Reto Brun

..Elimination of the disease is considered feasible provided better tools for diagnosis and treatment can be made available...

..In conclusion, a combination of factors rather than a single one may be responsible for the phenomenon of melarsoprol treatment failures in T. b. gambiense patients...

..To review recent literature on human African trypanosomiasis, focussing on genome sequencing, diagnosis and drug discovery, and typing of trypanosomes...

..WHO has stated that if national control programmes, international organisations, research institutes, and philanthropic partners engage in concerted action, elimination of this disease might even be possible...

..As the majority of sleeping sickness patients seeking treatment are in the 2nd stage of the disease, further development of the compound was stopped...

..evansi in vitro. In addition, preliminary in vivo toxicity tests were performed on all 67 diamidines with 69% of the compounds showing no acute toxicity at an intra-peritoneal dose of 100mg/kg...

..8, 62, and 9.5 were determined. This is the first report of a plant natural product with potent IN VIVO activity against TRYPANOSOMA BRUCEI...

..Thus, finally, new therapeutic agents against malaria and sleeping sickness are within reach...

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..In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug...

..falciparum SCID mouse model. ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potential...

..The method could probably be adapted to other protozoan parasites, especially those growing extracellularly...

..b. gambiense and T. b. rhodesiense forms of human sleeping sickness and both stages of the disease...

..Several other ways to evaluate in vitro anti-malarial activity do exist, all with their own assets and limitations...

..The melarsoprol-selected population apparently had lost TbAT1, whereas in the pentamidine-selected trypanosome population it was still present...

..5 and/or 25 mg/kg of body weight given by the subcutaneous route for 4 days. The best antibabesial properties were exhibited by terphenyls, benzimidazoles, diphenyl furans, pentamidine, and pentamidine analogues...

..Based on its trypanostatic rather than trypanocidal mode of action, it is a rather slow-acting drug...

..In conclusion, two diamidine compounds (DB 75 and DB 867) presented comparable efficacy at lower doses than the standard drug diminazene and could be considered as potential clinical candidates against T. evansi infection...

..The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model...

..After all selection criteria were applied, three diamidine compounds (DB 75, DB 867, and DB 1192) qualified as lead compounds and were considered to have the potential to act as preclinical candidates against T. evansi infection...

..In vivo, worm burden reductions of 100% were achieved with single oral doses of praziquantel, artesunate, and artemether at 50, 700, and 1,100 mg/kg of body weight, respectively...

..The phylogenetic relationship between the two species and T. b. brucei is being discussed, and the hypothesis is proposed that T. evansi arose from a clone of T. equiperdum which lost its maxicircles...

..We performed serologic tests because the patient was worried about HAT after receiving tsetse bites. The possibilities of an infection with human 'apathogenic' trypanosomes such as T. b. brucei, T. congolense or T. vivax are discussed...

..This panel of characterised strains with known drug sensitivities and resistances will be of great value for the screening of new active compounds, in comparison with the four standard drugs currently available...

..Despite these problems, melarsoprol is likely to remain the drug of choice for the next decade. We therefore did a randomised trial comparing the standard treatment schedule with a new, concise regimen...

..This is compatible with the epidemic population structure of T. brucei, in which clonal expansion of a few genotypes in a region occurs against a background of frequent recombination between strains...

..Compounds 3 and 4 showed strong activity against T. b. rhodesiense (IC50 values of 0.30 and 0.16 µM, respectively) and good selectivity (selectivity indices of 73.7 and 50.5, respectively)...

..falciparum, and from 1.8 µM to over 32.3 µM against T. brucei rhodesiense. The cytotoxic IC50 values ranged from 0.5-15.5 µM. Selectivity indices for P. falciparum were 0.1 to 18.2, and 0.1 to 1.2 for T. brucei rhodesiense...

..With other screening programs yielding hits, the pipeline for new HAT drugs might finally begin to fill...

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..In contrast, the weak activities of artemisinin and OZ277 against six other protozoan parasites were peroxide bond independent. These data support the iron-dependent artemisinin alkylation hypothesis...

..Two other stocks of T. evansi and again the T. equiperdum, all from equines, showed a new pattern ALAT-14. Otherwise the Chinese stocks had the same enzyme profile as T. evansi from elsewhere...

..Mouse liver microsome bioconversion of the methamidoxime prodrugs is significantly reduced from that of pafuramidine and suggests that the in vivo efficacy of these prodrugs is, in part, due to poor bioconversion...

..From these studies, the 4,4'-diaminodiphenylamine skeleton emerged as a good scaffold for antitrypanosomal drugs...

..These data warrant clinical testing of OZ277 against P. vivax malaria and support recent data on clinical activity against P. vivax for DB75...

..2.2]nonanes. Some of the 4-aminobicyclo[2.2.2]oct-2-ylamines exhibit moderate in vivo activity in mice against Trypanosoma brucei brucei...

..Fourteen of these compounds had cytotoxic indices ranging between 10 and 120 times higher than that of furamidine, and five analogues exhibited high selectivity for P. falciparum over T. brucei rhodesiense...

..This investigation suggests that the extent of accumulation alone is not responsible for killing trypanosomes and that organelle-specific accumulation may not predict in vitro activity...

..These findings indicate that factors other than drug resistance contribute to melarsoprol treatment failures...

..No correlation between antiplasmodial activity and in vitro inhibition of ferriprotoporphyrin IX biomineralisation was observed, suggesting that additional mechanism of action is likely to be involved...

..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...

..These results indicate that propagation of T. b. gambiense isolates after initial isolation in immunosuppressed M. natalensis or SCID mice can be done in a range of immunosuppressed rodents...

..The presence of flavonoids and quinones may at least in part explain the observed activities of some of the active extracts...

..The two DNA-containing structures in the trypanosome--the nucleus and the kinetoplast--begin to fluoresce within 1 min of introduction of DB99, unless drug resistant...

..Over-expression of MRPA was not detected in four melarsoprol-resistant trypanosome isolates from sleeping sickness patients...

..The methylthiosemicarbazones show moderate antiprotozoal activities whereas some of the esters of piperonylic acid, homopiperonylic acid and 2-naphtoic acid exhibit remarkable antitrypanosomal and antiplasmodial activity...

..cruzi against which various nitro heterocycles are already registered for use...

..of less than 10 nM. Against P. f. 8a, 8b, and 14b exhibited IC(50) values less than 10 nM. In an in vivo mouse model for T. b. r. four compounds 6a, 6c, 6d, and 8a were curative. Compound 6a produced cures at an oral dosage of 5 mg/kg...

..High-level arsenical resistance therefore appears to involve the loss of more than one transporter...

..Permeability across Caco-2 cell monolayers and microsomal metabolism were used to identify the underlying mechanisms of prodrug efficacy...

..g. 1c (IC(50) = 49 nM; SI > 5294), 28b (IC(50) = 69 nM; SI = 3072), 32b (IC(50) = 22 nM; SI = 29.5), 41b (IC(50) = 118 nM; SI = 881)] represent new antitrypanosomal lead compounds...

..brucei, distinguishing it from some other, mammalian cell toxic, trypanocidal nitroheterocycles...

..The biological activities of the alkaloids against the pathogens causing malaria tropica, leishmaniasis, Chagas' disease, and African sleeping sickness were evaluated...

..The oral activity of the prodrugs was modest with only one showing 2/4 cures in the same mouse model...

..2.2]octan-2-yl benzoate exhibit attractive antimalarial activity (IC(50)=0.23-0.72 microM). Two bicyclooctanone oximes are even as active as chloroquine (IC(50)=0.08-0.15 microM, chloroquine: IC(50)=0.12 microM against sensitive strains)...

..Selectivity against rat myoblasts (L6 cells) was found to be up to >2500-fold...

..The in vitro assay activity against the parasitic protozoa Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum was carried out with the compounds nangustine and pancracine...

..Both compounds were piscicidal against zebra fish and it is shown for the first time that piscatorin (2) and justicidin B (1) are the piscicidal principles of P. piscatorum, exhibiting a potency that is comparable to rotenone...

..Structural elucidation was achieved by chemical, spectroscopic, and chiroptical methods. Their biological activities against the pathogens of malaria, Leishmaniasis, Chagas disease, and African sleeping sickness were evaluated...

..Compounds 2, 3, and 4 showed moderate to good antiplasmodial and antitrypanosomal activities in vitro...

..051 and 0.695 microM against T. brucei rhodesiense and T. cruzi, respectively. The low IC50 value for T. b. rhodesiense indicates that helenalin type compounds may be interesting candidates for further evaluation...

..21-0.50 microg mL(-1)). The results suggested that the three pyrazolylnaphthoquinones and one of the 5-aminoisoxazole analogues could be starting points for lead optimization programs against T. cruzi and P. falciparum, respectively...

..The trypanocidal effect of the compounds was also evaluated in vitro against T. brucei rhodesiense as well as other related trypanosomatid parasites (i.e., Trypanosoma cruzi and Leishmania donovani)...

..The leishmanial enzyme was found to have a more extensive lipophilic binding region in the active site than the human enzyme. Compounds which bound within the pocket showed the highest selectivity...

..However, the pattern for the antitumor activity did not parallel any of the antiparasitic ones, indicating that non-common mechanisms of action may exist among these activities...

..68microM) of the so far prepared 4-amino-6,7-diarylbicyclo[2.2.2]octane derivatives, but is distinctly less active than suramin (IC(50)=0.0075microM)...

..Here we describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project...

..Some of the new compounds are amongst the most active antitrypanosomal agents in this series, and the selectivity index of a single derivative is superior in the 2-azabicyclo-nonane series...

..91 microM against Trypanosoma brucei rhodesiense and N(6)-diphenylethyl-5'-phenylcarboxamidoadenosine with an IC(50) value of 1.8 microM against chloroquine resistant Plasmodium falciparum...

..The amidoxime prodrugs of the naphthalene analogues were essentially ineffective...

..Especially the bis-(chlorophenyl)-azabicyclo[3.2.2]nonanes exhibit promising antitrypanosomal activity and were tested in vivo against Trypanosoma brucei brucei featuring moderate activities...

..More lipophilic trioxolanes tended to have better oral activities than their more polar counterparts. Trioxolanes with a wide range of neutral and basic, but not acidic, functional groups had good antimalarial profiles...

..Trypanocidal activity was evident, but compounds were equally toxic against trypanosomes lacking the P2 transporter, which indicates additional uptake routes for monobenzamidine-derived compounds...

..In addition, these polyphenols showed in vitro activity against chloroquine-sensitive (NF54) and -resistant (K1) P. falciparum strains in the low to submicromolar range...

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..699, r2=0.974, SEE, standard error of estimate=0.1, and F=120.04. The results have been used as a guide to design compounds that, potentially, have better activity against African trypanosomes...

..falciparum dUTPase constitutes a valid and attractive novel target for the development of much-needed new antimalarial drugs...

..In contrast, a number of the carbamates showed promising activity. The value of the carbamate prodrugs was clearly demonstrated by the results, which gave 4/4 cures on oral administration in the STIB900 mouse model...

..They also showed excellent potency by oral administration. A preliminary pharmacokinetic study revealed that the oral availability of 1a was excellent...

..falciparum, was also assessed. Compound 10 showed promising FabI inhibiting effect (IC (50) = 10 micrograms/mL) and appears to be the first anti-malarial natural product targeting FabI of P. falciparum...

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..b. rhodesiense, L. donovani and P. falciparum were in the range of 10 to 50 micrograms/mL. None of the compounds showed antibacterial or antiviral (including also HIV) activity...

..7-13.7, and this effect is comparable to that of the fully synthetic trioxolane drug development candidate OZ277, which is in phase II clinical trials...

..Joziknipholones A and B are active against the chloroquine resistant strain K1 of the malaria pathogen, Plasmodium falciparum, and show moderate activity against murine leukemic lymphoma L5178y cells...

..Eight bisbenzofurans displayed activity against L. donovani superior to that of pentamidine. Overall, bisamidines connected by two-carbon linkers exhibited the highest efficacies against T. b. rhodesiense, P. falciparum, and L. donovani...

..There was significantly lower activity against Leishmania donovani, one of the causative organisms of leishmaniasis...

..The structural elucidation was achieved by spectroscopic and chiroptical methods. Biological activities of these alkaloids against different protozoan parasites are described...

..2.2]octan-2-ones to investigate the influence of the replacement of the rigid bicyclo-octane structure by the more flexible bicyclo-nonane system on the antiplasmodial and antitrypanosomal activity...