TY - JOUR
T1 - Structure-activity relationship of an ozonide carboxylic acid (oz78) against fasciola hepatica
AU - Zhao, Qingjie
AU - Vargas, Mireille
AU - Dong, Yuxiang
AU - Zhou, Lin
AU - Wang, Xiaofang
AU - Sriraghavan, Kamaraj
AU - Keiser, Jennifer
AU - Vennerstrom, Jonathan L.
PY - 2010/5/27
Y1 - 2010/5/27
N2 - 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.
AB - 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.
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U2 - 10.1021/jm100226t
DO - 10.1021/jm100226t
M3 - Article
C2 - 20423101
AN - SCOPUS:77952677684
VL - 53
SP - 4223
EP - 4233
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 10
ER -