New Benzophenone-Derived Bisphosphonium Salts as Leishmanicidal Leads Targeting Mitochondria through Inhibition of Respiratory Complex II

A set of benzophenone-derived bisphosphonium salts was synthesized and assayed for lethal activity on the human protozoan parasite Leishmania. A subset of them, mostly characterized by phosphonium substituents with an intermediate hydrophobicity, inhibited parasite proliferation at low micromolar range of concentrations. The best of this subset,4,4-bis((tri-n-pentylphosphonium)methyl)benzophenone dibromide, showed a Very scarce toxicity on mammalian cells. This compound targets complex II of the respiratory chain of the parasite, based oil (i) a dramatically swollen mitochondrion ill treated parasites, (ii) fast decrease of cytoplasmic ATP (iii) a decrease of the electrochemical mitochondrial potential, and (iv) inhibition of the Oxygen consumption rate using succinate as substrate. Thus. this type of compounds represents I new lead in the development of leishmanicidal drugs.