ferroquine and Trypanosomiasis--African

Three new series of quinoline, quinolone, and benzimidazole derivatives were synthesized and evaluated in vitro against Trypanosoma brucei gambiense. In the quinoline series, the metallo antimalarial drug candidate (ferroquine, FQ) and its ruthenium analogue (ruthenoquine, RQ, compound 13) showed the highest in vitro activities with IC50 values around 0.1 μM. Unfortunately, both compounds failed to cure Trypanosoma brucei brucei infected mice in vivo. The other heterocyclic compounds were active in vitro with IC50 values varying from 0.8 to 34 μM. One of the most interesting results was a fluoroquinolone derivative (compound 2) that was able to offer a survival time of 8 days after a treatment at the single dose of 100 μmol/kg by intraperitoneal route. Although no clear-cut structure-activity relationships emerged, further pharmacomodulations are worth to be developed in this series.

Topics: Aminoquinolines; Animals; Benzimidazoles; Cell Line; Ferrous Compounds; Halogenation; Heterocyclic Compounds; Humans; Metallocenes; Mice; Quinolines; Quinolones; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African

Ferroquine (FQ, SSR97193) is a synthetic compound currently in development for the treatment of malaria. The use of a single compound to treat several parasitoses would be very convenient for multi-infected patients and also for financial considerations. In this work, the activity of FQ was investigated on three other Protista parasites: Kinetoplastidae (Leishmania and Trypanosoma) and the cosmopolite parasite Trichomonas vaginalis. FQ exhibited a significant in vitro activity on Trypanosoma brucei brucei and Trypanosoma brucei gambiense, the agents of African trypanosomiasis in a range from 0.2 to 3.1 μM. In vivo, intraperitoneally administered FQ demonstrated a weak but significant trypanocidal activity at 100 μmol/kg, which is however higher than the maximum tolerated dose. The drop of the parasitemia of the treated mice was significantly related to the amount of injected FQ. Furthermore, this organometallic compound was responsible for a delay in the appearance of bloodstream parasites at 50 μmol/kg. However, it was not able to cure infected mice. Although no synergy was identified in vitro between FQ and pentamidine, these results justify further investigations by evaluating analogues in this chemical series.

Topics: Aminoquinolines; Animals; Antiprotozoal Agents; Ferrous Compounds; Leishmania; Metallocenes; Mice; Parasitic Sensitivity Tests; Treatment Outcome; Trichomonas vaginalis; Trypanosoma; Trypanosomiasis, African