New benzophenone-derived bisphosphonium salts as leishmaniccidal 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`̌prime;-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 on, (i) a dramatically swollen mitochondrion in 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 a new lead in the development of leishmanicidal drugs.