Date of Award
2020
Document Type
Dissertation
Degree Name
Philosophy (Ph.D)
Department
Pharmaceutical Sciences
First Advisor
Tanaji Talele
Second Advisor
Vijaya Korlipara
Third Advisor
Sabesan Yoganathan
Abstract
Clostridium difficile infection (CDI) is the leading cause of healthcare-associated infection in the United States. Therefore, development of novel treatments for CDI is a high priority. Toward this goal, we began in vitro screening of a structurally diverse in-house library of 67 compounds against two pathogenic C. difficile strains (ATCC BAA 1870 and ATCC 43255), which yielded a hit compound, 2-methyl-8-nitroquinazolin-4(3H)-one (2) with moderate potency (MIC = 312/156 µM). Optimization of 2 gave lead compound 6a (2-methyl-7-nitrothieno[3,2-d]pyrimidin-4(3H)-one) with improved potency (MIC = 19/38 µM), selectivity over normal gut microflora, CC50s >606 µM against mammalian cell lines, and acceptable stability in simulated gastric and intestinal fluid. Further optimization of 6a at C2-, N3-, C4- and C7-positions resulted in a library of >50 compounds with MICs ranging from 3 – 800 µM against clinical isolates of C. difficile. Compound 8f (MIC = 3/6 µM) was identified as a promising lead for further optimization.
Recommended Citation
Shao, Xuwei, "CHEMICAL SPACE EXPLORATION AROUND THIENO[3,2-d]PYRIMIDIN-4(3H)-ONE SCAFFOLD LED TO A NOVEL CLASS OF HIGHLY ACTIVE CLOSTRIDIUM DIFFICILE INHIBITORS" (2020). Theses and Dissertations. 60.
https://scholar.stjohns.edu/theses_dissertations/60