New sugar-based molecular entities as potential therapeutics against infectious and neurodegenerative diseases

Abstract

The increasing average life expectancy in developed countries led to an escalating concern regarding geriatric infectious diseases. In particular nosocomial infections are known to be more frequent and severe in the elderly, being this susceptibility often related to neurodegenerative disorders. Alkyl 2-deoxy/2,6 dideoxy-arabino-hexopyranosides have been studied by the Carbohydrate Chemistry Group, revealing potent antimicrobial activity over Gram-positive bacteria, namely Bacillus species. Additionally, promising results arising from NMR interaction studies of 2,6-dideoxyglycosides with cystatin B amyloid fibrils demonstrated their potential for amyloid diseases. These findings were the driving force to explore the chemistry and bioactivity of 2-deoxy sugars against infection and neurodegenerative disorders. Thus, new alkyl 2-deoxy O-/and -S-glycosides, and alkyl 3-deoxy, 4-deoxy and 6-deoxy-O-glycoside analogues were synthesized, and the importance of the deoxygenation pattern was evaluated. Dodecyl 4,6-dideoxy-α-D-xylo-hexopyranoside was the most promising compound for further developments, presenting a MIC below 25 μM for Bacillus species and E. faecalis, and low toxicity. More importantly, the action of one of the lead compounds on the thermotropic behaviour of phosphatidylethanolamine-enriched membranes was investigated. The reorganization of the lipid matrix into a hexagonal phase causing bacteria cell lysis is the proposed mechanism for the antimicrobial action of this family of compounds. This is the first report of this unprecedented mode of action of glycosides responsible for specific carbohydrate-phospholipid interactions, triggering innovation on membrane-targeting antibiotics. Moreover, a deep literature investigation showed that carbohydrates also play a role toward neurodegenerative disease prevention. Thus, 2-deoxyglycosides embodying neuroprotective polyphenols were prepared, envisioning activity and bioavailability improvement of such molecules. In fact, certain resveratrol glycosides were more effective at protecting the neuronal cells from peroxide induced cytotoxicity than resveratrol itself, while showing coefficient partition measurements typical of central nervous system drugs and ideal for blood-brain-barrier penetration. This work clearly demonstrates the uniqueness and versatility of carbohydrates as exceptional scaffolds for medicinal chemistry applications.