Abstract
We report the chemical synthesis of a series of disaccharides of arabinofuranose with a glycosidic sulfur linker as mimics of the acceptor for arabinofuranosyltransferases with and without using any activator to avoid any complex reactions. These analogs were tested for in vitro activity against MTB strain H37Ra and 3 MAC clinical isolates. MICs were determined using a colorimetric microdilution broth assay. Bactericidal activity was studied with kill curves over a period of seven days. Intracellular activity against MTB H37Ra was determined in the Mono Mac 6 (MM6) human monocytic cell line.
Highlights
The resurgence of tuberculosis in developed nations as well as the appearance of multiple drug resistant forms of the disease throughout the world has raised the concern that this disease may resurface as serious public health problem1-3 and this attracted renewed attention in identifying the potent antimycobacterial agents
Since several natural and synthetic arabinosyl glycosides are known to be substrate of mycobacterial arabinosyl transferase,9 we hypothesized that simple arabinosyl disaccharide incorporating a sulfur atom that could potentially chelate the putative cation might function as specific inhibitors
The inhibitors of mycobacterial arabinofuranosyl transferases could be the ideal synthetic targets as neither D-arabinofuranose nor D-galactofuranose, the monomer composing arabinogalactan are found in mammalian cells
Summary
The resurgence of tuberculosis in developed nations as well as the appearance of multiple drug resistant forms of the disease throughout the world has raised the concern that this disease may resurface as serious public health problem and this attracted renewed attention in identifying the potent antimycobacterial agents. The biosynthetic pathways of cell wall components are potential targets for new drugs for tuberculosis. The inhibitors of mycobacterial arabinofuranosyl transferases could be the ideal synthetic targets as neither D-arabinofuranose nor D-galactofuranose, the monomer composing arabinogalactan are found in mammalian cells. Several oligosaccharides with sulfur in the glycosidic linkage are investigated as potential inhibitors of glycosyltransferases Such compounds should reduce hydrophilicity and enhance hydrolytic and enzymatic stability. We have initiated a program to synthesize a series of disaccharides with sulfur linkers as mimics of the acceptor for arabinofuranosyl transferase An octyl group has been shown to be suitable for studies of mycobacterial arabinosyltransferases and other glycosyltransferases.6b,7b,9b,10
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