Conjugation of Quinones with Natural Polyamines: Toward an Expanded Antitrypanosomatid Profile
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- 作者：Federica Lizzi ; Giacomo Veronesi ; Federica Belluti ; Christian Bergamini ; Almudena L贸pez-S谩nchez ; Marcel Kaiser ; Reto Brun ; R. Luise Krauth-Siegel ; Dennis G. Hall ; Luis Rivas ; Maria Laura Bolognesi
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：December 13, 2012
- 年：2012
- 卷：55
- 期：23
- 页码：10490-10500
- 全文大小：509K
- 年卷期：v.55,no.23(December 13, 2012)
- ISSN：1520-4804
文摘
A combinatorial library of quinone鈥損olyamine conjugates designed to optimize the antitrypanosomatid profile of hit compounds 1 and 2 has been prepared by a solid-phase approach. The conjugates were evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and several showed promising activity. A subset also inhibited trypanothione reductase in vitro and induced oxidase activity of the enzyme. A highly potent analogue (7) was identified with activity against T. brucei as low as 70 nM and a selectivity index of 72. Interestingly, the presence of a cadaverine tail confers to 7 the ability to target mitochondrial function in Leishmania. In fact, in L. donovani promastigotes, we verified for 7 a decrease of cytoplasmic ATP and mitochondrial potential. Therefore, the current results support the suitability of the conjugation approach for the development of novel polyamine conjugates with enhanced therapeutic potential.