(+)-Anthrabenzoxocinone

Due to the critical bacterial resistance and antibiotic crisis, the discovery of new antibiotics is an urgent need in the clinic than ever.Naturally occurring antibiotics have proven to be an indispensable source of the development of new antibacterial agents.Herein, we report the total synthesis of three families of biogenetically related natural antibiotics, including anthrabenzoxocinones (ABXs), fasamycins/naphthacemycins, and benastatins.The synthesis featured divergent and convergent approaches, which enabled efficient construction of the basic polycyclic skeletons in 6-10 steps on a large-scale, followed by a collective synthesis of 14 natural products and their corresponding analogs.The core scaffold of gem-dimethyl- anthracenone, a naturally occurring type II fatty acid-specific condensation enzyme (FabFspecific) antibiotic pharmacophore, was forged via a Ti(Oi-Pr)₄-mediated photoenolization/Diels-Alder (PEDA) reaction between 2-iso-Pr benzaldehyde and a variety of enones.A scale-up of the PEDA reaction was facilitated in an assembled continuous-flow reactor, which allowed us to overcome the issues associated with batch photochem.Subsequently, the synthetic natural antibiotics and their analogs would be utilized in structure-activity relationships (SAR) and mechanism studies, which should enable the discovery of new and leading antibiotic compounds

Anthrabenzoxocinones (ABXs) including (-)-ABXs and (+)-ABXs are a group of bacterial FabF-specific inhibitors with potent antimicrobial activity of resistant strains. Optimization of their chemical structures is a promising method to develop potent antibiotics. Through biosynthetic investigation, we herein identified and characterized two highly promiscuous enzymes involved in the (-)-ABX structural modification. The promiscuous halogenase and methyltransferase can respectively introduce halogen-modifications into various positions of the ABX scaffolds and methylation to highly diverse substrates. Manipulation of their activity in both of the (-)-ABXs and (+)-ABXs biosyntheses led to the generation of 14 novel ABX analogues of both enantiomers. Bioactivity assessment revealed that a few of the analogues showed significantly improved antimicrobial activity, with the C3-hydroxyl and chlorine substitutions critical for their activity. This study enormously expands the bioactive chemical space of the ABX family and FabF-specific inhibitors. The disclosed broad-selective biosynthetic machineries and structure-activity relationship provide a solid basis for further generation of potent antimicrobial agents.