Synthesis of oxygen‐substituted N‐alkyl 1‐deoxynojirimycin derivatives: Aza sugar α‐glucosidase inhibitors showing antiviral (HIV‐1) and immunosuppressive activity

The synthesis of a series of six less‐lipophilic analogues of the α‐glucosidase inhibitor N ‐decyl‐1‐deoxynojirimycin ( N ‐decyl‐dNM, 5 ) is described. With the incorporation of a single oxygen atom, particularly at position seven in the N ‐decyl side‐chain to give N ‐(7‐oxadecyl)‐dNM ( 8 ), the therapeutic ratio (α‐glucosidase I inhibitory activity over toxicity in HepG2 cells) increases considerably. Compound 8 inhibits purified porcine liver α‐glucosidase I with an IC 50 value of 0.28 μM. The position of the oxygen atom in the N ‐decyl side‐chain is of importance since N‐(3‐oxadecyl)‐dNM ( 7 ) is less active than 8 and, moreover, is toxic to HepG2 cells at 3 mM. Subsequently, the synthesis of eight ester derivatives of N ‐(7‐oxadecyl)‐dNM is described. All of these ester analogues are less active α‐glucosidase inhibitors than the parent compound 8 in HepG2 cells. The compounds were further analyzed for antiviral and immunomodulatory activity in vitro . It is found that the most potent α‐glucosidase I inhibitor from this study N ‐(7‐oxadecyl)‐dNM ( 8 ) inhibits HIV‐1‐induced syncytia formation and lymphocyte proliferation in vitro . Finally, compound 8 was investigated in vivo . N ‐(7‐Oxadecyl)‐dNM ( 8 ) reduced adjuvant‐induced arthritis in rats making this compound a potential candidate for treating autoimmune diseases like rheumatoid arthritis.