title: Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes.
abstract: A 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 EC(50) 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.
authors.affiliation: Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Taladriz
authors.forename: Alan
authors.initials: A
authors.lastname: Healy
authors.forename: Eddysson J
authors.initials: EJ
authors.lastname: Flores Pérez
authors.forename: Vanessa
authors.initials: V
authors.lastname: Herrero García
authors.forename: Carlos
authors.initials: C
authors.lastname: Ríos Martínez
authors.forename: Abdulsalam A M
authors.initials: AA
authors.lastname: Alkhaldi
authors.forename: Anthonius A
authors.initials: AA
authors.lastname: Eze
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Harry P
authors.initials: HP
authors.lastname: de Koning
authors.forename: Antonio
authors.initials: A
authors.lastname: Chana
authors.forename: Christophe
authors.initials: C
authors.lastname: Dardonville
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D004351:Drug Resistance; D006801:Humans; D008958:Models, Molecular; D033703:Nucleoside Transport Proteins / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010419:Pentamidine / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*
chemical_list: D002352:Carrier Proteins; D033703:Nucleoside Transport Proteins; D009943:Organophosphorus Compounds; C486446:P2 transporter, Trypanosoma brucei; D014344:Trypanocidal Agents; D010419:Pentamidine