ABSTRACT
Antibiotic resistance has grown significantly in the last three decades, while research and development of new antibiotic classes has languished. Therefore, new chemical frameworks for the control of microbial behavior are urgently required. This study presents a novel suite of compounds, based on a tricyclic 4-hydroxy-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione core, with significant antibiotic activity against the ESKAPE pathogens Staphylococcus aureus and Enterococcus faecalis and the "accidental pathogen" Staphylococcus epidermidis. A potent analogue with an N-heptyl-9-t-Bu substitution pattern emerged as a hit with MIC levels ≤2 µg/mL across four strains of MRSA. In addition, the same compound proved highly potent against Enterococcus spp. (0.25 µg/mL).
ABSTRACT
Aryl-heteroaryl coupling via double C-H activation is a powerful transformation that avoids the installation of activating groups. A double C-H activation of privileged biological scaffolds, 2-coumarins and 2-pyrones, is reported. Despite the rich chemistry of these molecular frameworks, the yields are very good. Excellent regioselectivity was achieved on the pyrones. This methodology was applied to the synthesis of flemichapparin C in three steps. Isotope effect experiments were carried out, and a mechanism is proposed.
