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

Tuberculosis is a disease caused primarily by the organism Mycobacterium tuberculosis ( Mtb ), which claims about 1.5 million lives every year. A challenge that impedes the elimination of this pathogen is the ability of Mtb 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 Mtb and therapeutics able to kill these phenotypically tolerant bacilli will be critical for completely eradicating Mtb . Our groups are focusing on characterizing the activity of derivatives of the marine natural product (+)-puupehenone ( 1 ). Recently, the Rohde group reported that puupehedione ( 2 ) and 15-α-methoxypuupehenol ( 3 ) exhibit enhanced activity in an in vitro multi-stress dormancy model of Mtb. To optimize the antimycobacterial activity of these terpenoids, novel 15-α-methoxy- and 15-α-acetoxy-puupehenol esters were prepared from (+)-puupehenone ( 1 ) accessed through a (+)-sclareolide-derived β-hydroxyl aldehyde. For added diversity, various congeners related to ( 1 ) were also prepared from a common borono-sclareolide donor, which resulted in the synthesis of epi -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 Mtb , and the most active compounds retained the enhanced activity against dormant Mtb 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 Mtb . Intriguingly, the closely related triisobutyl derivative 16 showed similar activity to 1 in actively dividing Mtb but lost about 178-fold activity against dormant Mtb . However, the monopivaloyl compound 13 showed a modest 3- to 4-fold loss in activity in both actively dividing and dormant Mtb relative to the activity of 1 revealing the importance of the free OH at C19 supporting the potential role of quinone methide formation as critical for activity in dormant Mtb . 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 Mtb .