piperidines and Trypanosomiasis--African

New drugs for the treatment of human African trypanosomiasis are urgently needed. A number of 2-aminopyrazines/2-aminopyridines were identified as promising leads following a focused screen of 5,500 compounds for Trypanosoma brucei subsp. brucei viability. Described compounds are trypanotoxic in the submicromolar range and show comparably low cytotoxicity on representative mammalian cell lines. Specifically, 6-([6-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl)]oxy)-N-(piperidin-4-yl)pyrazin-2-amine (CBK201352) is trypanotoxic for T. brucei subsp. brucei, T. brucei subsp. gambiense, and T. brucei subsp. rhodesiense and is nontoxic to mammalian cell lines, and in vitro preclinical assays predict promising pharmacokinetic parameters. Mice inoculated intraperitoneally (i.p.) with 25 mg/kg CBK201352 twice daily for 10 days, starting on the day of infection with T. brucei subsp. brucei, show complete clearance of parasites for more than 90 days. Thus, CBK201352 and related analogs are promising leads for the development of novel treatments for human African trypanosomiasis.

Topics: Aminopyridines; Animals; Benzopyrans; Cell Line; Humans; Mice; Mice, Inbred C57BL; Piperidines; Pyrazines; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosoma brucei gambiense; Trypanosoma brucei rhodesiense; Trypanosomiasis, African

Tetradecylphosphocholine (TPC), hexadecylphosphocholine (HPC), hexadecylphospho(N-N-N-trimethyl)hexanolamine (HPC6), octadecylphosphocholine (OPC), and octadecyl-[2-(N-methylpiperidinio)ethyl]-phosphate (OMPEP) were investigated for antitrypanosomal activity in vitro and in vivo. OMPEP showed the best trypanocidal efficacy in vitro; it was superior to the model compound HPC and comparable to the reference compound alpha-DFMO. HPC showed moderate activity in vivo in terms of increased life expectancy (up to 35% in the acute NMRI-mouse model or 49% if combined with phenylbutazone) and increased packed cell volume, if administered daily. However, HPC and the other alkylphosphocholines failed to prolong survival time of treated mice if given intermittently. Phenylbutazone had no own trypanocidal effect but increased the efficacy of alkylphosphocholines in vitro and in vivo: the combination of HPC and phenylbutazone acted apparently synergistic.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Drug Synergism; Drug Therapy, Combination; Female; Mice; Microbial Sensitivity Tests; Molecular Structure; Phenylbutazone; Phosphorylcholine; Piperidines; Platelet Activating Factor; Specific Pathogen-Free Organisms; Trypanosoma brucei brucei; Trypanosomiasis, African