Inhibitors of Intracellular Gram-Positive BacterialGrowth Synthesized via Povarov–Doebner Reactions

Staphylococcus aureus can survive both inside and outside of phagocytic and nonphagocytic host cells. Once in the intracellular milieu, most antibiotics have reduced ability to kill S. aureus, thus resulting in relapse of infection. Consequently, there is a need for antibacterial agents that can accumulate to lethal concentrations within host cells to clear intracellular infections. We have identified tetrahydrobenzo[a or c]phenanthridine and tetrahydrobenzo[a or c]acridine compounds, synthesized via a one-flask Povarov–Doebner operation from readily available amines, aldehydes, and cyclic ketones, as potent agents against drug-resistant S. aureus. Importantly, the tetrahydrobenzo[a or c]phenanthridine and tetrahydrobenzo[a or c]acridine compounds can accumulate in macrophage cells and reduce the burden of intracellular MRSA better than the drug of choice, vancomycin. We observed that MRSA could not develop resistance (by passage 30) against tetrahydrobenzo[a or c]acridine compound 15. Moreover, tetrahydr...