Parallel synthesis and biological evaluation of a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives bearing antitrypanosomal and antileishmanial activity

Combinatorial chemistry is one potential strategy for drug discovery. In the field of neglected diseases, where cost-effectiveness in synthesizing new antiparasitic agents is a major consideration, attention should focus on a strategy that can yield molecules with high hit rates and a concomitant reduced library size. In this respect, the concept of natural-product-derived compound collections is particularly attractive (1). This strategy recognizes natural product fragments as appropriate starting points for the development of compound collections. Here, we present a small library of compounds endowed with anti-trypanosomatid activity, obtained through a parallel approach. In the library design, we selected the quinone unit as the core structure for combinatorial derivatization. For instance, naphtoquinone-derivative lapachol was reported to exhibit marked anti-trypanosomal and leishmanicidal activity, while displaying no serious toxic effects in humans (2). Therefore, based on the 1,4-naphtoquinone and 1,4-anthraquinone natural scaffolds, we synthesized 16 compounds (1-16), which incorporated, at position 2, a selection of aromatic groups that would mimic a structural element of triclosan (2). All the derivatives showed inhibitory activity toward either Trypanosoma or Leishmania species, and were also in vitro tested to assess their biological profile at the quinone oxidoreductase enzyme. The latter activity could be relevant in defining quinone-derivative toxicity profiles in humans.