Redox-active dinitrodiphenylthioethers against Leishmania: synthesis, structure-activity relationships and mechanism of action studies.
BTB 06237 (2-[(2,4-dichloro-5-methylphenyl)sulfanyl]-1,3-dinitro-5-(trifluoromethyl) benzene), a compound previously identified through QSAR pharmacophore development and a virtual screen of the Maybridge database, possesses potent and selective activity against Leishmania parasites. In the present study, several analogs of BTB 06237 were synthesized and analyzed for activity against Leishmania axenic amastigotes, their ability to reduce the level of parasitemia in peritoneal macrophages, and their ability to generate reactive oxygen species (ROS) in L. donovani promastigotes. It was found that an aromatic ring must be present in the position occupied by the 2,4-dichloro-5-methylphenyl group in the lead compound, but changing the functional groups generally has little effect on the antileishmanial potency. Alterations to the 1,3-dinitro-5-(trifluoromethyl)benzene ring have more influence on antiparasitic activity with two aromatic nitro groups and a third electron-withdrawing group being required. This structural requirement corresponds with redox potential, the ability to generate ROS in the parasites, and dissipation of the mitochondrial membrane potential. Finally, we used this collection of data to design a new antileishmanial compound with strong activity in vitro and improved properties as an antileishmanial candidate.
Delfín
Dawn A
DA
The Ohio State University, College of Pharmacy, Division of Medicinal Chemistry and Pharmacognosy, 500 West 12th Avenue, Columbus, OH 43210, USA. delfin.1@osu.edu
Morgan
Rachel E
RE
Zhu
Xiaohua
X
Werbovetz
Karl A
KA
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D007893:Leishmania donovani / Q000187:drug effects* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000469:parasitology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D017382:Reactive Oxygen Species / Q000378:metabolism; D013440:Sulfides / Q000138:chemical synthesis / Q000494:pharmacology*; D014709:Vero Cells
D000981:Antiprotozoal Agents; D017382:Reactive Oxygen Species; D013440:Sulfides