Synthesis and Evaluation of Marine Natural Product-Inspired Meroterpenoids with Selective Activity toward Dormant .

Tuberculosis is a disease caused primarily by the organism (), which claims about 1.5 million lives every year. A challenge that impedes the elimination of this pathogen is the ability of to remain dormant after primary infection, thus creating a reservoir for the disease in the population that reactivates under more ideal conditions. A better understanding of the physiology of dormant and therapeutics able to kill these phenotypically tolerant bacilli will be critical for completely eradicating . Our groups are focusing on characterizing the activity of derivatives of the marine natural product (+)-puupehenone (). Recently, the Rohde group reported that puupehedione () and 15-α-methoxypuupehenol () exhibit enhanced activity in an in vitro multi-stress dormancy model of To optimize the antimycobacterial activity of these terpenoids, novel 15-α-methoxy- and 15-α-acetoxy-puupehenol esters were prepared from (+)-puupehenone () accessed through a (+)-sclareolide-derived β-hydroxyl aldehyde. For added diversity, various congeners related to () were also prepared from a common borono-sclareolide donor, which resulted in the synthesis of -puupehenol and the natural products (+)-chromazonarol and (+)-yahazunol. In total, we generated a library of 24 compounds, of which 14 were found to be active against , and the most active compounds retained the enhanced activity against dormant seen in the parent compound. Several of the 15-α-methoxy- and 15-α-acetoxy-puupehenol esters possessed potent activity against actively dividing and dormant . Intriguingly, the closely related triisobutyl derivative showed similar activity to in actively dividing but lost about 178-fold activity against dormant . However, the monopivaloyl compound showed a modest 3- to 4-fold loss in activity in both actively dividing and dormant relative to the activity of revealing the importance of the free OH at C19 supporting the potential role of quinone methide formation as critical for activity in dormant . Elucidating important structure-activity relationships and the mechanism of action of this natural product-inspired chemical series may yield insights into vulnerable drug targets in dormant bacilli and new therapeutics to more effectively target dormant .