Design and Synthesis of ?-O-Glucosylated 5-(Arylidene)-6-Aminouracils: Towards Water-Soluble 8-Aryl Xanthines as Effective Enzyme Inhibitors

Abstract

8-Aryl xanthines are selective enzyme inhibitors modified from naturally occurring methylxanthines. However, the low water solubility of substituted xanthines restricts their clinical applications. We developed a strategy to improve the water solubility of biologically privileged 8-aryl xanthines. A series of glucosylated 5-(arylidene)-6-aminouracil was synthesized as 8-aryl-1,3-dimethyl xanthine precursors and fully characterized with spectroscopic methods. Koenigs-Knorr reaction was used to synthesize beta-O-glucosylated aromatic aldehydes which were then reacted with 5,6-diamino-1,3-dimethyluracil to obtain the corresponding 5-(arylidene)-6-aminouracils. The strategy was validated by the ring-closing reaction of a beta-O-glucosylated 5-(arylidene)-6-aminouracil derivative with iodine (I-2) in dimethoxyethane. The water solubility of the glucosylated 8-aryl-1,3-dimethyl xanthine and its non-glycosylated counterpart was compared. Glucosylation improved the water solubility of the compound. The effect of glucosylation on the bioactivity of the compounds was investigated by measuring their inhibition effect on some common enzymes. The glucosylated 8-aryl xanthine demonstrated significantly better efficiency. Molecular docking was performed to elucidate the ligand-protein interactions. Since the target enzymes are primarily related to brain disorders, the blood-brain barrier (BBB) penetration ability of 8-aryl xanthine partners was investigated. According to adsorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions, glucosylated 8-aryl xanthine was found to be BBB permeable.