Expanding the chemical space for antiviral discovery: the potential of twistenediones.

Despite significant progress in drug discovery, there remains an urgent need to identify new structures capable of targeting drug-resistant diseases, as well as novel pathogens, to address the growing challenges in global health. This work highlights the underexplored potential of twistane-like structures as promising candidates for drug development, particularly as antiviral agents. We provide the first comprehensive study of their antiviral activity, in particular against SARS-CoV-2. We report the synthesis of a family of chiral indolyl-twistenediones, with the separation and characterization of both enantiomers via chiral semipreparative HPLC. The absolute configurations were determined using experimental and theoretical ECD techniques, supported by DFT calculations. A detailed biological study of their antiviral activity against various pathogenic RNA viruses demonstrates selective efficacy against members of the Coronaviridae family, specifically targeting a post-entry step in the viral replication cycle. Further investigation revealed a remarkable chiral distinction in the antiviral activity between the two enantiomers, opening new avenues for research in the 3D space of chiral cage compounds.