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macyranones: structure, biosynthesis, and binding mode of an unprecedented epoxyketone that targets the 20s proteasome.in our screening efforts to identify unique scaffolds from myxobacteria for the drug discovery process, we used lc-spe-nmr-ms techniques to isolate six linear peptides, termed macyranone a-f, from cystobacter fuscus mcy9118. the macyranones are characterized by a rare 2-methylmalonamide moiety and an α-amino ketone fragment including an α',β'-epoxyketone in macyranone a. gene disruption experiments confirmed the biosynthetic gene cluster of the macyranones as pks/nrps hybrid. detailed in silico ...201526050527
pls-prediction and confirmation of hydrojuglone glucoside as the antitrypanosomal constituent of juglans spp.naphthoquinones (nqs) occur naturally in a large variety of plants. several nqs are highly active against protozoans, amongst them the causative pathogens of neglected tropical diseases such as human african trypanosomiasis (sleeping sickness), chagas disease and leishmaniasis. prominent nq-producing plants can be found among juglans spp. (juglandaceae) with juglone derivatives as known constituents. in this study, 36 highly variable extracts were prepared from different plant parts of j. regia, ...201526035104
predicting antiprotozoal activity of benzyl phenyl ether diamine derivatives through qsar multi-target and molecular topology.multi-target qsar is a novel approach that can predict simultaneously the activity of a given chemical compound on different pharmacological targets. in this work, we have used molecular topology and statistical tools such as multilinear regression analysis and artificial neural networks, to achieve a multi-target qsar model capable to predict the antiprotozoal activity of a group of benzyl phenyl ether diamine derivatives. the activity was related to three parasites with a high prevalence rate ...201525754076
antiprotozoal activity and dna binding of dicationic acridones.dicationic acridone derivatives were synthesized and their antiparasitic activity was evaluated. acridones displayed in vitro nanomolar ic50 values against trypanosoma brucei rhodesiense stib900 with selectivity indices >1000. compounds 1b, 3a, and 3b were as potent as the reference drug melarsoprol in this assay. submicromolar-range activities were observed against wild-type (nf54) and resistant (k1) strains of plasmodium falciparum, whereas no significant activity was detected against trypanos ...201525642604
structure elucidation and activity of kolossin a, the d-/l-pentadecapeptide product of a giant nonribosomal peptide synthetase.the largest continuous bacterial nonribosomal peptide synthetase discovered so far is described. it consists of 15 consecutive modules arising from an uninterrupted, fully functional gene in the entomopathogenic bacterium photorhabdus luminescens. the identification of its cryptic biosynthesis product was achieved by using a combination of genome analysis, promoter exchange, isotopic labeling experiments, and total synthesis of a focused collection of peptide candidates. although it belongs to t ...201526118790
synthesis of 3-azabicyclo[3.2.2]nonanes and their antiprotozoal activities.several bicyclic compounds, 3-azabicyclo[3.2.2]nonanes, have been prepared. the new compounds were tested for their activities against one strain of the causative organism of malaria tropica, plasmodium falciparum k1, which is resistant against chloroquine and pyrimethamine. in addition, their cytotoxicity and their activity against the pathogen of the east african form of sleeping sickness, trypanosoma brucei rhodesiense, were investigated. structure-activity relationships are discussed conside ...201525746816
antiprotozoal selectivity of diimidazoline n-phenylbenzamides.we discovered three diimidazolines with high antiplasmodial selectivity that had ic50 values of 1.9-28 nm against cultured plasmodium falciparum. we also identified a gem-dimethyl diimidazoline with high antitrypanosomal selectivity that had an ic50 value of 26 nm against cultured trypanosoma brucei rhodesiense. two 2-imidazoline heterocycles in a para orientation on a n-phenylbenzamide or similar core structure were required for high antiprotozoal activity. ring expansion of the imidazoline as ...201527622464
role of moving average analysis for development of multi-target (q)sar models.in modern drug discovery era, multi target- quantitative structure activity relationship [mt- (q)sar] approaches have emerged as novel and powerful alternatives in the field of in-silico drug design so as to facilitate the discovery of new chemical entities with multiple biological activities. amongst various machine learning approaches, moving average analysis (maa) has frequently exhibited high accuracy of prediction of diverse biological activities against different biological targets and exp ...201525694075
exploring in vitro and in vivo hsp90 inhibitors activity against human protozoan parasites.a set of compounds, previously selected as potent hsp90α inhibitors, has been studied on a panel of human parasites. 5-aryl-3,4-isoxazolediamide derivatives (1) were active against two protozoa, trypanosoma brucei rhodesiense and plasmodium falciparum, with a good tolerability toward cytotoxicity on non-malignant l6 rat myoblast cell line, unlike the 1,5-diaryl,4-carboxamides-1,2,3-triazole derivatives (2) which, while showing a single-digit nm range activity against the same protozoa, were also ...201525547934
synthesis and antiprotozoal activities of new 3-azabicyclo[3.2.2]nonanes.some antimalarial agents in use typically bear basic side chains as ligands. such ligands were attached to the amino substituent of a bridgehead atom of already antiprotozoal active 3-azabicyclo[3.2.2]nonanes. structure verification was done by nmr measurements. the new compounds were tested for their antiplasmodial and antitrypanosomal activities against plasmodium falciparum k 1 (multiresistant) and trypanosoma brucei rhodesiense as well as for their cytotoxicity against l6 cells. their activi ...201525433423
the antiprotozoal potencies of newly prepared 3-azabicyclo[3.2.2]nonanes.3-azabicyclo[3.2.2]nonanes are already reported as antiprotozoal agents. structural variations were performed by attachment of several basic side chains, being part of drugs in use, to the ring nitrogen. the structures of the new compounds were established using one and two dimensional nmr measurements. all compounds were investigated for their antiplasmodial and antitrypanosomal activities against plasmodium falciparum k 1 (multiresistant) and trypanosoma brucei rhodesiense. their cytotoxicity ...201627585596
synthesis and potent antiprotozoal activity of mono/di amidino 2-anilinobenzimidazoles versus plasmodium falciparum and trypanosoma brucei rhodesiense.a series of mono and dicationic new 2-anilinobenzimidazole carboxamidines were prepared in a four step process starting from 4-amino-3-nitrobenzonitrile and corresponding o-phenylenediamines. their antiparasitic activity against plasmodium falciparum (p. falciparum) and trypanosoma brucei rhodesiense (t.b. rhodesiense) were evaluated in vitro. some of the dicationic compounds (10,12,14) showed equal or very close activity against t.b. rhodesiense with melarsoprol and also showed promising activi ...201627387356
antiprotozoal activity of bicycles featuring a dimethylamino group at their bridgehead.several dimethylamino-derivatives of the new compound-class 3-azabicyclo[3.2.2]nonanes were prepared. for better comparison of activity also a few analogues of bicyclo[2.2.2]octanes and 2-azabicyclo[3.2.2]nonanes were synthesized. their activities were examined in vitro against the multiresistant k1 strain of plasmodium falciparum and against trypanosoma brucei rhodesiense (stib 900). a couple of the newly synthesized compounds showed promising antiprotozoal activity and selectivity. the results ...201627344215
a new alkamide with an endoperoxide structure from acmella ciliata (asteraceae) and its in vitro antiplasmodial activity.from the aerial parts of acmella ciliata (h.b.k.) cassini (basionym spilanthes ciliata kunth; asteraceae), three alkamides were isolated and identified by mass- and nmr spectroscopic methods as (2e,6e,8e)-n-isobutyl-2,6,8-decatrienamide (spilanthol, (1)), n-(2-phenethyl)-2e-en-6,8-nonadiynamide (2) and (2e,7z)-6,9-endoperoxy-n-isobutyl-2,7-decadienamide (3). while 1 and 2 are known alkamides, compound 3 has not been described until now. it was found that the unusual cyclic peroxide 3 exists as a ...201627294907
ent-pimarane and ent-kaurane diterpenes from aldama discolor (asteraceae) and their antiprotozoal activity.aldama discolor (syn.viguiera discolor) is an endemic asteraceae from the brazilian "cerrado", which has not previously been investigated for its chemical constituents and biological activity. diterpenes are common secondary metabolites found in aldama species, some of which have been reported to present potential antiprotozoal and antimicrobial activities. in this study, the known ent-3-α-hydroxy-kaur-16-en-18-ol (1), as well as three new diterpenes, namely, ent-7-oxo-pimara-8,15-diene-18-ol (2 ...201627649126
an overview of trypanosoma brucei infections: an intense host-parasite interaction.trypanosoma brucei rhodesiense and t. brucei gambiense, the causative agents of human african trypanosomiasis, are transmitted by tsetse flies. within the vector, the parasite undergoes through transformations that prepares it to infect the human host. sequentially these developmental stages are the replicative procyclic (in which the parasite surface is covered by procyclins) and trypo-epimastigote forms, as well as the non-replicative, infective, metacyclic form that develops in the vector sal ...201628082973
extracellular vesicles from trypanosoma brucei mediate virulence factor transfer and cause host anemia.intercellular communication between parasites and with host cells provides mechanisms for parasite development, immune evasion, and disease pathology. bloodstream african trypanosomes produce membranous nanotubes that originate from the flagellar membrane and disassociate into free extracellular vesicles (evs). trypanosome evs contain several flagellar proteins that contribute to virulence, and trypanosoma brucei rhodesiense evs contain the serum resistance-associated protein (sra) necessary for ...201626771494
design, synthesis and antitrypanosomal activities of 2,6-disubstituted-4,5,7-trifluorobenzothiophenes.current treatments for human african trypanosomiasis (hat) are limited in their application, have undesirable dosing regimens and unsatisfactory toxicities highlighting the need for the development of a safer drug pipeline. our medicinal chemistry programme in developing rapidly accessible and modifiable heterocyclic scaffolds led to the design and synthesis of novel substituted benzothiophenes, with 6-benzimidazol-1-ylbenzothiophene derivatives demonstrating significant antitrypanosomal activit ...201626698538
development of multiplex serological assay for the detection of human african trypanosomiasis.human african trypanosomiasis (hat) is a disease caused by kinetoplastid infection. serological tests are useful for epidemiological surveillance. the aim of this study was to develop a multiplex serological assay for hat to assess the diagnostic value of selected hat antigens for sero-epidemiological surveillance. we cloned loci encoding eight antigens from trypanosoma brucei gambiense, expressed the genes in bacterial systems, and purified the resulting proteins. antigens were subjected to lum ...201626519611
population genetic structure and temporal stability among trypanosoma brucei rhodesiense isolates in uganda.the population structure and role of genetic exchange in african trypanosomes have been previously analyzed albeit with contradictory findings. to further investigate the role of genetic polymorphism on the population genetic structure of trypanosoma b. rhodesiense, we hypothesized that parasite genotypes are clonal and stable over time.201627142001
synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against trypanosoma brucei rhodesiense.2-(2-benzamido)ethyl-4-phenylthiazole (1) was one of 1035 molecules (grouped into 115 distinct scaffolds) found to be inhibitory to trypanosoma brucei, the pathogen causing human african trypanosomiasis, at concentrations below 3.6μm and non-toxic to mammalian (huh7) cells in a phenotypic high-throughput screen of a 700,000 compound library performed by the genomics institute of the novartis research foundation (gnf). compound 1 and 72 analogues were synthesized in this lab by one of two general ...201627102161
apolipoprotein l1 variant associated with increased susceptibility to trypanosome infection.african trypanosomes, except trypanosoma brucei gambiense and trypanosoma brucei rhodesiense, which cause human african trypanosomiasis, are lysed by the human serum protein apolipoprotein l1 (apol1). these two subspecies can resist human apol1 because they express the serum resistance proteins t. b. gambiense glycoprotein (tgsgp) and serum resistance-associated protein (sra), respectively. whereas in t. b. rhodesiense, sra is necessary and sufficient to inhibit apol1, in t. b. gambiense, tgsgp ...201627073096
comparative genomics of drug resistance in trypanosoma brucei rhodesiense.trypanosoma brucei rhodesiense is one of the causative agents of human sleeping sickness, a fatal disease that is transmitted by tsetse flies and restricted to sub-saharan africa. here we investigate two independent lines of t. b. rhodesiense that have been selected with the drugs melarsoprol and pentamidine over the course of 2 years, until they exhibited stable cross-resistance to an unprecedented degree. we apply comparative genomics and transcriptomics to identify the underlying mutations. o ...201626973180
structural characterization of the c-terminal coiled-coil domains of wild-type and kidney disease-associated mutants of apolipoprotein l1.trypanosomes that cause sleeping sickness endocytose apolipoprotein l1 (apol1)-containing trypanolytic factors from human serum, leading to trypanolytic death through generation of apol1-associated lytic pores in trypanosomal membranes. the trypanosome trypanosoma brucei rhodesiense counteracts trypanolysis by expressing the surface protein serum response-associated (sra), which can bind apol1 common variant g0 to block its trypanolytic activity. however, two missense variants in the c terminal ...201626945671
de novo genome assembly shows genome wide similarity between trypanosoma brucei brucei and trypanosoma brucei rhodesiense.trypanosoma brucei is a eukaryotic pathogen which causes african trypanosomiasis. it is notable for its variant surface glycoprotein (vsg) coat, which undergoes antigenic variation enabled by a large suite of vsg pseudogenes, allowing for persistent evasion of host adaptive immunity. while trypanosoma brucei rhodesiense (tbr) and t. b gambiense (tbg) are human infective, related t. b. brucei (tbb) is cleared by human sera. a single gene, the serum resistance associated (sra) gene, confers tbr it ...201626910229
the role of cytokines in the pathogenesis and staging of trypanosoma brucei rhodesiense sleeping sickness.human african trypanosomiasis due to trypanosoma brucei rhodesiense is invariably fatal if untreated with up to 12.3 million people at a risk of developing the disease in sub-saharan africa. the disease is characterized by a wide spectrum of clinical presentation coupled with differences in disease progression and severity. while the factors determining this varied response have not been clearly characterized, inflammatory cytokines have been partially implicated as key players. in this review, ...201626807135
development of resazurin-based assay in 384-well format for high throughput whole cell screening of trypanosoma brucei rhodesiense strain stib 900 for the identification of potential anti-trypanosomal agents.to accelerate the discovery of novel leads for the treatment of human african trypanosomiasis (hat), it is necessary to have a simple, robust and cost-effective assay to identify positive hits by high throughput whole cell screening. most of the fluorescence assay was made in black plate however in this study the hts assay developed in 384-well format using clear plate and black plate, for comparison. the hts assay developed is simple, sensitive, reliable and reproducible in both types of plates ...201626772786
apol1 nephropathy: from gene to mechanisms of kidney injury.the contribution of african ancestry to the risk of focal segmental glomerulosclerosis and chronic kidney disease has been partially explained by the recently described chromosome 22q variants in the gene apolipoprotein l1 (apol1). the apol1 variants appear at a high allele frequency in populations of west african ancestry as a result of apparent adaptive selection of the heterozygous state. heterozygosity protects from infection with trypanosoma brucei rhodesiense. this review will describe the ...201625561578
kynurenine pathway activation in human african trypanosomiasis.the kynurenine pathway of tryptophan oxidation is associated with cns inflammatory pathways. inhibition of this pathway ameliorates cns inflammation in rodent models of the late (meningoencephalitic) stage of human african trypanosomiasis (hat). in this study we evaluate whether the kynurenine pathway is activated in clinical hat and if it is associated with cns inflammatory responses.201628013248
synthesis, dna binding and antitrypanosomal activity of benzimidazole analogues of dapi.a series of novel benzimidazole diamidines were prepared from the corresponding dicyano analogues either by applying pinner methodology (5a-c, 10 and 13a) or by making amidoximes intermediates that were reduced to the corresponding amidines (15a-c). the new amidines were evaluated in vitro against the protozoan parasite trypanosoma brucei rhodesiense (t. b. r.). the thiophene analogue 5b and the n-methyl compound 15a showed superior antitrypanosomal activity compared to that of the parent i.201627843114
quantifying heterogeneity in host-vector contact: tsetse (glossina swynnertoni and g. pallidipes) host choice in serengeti national park, tanzania.identifying hosts of blood-feeding insect vectors is crucial in understanding their role in disease transmission. rhodesian human african trypanosomiasis (rhat), also known as acute sleeping sickness is caused by trypanosoma brucei rhodesiense and transmitted by tsetse flies. the disease is commonly associated with wilderness areas of east and southern africa. such areas hold a diverse range of species which form communities of hosts for disease maintenance. the relative importance of different ...201627706167
a primate apol1 variant that kills trypanosoma brucei gambiense.humans are protected against infection from most african trypanosomes by lipoprotein complexes present in serum that contain the trypanolytic pore-forming protein, apolipoprotein l1 (apol1). the human-infective trypanosomes, trypanosoma brucei rhodesiense in east africa and t. b. gambiense in west africa have separately evolved mechanisms that allow them to resist apol1-mediated lysis and cause human african trypanosomiasis, or sleeping sickness, in man. recently, apol1 variants were identified ...201627494254
loop-mediated isothermal amplification for detection of the 5.8s ribosomal ribonucleic acid internal transcribed spacer 2 gene found in trypanosoma brucei gambiense.the loop-mediated isothermal amplification (lamp) assay with its advantages of cost effectiveness, rapidity, and simplicity, has evolved as a sensitive and specific method for the detection of african trypanosomes. highly sensitive lamp reactions specific for trypanosoma brucei rhodesiense or that recognize but do not discriminate between trypanosoma brucei brucei, t. b. rhodesiense, trypanosoma brucei gambiense, and trypanosoma evansi have been developed. a sensitive lamp assay targeting the t. ...201727273643
the relationship of endotoxaemia to peripheral and central nervous system inflammatory responses in human african trypanosomiasis.endotoxaemia has been described in cases of human african trypanosomiasis (hat), but it is unclear if this phenomenon influences inflammatory pathology either in the periphery or central nervous system (cns). we studied endotoxin concentrations in the plasma and cerebrospinal fluid (csf) of trypanosoma brucei rhodesiense patients using the chromogenic limulus amoebocyte lysate assay. the relationship of endotoxin concentration to the presentation of gross signs of inflammation and the inflammato ...201727894360
evaluating the impact of targeting livestock for the prevention of human and animal trypanosomiasis, at village level, in districts newly affected with t. b. rhodesiense in uganda.uganda has suffered from a series of epidemics of human african trypanosomiasis (hat), a tsetse transmitted disease, also known as sleeping sickness. the area affected by acute trypanosoma brucei rhodesiense hat (rhat) has been expanding, driven by importation of infected cattle into regions previously free of the disease. these regions are also affected by african animal trypanosomiasis (aat) demanding a strategy for integrated disease control.201728162093
synthesis and antitrypanosomal activities of novel pyridylchalcones.a library of novel pyridylchalcones were synthesised and screened against trypanosoma brucei rhodesiense. eight were shown to have good activity with the most potent 8 having an ic50 value of 0.29 μm. cytotoxicity testing with human kb cells showed a good selectivity profile for this compound with a selectivity index of 47. little activity was seen when the library was tested against leishmania donovani. in conclusion, pyridylchalcones are promising leads in the development of novel compounds fo ...201728189085
antiprotozoal glutathione derivatives with flagellar membrane binding activity against t. brucei rhodesiense.a new series of n-substituted s-(2,4-dinitrophenyl)glutathione dibutyl diesters were synthesized to improve in vitro anti-protozoal activity against the pathogenic parasites trypanosoma brucei rhodesiense, trypanosoma cruzi and leishmania donovani. the results obtained indicate that n-substituents enhance the inhibitory properties of glutathione diesters whilst showing reduced toxicity against kb cells as in the cases of compounds 5, 9, 10, 16, 18 and 19. we suggest that the interaction of n-sub ...201728131508
antiprotozoal activity-based profiling of a dichloromethane extract from anthemis nobilis flowers.a dichlomethane extract of anthemis nobilis flower cones showed promising in vitro antiprotozoal activity against trypanosoma brucei rhodesiense and leishmania donovani, with ic50 values of 1.43 ± 0.50 and 1.40 ± 0.07 μg/ml, respectively. a comprehensive profiling of the most active fractions afforded 19 sesquiterpene lactones, including 15 germacranolides, two seco-sesquiterpenes, one guaianolide sesquiterpene lactone, and one cadinane acid. of these, 13 compounds were found to be new natural p ...201728116906
new derivatives of 7-chloroquinolin-4-amine with antiprotozoal activity.novel ω-aminoacyl and -alkyl derivatives of 7-chloroquinolin-4-amine were prepared and their structures confirmed by nmr spectroscopy. their antiprotozoal activities were examined in vitro against the sensitive nf54 strain as well as against the multiresistant k1 strain of plasmodium falciparum and against trypanosoma brucei rhodesiense (stib 900). the results were compared with the activities of clinically used drugs. their antitrypanosomal activities were only moderate whereas their antiplasmo ...201728031151
the production and antiprotozoal activity of abietane diterpenes in salvia austriaca hairy roots grown in shake flasks and bioreactor.the biomass and concentration of bioactive quinone methide-type diterpenes in hairy roots of salvia austriaca were determined and compared with levels of these metabolites in roots of field-grown plants. the cultures were maintained in shake flasks and a nutrient sprinkle bioreactor. diterpene production was more efficient in the shake flask root culture than the bioreactor one. biomass and diterpene production within the shake flask culture was evaluated using schenk and hildebrandt (sh), gambo ...201727070932
gold compounds as cysteine protease inhibitors: perspectives for pharmaceutical application as antiparasitic agents.gold compounds form a new class of promising metal-based drugs with a number of potential therapeutic applications, particularly in the fields of anticancer and antimicrobial treatments. previous research revealed that a group of structurally diverse gold compounds cause conspicuous inhibition of the protease activities of the human proteasome. given the pharmacological importance of protease inhibition, the present study further explored whether these gold compounds might inhibit a few other pr ...201728283781
relationship between trypanosoma brucei rhodesiense genetic diversity and clinical spectrum among sleeping sickness patients in uganda.human african trypanosomiasis (hat) due to trypanosoma brucei rhodesiense in east and southern africa is reported to be clinically diverse. we tested the hypothesis that this clinical diversity is associated with a variation in trypanosome genotypes.201729078807
estimating the economic and social consequences for patients diagnosed with human african trypanosomiasis in muchinga, lusaka and eastern provinces of zambia (2004-2014).acute human african trypanosomiasis (rhat) caused by trypanosoma brucei rhodesiense is associated with high mortality and is fatal if left untreated. only a few studies have examined the psychological, social and economic impacts of rhat. in this study, mixed qualitative and quantitative research methods were used to evaluate the socio-economic impacts of rhat in mambwe, rufunsa, mpika and chama districts of zambia.201729017597
the genomic landscape of african populations in health and disease.a deeper appreciation of the complex architecture of african genomes is critical to the global effort to understand human history, biology and differential distribution of disease by geography and ancestry. here, we report on how the growing engagement of african populations in genome science is providing new insights into the forces that shaped human genomes before and after the out-of-africa migrations. as a result of this human evolutionary history, african ancestry populations have the great ...201728977439
antiprotozoal sesquiterpene lactones and other constituents from tarchonanthus camphoratus and schkuhria pinnata.in continuation of a search for new antiprotozoal agents from plants of the family asteraceae, tarchonanthus camphoratus and schkuhria pinnata have been investigated. by following the promising in vitro activity of the dichloromethane extracts from their aerial parts, bioassay-guided chromatographic isolation yielded two known sesquiterpene lactones (1 and 2) from t. camphoratus and 20 known compounds of this type from s. pinnata. from the latter, a new eudesmanolide, (1r*,5s*,6r*,7r*,8r*,10r*)- ...201729244495
inhibitory effects of (+)-spectaline and iso-6-spectaline from senna spectabilis on the growth and ultrastructure of human-infective species trypanosoma brucei rhodesiense bloodstream form.in our ongoing work searching for new trypanocidal lead compounds from malaysian plants, two known piperidine alkaloids (+)-spectaline (1) and iso-6-spectaline (2) were isolated from the leaves of senna spectabilis (sin. cassia spectabilis). analysis of the 1h and 13c nmr spectra showed that 1 and 2 presented analytical and spectroscopic data in full agreement with those published in the literature. all compounds were screened in vitro against trypanosoma brucei rhodesiense in comparison to the ...201729175017
metabolic profiling of central nervous system disease in trypanosoma brucei rhodesiense infection.the progression of human african trypanosomiasis from the early hemolymphatic stage to the late meningoencephalitic stage is of critical diagnostic importance as it determines the choice of potentially toxic drug regimens. current diagnostic criteria involving analysis of cerebrospinal fluid (csf) for parasites and/or pleocytosis are sensitive, but recent evidence suggests that specificity may be poor.201728927234
hsp70/j-protein machinery from glossina morsitans morsitans, vector of african trypanosomiasis.tsetse flies (glossina spp.) are the sole vectors of the protozoan parasites of the genus trypanosoma, the causative agents of african trypanosomiasis. species of glossina differ in vector competence and glossina morsitans morsitans is associated with transmission of trypanosoma brucei rhodesiense, which causes an acute and often fatal form of african trypanosomiasis. heat shock proteins are evolutionarily conserved proteins that play critical roles in proteostasis. the activity of heat shock pr ...201728902917
genome-wide snp analysis reveals distinct origins of trypanosoma evansi and trypanosoma equiperdum.trypanosomes cause a variety of diseases in man and domestic animals in africa, latin america and asia. in the trypanozoon subgenus, trypanosoma brucei gambiense and t. b. rhodesiense cause human african trypanosomiasis, while t. b. brucei, t. evansi and t. equiperdum are responsible for nagana, surra and dourine in domestic animals, respectively. the genetic relationships between t. evansi and t. equiperdum and other trypanozoon species remain unclear because the majority of phylogenetic analys ...201728541535
lead selection of antiparasitic compounds from a focused library of benzenesulfonyl derivatives of heterocycles.a library of 89 synthetic benzenesulfonyl derivatives of heterocycles with drug-like properties was assayed for in vitro antiparasitic activity and the results were added to our previously reported derivatives for a comprehensive sar evaluation. four compounds showed an ic50 between 0.25 and 3μm against leishmania donovani and low cytotoxicity. compound g{16} (1-(2,3,5,6-tetramethylphenylsulfonyl)-2-methylindoline), was particularly interesting with an ic50 similar to the reference drug miltefos ...201728789893
bifurcatriol, a new antiprotozoal acyclic diterpene from the brown alga bifurcaria bifurcata.linear diterpenes that are commonly found in brown algae are of high chemotaxonomic and ecological importance. this study reports bifurcatriol (1), a new linear diterpene featuring two stereogenic centers isolated from the irish brown alga bifurcariabifurcata. the gross structure of this new natural product was elucidated based on its spectroscopic data (ir, 1d and 2d-nmr, hrms). its absolute configuration was identified by experimental and computational vibrational circular dichroism (vcd) spec ...201728767061
alkamides from anacyclus pyrethrum l. and their in vitro antiprotozoal activity.in our ongoing study to evaluate the antiprotozoal activity of alkamides from asteraceae, a dichloromethane extract from the roots of anacycluspyrethrum l. showed a moderate in vitro activity against the nf54 strain of plasmodium falciparum and against leishmaniadonovani (amastigotes, mhom/et/67/l82 strain). seven pure alkamides and a mixture of two further alkamides were isolated by column chromatography followed by preparative high performance liquid chromatography. the alkamides were identifi ...201728498323
antiparasitic sesquiterpenes from the cameroonian spice scleria striatinux and preliminary in vitro and in silico dmpk assessment.the antiparasitic activity and preliminary in vitro and in silico drug metabolism and pharmacokinetic (dmpk) assessment of six isomeric sesquiterpenes (1-6), isolated from the cameroonian spice scleria striatinux de wild (cyperaceae) is reported. the study was prompted by the observation that two of the compounds (1 and 2) exhibited varying levels of antiparasitic activity on plasmodium falciparum, trypanosoma brucei rhodesiense, trypanosoma cruzi and leishmania donovani. the in silico method em ...201728421410
anti-trypanosomatid elemanolide sesquiterpene lactones from vernonia lasiopus o. hoffm.sleeping sickness or human african trypanosomiasis (hat) is a neglected tropical disease (ntd) threatening millions of peoples' lives with thousands infected. the disease is endemic in poorly developed regions of sub-saharan africa and is caused by the kinetoplastid "protozoan" parasite trypanosoma brucei. the parasites are transmitted to humans through bites of infected tsetse flies of the genus glossina. the few available drugs for treatment of this disease are highly toxic, difficult to admin ...201728397756
development of novel peptide-based michael acceptors targeting rhodesain and falcipain-2 for the treatment of neglected tropical diseases (ntds).this paper describes the development of a class of peptide-based inhibitors as novel antitrypanosomal and antimalarial agents. the inhibitors are based on a characteristic peptide sequence for the inhibition of the cysteine proteases rhodesain of trypanosoma brucei rhodesiense and falcipain-2 of plasmodium falciparum. we exploited the reactivity of novel unsaturated electrophilic functions such as vinyl-sulfones, -ketones, -esters, and -nitriles. the michael acceptors inhibited both rhodesain an ...201728763614
antileukemic ancistrobenomine b and related 5,1'-coupled naphthylisoquinoline alkaloids from the chinese liana ancistrocladus tectorius.a striking feature of the metabolite pattern of the southeast asian liana ancistrocladus tectorius (ancistrocladaceae) is the predominance of 5,1'-coupled naphthylisoquinoline alkaloids. about 20 alkaloids of this coupling type have so far been discovered in this plant species. here, we report on the isolation of four new 5,1'-linked naphthylisoquinolines from the twigs and stems of a. tectorius. two of them, the ancistrobenomines b (5) and c (6), belong to the very rare group of alkaloids with ...201728688886
bistacrines as potential antitrypanosomal agents.human african trypanosomiasis (hat) is caused by two subspecies of the genus trypanosoma, namely trypanosoma brucei rhodesiense and trypanosoma brucei gambiense. the disease is fatal if left untreated and therapy is limited due to only five non-adequate drugs currently available. in preliminary studies, dimeric tacrine derivatives were found to inhibit parasite growth with ic50-values in the nanomolar concentration range. this prompted the synthesis of a small, but smart library of monomeric and ...201728698054
steroid alkaloids from holarrhena africana with strong activity against trypanosoma brucei rhodesiense.in our continued search for natural compounds with activity against trypanosoma brucei, causative agent of human african trypanosomiasis (hat, "sleeping sickness"), we have investigated extracts from the leaves and bark of the west african holarrhenaafricana (syn. holarrhena floribunda; apocynaceae). the extracts and their alkaloid-enriched fractions displayed promising in vitro activity against bloodstream forms of t. brucei rhodesiense (tbr; east african hat). bioactivity-guided chromatographi ...201728684718
host-seeking efficiency can explain population dynamics of the tsetse fly glossina morsitans morsitans in response to host density decline.females of all blood-feeding arthropod vectors must find and feed on a host in order to produce offspring. for tsetse-vectors of the trypanosomes that cause human and animal african trypanosomiasis-the problem is more extreme, since both sexes feed solely on blood. host location is thus essential both for survival and reproduction. host population density should therefore be an important driver of population dynamics for haematophagous insects, and particularly for tsetse, but the role of host d ...201728672001
the double-edged sword of evolution.two gene variants provide different levels of protection against sleeping sickness, but this comes with an increased risk of developing chronic kidney disease.201728671870
polymerase chain reaction identification of trypanosoma brucei rhodesiense in wild tsetse flies from nkhotakota wildlife reserve, malawi.trypanosoma brucei rhodesiense is the causative agent of acute human african trypanosomiasis. identification of t. b. rhodesiense in tsetse populations is essential for understanding transmission dynamics, assessng human disease risk, and monitoring spatiotemporal trends and impact of control interventions. accurate detection and characterisation of trypanosomes in vectors relies on molecular techniques. for the first time in malawi, a molecular technique has been used to detect trypanosomes in ...201728567189
apol1 renal risk variants have contrasting resistance and susceptibility associations with african trypanosomiasis.reduced susceptibility to infectious disease can increase the frequency of otherwise deleterious alleles. in populations of african ancestry, two apolipoprotein-l1 (apol1) variants with a recessive kidney disease risk, named g1 and g2, occur at high frequency. apol1 is a trypanolytic protein that confers innate resistance to most african trypanosomes, but not trypanosoma brucei rhodesiense or t.b. gambiense, which cause human african trypanosomiasis. in this case-control study, we test the preva ...201728537557
the structure of serum resistance-associated protein and its implications for human african trypanosomiasis.only two trypanosome subspecies are able to cause human african trypanosomiasis. to establish an infection in human blood, they must overcome the innate immune system by resisting the toxic effects of trypanolytic factor 1 and trypanolytic factor 2 (refs. 1,2). these lipoprotein complexes contain an active, pore-forming component, apolipoprotein l1 (apol1), that causes trypanosome cell death 3 . one of the two human-infective subspecies, trypanosoma brucei rhodesiense, differs from non-infective ...201829358741
indole and benzimidazole bichalcophenes: synthesis, dna binding and antiparasitic activity.a novel series of indole and benzimidazole bichalcophene diamidine derivatives were prepared to study their antimicrobial activity against the tropical parasites causing african sleeping sickness and malaria. the dicyanoindoles needed to synthesize the target diamidines were obtained through stille coupling reactions while the bis-cyanobenzimidazoles intermediates were made via condensation/cyclization reactions of different aldehydes with 4-cyano-1,2-diaminobenzene. different amidine synthesis ...201829126729
beyond immune escape: a variant surface glycoprotein causes suramin resistance in trypanosoma brucei.suramin is one of the first drugs developed in a medicinal chemistry program (bayer, 1916), and it is still the treatment of choice for the hemolymphatic stage of african sleeping sickness caused by trypanosoma brucei rhodesiense. cellular uptake of suramin occurs by endocytosis, and reverse genetic studies with t. b. brucei have linked downregulation of the endocytic pathway to suramin resistance. here we show that forward selection for suramin resistance in t. brucei spp. cultures is fast, hig ...201828963732
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