Date of Award

Fall 12-16-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Yuxiang Dong

Abstract

Schistosomiasis is a tropical parasitic disease caused by infections with flukes of the genus Schistosoma, affecting as many as 440 million individuals worldwide, with 779 million living at risk of infection. A new drug for schistosomiasis is urgently needed as praziquantel (PZQ) is currently the drug of last resort and the development of resistance cannot be ignored, particularly in view of its large-scale use in many endemic countries. Furthermore, PZQ is active against adult but not juvenile schistosomes; this may be an important factor in the frequently observed treatment ‘failures’ in areas endemic for schistosomiasis.

The introduction of PZQ in 1982 likely led to decisions to abandon the development of a number of promising antischistosomal agents that were discovered in the same time period. One of these was AH01, the lead compound from a series of aryl hydantoins that were investigated in some detail at Hoffmann La-Roche. A number of characteristics of AH01 justify it as a compelling antischistosomal prototype. This work confirmed the high antischistosomal efficacy of AH01 and demonstrated that the aryl hydantoin is also effective against juvenile infections. Further, AH01 had no measurable interaction with the androgen receptor in a ligand competition assay, but it did block DHT-induced cell proliferation in androgen-dependent cell line. Building on this foundation, a number of AH01 analogs were designed and synthesized to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand-AR interactions. This work identified several new derivatives of AH01 with high antischistosomal efficacy that were less antiandrogenic than AH01. These data provide direction for the ongoing optimization of antischistosomal hydantoins.

We also discovered that urea carboxylic acid UC00, the hydrolysis product of AH01, and AR33, a side-reaction product formed in the synthesis of the aryl hydantoins, have substantial in vivo antischistosomal efficacy. Based on this finding, new urea carboxylic acids and N,N'-diaryl ureas were designed and synthesized. The most promising compound identified in this work was N,N’-di(quinoxalin-2-yl)urea. This new lead compound can serve as a new direction for further optimization.

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