Facile and Divergent Optimization of Chromazonarol Enabled the Identification of Simplified Drimane Meroterpenoids as Novel Pharmaceutical Leads

Abstract

The coverage of drimane hydroquinones chemical space was expanded by the facile construction of the focused libraries of (+)-chromazonarol relevant natural products, isomers and analogues for advance as pharmaceutical leads. Through the synergistic interaction of the programmable synthesis and bioactivity-guided screening, the structure-activity relationship of (+)-chromazonarol relevant (non)-natural products was delineated. The first divergent derivatization of (+)-chromazonarol demonstrated that the phenolic hydroxyl group is one inviolable requirement for antifungal effect. Pin-point modification of (+)-yahazunol manifested the position of hydroxyl group was crucial for both antifungal and anti-tumor activities. (+)-Albaconol, (+)-neoalbaconol and two yahazunol isomers (24 and 25) were witnessed to be the novel pharmaceutical leads. The probable macromolecular targets were estimated to deliver new information about the biological potential resident in (+)-yahazunol relevant products. This work also featured the first synthesis of (+)-albaconol and (+)-neoalbaconol, the first biological exploration of (+)-dictyvaric acid and an improved preparation of (+)-8-epi-puupehedione and a promising pelorol analogue.