2‑Phenoxy-1,4-naphthoquinones: From a Multitarget Antitrypanosomal to a Potential Antitumor Profile

A small library of 2-phenoxy-1,4-naphthoquinone
and 2-phenoxy-1,4-anthraquinone
derivatives was initially developed to optimize the antitrypanosomatid
profile of the multitarget hit compound B6 (1). The whole
series was evaluated against the three most important human trypanosomatid
pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and two compounds (14 and 21) showed
good activity, despite a concomitant mammalian cytotoxicity. Furthermore,
a subset also inhibited the glycolytic TbGAPDH enzyme in vitro. In light of these results and aware of the antitumor
properties of quinones, the anticancer potential of some selected
derivatives was investigated. Intriguingly, the tested compounds displayed
antitumor activity, while being less toxic against noncancerous cells.
The observed cytotoxic potency was ascribed to a multitarget mechanism
of action accounting for hGAPDH inhibition and mitochondrial
toxicity. Overall, the development of further derivatives, able to
finely modulate multiple pathways of cancer or parasite cell metabolism,
might lead to more effective treatments against these devastating
diseases.