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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 (IC<jats:sub>50<\/jats:sub>s) determined<jats:italic>in vitro<\/jats:italic>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<jats:italic>K<jats:sub>i<\/jats:sub><\/jats:italic>values, indicating affinity values for this permease in the low to submicromolar range. Uptake of DB75, DB820, and CPD0801 was significantly reduced in<jats:italic>tbat1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>parasites and was sensitive to inhibition by adenine, showing that all three compounds are substrates for the P2 transporter. Uptake<jats:italic>in vitro<\/jats:italic>was significantly less than that seen with parasites freshly isolated from infected rats, correlating with a downregulation of P2 activity<jats:italic>in vitro<\/jats:italic>. We conclude that DB75, DB820, and CPD0801 are actively accumulated by<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Trypanosoma brucei brucei<\/jats:named-content>, 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<jats:italic>in vitro<\/jats:italic>drug sensitivity assays.<\/jats:p>","DOI":"10.1128\/aac.01551-10","type":"journal-article","created":{"date-parts":[[2011,3,15]],"date-time":"2011-03-15T18:53:46Z","timestamp":1300215226000},"page":"2352-2361","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":55,"title":["Trypanocidal Furamidine Analogues: Influence of Pyridine Nitrogens on Trypanocidal Activity, Transport Kinetics, and Resistance Patterns"],"prefix":"10.1128","volume":"55","author":[{"given":"Christopher P.","family":"Ward","sequence":"first","affiliation":[{"name":"Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United 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