Date of Award

December 2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

M. Mahmun Hossain

Committee Members

James M. Cook, Mark Dietz, Arsenio Andy Pacheco, Jian Chen

Abstract

The synthesis of BRL-37959 has previously been reported. As an NSAID, the compound was tested for and found that it had very low gastric irritancy. Commercially available NSAIDs are non-selective COX inhibitors that enhance the risk of gastric, duodenal mucosal injury or erosions and ulcer problems as well as lead to nephrotoxicity. The COX-2 selective inhibitor Celecoxib (Celebrex) increases the risk of serious cardiovascular (CV) thrombotic events, myocardial infarction and stroke as well as increased nephrotoxicity. COX inhibitors are active against inflammation, pain, fever and different types of cancers. Considering the enormous potential benefits and side effects of non-selective COX inhibitors and selective COX-2 inhibitor. Our research goal was to find a COX inhibitor that binds with both COX-1 and COX-2 in such a ratio that it would be a safer drug. Another aim was to develop a synthesis method of the target inhibitor that will be simple, cost-effective and ensure high yield. Benzofuran is an important building block of BRL- 37959. In Dr. Hossain's lab, Matt Dudley had developed a novel, unprecedented, one pot procedure to synthesize various benzofuran derivatives. We have followed the efficient, large scale potential, high yield and simple process to synthesize benzofuran. Based on the synthesis of benzofuran, we have developed a short and more cost-effective procedure for the synthesis of BRL-37959. The older method was tedious and resulted in very low yields (≤ 5%). This new method is simple and uses inexpensive starting materials, as well as giving high overall yields (62%). In enzyme screening, we found that BRL-37959 selectively binds with COX-1. We followed our improved method and successfully made some analogs with higher yield.

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