Design, Synthesis And Activity Evaluation Of Galactofuranse Analogues

Objectives Uridine diphosphate-galactose mutase receptor analogues of 2-(1,2-dihydroxy-ethyl)-pyrrolidine-3,4-diol and 2-(1,2-dihydroxy-ethyl)-5-methyl-pyrrolidine-3,4-diol were designed, synthetized and evaluated for antituberculosis activity in vitro,which effected with two uridine diphosphate-galactose mutase in molecular docking.Methods The synthesis route was designed by using reverse synthesis analysis ideas.Cyclic nitrones was an important intermediates, which was completed with D-galactose as the chiral material, after hydroxyl protection, via multistep reactions such as glycosides hydrolysis, nitrogen source introduction, intramolecular cyclization. Then it was catalyzed and hydrogenated directly to get 2-(1,2-dihydroxy-ethyl)-pyrrolidine-3,4-diol. The 2-(1,2-dihydroxy-ethyl)-5-methyl-pyrrolidine-3,4-diol was synthesized with high stereoselectivity addition reaction of cyclic nitrones and Grignard, followed with catalytic hydrogenation.The binding activity between these and uridine diphosphate-galactose mutase was predicted by using molecular docking method. The MIC of the two target compounds for the standard strains of Mycobacterium tuberculosis, H37 Rv was measured by two times dilution method with isoniazid as positive drug.Results The preparation of target compounds was completed by 1H-NMR evidence according to a predetermined synthetic route. The results by using the computer simulating the molecular docking between the target compounds and uridine diphosphate-galactose mutase showed as following: the total score of molecular docking of 2-(1,2-dihydroxyethyl)-pyrrolidine-3,4-diol was 5.1510; the total score of molecular docking of 2-(1,2-dihydroxy-ethyl)-5-methyl-pyrrolidine-3,4-diol was 2.8797, which illustrated that the former had better affinity than the latter to two uridine diphosphate galactose mutase. The results in vitro antitubercular activity were as following: the MIC value of 2-(1,2-dihydroxy-ethyl)-pyrrolidine-3,4-diol was 0.048 μg/m L; the MIC value of 2-(1,2-dihydroxy-ethyl)-5-methyl-pyrrolidine-3,4-diol was 0.097 μg/m L, which illustrated that the former had better antibacterial activity than the latter.Conclusions The preparation of 2-(1,2-dihydroxy-ethyl)-pyrrolidine-3,4-diol and 2-(1,2-dihydroxy-ethyl)-5-methyl-pyrrolidine-3,4-diol were completed with D-galactose as a raw material and cyclic nitrones as an intermediate. These two compounds showed certain inhibitory effects against mycobacterium tuberculosis strains, and the former is better than the latter. The result was the same as molecular docking, which showed that they may achieve activity of anti tuberculosis by uridining diphosphate-galactose mutase. It provided a new mentality for the development of new anti-TB drugs.