Open AccessDesign, Synthesis, and Characterization of Novel Small Molecules as Broad Range Antischistosomal Agents
Author(s) -
Reid S. Tarpley,
Anastasia R. Rugel,
Analía López,
Travis Menard,
Guzman,
Alexander B. Taylor,
Xiaoguang Cao,
Frédéric D. Chevalier,
T Anderson,
P. John Hart,
Philip T. LoVerde,
Stanton F. McHardy
Publication year - 2018
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.8b00257
Subject(s) - oxamniquine , praziquantel , schistosomiasis , schistosoma haematobium , schistosoma japonicum , schistosoma mansoni , drug , drug discovery , anthelmintic , biology , computational biology , pharmacology , immunology , helminths , bioinformatics , ecology
Schistosomiasis is a major human parasitic disease afflicting more than 250 million people, historically treated with chemotherapies praziquantel or oxamniquine. Since oxamniquine is species-specific, killing Schistosoma mansoni but not other schistosome species ( S. haematobium or S. japonicum ) and evidence for drug resistant strains is growing, research efforts have focused on identifying novel approaches. Guided by data from X-ray crystallographic studies and Schistosoma worm killing assays on oxamniquine, our structure-based drug design approach produced a robust structure-activity relationship (SAR) program that identified several new lead compounds with effective worm killing. These studies culminated in the discovery of compound 12a , which demonstrated broad-species activity in killing S. mansoni (75%), S. haematobium (40%), and S. japonicum (83%).