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Conjugation of quinones with natural polyamines: toward an expanded antitrypanosomatid profile.

Abstract：

:A combinatorial library of quinone-polyamine 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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Lizzi F,Veronesi G,Belluti F,Bergamini C,López-Sánchez A,Kaiser M,Brun R,Krauth-Siegel RL,Hall DG,Rivas L,Bolognesi ML

doi

10.1021/jm301112z

subject

Has Abstract

pub_date

2012-12-13 00:00:00

pages

10490-500

issue

23

eissn

0022-2623

issn

1520-4804

journal_volume

55

pub_type

杂志文章

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