University of Nebraska Medical Center DigitalCommons@UNMC Theses & Dissertations Graduate Studies Fall 12-16-2016 Design, Synthesis, and Evaluation of Aryl Hydantoins and Ureas as Antischistosomal Agents Chunkai Wang University of Nebraska Medical Center Follow this and additional works at: https://digitalcommons.unmc.edu/etd Part of the Medicinal and Pharmaceutical Chemistry Commons Recommended Citation Wang, Chunkai, "Design, Synthesis, and Evaluation of Aryl Hydantoins and Ureas as Antischistosomal Agents" (2016). Theses & Dissertations. 157. https://digitalcommons.unmc.edu/etd/157 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@UNMC. It has been accepted for inclusion in Theses & Dissertations by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. DESIGN, SYNTHESIS, AND EVALUATION OF ARYL HYDANTOINS AND UREAS AS ANTISCHISTOSOMAL AGENTS BY Chunkai Wang Design, synthesis, and evaluation of aryl hydantoins and ureas as antischistosomal agents by Chunkai Wang A DISSERTATION Presented to the Faculty of the University of Nebraska Graduate College in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Pharmaceutical Sciences Graduate Program Under the Supervision of Professor Yuxiang Dong University of Nebraska Medical Center Omaha, Nebraska October, 2016 Supervisory Committee: Yuxiang Dong, Ph.D. Jonathan L. Vennerstrom, Ph.D. Joseph Vetro, Ph.D. Jialin Zheng, M.D. i ACKNOWLEDGMENTS I would like to express my sincere and deep gratitude to my academic advisor Dr. Yuxiang Dong and the big boss Dr. Jonathan L Vennerstrom for their guidance, mentorship, encouragements and discussions. I would also like to thank the committee members, Dr. Jialin Zheng and Dr. Joseph A Vetro, for their valuable scientific inputs. I am thankful to the members of Dr. Vennerstrom’s research group (Dr. Xiaofang Wang, Dr. Jianbo Wu, Derek A Leas, Dr. Yogesh A Sonawane, and Dr. Qingjie Zhao) for the support and friendship. I am also thankful to Dr. Sakthivelin Muniyan and Matthew A Ingersoll in Dr. Ming-Fong Lin’s laboratory for teaching me cell culture. The dissertation could not be achieved without the help of them. I am thankful to the administrative staff and the faculty of the Department of Pharmaceutical Sciences at the University of Nebraska Medical Center and the Department of Chemistry at the University of Nebraska Omaha, especially Katina M Winters, Elaine Payne, Dr. James Wood, Dr. James Hagen and Dr. Frederic C Laquer, for their suggestions and support during my study. I would like to thank Edward L Ezell for helping me get started in the NMR Lab. I am also grateful for our collaborator at Swiss Tropical and Public Health Institute, Dr. Jennifer Keiser. I wish to express my gratitude to Dr. Gary C Yee and Esther Yee for their immense support and advice during my Ph.D. studies. ii Last and most importantly, I am thankful to my parents, wife, and two wonderful sons, for their support, sacrifices and patience over the years. iii Design, synthesis, and evaluation of aryl hydantoins and ureas as antischistosomal agents Chunkai Wang, Ph.D. University of Nebraska Medical Center, 2016 Advisor: Yuxiang Dong, Ph.D. 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. For this aryl hydantoin, there appears to be no correlation between antischistosomal activity and androgen receptor interaction. 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 iv with low cytotoxicity and promising in vivo antischistosomal activities that set the stage for further optimization. This work also discovered that urea carboxylic acid UC00, the product formed by hydrolysis of the hydantoin substructure and AR33, a side-reaction product formed in the synthesis of the aryl hydantoins, have substantial in vivo antischistosomal efficacy. Base on this finding, novel N,N'-diaryl ureas were designed and synthesized as new analogues of AH01. 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. v TABLE OF CONTENTS ACKNOWLEDGEMENTS...................................................................................i ABSTRACT.......................................................................................................iii TABLE OF CONTENTS.....................................................................................v LIST OF FIGURES..........................................................................................viii LIST OF SCHEMES..........................................................................................ix LIST OF TABLES...............................................................................................x Chapter 1. Introduction 1.1. Schistosomiasis overview.....................................................................1 1.2. Life cycle of schistosome......................................................................1 1.3. Global distribution.................................................................................2 1.4. Prevention............................................................................................2 1.5. Clinical features....................................................................................3 1.6. Clinically used drug (Praziquantel) ......................................................4 1.7. Aryl hydantoins and antischistosomal activity......................................7 1.8. References.........................................................................................11 Chapter 2. Antischistosomal versus Antiandrogenic Properties of Aryl Hydantoin Ro 13- 3978 Abstract..............................................................................................19 2.1. Introduction........................................................................................19 2.2. Chemistry...........................................................................................22 2.3. Results and Discussion......................................................................24 2.4. Summary............................................................................................30 2.5. Experimental......................................................................................30 2.6. References.........................................................................................37 Chapter 3. Revisiting the SAR of the Antischistosomal Aryl Hydantoin Ro 13-3978 vi Abstract...............................................................................................40 3.1. Introduction.........................................................................................42 3.2. Design.................................................................................................44 3.3. Chemistry............................................................................................49 3.4. Results and Discussion.......................................................................59 3.5. Summary.............................................................................................60 3.6. Experimental Section...........................................................................61 3.7. References..........................................................................................92 Chapter 4. Urea carboxylic acid antischistosomal agents Abstract...............................................................................................95 4.1. Introduction.........................................................................................95 4.2. Design.................................................................................................96 4.3. Chemistry............................................................................................96 4.4. Discussion.........................................................................................101 4.5. Summary...........................................................................................101