Generation and capture of naphthoquinonynes: a new frontier in the development of trypanocidal quinones via aryne chemistry

Abstract

The regioselective synthesis of functionalized naphthoquinones via the formation and capture of naphthoquinonynes has been used to prepare trypanocidal compounds. The target compounds are functionalized on the aromatic ring, leaving the quinoidal ring intact. Using this technique, eighteen functionalized naphthoquinones were succesfull obtained, divided in two main groups: the first scope using N-nucleophiles, and the second scope using pyridine N-oxides, with yields up to 74%. Evaluation against bloodstream trypomastigotes of T. cruzi has identified fourteen compounds that are more potent than benznidazole (Bz); for instance, compounds 29b-I and 30b, with IC₅₀/24 h values of 10.5 and 10.1 μM, respectively, are approximately 10-fold more active than Bz. This study provides the first examples of the application of naphthoquinonyne chemistry for the synthesis of new compounds with potent trypanocidal activities.

Scheme 1. Biological activity of representative quinones and methods for A-ring functionalization.

Scheme 2. (A) Synthesis of naphthoquinonyne precursors 27a and 27b; (B) mechanisms of the formation of naphthoquinonyne 27′ and (C) thia-Fries rearrangement towards product 27a-I.

Scheme 3. (A) Naphthoquinonyne capture with N-nucleophiles; (B) unsuccessful N-nucleophiles attempted in the first scope; (C) Naphthoquinonyne capture with N-nucleophiles and (D) proposed mechanistic pathways for the formation of 29b-I and 29b-II.