title: SAR Studies of Diphenyl Cationic Trypanocides: Superior Activity of Phosphonium over Ammonium Salts.
abstract: In previous studies, we have shown that phosphonium salt diphenyl derivatives are attractive antitrypanosomal hit compounds with EC50 values against Trypanosoma brucei in the nanomolar range. To evaluate the role of the cationic center on the trypanocidal activity and extend the structure-activity relationship (SAR) of this series, trialkylammonium, pyridinium, and quinolinium salt analogues were synthesized and evaluated in vitro against T. b. brucei. Similar SARs were observed with ammonium and phosphonium salts showing that charge dispersion and lipophilic groups around the cationic center are crucial to obtain submicromolar activities. The new compounds were equally effective against wild type (T. b. brucei s427) and resistant strains (TbAT1-KO and TbB48) of trypanosomes indicating that the P2 and high affinity pentamidine transporters (HAPT) are not essential to their trypanocidal action. Similarly to phosphonium salt derivatives, diffusion seems to be the main route of entry into trypanosomes.
authors.affiliation: Instituto de Química Médica, IQM-CSIC , Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Christophe
authors.initials: C
authors.lastname: Dardonville
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow, United Kingdom ; Department of Biology, College of Science, Aljouf University , Sakaka, Saudi Arabia.
authors.forename: Abdulsalam A M
authors.initials: AA
authors.lastname: Alkhaldi
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow, United Kingdom.
authors.forename: Harry P
authors.initials: HP
authors.lastname: De Koning
keywords: P2-transporter; Trypanosoma brucei; ammonium salt; high affinity pentamidine transporter (HAPT); pyridinium salt; quinolinium salt