jm2014259_si_001.pdf (1.53 MB)
Download fileSynthesis and Structure–Activity Analysis of New Phosphonium Salts with Potent Activity against African Trypanosomes
journal contribution
posted on 2016-02-21, 16:47 authored by Andrea Taladriz, Alan Healy, Eddysson J. Flores Pérez, Vanessa Herrero
García, Carlos Ríos Martínez, Abdulsalam A. M. Alkhaldi, Anthonius A. Eze, Marcel Kaiser, Harry P. de Koning, Antonio Chana, Christophe DardonvilleA series of 73 bisphosphonium salts and 10 monophosphonium
salt
derivatives were synthesized and tested in vitro against several wild
type and resistant lines of Trypanosoma brucei (T. b. rhodesiense STIB900, T. b. brucei strain 427, TbAT1-KO, and TbB48).
More than half of the compounds tested showed a submicromolar EC50 against these parasites. The compounds did not display any
cross-resistance to existing diamidine therapies, such as pentamidine.
In most cases, the compounds displayed a good selectivity index versus
human cell lines. None of the known T. b. brucei drug
transporters were required for trypanocidal activity, although some
of the bisphosphonium compounds inhibited the low affinity pentamidine
transporter. It was found that phosphonium drugs act slowly to clear
a trypanosome population but that only a short exposure time is needed
for irreversible damage to the cells. A comparative molecular field
analysis model (CoMFA) was generated to gain insights into the SAR
of this class of compounds, identifying key features for trypanocidal
activity.