Conjugation of quinones with natural polyamines : towards an expanded anti-trypanosomatid profile

Lizzi, F. and Veronesi, G. and Belluti, F. and Bergamini, C. and Lopez-Sanchez, A. and Kaiser, M. and Brun, R. and Krauth-Siegel, R. L. and Hall, D. and Rivas, L. and Bolognesi, M. L.. (2012) Conjugation of quinones with natural polyamines : towards an expanded anti-trypanosomatid profile. Journal of medicinal chemistry, 55 (23). pp. 10490-10500.

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Official URL: http://edoc.unibas.ch/dok/A6094111

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A combinatorial library of quinone-polyamine conjugates designed to optimize the anti-trypanosomatid profile of hit compounds 1 and 2 has been prepared by a solid phase approach. The conjugates were evaluated against three most important human trypanosomatid pathogens (T. b. rhodesiense, T. cruzi, and L. 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
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:Brun, Reto and 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 07:39

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