Structure-activity relationship of an ozonide carboxylic acid (OZ78) against Fasciola hepatica.
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.
Zhao
Qingjie
Q
College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Vargas
Mireille
M
Dong
Yuxiang
Y
Zhou
Lin
L
Wang
Xiaofang
X
Sriraghavan
Kamaraj
K
Keiser
Jennifer
J
Vennerstrom
Jonathan L
JL
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
D000871:Anthelmintics; C518172:OZ78 compound; D000218:Adamantane