Abstract

Continuing our program to develop compounds with potential activity against Trypanosoma cruzi, in this work we have designed and synthesized and evaluated in vitro on the trypomastigote form a new series of 2,3-diketopiperazines derivatives. By means of a two-step sequence, where one of them was a catalytic and selective C(sp3)-H-bond reaction, nine final compounds (5a-i) were obtained. Most of these 2,3-diketopiperazines were highly active against the trypomastigote strain NINOA (LC50 < 100 ?M) compared to the reference drugs benznidazole (Bzn) and nifurtimox (Nfx). Likewise, compounds 5c and 5h showed high potency against the trypomastigote strain A1 (LC50 = 25.2 and 40.49 ?M, respectively), with 5c being four to five times more active than the reference drugs. In addition, the cytotoxicity of these compounds was determined in the murine macrophage J774 cell line, presenting in most cases, higher selectivity rates compared to Bzn and Nfx. In silico studies suggested that these 2,3-diketopiperazine derivatives could be inhibitors of the Fe-SOD enzyme at the cytosolic and mitochondrial level. Finally, these compounds would also have good oral bioavailability according to theoretical predictions. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.