The objective of this dissertation is to describe the design, synthesis, and characterization of 7-substituted-2,4,9-trithiaadamantane (tripod) derivatives as new anti-influenza drug candidates, specifically blockers for the M2 ion channel of the influenza A virus. Of the four current FDA-approved anti-influenza chemotherapeutics, only two function by blocking the M2 ion channel of the virus. However, due to the developed mutations of certain amino acid residues lining the interior pore of the ion channel, the two drugs, amantadine and rimantadine, now have little to no effect on the most common virus strains. The recently elucidated structure of the M2 proton channel has provided structural insight and new knowledge leading to the development of these novel drug candidates that may have an enhanced affinity for mutated ion channels and also a shorter biodistribution time, decreasing host toxicity. The drugs described within this work have incorporated sulfur atoms into the base of the molecule accommodating the larger diameter of the mutated pore and allowing an ease of biodegradation.
Chapter 1 of this work gives an introduction to the influenza virus, the ion channel structure and function, as well as new drug developments and previous work with trithiaadamantanes. Also discussed will be some current antiviral drugs used to treat influenza, and possible drug candidates currently being developed by other research groups. The rationale for drug design based on specific mutations believed to occur in the most abundant influenza strains will be looked at in context of designing new drug candidates.
Chapter 2 of this dissertation describes the multi-step syntheses of the novel 2,4,9-trithiaadamantan-7-amine and 1-(2,4,9-trithiaadamantan-7-yl)ethan-1-amine derivatives as possible influenza A ion channel blockers. Also discussed are attempted synthetic routes to these molecules.
The starting material to the synthesized drug candidates is not commercially available and is made via a six-step route, which yields a mere 10-20% at best, and requires several purification steps. Chapter 3 will focus on several new routes that were explored for the improved synthesis of this starting material, methyl-2,4,9-trithiaadamantan-7- carboxylate, as well as the synthesis of other molecules that could serve as enhanced starting compounds.
|Advisor:||Modarelli, David, Ziegler, Christopher|
|Commitee:||Londraville, Richard, Taschner, Michael, Youngs, Wiley|
|School:||The University of Akron|
|School Location:||United States -- Ohio|
|Source:||DAI-B 76/08(E), Dissertation Abstracts International|
|Subjects:||Pharmacology, Organic chemistry|
|Keywords:||Design, Influenza a, Synthesis, Trithiaadamantane|
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