title: Structure-activity relationship of an ozonide carboxylic acid (OZ78) against Fasciola hepatica.
abstract: In this paper, we describe the SAR of ozonide carboxylic acid OZ78 (1) as the first part of our search for a trematocidal synthetic peroxide drug development candidate. We found that relatively small structural changes to 1 resulted most commonly in loss of activity against Fasciola hepatica in vivo. A spiroadamantane substructure and acidic functional group (or ester prodrug) were required for activity. Of 26 new compounds administered at single 100 mg/kg oral doses to F. hepatica infected rats, 8 had statistically significant worm burden reductions, 7 were partially curative, and 1 (acylsulfonamide 6) was completely curative and comparable to 1 in flukicidal efficacy. This study also showed that the activity of 1 is peroxide-bond-dependent, suggesting that its flukicidal efficacy depends upon hemoglobin digestion in F. hepatica.
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Zhao
authors.forename: Mireille
authors.initials: M
authors.lastname: Vargas
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Dong
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Wang
authors.forename: Kamaraj
authors.initials: K
authors.lastname: Sriraghavan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000871:Anthelmintics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005210:Fasciola hepatica; D005211:Fascioliasis / Q000188:drug therapy* / Q000469:parasitology; D005260:Female; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000871:Anthelmintics; C518172:OZ78 compound; D000218:Adamantane