ArticleAntimicrobial agents and chemotherapy2011
Trypanocidal furamidine analogues: influence of pyridine nitrogens on trypanocidal activity, transport kinetics, and resistance patterns.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 64 citations in OpenAlex.
- Article
- Uncovering the Unusual Inhibition Mechanism of a Trypanosome Alternative Oxidase Inhibitor Displaying Broad-Spectrum Activity against African Animal Trypanosomes.Journal of medicinal chemistry · 2025Article
- Antitrypanosomal and Antileishmanial Activities ofMolecules (Basel, Switzerland) · 2025Article
- Drug resistance in animal trypanosomiases: Epidemiology, mechanisms and control strategies.International journal for parasitology. Drugs and drug resistance · 2024Review
- Synthesis and Biophysical and Biological Studies ofJournal of medicinal chemistry · 2023Article
- Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose.Journal of medicinal chemistry · 2023Article
- Arylimidamides Have Potential for Chemoprophylaxis against Blood-Transmitted Chagas Disease.Pathogens (Basel, Switzerland) · 2023Article
- Nucleoside Transport and Nucleobase Uptake Null Mutants inInternational journal of molecular sciences · 2022Article
- Differences in Transporters Rather than Drug Targets Are the Principal Determinants of the Different Innate Sensitivities ofInternational journal of molecular sciences · 2022Article
- An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection.PLoS neglected tropical diseases · 2021Article
- Article
- New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story.Tropical medicine and infectious disease · 2020Review
- The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History.Tropical medicine and infectious disease · 2020Review
- Investigation of 5'-Norcarbocyclic Nucleoside Analogues as Antiprotozoal and Antibacterial Agents.Molecules (Basel, Switzerland) · 2019Article
- Targeting Channels and Transporters in Protozoan Parasite Infections.Frontiers in chemistry · 2018Review
- Drug resistance in protozoan parasites.Emerging topics in life sciences · 2017Article
- 9-(2'-Deoxy-2'-Fluoro-β-d-Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance.Antimicrobial agents and chemotherapy · 2017Article
- Antileishmanial Mechanism of Diamidines Involves Targeting Kinetoplasts.Antimicrobial agents and chemotherapy · 2016Article
- An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells.Antimicrobial agents and chemotherapy · 2016Article
- Reduced Mitochondrial Membrane Potential Is a Late Adaptation of Trypanosoma brucei brucei to Isometamidium Preceded by Mutations in the γ Subunit of the F1Fo-ATPase.PLoS neglected tropical diseases · 2016Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Current therapies for human African trypanosomiasis (HAT) are unsatisfactory and under threat from emerging drug resistance linked to the loss of transporters, e.g., the P2 aminopurine transporter (TbAT1). Here we compare the uptake and trypanocidal properties of furamidine (DB75), recently evaluated in clinical trials against stage 1 (haemolymphatic) HAT, and two aza analogues, DB820 and CPD0801 (DB829), which are candidate compounds for treatment of stage 2 (neurological) disease. Values of 50% inhibitory concentrations (IC50s) determined in vitro against both wild-type and transporter mutant parasites were submicromolar, with DB75 trypanotoxicity shown to be better than and DB820 trypanotoxicity similar to that of the widely used veterinary trypanocide diminazene, while CPD0801 was less active. Activity correlated with uptake and with the minimum drug exposure time necessary to kill trypanosomes: DB75 accumulated at double and 10-fold the rates of DB820 and CPD0801, respectively. All three compounds inhibited P2-mediated adenosine transport with similar Ki values, indicating affinity values for this permease in the low to submicromolar range. Uptake of DB75, DB820, and CPD0801 was significantly reduced in tbat1-/- parasites and was sensitive to inhibition by adenine, showing that all three compounds are substrates for the P2 transporter. Uptake in vitro was significantly less than that seen with parasites freshly isolated from infected rats, correlating with a downregulation of P2 activity in vitro. We conclude that DB75, DB820, and CPD0801 are actively accumulated by Trypanosoma brucei brucei, with P2 as the main transport route. The aza analogues of DB75 accumulate more slowly than furamidine itself and reveal less trypanocidal activity in standard in vitro drug sensitivity assays.
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