Graduation Year

2019

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

James W. Leahy, Ph.D.

Committee Member

Edward Turos, Ph.D.

Committee Member

Bill J. Baker, Ph.D.

Committee Member

Rays H. Y. Jiang, Ph.D.

Keywords

Infectious diseases, Leishmania donovani, promastigotes, amastigotes, parasite, chaperone proteins, malaria

Abstract

Infectious diseases have had an impact on populations since the beginning of humanity. Despite huge advances in the fight against these conditions, they continue to be the leading cause of death and disability for a large portion of the world’s populace. Those most adversely affected predominately live in the more improvised areas of the developing world. Often treatments are made inaccessible to these areas due to cost, complicated administration requirements, severe side effects, and / or compound instability. Even when treatments are available the accelerated development of resistance has created an urgent need for the creation of new molecules with activity against these microorganisms. This dissertation focuses on research towards the synthesis and optimization of small novel compounds for use as antiparasitic leads with the intent of treating infectious diseases.

The first chapter of this manuscript provides an overview of the history, biology and current medicines available for the tropical diseases: leishmaniasis and malaria. This chapter gives insight into each disease and illustrates the complications and necessity of novel treatment development.

This introduction is followed by Chapters 2 and 3 describing an investigation towards the development of antileishmaniasis agents. Research focus on the modification of a compound (SNX 2112) a known heat shock protein 90 (Hsp90) inhibitor. Hsp90 has been shown as vital to the differentiation of the protozoan parasite (that causes leishmaniasis) into the infective stage. SNX 2112 was identified as effective against Leishmania donovani and was the starting point for the development of an analog series. This sequence of analogs began with the development of a modified quinazoline core to replace the carboxamide top portion. This modification was developed to reduce overall synthetic steps while maintaining similar binding features to the original compound. A docking study of one of these analogs identified a hydrophobic pocket in the active site of Hsp90. A series of analogs were created with changes to the tetrahydroindazole core of the Hsp90 through an ether linkage to attempt to extend into this identified pocket.

Chapter four covers additional research into the synthesis of modified analogs for malaria treatments. Including synthesis of novel modified heterocycles of chloroquine, primaquine and mefloquine like molecules. These analogs maintain the common N-linked side chain of chloroquine and primaquine while featuring alternative heterocyclic cores which may lead to gains in antimalarial activity or escape current resistance.

Download

Included in

Chemistry Commons

Share

COinS