Synthesis of novel rapanone derivatives via organocatalytic reductive C-alkylation: biological evaluation of antioxidant properties, in vivo zebrafish embryo toxicity, and docking studies

Abstract

A biologically crucial natural product rapanone 1 was isolated from Embelia ribes at the gram scale with excellent purity. Semi-synthetic analogs of 1 semi-synthesized through reductive C-alkylation could increase the therapeutic value of the compounds. Herein, a new synthetic methodology was developed as a single-step reductive C-alkylation protocol using a metal-free, room-temperature-based reaction condition that can be scaled up to gram-scale synthesis with an excellent yield of up to 93%. A straightforward purification protocol was employed for the product obtained by this method. The derivatives of 1 showed antioxidant activity, which was evaluated using DPPH and ABTS scavenging assays. Compounds 5a–5ze showed an IC₅₀ value of 2.48–3.37 μM and 1.81–3.12 μM. Substitution by electron-donating groups on the quinone moiety seems to play an essential role in the increased antioxidant activity of compounds 5a–5i, 5v, 5w, 5zc, and 5z. Further, the in vivo embryotoxicity of 1 and its derivatives was analyzed in a zebrafish-based aquatic toxicology model. Zebrafish embryos were exposed to 1 and 5a–5ze at 20 to 160 μM concentrations. They showed reduced toxicity and a survival rate of 90–98% after 96 hpf of treatment; similarly, the compounds 5a–5i, 5v, 5w, 5zc, and 5zd did not significantly affect the hatching rates of 75.66–85.33% or developmental abnormalities of the embryos after 48 hpf of treatment. In silico molecular docking studies for the parent compound, along with its derivatives 5a–5i, 5v–5w, 5zc–5zd, and standard L-ascorbic acid (L-Aa) indicated favorable interactions with the active site of the crystal structure, coupled with the assay protein PDB:1ZB6, which was responsible for the observed biological understanding and potential.