Tyramine Derivatives as Potent Therapeutics for Type 2 Diabetes: Synthesis and In Vitro Inhibition of α-Glucosidase 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 and 11, 12 and 16. OBJECTIVE: In continuation of our research to synthesize and identify potent inhibitors of an 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 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 microM, respectively) than the acarbose, the standard inhibitor of an alpha-glucosidase enzyme, (IC50= 840.0+/-1.73 microM). 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 non-competitive 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 microM, 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.