Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes

Taladriz, A. and Healy, A. and Flores, Perez and Herrero, Garcia and Rios, Martinez and Alkhaldi, A. A. and Eze, A. A. and Kaiser, M. and de Koning, H. P. and Chana, A. and Dardonville, C.. (2012) Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes. Journal of medicinal chemistry, 55 (6). pp. 2606-2622.

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Official URL: http://edoc.unibas.ch/dok/A6094397

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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
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:05 Dec 2017 10:10
Deposited On:19 Jul 2013 07:40

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