Alkyltriphenylphosphonium Turns Redox-Cycling Naphthoquinoneimidazoles into Potent Membrane Depolarizers Against <i>Mycobacteria</i>

Mycobacterial bioenergetics is an attractive therapeutic target for anti-tuberculosis drug discovery due to its pivotal role in viability. Building upon our earlier work on redox cycling dioxonaphthoimidazoliums that are activated by a positive charge on the imidazolium nitrogen, we herein studied the effect of a distal positive charge on the antibacterial activity of naphthoquinoneimidazoles. The potency and selectivity-enhancing properties of the linker length was affirmed by structure-activity relationship studies. The most active compound against M. tb H37Rv displayed good selectivity index (SI = 34) and strong bactericidal activity, which occurred through bacterial membrane depolarization that resulted in rapid loss of the membrane potential and depletion of intracellular ATP. Through this work, we demonstrated a switch of the scaffold’s mode-of-action via relocation of positive charge while retaining its excellent antibacterial activity and selectivity.