Design, synthesis and activity of thio-linked arabinofuranosyl disaccharides against mycobacterial tuberculosis (MTB) and Mycobacterium avium complex (MAC)
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.
... lular activity against MTB H37Ra was determined in the Mono Mac 6 (MM6) human monocytic cell line. ARKAT-USA, Inc. of this genus. The biosynthetic pathways of cell wall components are potential targets for new drugs for tuberculosis. Much of the pathogenicity of M. tuberculosis results from its unique and complex cell envelope. The major components of this mycobacterial envelope are the mycolyl arabinogalactanpeptidoglycan complexes (mAGPs) and the lipoarabinomannan (LAM)associated lipoglycans. The biosynthetic pathways of cell wall components are potential targets for new drugs for tuberculosis. The recent advances in the characterization of mycobacteria cell walls have led to the identification of a vast array of highly unique biochemical targets that could lead to a new generation of potent and selective anti tubercular agents. 5 Arabinogalactan, a major and essential component of the cell wall, is an attractive target for drug development as neither D-arabinofuranose nor D-galactofuranose, the monomers composing arabinogalactan, are found in mammalian cells. 6 The effectiveness of antituberculosis drug, Ethambutol, 7 which inhibits the synthesis of arabinan, 8 a cell envelope component, illustrates the importance of this structure to the survival of the organism. 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. Recently, several oligosaccharides with sulfur in the glycosidic linkage are investigated as potential inhibitors of glycosyltransferases. Such compounds should also 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. Such compounds should also reduce hydrophilicity and enhance hydrolytic and enzymatic stability. Herein we report for the first time the synthesis, characterization and biological evaluation of several regioselectively protected D-arabinofuranosyl-(1,5)-D-arabinofuranosides with thiolinked octyl groups. An octyl group has been shown to be suitable for studies of mycobacterial arabinosyltransferases and other glycosyltransferases. 6b,7b,9b,10 Results and Discussion Thio-linked oligosaccharides involving hexoses have been synthesized earlier by a variety of procedures, (a) a SN2 type reaction involving the reaction of a thiolate anion on a glycosyl halide, 11 and (b) the displacement of a leaving group by a 1-thioglycose. 12 Initially our approach was based on the former procedure to yield thio-linked arabinofuranoside, 9a, b, c but the latter procedure was applied in a modified displacement reaction for the synthesis of the rest of the disaccharides to avoid using the toxic mercury salts as an activator and also to avoid any complex side reactions. An attempt was also made to couple the 2,3,5-tri-O-benzoyl arabinofuranosyl trichloroacetimidate 13 with octyl-2,3-di-O-acetyl-5-thio--D-arabinofuranoside 13 using