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.

Graphical abstractAn efficient and practical synthesis of kifunensine thioanalogs via the intramolecular Staudinger/aza-Wittig/cyclization and double Pummerer rearrangements was reported. These compounds exhibited significant anti-HIV-RT inhibitory activity but poor inhibition against α-mannosidase.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Kifunensine thioanalogs. ► Staudinger/aza-Wittig/cyclization. ► Double Pummerer rearrangement. ► Significant anti-HIV-RT activity.