Date of Award

12-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Medicinal Chemistry

Research Advisor

Richard E. Lee, Ph.D.

Committee

Isaac O. Donkor, Ph.D.; Bernd Meibohm, Ph.D.; Glen E. Palmer, Ph.D.; Charles Rock, Ph.D.

Keywords

Helicobacter pylori, Hit-to-lead optimization, Phenotypic high-throughput screen, Respiratory Complex I, Structure-Activity Relationship, Thienopyrimidines

Abstract

The rate of successful treatment for Helicobacter pylori infections, with the clarithromycin triple therapy, is only 75%. The triple therapy, which consists of a proton pump inhibitor and two broad-spectrum antibiotics such as clarithromycin and amoxicillin, is becoming less effective due to the rise of strains with resistance against these antibiotics. In the search for narrow spectrum drugs for the treatment of H. pylori infections, a high-throughput screen was performed to identify selective compounds against H. pylori. This screen revealed two selective and structurally related thienopyrimidines. Structure-activity relationship of the thienopyrimidines against H. pylori was examined through the synthesis of 27 analogs, efforts that merged elements of the two scaffolds. The resulting leads, including compound 25, demonstrate high potency with an acceptable cytotoxicity profile against the human FaDu cells. Mode of action studies were performed by the generation and sequencing of resistant mutants. These experiments identified H. pylori’s respiratory Complex I as the putative target of the series, with the amino acid changes found in the NuoD subunit. Lead compounds demonstrated efficacy in an ex vivo model but not in the in vivo studies in a H. pylori murine infection model, suggesting further optimization of the pharmacological properties is required for this series. A scaffold hopping exercise was performed to discover novel scaffolds with improved ADME properties. The pyrrolopyrimidine 56 emerged with good anti-H. pylori activity, an improved solubility and is less bound to human plasma protein. Lead optimization efforts are ongoing, to realize proof of concept of this series of compounds in the in vivo efficacy studies.

ORCID

https://orcid.org/0000-0002-2240-5928

DOI

10.21007/etd.cghs.2019.0580

Additional Files
694906_supp_656B36F6-2069-11EA-9AF3-B8B594EF0FC5.pdf (391 kB)
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