Synthesis of glucose- and mannose-derived N-acetylamino imidazopyridines and their evaluation as inhibitors of glycosidases

The correlation between basicity and inhibitory power of tetrahydropyridoaz ole type glycosidase inhibitors has been used to determine the effect of su bstituents at positions 2 and 3. The gluco-and manno-configurated 2-acetami do derivatives 11 and 13 were prepared from the lactam 15 in four steps via the amidines 17 and 18. Similarly, 15 was transformed into the 3-acetamido analogues 12 and 14 in three steps. The acetamido imidazoles are significa ntly less basic than the parent pyridoimidazoles, but possess essentially t he same conformation. Correlation of the basicity of 11 and 12 and their in hibition of beta-glucosidases from almonds and from Caldocellum saccharolyt icum and, similarly, of the basicity of 13 and 14 and the inhibition of sna il beta-mannosidase shows a detrimental effect of the 3-acetamido group. Th e 2-acetamido group does not interfere with the inhibition. The inhibition of yeast alpha-glucosidase by 11 is surprisingly strong, evidencing a bindi ng interaction of the 2-acetamido group with this enzyme.