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.