1,2,3-triazole-[2′,5′-bis-o-(tert-butyldimethylsilyl)-β-D- ribofuranosyl]-3′-spiro-5″-(4″-amino-1″,2″- oxathiole 2″,2″-dioxide) (TSAO) analogues: synthesis and Anti-HIV-1 activity

Several 4- or 5-monosubsituted and 4,5-disubstituted 1,2,3-triazole analogues of the anti-HIV-1 lead compound [1-[2′,5′-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl] thymine]-3′-spiro-5″(4″-amino-1″,2″-oxathiole 2″,2″-dioxide) (TSAO-T) have been prepared and evaluated as inhibitors of HIV-1-induced cytopathicity. These analogues have been prepared by 1,3-diplar cycloaddition of [2,5-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3-spiro-5′- (4′-amino- and 4′-(N-acetylamino)-1′,2′-oxathiole 2′,2′-dioxide) (TSAO) azides to various substituted acetylenes. Several 4- and 5-substituted 1,2,3-triazole-TSAO analogues proved superior to the unsubstituted derivative by 1-2 orders of magnitude. In particular the 5-substituted amido-, (methylamido)-, and (dimethylamido)-1,2,3-triazole derivatives of TSAO were endowed with potent anti-HIV-1 activity (50% effective concentration: 0.056-0.52 μM). They show a similar resistance spectrum as previously noted for TSAO-T and related derivatives.