Nuclease activity and ultrastructural effects of new sulfonamides with anti-leishmanial and trypanocidal activities.
Our aim was to evaluate the in vitro efficacy of a series of N-benzenesulfonamides of amine substituted aromatic rings, sulfonamides 1-6, against Trypanosoma cruzi and Leishmania spp. and to compare their trypanocidal and leishmanicidal profile. In order to elucidate the probable mechanism of action, the interaction of selected sulfonamides with pUC18 plasmid DNA was investigated by nuclease activity assays. In addition, the cellular targets of these sulfonamides in treated parasites were also searched by transmission and scanning electron microscopy. The most active compounds 4-nitro-N-pyrimidin-2-ylbenzenesulfonamide 1a and 4-chloro-N-5-methyl-thiazol-2-yl-benzenesulfonamide 2d displayed significant in vitro activity against Leishmania spp. promastigotes, without toxicity to J774 macrophages. Selected sulfonamides 1a, 4-nitro-N-pyrazin-2-yl-benzenesulfonamide 1n and 2d were also active against Leishmania infantum intracellular amastigotes. Compounds 1n and 2d showed nuclease activity in the presence of copper salt analogous to our previous results with sulfonamide 1a. Mechanistic data reveal the involvement of a redox process. Evidence for the formation of reactive oxygen species (ROS) responsible for DNA strand scission is provided for sulfonamides 1a, 1n and 2d. Transmission electron microscopic (TEM) analysis of L. infantum promastigotes treated with compounds 1a, 1n and 2d shows an overall cellular disorganization effects which are mainly addressed to DNA bearing structures such as the nucleus, mitochondria and kinetoplast. Disruption of double nuclear membrane and loss of cellular integrity along with accumulation of cytoplasmic electrodense bodies were also frequently observed.
Department of Parasitology, Faculty of Pharmacy, University Complutense of Madrid, Plaza Ramón y Cajal s/n, 28040-Madrid, Spain.
Pablo
P
Bilbao-Ramos
Cristina
C
Galiana-Roselló
M Auxiliadora
MA
Dea-Ayuela
Marta
M
González-Alvarez
Celeste
C
Vega
Miriam
M
Rolón
Jorge
J
Pérez-Serrano
Francisco
F
Bolás-Fernández
M Eugenia
ME
González-Rosende
D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003851:Deoxyribonucleases / Q000378:metabolism*; D018314:Leishmania infantum / Q000187:drug effects* / Q000648:ultrastructure*; D008264:Macrophages; D051379:Mice; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D015394:Molecular Structure; D009593:Nitroimidazoles / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
D000981:Antiprotozoal Agents; D009593:Nitroimidazoles; D013449:Sulfonamides; D010767:Phosphorylcholine; C039128:miltefosine; D003851:Deoxyribonucleases; C009999:benzonidazole