Potential multifunctional inhibitors of HIV-1 reverse transcriptase. Novel[AZT]-[TSAO-T] and [d4T]-[TSAO-T] heterodimers modified in the linker and in the dideoxynucleoside region

In an attempt to combine the anti-HIV-inhibitory capacity of nucleoside rev erse transcriptase (RT) inhibitors (NRTI) and non-nucleoside RT inhibitors (NNRTI), several heterodimer analogues of the previously reported [AZT]-(CH 2)(3)-[TSAO-T] prototype have been prepared. In these novel series, other N RTIs, an expanded range of linkers with different conformational freedom an d other attachment sites for these linkers on the base part of the NRTI ana logue have been explored. Moreover, in order to circumvent the dependence o f the NRTI moiety of the heterodimer an activation by cellular nucleoside k inases, novel heterodimers in which the NRTI is bearing a masked monophosph ate group at the 5'-position are described. Among the novel heterodimers, s everal derivatives show a potent anti-HIV-1 activity, which proved comparab le, or even superior, to that of the AZT heterodimer prototype. The nature of the NRTI was important far the eventual anti-HIV-1 activity. In particul ar, the d4T heterodimer derivative containing a propyl linker between the N -3 positions of the base of TSAO-T and d4T was similar to 5- to 10-fold mor e inhibitory to HIV-1 than the corresponding AZT heterodimer prototype.