Angular naphthopyrones as antibacterial agents : investigations into the antibacterial activity of benzo[f]chromanones and related compounds

Abstract

Antibiotics have been hailed as one of medicine's greatest achievements, but the effectiveness of current drugs is waning. Chapter 1 introduces the need for novel antibacterials, current approaches towards drug discovery, and the suitability of benzo[f]chromanone as a scaffold for antibacterial drug development. A summary of synthetic methods for the preparation of benzo[f]chromanones IS presented in Chapter 2. The suitability of polyphosphoric acid (PPA) cyclisation methodology was investigated for the preparation of a library of benzo[f]chromanones. Of the 19 naphthalene-based compounds synthesized and characterised in Section 3.1, six were novel naphthopyrones ({u00B1})-84, ({u00B1})-85, ({u00B1})-103, ({u00B1})-112, ({u00B1})-113 and ({u00B1})-115) and two were novel naphthocyclopentanones ({u00B1})-96 and ({u00B1})-101). A reproducible synthetic route for the preparation of alkylated 2-hydroxy-benzo[f]chromanones was developed and described in Section 3.2. Through this route 2-hydroxybenzo[f]chromanones ({u00B1})-37 and ({u00B1})-136) were prepared and characterized. Other previously unreported compounds prepared via this route included two naphthofuranones (120, ({u00B1})-137), an epoxide ({u00B1})-135), and an a,13-unsaturated ketone (134). Section 3.3 details investigations into alternative synthetic routes for the preparation of 2-hydroxybenzo[f]chromanones. 30 Compounds prepared in this work were subjected to antibacterial testing. The results of the microbial assays are detailed in Section 3.4. The majority of the compounds tested were found to exhibit antibacterial activity towards Gram-positive bacteria, including Mycobacterium smegmatis, a non virulent model organism for M. tuberculosis. The compounds identified with the greatest zones of inhibition against M. smegmatis included the novel naphthofuranone 120, naphthocyclopentanone ({u00B1})-96 and a, 13-unsaturated ketone 79. These compounds represent leads in the development of drugs for the treatment for tuberculosis. The experimental details are provided in Chapter 4.