Synthesis and Structure鈥揂ctivity Analysis of New Phosphonium Salts with Potent Activity against African Trypanosomes

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• 作者：Andrea Taladriz ; Alan Healy ; Eddysson J. Flores P茅rez ; Vanessa Herrero Garc铆a ; Carlos R铆os Mart铆nez ; Abdulsalam A. M. Alkhaldi ; Anthonius A. Eze ; Marcel Kaiser ; Harry P. de Koning ; Antonio Chana ; Christophe Dardonville
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 22, 2012
• 年：2012
• 卷：55
• 期：6
• 页码：2606-2622
• 全文大小：522K
• 年卷期：v.55,no.6(March 22, 2012)
• ISSN：1520-4804

文摘

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 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.