Synthesis of tetracyclic iminosugars fused benzo[e][1,3]thiazin-4-one and their HIV-RT inhibitory activity

Abstract

Several aza-C-pseudonucleosides bearing 1,3-benzothiazin-4-one (6 and 7) were prepared by the one-pot three-component condensation from the iminosugar aldehyde 3, amino acid ethyl/methyl ester hydrochlorides 4(a-c), and 2-mercaptobenzoic acid 5. After removal of Boc and the isopropylidene groups, the target novel tetracyclic iminosugars fused benzo[e][1,3]thiazin-4-one 1(a-c) and 2(a-b) were first afforded by the intramolecular cyclo-amidation reaction. Their structures were determined by their (1)H, (13)C NMR, and HRMS (ESI) spectra and X-ray. The tetracyclic iminosugars 1(a-c) and 2(a-b) were examined for their HIV reverse transcriptase (RT) inhibitory activities. The result showed that all compounds could effectively inhibit RT activity. Among them, compound 2a was the best one with the IC50 value of RT inhibitory activity of 0.82μM. Structure-activity relationship analysis suggested that 1'R configuration in the tetracyclic azasugars was of benefit to their anti-HIV RT activity.

Keywords: Anti-HIV RT activity; Aza-C-pseudonucleoside; Benzo[e][1,3]thiazin-4-one; One-pot three-component reaction; Tetracyclic iminosugar.