SYNTHESIS OF NUCLEOSIDYL RIFAMYCINS AS INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

In the search for potential nucleoside/non-nucleoside mixed type inhib itors of human immunodeficiency virus type 1 (HIV-1) reverse transcrip tase, we synthesized a new set of rifamycin S derivatives, containing AZT connected via its hydroxyl at 5' C, through a spacer, to the third C of rifamycin S. The length of the spacer was eight, nine or 14 atom s. Rifamycin S was also used in its 21,23-O,O-isopropylidene derivativ e form, and in one case thymidine replaced AZT. These nucleosidyl rifa mycins were weak inhibitors of isolated HIV-1 reverse transcriptase. T he inhibitory power was weak most probably because their large molecul ar volume hindered the inhibition process. With the exception of the t hymidine derivative, the AZT derivatives, at concentrations in the ran ge 0.04-0.07 mu M, proved non-toxic and inhibited the replication of H IV-1 in C8166 T lymphocytes. This activity appears to be owing to AZT released by the derivatives upon hydrolysis in solution. The present c ompounds require further development as mixed type reverse transcripta se inhibitors and can be considered non-toxic lipophilic prodrugs of A ZT.