Synthesis of inhibitors against Mycobacterium tuberculosis.

摘要

Infections by Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), have reemerged as a public health threat in recent years. The resurgence in TB has sparked renewed interest in identifying new antibiotics that can be used to treat this disease, which claims nearly three million lives worldwide each year. This disease has been difficult to treat, which can be attributed in part to the unusual structure of the cell wall of the organism. In order to identify new anti-tuberculosis agents, our research goal is to develop new analogues that mimic the linker, alpha-L-Rha-(1→3)-GlcNAc-1-phosphate of the cell wall. We carried out two studies. In our first study, we synthesized analogues that replace the N-acetylglucosamine fragment of the disaccharide linker with a D-threonine amino acid.; The second study focused on the synthesis of analogues formed by modifying the C-1' and C-4' positions of L-rhamnose. We attached a heterocycle (imidazole or thiazole) to the C-4' position of L-rhamnose and a octyl group to the C-1' position. Difficulties arose in the reduction of C-4' hydroxyl in these analogues. Biological investigation of these analogues were performed by our collaborators Dr. P. J. Brennan and Dr. D. C. Crick at Colorado State University, USA. Unfortunately, all the compounds showed no inhibitory activity. However, these results provided us the needed information and knowledge to design our future work.