Tyraminc Derivatives As Potent Therapeutics For Type 2 Diabetes: Synthesis And In Vitro Inhibition Of Alpha-Glucosidasc Enzyme

Background: Tyramine derivatives 3-16 were prepared and tested first time for their alpha-glucosidase (Sources: Saccharomyces cerevisiae) inhibitory activity by using an in vitro mechanism-based biochemical assay. All the compounds were found to be new, except compounds 3, 10-12 and 16.Objective: In continuation of our research to synthesize and identify potent inhibitors of alpha-glucosidase enzyme, we intended to synthesize new inhibitors of alpha-glucosidase enzyme with enhanced efficacy in order to provide the basis for the better treatment of the type-II diabetic.Methods: Tyramine (1) was allowed to react with a variety of aryl chlorides (2) to yield the corresponding amides. Synthesized compounds were then purified through normal phase column chromatography. Compounds 3-16 were then assessed for their alpha-glucosidase inhibitory activity in an in vitro biochemical assay. The cytotoxicity of compounds 3-16 was determined by using 3T3 mouse fibroblast cell lines.Results: Compounds 3-5, 8, 13, and 15-16 were found to be more active (IC50 = 103.1 +/- 0.46, 37.3 +/- 4.51, 56.7 +/- 4.2, 23.9 +/- 2.31, 43.6 +/- 2.88, 55.8 +/- 1.73, and 38.2 +/- 0.86 mu M, respectively) than the acarbose, the standard inhibitor of alpha-glucosidase enzyme, (IC50 = 840.0 +/- 1.73 mu M). To determine the dissociation constants and mode of inhibition, the kinetic studies were also performed for compounds 4 and 8 (the most potent inhibitors). It was observed that compounds 4 and 8 possess noncompetitive properties as the inhibitors of alpha-glucosidase. All the compounds were found to be non-cytotoxic, except 5 and 12 (IC50 = 14.7 +/- 0.24 and 6.6 +/- 0.38 mu M, respectively).Conclusion: The current study gives the facile synthesis and identification of potent inhibitors of alpha-glucosidase. The new inhibitors reported here may be investigated further for the designing and development of novel anti-diabetic agents.