ABSTRACT
A new family of quinolinone derivatives has been synthesized and evaluated for their antikinetoplastid activities against Leishmania donovani and Trypanosoma brucei brucei. Results from these structure-activity relationship studies enabled identification of compounds 3a and 4g as the most active compounds against L. donovani promastigotes and amastigotes parasites (IC(50) values in a range of 2-11 µM). Additionally, compound 3b has emerged from this study as the most active compound in the series against T. b. brucei with a MEC value of 12 µM. These three compounds are worth of further in vivo evaluation.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Leishmania donovani/drug effects , Quinolones/chemical synthesis , Quinolones/pharmacology , Trypanosoma brucei brucei/drug effects , Animals , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/toxicity , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Design , Mice , Quinolones/chemistry , Quinolones/toxicity , Structure-Activity RelationshipSubject(s)
Antiprotozoal Agents/pharmacology , Drug Resistance , Leishmania donovani/drug effects , Leishmaniasis, Visceral/diagnosis , Leishmaniasis, Visceral/prevention & control , Phosphorylcholine/analogs & derivatives , Amphotericin B/pharmacology , Amphotericin B/therapeutic use , Antiprotozoal Agents/therapeutic use , Female , Humans , Inhibitory Concentration 50 , Leishmaniasis, Visceral/parasitology , Maintenance Chemotherapy , Middle Aged , Phosphorylcholine/pharmacology , Phosphorylcholine/therapeutic use , RecurrenceABSTRACT
A Leishmania donovani promastigote line resistant to 160microM sitamaquine, named SITA-160R, was selected in vitro by continuous stepwise drug pressure. SITA-160R line was able to infect murine peritoneal macrophages in vitro in the same manner as the wild-type line (WT) but was less infective for Balb/c mice than its parent WT clone. This line was about five and three times more resistant to sitamaquine than the WT line on promastigote and intramacrophage amastigote forms, respectively. No cross-resistance with other antileishmanial agents was observed and this resistance was stable when parasites were subcultured in drug-free medium for a long time or after in vivo passage.