Date of Award

5-2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Clinical-Bioanalytical Chemistry

Department

Chemistry

First Advisor

Su, Bin

Second Advisor

Kalafatis, Michael

Third Advisor

Anderson, David

Abstract

The work entitled “Fragment Based Drug Design based on 6,7- Dimethoxyquinazoline core structure” presents a unique approach to drug discovery, specifically focusing on the pharmacophore 6,7-dimethoxyquinazoline. This study explores the structural diversity of 6,7-Dimethoxyquinazoline derivatives to identify other pharmacologically relevant targets, with evidence indicating that this core structure possesses intrinsic properties that make it suitable as a base structure of small molecule drugs. Furthermore, this pharmacophore has been observed in various approved therapeutics or drug candidates under investigation, highlighting its importance in drug discovery. My research showcases of 6,7-dimethoxyquinazoline core structure been derivatized to generate an anti-trypanosomiasis drug candidates and anti-cancer drug candidates. In the first project, the pharmacophore was identified through a high- throughput screen as having the potential to function as an anti-parasitic drug. A protein pulldown assay was subsequently performed, and the molecular mechanism of action was explored. A compound library was synthesized to check the efficiency of the pharmacophore, leading to a more detailed structure-activity relationship (SAR) analysis for future lead optimization. In the second project, the molecular docking approach identified the 6,7-dimethoxyquinazoline core as the interacting partner with EPH receptor A2 (ephrin type-A receptor 2) that is involved in cellular adhesion and growth. A series of analogs were synthesized and evaluated to determine whether they could inhibit tumor cell growth. Overall, the study demonstrated the potential of the 6,7-dimethoxyquinazoline pharmacophore as a versatile platform for drug discovery. The work also built a foundation for further structural modification to improve the absorption, distribution, metabolism, and excretion (ADME) of small molecule drugs based on a well-documented core structure. By exploring the pharmacophore 6,7-dimethoxyquinazoline reveals its potential for drug discovery for different diseases.

In conclusion, the study demonstrates the potential of the 6,7- dimethoxyquinazoline pharmacophore as core structure for small molecule drugs. The work emphasizes the importance of understanding the SAR of compounds in the development of novel therapeutics. Overall, this study has the potential to contribute to the development of new small molecule drug candidates to combat trypanosomiasis and brain cancer.

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