Synthesis of kifunensine thioanalogs and their inhibitory activities against HIV-RT and α-mannosidase.

An efficient and practical synthesis of kifunensine thioanalogs 1a-c was reported. The bicyclic azasugars fused thiazolidin-4-one 4a-c as key intermediates were first synthesized in good yields of 74-80% via one-pot tandem Staudinger/aza-Wittig/cyclization by using the pivotal azidosugars 3a and 3b derived from D-mannose. Followed by double Pummerer rearrangements and deprotection, the target thiokifunensine 1a and its epimers 1b and 1c were obtained in good yields. Compounds 1a-c were preliminary evaluated for their HIV-RT and α-mannosidase (Jack bean) inhibitory activities. The results showed that such compounds exhibited significant anti-HIV-RT inhibitory activity but poor inhibitory against α-mannosidase. To gain further insight into the inhibitory mechanism of compounds 1a-c, the analog compounds 9a-c were also prepared after deprotection from 4a-c, respectively. Activity comparison between compounds 1a-c and 9a-c suggests that the better activities of 1a-c than those of the 9a-c is possibly due to the additional carbonyl at thiazolidine-4-one ring in fused bicyclic azasugars.