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

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