title: Salicylanilide inhibitors of Toxoplasma gondii.
abstract: Toxoplasma gondii (T. gondii) is an apicomplexan parasite that can cause eye disease, brain disease, and death, especially in congenitally infected and immune-compromised people. Novel medicines effective against both active and latent forms of the parasite are greatly needed. The current study focused on the discovery of such medicines by exploring a family of potential inhibitors whose antiapicomplexan activity has not been previously reported. Initial screening efforts revealed that niclosamide, a drug approved for anthelmintic use, possessed promising activity in vitro against T. gondii. This observation inspired the evaluation of the activity of a series of salicylanilides and derivatives. Several inhibitors with activities in the nanomolar range with no appreciable in vitro toxicity to human cells were identified. An initial structure-activity relationship was explored. Four compounds were selected for evaluation in an in vivo model of infection, and two derivatives with potentially enhanced pharmacological parameters demonstrated the best activity profiles.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Pediatrics (Infectious Diseases), Committees on Genetics, Immunology, and Molecular Medicine, Institute of Genomics and Systems Biology, and The College, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Fomovska
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wood
authors.forename: Ernest
authors.initials: E
authors.lastname: Mui
authors.forename: Jitenter P
authors.initials: JP
authors.lastname: Dubey
authors.forename: Leandra R
authors.initials: LR
authors.lastname: Ferreira
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hickman
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Lee
authors.forename: Susan E
authors.initials: SE
authors.lastname: Leed
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Auschwitz
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
authors.forename: Caroline
authors.initials: C
authors.lastname: Sommerville
authors.forename: Stuart
authors.initials: S
authors.lastname: Woods
authors.forename: Craig
authors.initials: C
authors.lastname: Roberts
authors.forename: Rima
authors.initials: R
authors.lastname: McLeod
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000977:Antiparasitic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D004351:Drug Resistance; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010963:Plasmodium falciparum / Q000187:drug effects; D012458:Salicylanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000187:drug effects*; D014123:Toxoplasmosis / Q000188:drug therapy
chemical_list: D000962:Antimalarials; D000977:Antiparasitic Agents; D012458:Salicylanilides