosoma brucei gambiense and trypanosoma brucei rhodesiense, which cause sleeping sickness in humans, and the nonhuman infective trypanosoma brucei brucei. t. b. gambiense is the most clinically relevant subspecies, being responsible for more than 90% of all trypanosomal disease in humans. the genome sequence is now available ...200818570680
novel trypanocidal analogs of 5'-(methylthio)-adenosine.the purine nucleoside 5'-deoxy-5'-(hydroxyethylthio)-adenosine (heta) is an analog of the polyamine pathway metabolite 5'-deoxy-5'-(methylthio)-adenosine (mta). heta is a lead structure for the ongoing development of selectively targeted trypanocidal agents. thirteen novel heta analogs were synthesized and examined for their in vitro trypanocidal activities against bloodstream forms of trypanosoma brucei brucei lab 110 eatro and at least one drug-resistant trypanosoma brucei rhodesiense clinical ...200817954686
synthesis and antiprotozoal activity of novel bis-benzamidino imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridines.the key dinitrile intermediates 4a-d were synthesized by reaction of phenacyl bromide 1 and the appropriate 2-amino-5-bromopyridines to yield 3a-d. suzuki coupling of 3a-d with 4-cyanophenylboronic acid yielded the 2,6-bis(4-cyanophenyl)-imidazo[1,2-a]pyridine derivatives 4a-d. the bis-amidoximes 5a-d, obtained from 4a-d by the action of hydroxylamine, were converted to the bis-o-acetoxyamidoximes which on catalytic hydrogenation in a mixture of ethanol/ethyl acetate gave the acetate salts of 2, ...200817976993
african trypanosomiasis: sensitive and rapid detection of the sub-genus trypanozoon by loop-mediated isothermal amplification (lamp) of parasite dna.control of human african trypanosomiasis (hat) is dependent on accurate diagnosis and treatment of infected patients. however, sensitivities of tests in routine use are unsatisfactory, due to the characteristically low parasitaemias in naturally infected individuals. we have identified a conserved sequence in the repetitive insertion mobile element (rime) of the sub-genus trypanozoon and used it to design primers for a highly specific loop-mediated isothermal amplification (lamp) test. the test ...200817991469
evaluation of antiprotozoal and antimycobacterial activities of the resin glycosides and the other metabolites of scrophularia cryptophila.resin glycosides are secondary metabolites exclusive to the convolvulaceous plants. in this study, crypthophilic acids a-c (1-3), the first resin glycosides occurring in another family (scrophulariaceae), and the other constituents of scrophularia cryptophila were examined for in vitro antiprotozoal and antimycobacterial potentials. except for crypthophilic acid b (2), all tested compounds exhibited growth-inhibitory effect against trypanosoma brucei rhodesiense, with l-tryptophan (6) and buddle ...200817761408
epimers of bicyclo[2.2.2]octan-2-ol derivatives with antiprotozoal activity.(2sr,6rs,7rs)-4-dialkylaminobicyclo[2.2.2]octan-2-ols and several of their esters have shown promising activity against the causative organisms for malaria and sleeping sickness. the base-catalyzed epimerization of the alcohols was carried out by different methods giving their (2rs,6rs,7rs)-isomers. best results were obtained by the consecutive use of potassium tert-butoxide and sodium. the isomeric alcohols were converted to selected esters. all new compounds were tested for their activity agai ...200817698258
in vitro and in vivo antitrypanosomal activitiy of two microbial metabolites, ks-505a and alazopeptin.our on-going screening program to discover new antitrypanosomal antibiotics has been evaluating compounds isolated from soil microorganisms as well as investigating the antibiotic libraries of the kitasato institute for life sciences and biofrontier laboratories of kyowa hakko kogyo co., ltd. we have now discovered two compounds, ks-505a and alazopeptin, which exhibit moderate antitrypanosomal characteristics. we report here the in vitro and in vivo antitrypanosomal activities and cytotoxicities ...200819168977
analysis of risk factors for t. brucei rhodesiense sleeping sickness within villages in south-east uganda.sleeping sickness (hat) caused by t.b. rhodesiense is a major veterinary and human public health problem in uganda. previous studies have investigated spatial risk factors for t.b. rhodesiense at large geographic scales, but none have properly investigated such risk factors at small scales, i.e. within affected villages. in the present work, we use a case-control methodology to analyse both behavioural and spatial risk factors for hat in an endemic area.200818590541
mutual self-defence: the trypanolytic factor story.around 1900 laveran and mesnil discovered that african trypanosomes (prototype: trypanosoma brucei brucei) do not survive in the blood of some primates and humans. the nature of the trypanolytic factor present in these sera has been the focus of a long-standing debate between different groups, but recent developments have allowed the proposal of a coherent model incorporating most seemingly divergent views and providing an interesting example of the complex interplay that continuously occurs bet ...200818675374
the continuing problem of human african trypanosomiasis (sleeping sickness).human african trypanosomiasis, also known as sleeping sickness, is a neglected disease, and it continues to pose a major threat to 60 million people in 36 countries in sub-saharan africa. transmitted by the bite of the tsetse fly, the disease is caused by protozoan parasites of the genus trypanosoma and comes in two types: east african human african trypanosomiasis caused by trypanosoma brucei rhodesiense and the west african form caused by trypanosoma brucei gambiense. there is an early or hemo ...200818756506
development of drug resistance in trypanosoma brucei rhodesiense and trypanosoma brucei gambiense. treatment of human african trypanosomiasis with natural products (review).human african trypanosomiasis is an infectious disease which has resulted in the deaths of thousands of people in sub-saharan africa. two subspecies of the protozoan parasite trypanosoma brucei are the causative agents of the infection, whereby t. b. gambiense leads to chronic development of the disease and t. b. rhodesiense establishes an acute form, which is fatal within months or even weeks. current chemotherapy treatment is complex, since special drugs have to be used for the different devel ...200818813846
synthesis and antiprotozoal activity of cationic 2-phenylbenzofurans.a series of cationically substituted 2-phenylbenzofurans 1- 49 have been synthesized, and their in vitro antiprotozoal properties against trypanosoma brucei rhodesiense, plasmodium falciparum, and leishmania donovani, as well as cytotoxicity against mammalian cells, have been evaluated. eight dications exhibited antitrypanosomal activities comparable to that of pentamidine and melarsoprol. twenty-six compounds were more active than pentamidine, and seven dications demonstrated increased activiti ...200818841956
trypanosoma brucei rhodesiense transmitted by a single tsetse fly bite in vervet monkeys as a model of human african trypanosomiasis.we have investigated the pathogenicity of tsetse (glossina pallidipes)-transmitted cloned strains of trypanosoma brucei rhodesiense in vervet monkeys. tsetse flies were confirmed to have mature trypanosome infections by xenodiagnosis, after which nine monkeys were infected via the bite of a single infected fly. chancres developed in five of the nine (55.6%) monkeys within 4 to 8 days post infection (dpi). all nine individuals were successfully infected, with a median pre-patent period of 4 (rang ...200818846231
diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities.trypanothione reductase (tr) is an essential enzyme of trypanosomatids and therefore a promising target for the development of new drugs against african sleeping sickness and chagas' disease. diaryl sulfides with a central anilino moiety, decorated with a flexible n-alkyl side chain bearing a terminal ammonium ion, are a known class of inhibitors. using computer modelling, we revised the binding model for this class of tr inhibitors predicting simultaneous interactions of the ammonium ion-termin ...200818931800
[the controversial story of the human trypanolytic factor]. 200818950568
isolation of aerucyclamides c and d and structure revision of microcyclamide 7806a: heterocyclic ribosomal peptides from microcystis aeruginosa pcc 7806 and their antiparasite evaluation.aerucyclamides c and d were isolated from the cyanobacterium microcystis aeruginosa pcc 7806, and their structures established by nmr spectroscopy and chemical transformation and degradation. acidic hydrolysis of aerucyclamide c (cf(3)co(2)h, h(2)o) resulted in microcyclamide 7806a. this chemical evidence combined with spectroscopic and physical data suggest a structure revision for microcyclamide 7806a, which incorporates an o-acylated thr ammonium residue instead of the originally proposed met ...200818973386
african trypanosomiasis in two short-term australian travelers to malawi.we report two microbiologically confirmed cases of trypanosomiasis in short-term australian travelers to malawi. the initial diagnosis was followed by medi-evacuation to south africa where suramin therapy was commenced. the treatment course was completed on return to australia, with subsequent follow-up. this diagnosis should be considered in travelers returning from an endemic region.200819006517
traversal of human and animal trypanosomes across the blood-brain barrier.the neurological complications of human african trypanosomiasis (hat) in man caused by the unicellular protozoan parasites trypanosoma brucei gambiense and t. b. rhodesiense are a consequence of the penetration of the blood-brain barrier (bbb) by trypanosomes that enter the central nervous system (cns). yet the mechanisms by which african trypanosomes cross the true bbb comprised of brain microvascular endothelial cells (bmecs) remain unclear. human bbb models used to determine how african trypa ...200819016378
challenges in the diagnosis and management of sleeping sickness in tanzania: a case report.in tanzania sleeping sickness presents a serious threat to human health with a country-wide average of 400 cases reported annually. both wild and domestic animals have been found to play a significant role in the epidemiology of sleeping sickness. serengeti national park in northern tanzania, has experienced a number of sleeping sickness epidemics since 1922. the epidemics were associated with abundant game animals in the areas and glossina swynnertoni was incriminated as the main vector. howeve ...200819024343
the burden of human african trypanosomiasis.human african trypanosomiasis (hat, or sleeping sickness) is a protozoan parasitic infection caused by trypanosoma brucei rhodesiense or trypanosoma brucei gambiense. these are neglected tropical diseases, and t.b. rhodesiense hat is a zoonosis. we review current knowledge on the burden of hat in sub-saharan africa, with an emphasis on the disability-adjusted life year (daly), data sources, and methodological issues relating to the use of this metric for assessing the burden of this disease. we ...200819104653
aggravation of pathogenesis mediated by ochratoxin a in mice infected with trypanosoma brucei rhodesiense.mice fed 1.5 mg ochratoxin a (ota) per kg body weight and infected with trypanosoma brucei rhodesiense were compared with trypanosome-infected placebo-fed and uninfected ota-fed controls. uninfected ota-fed mice showed fever, lethargy, facial and eyelid oedemas, mild hepatitis and nephritis, and high survival. infected placebo-fed controls had mean pre-patent period (ppp) of 3.26 days, lethargy, dyspnoea, fever, facial and scrotal oedema, survival of 33-65 days, reduced red cell counts (rcc: 10. ...200919154650
characterization of trifluralin binding with recombinant tubulin from trypanosoma brucei.the binding kinetics of five novel trifluralin analogs with recombinant alpha- and beta-tubulin proteins from trypanosoma brucei rhodesiense was determined. native tubulin from rats was used to determine the extent of binding of each analog to mammalian tubulin. the results of this study clearly demonstrate two important characteristics of the binding of these trifluralins to tubulin. firstly, they have specific affinity for trypanosomal tubulin compared with mammalian tubulin irrespective of th ...200919050925
efficacy of the novel diamidine compound 2,5-bis(4-amidinophenyl)- furan-bis-o-methlylamidoxime (pafuramidine, db289) against trypanosoma brucei rhodesiense infection in vervet monkeys after oral administration.owing to the lack of oral drugs for human african trypanosomiasis, patients have to be hospitalized for 10 to 30 days to facilitate treatment with parenterally administered medicines. the efficacy of a novel orally administered prodrug, 2,5-bis(4-amidinophenyl)-furan-bis-o-methlylamidoxime (pafuramidine, db289), was tested in the vervet monkey (chlorocebus [cercopithecus] aethiops) model of sleeping sickness. five groups of three animals each were infected intravenously with 10(4) trypanosoma br ...200919064893
east african trypanosomiasis in a pregnant traveler. 200919891893
a luciferase based viability assay for atp detection in 384-well format for high throughput whole cell screening of trypanosoma brucei brucei bloodstream form strain 427.abstract:200919909542
synthesis and antiparasitic and antifungal evaluation of 2'-arylsubstituted-1h,1'h-[2,5']bisbenzimidazolyl-5-carboxamidines.a series of 2'-arylsubstituted-1h,1'h-[2,5']-bisbenzimidazolyl-5-carboxamidines were prepared in a six-step process starting from 4-amino-3-nitrobenzonitrile. the antiparasitic activity against trypanosoma brucei rhodesiense (t.b.r.), plasmodium falciparum (p.f.), leishmania donovani (l.d.) and trypanosoma cruzi (t.c.) and antifungal activity against candida albicans and candida krusei were evaluated in vitro. several compounds showed promising in vitro activity against t.b.r., p.f. and c. albic ...200919010569
c-terminal mutants of apolipoprotein l-i efficiently kill both trypanosoma brucei brucei and trypanosoma brucei rhodesiense.apolipoprotein l-i (apol1) is a human-specific serum protein that kills trypanosoma brucei through ionic pore formation in endosomal membranes of the parasite. the t. brucei subspecies rhodesiense and gambiense resist this lytic activity and can infect humans, causing sleeping sickness. in the case of t. b. rhodesiense, resistance to lysis involves interaction of the serum resistance-associated (sra) protein with the c-terminal helix of apol1. we undertook a mutational and deletional analysis of ...200919997494
antiplasmodial, anti-trypanosomal, anti-leishmanial and cytotoxicity activity of selected tanzanian medicinal plants.the antiplasmodial, anti-trypanosomal and anti-leishmanial activity of 25 plant extracts obtained from seven tanzanian medicinal plants: annickia (enantia) kummeriae (annonaceae), artemisia annua (asteraceae), pseudospondias microcarpa (anacardiaceae), drypetes natalensis (euphorbiaceae), acridocarpus chloropterus (malpighiaceae), maytenus senegalensis (celastraceae) and neurautanenia mitis (papilonaceae), were evaluated in vitro against plasmodium falciparum k1, trypanosoma brucei rhodesiense s ...200920734703
anti-african trypanocidal and antimalarial activity of natural flavonoids, dibenzoylmethanes and synthetic analogues.the known anti-protozoal activity of flavonoids has stimulated the testing of other derivatives from natural and synthetic sources.200919178775
trypanocidal, leishmanicidal and cytotoxic effects of anthecotulide-type linear sesquiterpene lactones from anthemis auriculata.trypanosomiasis and leishmaniasis pose major public health threats for many countries, particularly those in sub-saharan africa and south america. in the present study, we evaluated the in vitro antiprotozoal activity of three irregular, linear sesquiterpene lactones recently isolated from greek anthemis auriculata, namely anthecotulide (1), 4-hydroxyanthecotulide (2) and 4-acetoxyanthecotulide (3). trypomastigote forms of trypanosoma brucei rhodesiense and t. cruzi as well as axenic amastigotes ...200919200703
isolation of secondary metabolites from hortia oreadica (rutaceae) leaves through high-speed counter-current chromatography.high-speed counter-current chromatography (hsccc) with a two-phase solvent system (hexane-ethanol-acetonitrile-water 10:8:1:1, v/v) was applied to examine the leaves of hortia oreadica, which afforded the known limonoid guyanin (1), the alkaloids rutaecarpin (2) and dictamnine (6), the dihydrocinnamic acid derivatives methyl 5,7-dimethoxy-2,2-dimethyl-2h-1-benzopyran-6-propanoate (3), 5,8-dimethoxy-2,2-dimethyl-2h-1-benzopyran-6-propanoic acid (4), together with the new e-3,4-dimethoxy-alpha(3-h ...200919249788
novel functionalized melamine-based nitroheterocycles: synthesis and activity against trypanosomatid parasites.human african trypanosomiasis (hat), caused by the protozoan parasite trypanosoma brucei spp., is a major health problem in sub-saharan africa. new drugs are urgently required for the disease. selective uptake of toxic compounds into trypanosomes has been achieved by exploiting plasma membrane transporters. for example, the p2 aminopurine transporter, along with other transporters, selectively concentrates melamine and benzamidine moieties into trypanosomes. we have previously reported the use o ...200919262935
structure-activity study of pentamidine analogues as antiprotozoal agents.diamidine 1 (pentamidine) and 65 analogues (2-66) have been tested for in vitro antiprotozoal activities against trypanosoma brucei rhodesiense, plasmodium falciparum, and leishmania donovani, and for cytotoxicity against mammalian cells. dications 32, 64, and 66 exhibited antitrypanosomal potencies equal or greater than melarsoprol (ic(50) = 4 nm). nine congeners (2-4, 12, 27, 30, and 64-66) were more active against p. falciparum than artemisinin (ic(50) = 6 nm). eight compounds (12, 32, 33, 44 ...200919267462
synthesis of a series of n6-substituted adenosines with activity against trypanosomatid parasites.the involvement of purine salvage in the accumulation of current trypanocidal drugs is important for the treatment of african sleeping sickness. the substrate specificity of essential nucleoside transporters is therefore of physiological and pharmacological interest. with the intention to contribute to the knowledge in the field, a series of 16 adenosine derivatives with substituents in n(6)-position were prepared in order to evaluate their potential to inhibit trypanosoma brucei spp. in vitro. ...200919285758
novel s-adenosylmethionine decarboxylase inhibitors for the treatment of human african trypanosomiasis.trypanosomiasis remains a significant disease across the sub-saharan african continent, with 50,000 to 70,000 individuals infected. the utility of current therapies is limited by issues of toxicity and the need to administer compounds intravenously. we have begun a program to pursue lead optimization around mdl 73811, an irreversible inhibitor of s-adenosylmethionine decarboxylase (adometdc). this compound is potent but in previous studies cleared rapidly from the blood of rats (t. l. byers, t. ...200919289530
temporal and spatial epidemiology of sleeping sickness and use of geographical information system (gis) in kenya.in kenya, sleeping sickness (ss) caused by trypanosoma brucei rhodesiense is confined to the nyanza and western provinces tsetse belts. over the last two decades, the disease has exhibited great spatial variability in its spread and distribution. the objectives of the study were to map the spatial and temporal distribution of ss and determine possible risk factors associated with the disease in western kenya.200919326704
kynurenine pathway inhibition reduces central nervous system inflammation in a model of human african trypanosomiasis.human african trypanosomiasis, or sleeping sickness, is caused by the protozoan parasites trypanosoma brucei rhodesiense or trypanosoma brucei gambiense, and is a major cause of systemic and neurological disability throughout sub-saharan africa. following early-stage disease, the trypanosomes cross the blood-brain barrier to invade the central nervous system leading to the encephalitic, or late stage, infection. treatment of human african trypanosomiasis currently relies on a limited number of h ...200919339256
new bicyclic amines: synthesis and sars of their action against the causative organisms of malaria and sleeping sickness.diaryl-substituted bicyclic amines are a scarcely investigated class of compounds. only few of them are described and their biological activities are reported poorly. during our work in the field of heterocyclic chemistry, we found that 4-dialkylaminobicyclo[2.2.2]octan-2-ones and -ols show antiprotozoal properties against plasmodium falciparum k(1) and trypanosoma brucei rhodesiense, the causative organisms of malaria tropica and of human african trypanosomiasis. therefore, we synthesized over ...200919355897
antiplasmodial and antitrypanosomal activity of bicyclic amides and esters of dialkylamino acids.several bicyclic amides and esters of dialkylamino acids were prepared. their activities against a multiresistant strain of plasmodium falciparum and against trypanosoma brucei rhodesiense (stib 900) were examined. structure-activity relationships were discussed. particularly the ester compounds showed good antiplasmodial and antitrypanosomal activity and a single compound was tested in vivo against plasmodium berghei.200919395265
in vitro and in vivo antitrypanosomal activities of three peptide antibiotics: leucinostatin a and b, alamethicin i and tsushimycin.in the course of our screening for antitrypanosomal compounds from soil microorganisms, as well as from the antibiotics library of the kitasato institute for life sciences, we found three peptide antibiotics, leucinostatin (a and b), alamethicin i and tsushimycin, which exhibited potent or moderate antitrypanosomal activity. we report here the in vitro and in vivo antitrypanosomal properties and cytotoxicities of leucinostatin a and b, alamethicin i and tsushimycin compared with suramin. we also ...200919407848
synthesis and antiprotozoal activities of dicationic bis(phenoxymethyl)benzenes, bis(phenoxymethyl)naphthalenes, and bis(benzyloxy)naphthalenes.a series of 37 dicationically substituted bis(phenoxymethyl)benzene bis(phenoxymethyl)naphthalene, and bis(benzyloxy)naphthalene analogues of pentamidine was prepared and evaluated for antiprotozoal activities and cytotoxicity in in vitro. 1,3-bis(4-amidinophenoxymethyl)benzene (1) was the most active against trypanosoma brucei rhodesiense (ic(50)=2.1 nm). 1,3-bis[4-(n-isopropylamidino)phenoxymethyl]benzene (2) was most active against plasmodium falciparum (ic(50)=3.6 nm) and displayed a selecti ...200919409677
the antiprotozoal activity of sixteen asteraceae species native to sudan and bioactivity-guided isolation of xanthanolides from xanthium brasilicum.in vitro screening of the dichloromethane extracts of 16 asteraceae species native to sudan for activity against major protozoan pathogens revealed that a xanthium brasilicum vell. [syn. x. strumarium var. brasilicum (vell.) baker in mart.] extract was the most active against trypanosoma brucei rhodesiense, the etiological agent of east african human trypanosomiasis (ic(50) = 0.1 microg/ml). this plant extract also exhibited noticeable activities against t. cruzi (chagas disease), leishmania don ...200919431098
trypanocidal activity of 8-methyl-5'-{[(z)-4-aminobut-2-enyl]-(methylamino)}adenosine (genz-644131), an adenosylmethionine decarboxylase inhibitor.genzyme 644131, 8-methyl-5'-{[(z)-4-aminobut-2-enyl](methylamino)}adenosine, is an analog of the enzyme activated s-adenosylmethionine decarboxylase (adometdc) inhibitor and the trypanocidal agent mdl-7381, 5-{[(z)-4-aminobut-2-enyl](methylamino)}adenosine. the analog differs from the parent in having an 8-methyl group on the purine ring that bestows favorable pharmacokinetic, biochemical, and trypanocidal activities. the compound was curative in acute trypanosoma brucei brucei and drug-resistan ...200919451291
quantitative structure--antiprotozoal activity relationships of sesquiterpene lactones.prompted by results of our previous studies where we found high activity of some sesquiterpene lactones (stls) against trypanosoma brucei rhodesiense (which causes east african sleeping sickness), we have now conducted a structure-(in-vitro)-activity study on a set of 40 stls against t. brucei rhodesiense, t. cruzi, leishmania donovani and plasmodium falciparum. furthermore, cytotoxic activity against l6 rat skeletal myoblast cells was assessed. some of the compounds possess high activity, espec ...200919513006
antiprotozoal activity of 1-phenethyl-4-aminopiperidine derivatives.a series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (trypanosoma brucei rhodesiense, trypanosoma cruzi, leishmania donovani, and plasmodium falciparum). this screening identified 29 molecules selectively active against bloodstream-form t. b. rhodesiense trypomastigotes, with 50% inhibitory concentrations (ic50) ranging from 0.12 to 10 microm, and 33 compounds active against the chloroquine- and pyrimethamine-resistant k1 strain of p. falciparum (ic ...200919564359
immunospecific immunoglobulins and il-10 as markers for trypanosoma brucei rhodesiense late stage disease in experimentally infected vervet monkeys.to determine the usefulness of il-10 and immunoglobulin m (igm) as biomarkers for staging hat in vervet monkeys, a useful pathogenesis model for humans.200919573160
the trypanosoma brucei flagellum: moving parasites in new directions.african trypanosomes are devastating human and animal pathogens. trypanosoma brucei rhodesiense and t. b. gambiense subspecies cause the fatal human disease known as african sleeping sickness. it is estimated that several hundred thousand new infections occur annually and the disease is fatal if untreated. t. brucei is transmitted by the tsetse fly and alternates between bloodstream-form and insect-form life cycle stages that are adapted to survive in the mammalian host and the insect vector, re ...200919575562
synthesis and antiprotozoal activity of pyridyl analogues of pentamidine.a series of novel pyridyl analogues 1-18 of antiprotozoal drug 1,5-bis(4-amidinophenoxy)pentane (pentamidine) has been synthesized and tested for in vitro activities against trypanosoma brucei rhodesiense, plasmodium falciparum, and leishmania donovani, and for cytotoxicity against mammalian cells. antiprotozoal properties of compounds 1-18 depended on the placement of cationic moieties on the pyridine rings as well as the nature of substituents on the amidine groups. diamidine 6 with cationic m ...200919606902
new treatment option for second-stage african sleeping sickness: in vitro and in vivo efficacy of aza analogs of db289.african sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. it is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. in this study, the aromatic diamidine db75 (furamidine) and two aza analogs, db820 and db829 (cpd-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against african trypanosomes. the active parent diamidines showed sim ...200919620327
protease activated receptor signaling is required for african trypanosome traversal of human brain microvascular endothelial cells.using human brain microvascular endothelial cells (hbmecs) as an in vitro model for how african trypanosomes cross the human blood-brain barrier (bbb) we recently reported that the parasites cross the bbb by generating calcium activation signals in hbmecs through the activity of parasite cysteine proteases, particularly cathepsin l (brucipain). in the current study, we examined the possible role of a class of protease stimulated hbmec g protein coupled receptors (gpcrs) known as protease activat ...200919621073
processing and presentation of variant surface glycoprotein molecules to t cells in african trypanosomiasis.th1 cell responses to the variant surface glycoprotein (vsg) of african trypanosomes play a critical role in controlling infection through the production of ifn-gamma, but the role of apcs in the induction and regulation of t cell-mediated protection is poorly understood. in this study, we have investigated the ag presentation capabilities of dendritic cells (dcs) and macrophages during early trypanosome infection in relatively resistant responder and susceptible nonresponder mouse strains. sple ...200919675169
controlling sleeping sickness - a review.following a period characterized by severe epidemics of sleeping sickness, restoration of effective control and surveillance systems has raised the question of eliminating the disease from sub-saharan africa. given sufficient political and financial support, elimination is now considered a reasonable aim in countries reporting zero or less than 100 cases per year. this success may lead health authorities across the affected region to downgrade the disease from 'neglected' to simply being ignored ...200919691861
synthesis and activity of azaterphenyl diamidines against trypanosoma brucei rhodesiense and plasmodium falciparum.a series of azaterphenyl diamidines has been synthesized and evaluated for in vitro antiprotozoal activity against both trypanosoma brucei rhodesiense (t. b. r.) and plasmodium falciparum (p. f.) and in vivo efficacy in the stib900 acute mouse model for t. b. r. six of the 13 compounds showed ic(50) values less than 7 nm against t. b. r. twelve of those exhibited ic(50) values less than 6 nm against p. f. and six of those showed ic(50) values 0.6 nm, which are more than 25-fold as potent as fura ...200919699098
adenosine kinase of t. b. rhodesiense identified as the putative target of 4-[5-(4-phenoxyphenyl)-2h-pyrazol-3-yl]morpholine using chemical proteomics.human african trypanosomiasis (hat), a major parasitic disease spread in africa, urgently needs novel targets and new efficacious chemotherapeutic agents. recently, we discovered that 4-[5-(4-phenoxyphenyl)-2h-pyrazol-3-yl]morpholine (compound 1) exhibits specific antitrypanosomal activity with an ic(50) of 1.0 microm on trypanosoma brucei rhodesiense (t. b. rhodesiense), the causative agent of the acute form of hat.200919707572
novel 2h-isoquinolin-3-ones as antiplasmodial falcipain-2 inhibitors.a series of 1-aryl-6,7-disubstituted-2h-isoquinolin-3-ones (2-10) was synthesized and evaluated for their inhibition against plasmodium falciparum cysteine protease falcipain-2, as well as against cultured p. falciparum strain fcbr parasites. all compounds displayed inhibitory activity against recombinant falcipain-2 and against in vitro cultured intraerythrocytic p. falciparum, with the exception of 9. the new compounds exhibited no selectivity against human cysteine proteases such as cathepsin ...200919709887
on-bead screening of a combinatorial fumaric acid derived peptide library yields antiplasmodial cysteine protease inhibitors with unusual peptide sequences.a new class of cysteine protease inhibitors based on fumaric acid derived oligopeptides was successfully identified from a high-throughput screening of a solid-phase bound combinatorial library. as target enzymes falcipain and rhodesain were used, which play important roles in the life cycles of the parasites which cause malaria (plasmodium falciparum) and african sleeping sickness (trypanosoma brucei rhodesiense). the best inhibitors with unusual amino acid sequences not reported before for thi ...200919715342
synthesis and sar of alkanediamide-linked bisbenzamidines with anti-trypanosomal and anti-pneumocystis activity.a series of alkanediamide-linked bisbenzamidines was synthesized and tested in vitro against a drug-sensitive strain of trypanosoma brucei brucei, a drug-resistant strain of trypanosoma brucei rhodesiense and pneumocystiscarinii. bisbenzamidines linked with longer alkanediamide chains were potent inhibitors of both strains of t. brucei. however, bisbenzamidines linked with shorter alkanediamide chains were the most potent compounds against p. carinii. n,n'-bis[4-(aminoiminomethyl)phenyl] hexaned ...200919736009
synthesis and antiprotozoal properties of pentamidine congeners bearing the benzofuran motif.forty-eight cationically substituted pentamidine congeners possessing benzofuran rings were synthesized by a copper mediated heteroannulation of substituted o-iodophenols with phenyl acetylenes. activities of compounds 1-48 against trypanosoma brucei rhodesiense, plasmodium falciparum, and leishmania donovani and cytotoxicities for mammalian cells were influenced by the nature of cationic substituents, placement of the benzofuran fragment, and the length of the carbon linker between aromatic moi ...200919757840
the epidemiology of trypanosomiasis in rumphi district, malawi: a ten year retrospective study.human african trypanosomiasis (hat) is caused by two species of the tsetse fly vectored protozoan hemoflagellates belonging to trypanosma brucei, namely t.b gambiense which predominates in western africa and follows a chronic disease course and t.b rhodensiense which is more prevalent in southern and eastern africa, malawi included, and follows a more acute and aggressive disease course. previous studies in the democratic republic of congo, angola, uganda and sudan have demonstrated that the pre ...200919780474
distinct and overlapping roles for two dicer-like proteins in the rna interference pathways of the ancient eukaryote trypanosoma brucei.trypanosoma brucei is one of the most ancient eukaryotes where rna interference (rnai) is operational and is the only single-cell pathogen where rnai has been extensively studied and used as a tool for functional analyses. here, we report that the t. brucei rnai pathway, although relying on a single argonaute protein (ago1), is initiated by the activities of two distinct dicer-like enzymes. both tbdcl1, a mostly cytoplasmic protein, and the previously undescribed nuclear enzyme tbdcl2 contribute ...200919815526
synthesis, inhibition potency, binding mode, and antiprotozoal activities of fluorescent inhibitors of trypanothione reductase based on mepacrine-conjugated diaryl sulfide scaffolds.trypanothione reductase (tr) is a flavoenzyme unique to trypanosomatid parasites and a target for lead discovery programs. various inhibitor scaffolds have emerged in the past, exhibiting moderate affinity for the parasite enzyme. herein we show that the combination of two structural motifs of known tr inhibitors - diaryl sulfides and mepacrine - enables the simultaneous addressing of two hydrophobic patches in the active site. the binding efficacy of these conjugates is enhanced over that of th ...200919847846
hydrodynamic gene delivery of baboon trypanosome lytic factor eliminates both animal and human-infective african trypanosomes.several species of african trypanosomes cause fatal disease in livestock, but most cannot infect humans due to innate trypanosome lytic factors (tlfs). human tlfs are pore forming high-density lipoprotein (hdl) particles that contain apolipoprotein l-i (apol-i) the trypanolytic component, and haptoglobin-related protein (hpr), which binds free hemoglobin (hb) in blood and facilitates the uptake of tlf via a trypanosome haptoglobin-hemoglobin receptor. the human-infective trypanosoma brucei rhode ...200919858474
antiplasmodial and antitrypanosomal activities of aminobicyclo[2.2.2]octyl omega-aminoalkanoates.several 4-aminobicyclo[2.2.2]octyl esters of omega-dialkylamino acids were prepared. their activities against the multidrug-resistant k(1) strain of plasmodium falciparum and trypanosoma brucei rhodesiense (stib 900) were determined using microplate assays and compared to those of formerly prepared analogues. the biological activity was influenced by the relative configuration in ring position 2, by the chain length of the acid moiety and by the amino substitution. the most active antiplasmodial ...200918571774
alkyl and dialkylaminoethyl derivatives of 5-amino-2-azabicyclo[3.2.2]nonanes and their antiplasmodial and antitrypanosomal activities.n-alkyl and n-(2-dialkylaminoethyl) derivatives of 5-amino-2-azabicyclo-nonanes were prepared and tested in vitro for their activities against the multidrug-resistant k1 strain of plasmodium falciparum and trypanosoma brucei rhodesiense (stib 900). most of the new compounds showed lower antitrypanosomal activity than their parent compounds. with respect to their activity against p. falciparum the n-alkyl derivatives exhibited worse selectivity due to decreased antiplasmodial activity or higher c ...201019879671
parallel synthesis of a series of non-functional atp/nad analogs with activity against trypanosomatid parasites.non-functional analogs of the cofactors atp and nad are putative inhibitors of atp- or nad-dependant enzymes. since pathogenic protozoa rely heavily on the salvage of purine nucleosides from the bloodstream of their host, such compounds are of interest as antiplasmodial and antitrypanosomal agents with a multitude of molecular targets. by replacing the negatively charged phosphate residues with a constrained unsaturated amide spacer and the nicotinamide moiety of nad with various lipophilic subs ...201019484371
mechanism of trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor.human innate immunity against most african trypanosomes, including trypanosoma brucei brucei, is mediated by a minor subclass of toxic serum hdl, called trypanosome lytic factor-1 (tlf-1). this hdl contains two primate specific proteins, apolipoprotein l-1 and haptoglobin (hp)-related protein, as well as apolipoprotein a-1. these assembled proteins provide a powerful defense against trypanosome infection. trypanosoma brucei rhodesiense causes human african sleeping sickness because it has evolve ...201020805508
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