Synthesis and Antibacterial Activity of Diphenyl Ethers/Amines

Abstract

There has been a persistent increase in the occurrence of antibiotic resistance to many common bacterial pathogens such as S. aureus, S. pneumoniae and E. faecalis. This, along with malaria and tuberculosis constitute major causes of mortality in humans. Therefore, there is need to design and synthesize antibacterial agents having specific targets identified after post-genome era. Fatty acid biosynthesis is one such important target for the development of new bioactive molecules. Diphenyl ethers, such as triclosan, are known to inhibit enoyl-ACP-reductase (FabI) enzyme responsible for bacterial fatty acid biosynthesis in most of the organisms. The work described in the thesis explores the potential of diphenyl ethers and amines for their antibacterial activity. All the diaryl compounds were synthesized by nucleophilic aromatic substitution of aryl halide with substituted phenols and amines. Functional group manipulation gave varied compounds that were purified by chromatography techniques and characterized using 1H NMR, 13C NMR and mass spectral analysis. All the synthesized compounds were screened in vitro for their minimal inhibitory concentration (MIC) against Gram positive strains [S. aureus (NCTC 6571, MTCC 96), S. epidermidis (MTCC 2639)] and Gram negative strains [B. subtilis, E. coli (MTCC 1302), P.aeruginosa (MTCC 647, MTCC 3541) and Pseudomonas putida] by microbroth dilution assay. Some of the synthesized compounds were active against important stains. For example diphenyl amines (4.12- 4.23) were active against Staphylococcus aureus whereas diphenyl ethers (2.5- 2.21 and 3.9- 3.24) were active against P. aeruginosa species. The results were supported by docking studies where flipping of the conformation in case of diphenyl ethers was observed as compared to previous studies. The problem of poor solubility of triclosan in the aqueous media was resolved by assessing the impact of surfactants used to enhance the solubility. It was found that Triton X-100 at concentrations between 0.05 mM and 0.02 mM effective to improve the aqueous solubility of triclosan without affecting its IC50 value.