pafuramidine and Trypanosomiasis--African

Aromatic diamidines are potent trypanocides. Pentamidine, a diamidine, has been used for more than 60 years to treat human African trypanosomiasis (HAT); however, the drug must be administered parenterally and is active against first-stage HAT only, prior to the parasites causing neurological deterioration through invasion of the CNS. A major research effort to design novel diamidines has led to the development of orally active prodrugs and, remarkably, a new generation of compounds that can penetrate the CNS. In this review, progress in the development of diamidines for the treatment of HAT is discussed.

Topics: Animals; Benzamidines; Biotransformation; Brain; Clinical Trials as Topic; Drug Design; Drug Resistance; Humans; Pentamidine; Prodrugs; Trypanocidal Agents; Trypanosoma brucei gambiense; Trypanosoma brucei rhodesiense; Trypanosomiasis, African

Diamidine-containing compounds have a long history of use in the treatment of African trypanosomiasis and leishmaniasis. The discovery that diamidine prodrugs possess in vivo antimicrobial activity when administered orally has led to a renewed interest in this class of compounds for the treatment of parasitic infections. In this review, the selectivity of diamidines against trypanosomes, Leishmania and Plasmodium is rationalized through mechanism-of-action studies. An overview of the antiprotozoal activities of newer diamidines and diamidine prodrugs is also presented, along with a summary of the progress made toward the clinical development of new diamidines for use against these parasitic diseases.

Topics: Animals; Antimalarials; Antiprotozoal Agents; Benzamidines; Chagas Disease; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Leishmania; Leishmaniasis; Malaria, Falciparum; Pentamidine; Plasmodium falciparum; Prodrugs; Trypanocidal Agents; Trypanosoma brucei gambiense; Trypanosoma cruzi; Trypanosomiasis, African

Access to treatment is a multi-step process and little progress has been made to improve treatments for sleeping sickness over the past 50 years. The current strategy is based on diagnostic tools developed in the 1960s while available drugs are still the same as those developed in the middle of the last century. Strategic opportunities can only be based on two achievements: improved diagnosis and safer drugs. This paper reviews the development of new diagnostic tools and drugs and the opportunity offered by new technologies for their further improvement.. The prodrug DB289 shows excellent oral activity with low toxicity for the treatment of early-stage sleeping sickness; it has recently entered phase II(b) clinical trials. The recent ability to identify and test specific host and parasite biomarkers has allowed the development of new, more-specific and sensitive, diagnostic and stage-determination tools. The accurate diagnosis of an infection by use of proteomic signature analysis has been achieved. Urinary nitrites and nitrates follow closely the increase of brain nitric oxide associated with the penetration of trypanosomes in the brain. Sleep-onset rapid eye movement-like episodes have been shown to occur at onset of late-stage trypanosomiasis. This unique disturbance of the wake/sleep cycle seems to be the first pathognomonic sign in the occurrence of late-stage trypanosomiasis.. Following the description of the disease, and diagnostic tools and drugs that have been used, and are still in use today, the authors show how it has influenced over time the evolution of strategies for surveillance and control. Recent developments and prospects for new, more-specific and sensitive diagnostic tools and a safer drug will undoubtedly improve the accuracy of patient recruitment and facilitate treatment, and provide ways towards new strategic opportunities.

Topics: Animals; Benzamidines; Biomarkers; Humans; Trypanocidal Agents; Trypanosoma brucei gambiense; Trypanosoma brucei rhodesiense; Trypanosomiasis, African

Human African trypanosomiasis re-emerged in the 1980s. However, little progress has been made in the treatment of this disease over the past decades. The first-line treatment for second-stage cases is melarsoprol, a toxic drug in use since 1949. High therapeutic failure rates have been reported recently in several foci. The alternative, eflornithine, is better tolerated but difficult to administer. A third drug, nifurtimox, is a cheap, orally administered drug not yet fully validated for use in human African trypanosomiasis. No new drugs for second-stage cases are expected in the near future. Because of resistance to and limited number of current treatments, there may soon be no effective drugs available to treat trypanosomiasis patients, especially second-stage cases. Additional research and development efforts must be made for the development of new compounds, including: testing combinations of current trypanocidal drugs, completing the clinical development of nifurtimox and registering it for trypanosomiasis, completing the clinical development of an oral form of eflornithine, pursuing the development of DB 289 and its derivatives, and advancing the pre-clinical development of megazol, eventually engaging firmly in its clinical development. Partners from the public and private sector are already engaged in joint initiatives to maintain the production of current drugs. This network should go further and be responsible for assigning selected teams to urgently needed research projects with funds provided by industry and governments. At the same time, on a long term basis, ambitious research programmes for new compounds must be supported to ensure the sustainable development of new drugs.

Topics: Africa South of the Sahara; Animals; Benzamidines; Drug Therapy, Combination; Eflornithine; Humans; Melarsoprol; Nifurtimox; Thiadiazoles; Trypanocidal Agents; Trypanosoma brucei gambiense; Trypanosoma brucei rhodesiense; Trypanosomiasis, African

Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT.. The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent.. Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3.

Topics: Administration, Oral; Adolescent; Adult; Angola; Antiprotozoal Agents; Benzamidines; Democratic Republic of the Congo; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Pentamidine; Treatment Outcome; Trypanosomiasis, African; Young Adult

Sleeping sickness (human African trypanosomiasis [HAT]) is a neglected tropical disease with limited treatment options that currently require parenteral administration. In previous studies, orally administered pafuramidine was well tolerated in healthy patients (for up to 21 days) and stage 1 HAT patients (for up to 10 days), and demonstrated efficacy comparable to pentamidine.. This was a Phase 3, multi-center, randomized, open-label, parallel-group, active control study where 273 male and female patients with first stage Trypanosoma brucei gambiense HAT were treated at six sites: one trypanosomiasis reference center in Angola, one hospital in South Sudan, and four hospitals in the Democratic Republic of the Congo between August 2005 and September 2009 to support the registration of pafuramidine for treatment of first stage HAT in collaboration with the United States Food and Drug Administration. Patients were treated with either 100 mg of pafuramidine orally twice a day for 10 days or 4 mg/kg pentamidine intramuscularly once daily for 7 days to assess the efficacy and safety of pafuramidine versus pentamidine. Pregnant and lactating women as well as adolescents were included. The primary efficacy endpoint was the combined rate of clinical and parasitological cure at 12 months. The primary safety outcome was the frequency and severity of adverse events. The study was registered on the International Clinical Trials Registry Platform at www.clinicaltrials.gov with the number ISRCTN85534673.. The overall cure rate at 12 months was 89% in the pafuramidine group and 95% in the pentamidine group; pafuramidine was non-inferior to pentamidine as the upper bound of the 95% confidence interval did not exceed 15%. The safety profile of pafuramidine was superior to pentamidine; however, 3 patients in the pafuramidine group had glomerulonephritis or nephropathy approximately 8 weeks post-treatment. Two of these events were judged as possibly related to pafuramidine. Despite good tolerability observed in preceding studies, the development program for pafuramidine was discontinued due to delayed post-treatment toxicity.

Topics: Administration, Oral; Adolescent; Adult; Aged; Angola; Benzamidines; Child; Democratic Republic of the Congo; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Injections, Intramuscular; Kidney Diseases; Male; Middle Aged; Pentamidine; Pregnancy; Sudan; Treatment Outcome; Trypanosoma brucei gambiense; Trypanosomiasis, African; Young Adult

Dicationic 2,6-diphenylpyrazines, aza-analogues and prodrugs were synthesized; evaluated for DNA affinity, activity against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) in vitro, efficacy in T. b. r. STIB900 acute and T. b. brucei GVR35 CNS mouse models. Most diamidines gave poly(dA-dT)2 ΔTm values greater than pentamidine, IC50 values: T. b. r. (4.8-37nM) and P. f. (10-52nM). Most diamidines and prodrugs gave cures for STIB900 model (11, 19a and 24b 4/4 cures); 12 3/4 cures for GVR35 model. Metabolic stability half-life values for O-methylamidoxime prodrugs did not correlate with STIB900 results.

Topics: Animals; Antiprotozoal Agents; Aza Compounds; Cations; Cell Line; Cell Survival; Disease Models, Animal; Mice; Myoblasts; Parasitic Sensitivity Tests; Pentamidine; Plasmodium falciparum; Poly dA-dT; Prodrugs; Pyrazines; Rats; Structure-Activity Relationship; Transition Temperature; Trypanosoma brucei rhodesiense; Trypanosomiasis, African

Seven novel diamidino 2,5-bis(aryl)thiazoles (5a-g) were synthesized and evaluated against Trypanosoma brucei rhodensiense (T. b. r.) and Plasmodium falciparum (P. f.). The diamidines were obtained directly from the corresponding bis-nitriles (4a-g) by the action of lithium bis(trimethylsilyl)amide. The bis-nitriles 4a-f were synthesized in four steps starting with the Stille coupling of 2-tributyltinthiazole with the appropriate cyanoaryl halide. The bis-nitrile 5g was obtained by the palladium facilitated coupling of the mixed tin-silyl reagent 2-trimethylsilyl-5-trimethyltinthiazole with 2-bromo-5-cyanopyridine. The amidoxime potential prodrugs 6a-e, 6g were obtained by the reaction of hydroxylamine with the bis-nitriles. O-Methylation of the amidoximes gave the corresponding N-methoxyamidines 7a-c, 7e, 7g. The diamidines showed strong DNA binding affinity as reflected by DeltaT(m) measurements. Four of the diamidines 5a, 5b, 5d and 5e were highly active in vitro against P. f. giving IC(50) values between 1.1 and 2.5nM. The same four diamidines showed IC(50) values between 4 and 6nM against T. b. r. The selectivity indices ranged from 233 to 9175. One diamidine 5a produced one of four cures at an ip dose of 4x5mg/kg in the STIB900 mouse model for acute African trypanosomiasis. The amidoxime and N-methoxyamidine of 5a were the only produgs to provide cures (1/4 cures) in the same mouse model on oral dosage at 4x25mg/kg.

Topics: Administration, Oral; Animals; Antimalarials; Antiprotozoal Agents; Disease Models, Animal; DNA, Protozoan; Drug Stability; Malaria, Falciparum; Mice; Parasitic Sensitivity Tests; Pentamidine; Plasmodium falciparum; Rats; Stereoisomerism; Structure-Activity Relationship; Thiazoles; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African

Human African trypanosomiasis (HAT), also called African sleeping sickness, is a neglected tropical parasitic disease indigenous to sub-Saharan Africa. Diamidine compounds, including pentamidine and CPD-0801, are potent anti-trypanosomal molecules. The latter is a potential drug in the development at the UNC based Consortium for Parasitic Drug Development. An orally bioavailable prodrug of CPD-0801, DB868, is metabolized primarily in the liver to the active form. A monoclonal antibody developed against a pentamidine derivative has shown significant reactivity with CPD-0801 (EC(50) 65.1 nM), but not with the prodrug (EC(50)>18,000 nM). An inhibitory enzyme-linked immunosorbent assay (IELISA) has been used to quantitatively monitor prodrug metabolism by detecting the production of the active compound over time in a sandwich culture rat hepatocyte system and in rats. These results were compared with the results of the standard LC/MS/MS assay. Spearman coefficients of 0.96 and 0.933 (in vitro and in vivo, respectively) indicate a high correlation between these two measurement methods. This novel IELISA provides a facile, inexpensive, and accurate method for drug detection that may aide in elucidating the mechanisms of action and toxicity of existing and future diamidine compounds.

Topics: Animals; Antibodies, Monoclonal; Antibody Specificity; Benzamidines; Cross Reactions; Enzyme-Linked Immunosorbent Assay; Female; Hepatocytes; Humans; Immunoglobulin G; Male; Mice; Mice, Inbred BALB C; Pentamidine; Prodrugs; Rats; Rats, Sprague-Dawley; Rats, Wistar; Tandem Mass Spectrometry; Trypanocidal Agents; Trypanosomiasis, African

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 brucei rhodesiense KETRI 2537 cells. On the seventh day postinfection (p.i.) in an early-stage infection, animals in groups 1, 2, and 3 were treated orally with pafuramidine at dose rates of 1, 3, or 10 mg/kg of body weight, respectively, for five consecutive days. The animals in groups 4 and 5 were treated with 10 mg/kg for 10 consecutive days starting on the 14th day p.i. (group 4) or on the 28th day p.i. (group 5), when these animals were in the late stage of the disease. In the groups treated in the early stage, 10 mg/kg of pafuramidine completely cured all three monkeys, whereas lower doses of 3 mg/kg and 1 mg/kg cured only one of three and zero of three monkeys, respectively. Treatment of late-stage infections resulted in cure rates of one of three (group 4) and zero of three (group 5) monkeys. These studies demonstrated that pafuramidine was orally active in monkeys with early-stage T. brucei rhodesiense infections at dose rates above 3 mg/kg for 5 days. It was also evident that the drug attained only minimal efficacy against late-stage infections, indicating the limited ability of the molecule to cross the blood-brain barrier. This study has shown that oral diamidines have potential for the treatment of early-stage sleeping sickness.

Topics: Administration, Oral; Animals; Benzamidines; Chlorocebus aethiops; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Pentamidine; Prodrugs; Random Allocation; Time Factors; Treatment Outcome; Trypanocidal Agents; Trypanosoma brucei rhodesiense; Trypanosomiasis, African

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 similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol- and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.

Topics: Animals; Benzamidines; Central Nervous System; Female; Furans; Mice; Molecular Structure; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosoma brucei gambiense; Trypanosoma brucei rhodesiense; Trypanosomiasis, African

The choice of drugs for the treatment of sleeping sickness is extremely limited. To redress this situation, the recently synthesised diamidine, 2,5-bis(4-amidinophenyl)-furan (DB75, furamidine) and its methamidoxime prodrug, 2,5-bis(4-amidinophenyl)-furan-bis-O-methylamidoxime (DB289, pafuramidine) were, together with pentamidine, evaluated for efficacy in acute rodent models. The activity was compared in three common mouse models that mimic the first stage of human African trypanosomiasis. The mice were infected with the pleomorphic T .b. rhodesiense strains KETRI2537 and STIB900 or with the monomorphic T. b. brucei strain STIB795. Importantly, DB75 showed activity superior to that of pentamidine at comparable doses in all three mouse models. Complete cures were achieved with oral dosing of the prodrug DB289 in all three models without any overt toxicity. This shows that the prodrug strategy was successful in terms of reducing toxicity and increasing efficacy and oral bioavailability.

Topics: Administration, Oral; Animals; Antiprotozoal Agents; Benzamidines; Female; Humans; Mice; Molecular Structure; Pentamidine; Prodrugs; Trypanosoma brucei gambiense; Trypanosomiasis, African

Five O-alkoxyamidine analogues of the prodrug 2,5-bis[4-methoxyamidinophenyl]furan were synthesized and evaluated against Trypanosoma brucei rhodesiense in the STIB900 mouse model by oral administration. The observed in vivo activity of these prodrugs demonstrates that compounds with an O-methoxyamidine or O-ethoxyamidine group effectively cured all trypanosome-infected mice, whereas prodrugs with larger side-chains did not completely cure the mice. Permeability across Caco-2 cell monolayers and microsomal metabolism were used to identify the underlying mechanisms of prodrug efficacy.

Topics: Administration, Oral; Animals; Benzamidines; Biological Transport; Caco-2 Cells; Disease Models, Animal; Humans; In Vitro Techniques; Mice; Microsomes, Liver; Permeability; Prodrugs; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma brucei rhodesiense; Trypanosomiasis, African

DB75 (2,5-bis(4-amidinophenyl)furan) is a promising antimicrobial agent against African trypanosomiasis and Pneumocystis carinii pneumonia. However, it suffers from poor oral activity in rodent models for both infections. In contrast, a novel prodrug of DB75, 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289), has excellent oral activity. DB289 is currently undergoing clinical investigation as a candidate drug to treat primary stage African trypanosomiasis and Pneumocystis carinii pneumonia. In this study, metabolites of DB289 formed after incubation with freshly isolated rat hepatocytes were characterized using liquid chromatography/ion trap mass spectrometry. Administration of DB289 and octadeuterated DB289 in a 1 : 1 mixture greatly facilitated metabolite identification by providing isotope patterns with twin ions separated by 8 m/z units in the ratio 1 : 1, in the extracted ion chromatograms of molecular ions and in the product ion mass spectra of metabolites. Ten metabolites were identified. Series of O-demethylations and N-dehydroxylations led to the metabolic activation of DB289 to DB75 with the production of four intermediate phase I metabolites. Phase II glucuronidation and sulfation led to the formation of four glucuronide and one sulfate metabolites.

Topics: Administration, Oral; Animals; Benzamidines; Chromatography, High Pressure Liquid; Hepatocytes; Mass Spectrometry; Molecular Structure; Pneumonia, Pneumocystis; Prodrugs; Rats; Trypanosomiasis, African

The current epidemic of sleeping sickness, also known as human African trypanosomiasis in sub-Saharan Africa places nearly 60 million people at risk for developing this life threatening infection. Although effective treatments for early-stage sleeping sickness exist, these drugs usually require extended dosing schedules and intravenous administration. New treatments are also needed for cerebral (late) stage trypanosomiasis. 2,5-Bis(4-amidinophenyl)furan (DB75), a pentamidine analog, has potent in vitro and in vivo anti-trypanosomal activity. However, DB75 does not exhibit significant oral bioavailability and has proved to be ineffective against mouse models of late-stage sleeping sickness regardless of administration route. To circumvent the limited oral bioavailability of DB75, an N-methoxy prodrug 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289) was designed and developed initially as a compound to treat AIDS-related Pneumocystis carinii pneumonia (PCP). Despite excellent oral activity against early-stage sleeping sickness, oral administration of DB289 exhibited limited efficacy in mouse models of late-stage disease. DB289 has recently entered Phase II(b) clinical trials to treat primary-stage sleeping sickness in Central Africa. The current study takes advantage of the innate fluorescence of DB75 and DB289 along with specific and sensitive quantitative analyses to examine plasma and brain distribution of these compounds. Animals were dosed with intravenous DB75, oral DB289, and intravenous DB289. Following intravenous administration, DB75 was readily detectable in whole brain extracts and persisted for long periods. Fluorescence microscopy revealed that DB75 did not penetrate into brain parenchyma, however, but was sequestered within cells lining the blood-brain and blood-cerebrospinal fluid barriers. In contrast, brain tissue of mice treated with oral DB289 exhibited diffuse fluorescence within the brain parenchyma, suggesting that the prodrug was not trapped within blood-brain barrier cells (BBB). However, maximal brain concentrations of the active compound DB75 were very low (13 nmol/mg of tissue at 24 h). Intravenous administration of DB289 resulted in a qualitatively similar fluorescence pattern to oral DB289, indicating again that DB289 and DB75 were present within brain parenchyma, not only in barrier regions. Furthermore, peak DB75 tissue levels were higher (61 nmol/mg of tissue at 24 h) than with oral prodrug. The near five-fold inc

Topics: Administration, Oral; Animals; Benzamidines; Blood-Brain Barrier; Brain; Injections, Intravenous; Male; Mice; Microscopy, Fluorescence; Prodrugs; Tissue Distribution; Trypanocidal Agents; Trypanosoma brucei gambiense; Trypanosomiasis, African

6-[5-(4-Amidinophenyl)furan-2-yl]nicotinamidine (8a) was synthesized from 6-[5-(4-cyanophenyl)furan-2-yl]nicotinonitrile (4a), through the bis-O-acetoxyamidoxime followed by hydrogenation. Compound 4a was prepared via selective bromination of 6-(furan-2-yl)nicotinonitrile (2a) with N-bromosuccinimide, followed by Suzuki coupling with 4-cyanophenylboronic acid. In a similar way, diamidines 8b and 8c were prepared from the dicyano derivatives 4c and 4d, respectively. N-Methoxy-6-[5-[4-(N-methoxyamidino)phenyl]-furan-2-yl]-nicotinamidine (6a) was prepared via methylation of the respective diamidoxime 5a with dimethylsulfate. Prodrugs 6b and 6c were also prepared by methylation of the respective diamidoximes 5b and 5d. The symmetrical diamidines 14a,b were synthesized through the corresponding bis-O-acetoxyamidoxime followed by hydrogenation. The key compounds 11a,b were conveniently obtained by Stille coupling between 2,5-bis(tri-n-butylstannyl)furan and the corresponding heteroaryl halides. These compounds have been evaluated in vitro for activity against Trypanosoma b.rhodesiense (T. b. r.) and P. falciparum (P. f.). The diamidines 8a, 8c, and 14b gave IC(50) values versus T. b. r. 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.

Topics: Animals; Antimalarials; Antiprotozoal Agents; Aza Compounds; Benzamidines; Mice; Plasmodium falciparum; Prodrugs; Structure-Activity Relationship; Trypanosoma brucei rhodesiense; Trypanosomiasis, African