Synthesis of zanthoxylamide protoalkaloids and their in silico ADME-Tox screening and in vivo toxicity assessment in zebrafish embryos

Abstract

Inspired by the simple and attractive structure of zanthoxylamide protoalkaloids: armatamide, rubecenamide, lemairamin, rubemamine and zanthosine; isolated from plants of the genus Zanthoxylum. We report the synthesis of a series of 29 substituted N-phenylethyl cinnamamides through the direct amidation of a variety of cinnamic acids with a broad range of phenylethylamines promoted by tris-(2,2,2-trifluoroethyl) borate (B(OCH₂CF₃)₃) in excellent yields and under mild reaction conditions. Then, the toxicological profile of the prepared compounds was studied through in silico computational methods, analyzing eight toxicity risks (hepatotoxicity, mutagenic, carcinogenicity, tumorigenic, immunotoxicity, cytotoxicity, irritant and reproductive effects) and two toxicity targets (AOFA and PGH1), while the acute toxicity toward zebrafish embryos (96 hpf-LC₅₀, 50% lethal concentration) was also determined in the present study. From the results of the toxicity tests, we concluded that zanthoxylamide protoalkaloids can be classified as slightly toxic compounds, with a LC₅₀ values around 217 μM that gave an understanding of their toxicity on living organisms and their possible environmental impact.

Keywords: ADME-Tox properties; Toxicology profile; Umami amides; Zanthoxylamide protoalkaloids; Zebrafish embryo model.