Synthesis and biological evaluation of potent glycosidase inhibitors: 4-deoxy-4,4-difluoroisofagomine and analogues

A series of 4,4-difluoroisofagomine analogues were synthesized. These compounds were tested for inhibition of eight glycosidases. The 3R,5R isomer 1 is a new and potent inhibitor against β-glucosidase from almonds with Ki value of 1.2 μM. The influence of the gem-difluoromethylene group (CF2) on binding to glycosidases is discussed. It is concluded that only non-essential hydroxyl groups can be replaced by the gem-difluoro group and that in such a case (β-glycosidase) the change in inhibition is, interestingly, a result of the change in base strength.