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 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.
Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, E-28040 Madrid, Spain.
J Román
JR
Luque-Ortega
Peter
P
Reuther
Luis
L
Rivas
Christophe
C
Dardonville
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001577:Benzophenones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors*; D004734:Energy Metabolism; D007891:Leishmania / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000469:parasitology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D013386:Succinates / Q000378:metabolism; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D001577:Benzophenones; D013386:Succinates; D014344:Trypanocidal Agents; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II