The synthesis of potential "combined prodrugs" where phosphonoformic acid (PFA) or phosphonoacetic acid (PAA) was attached to the 5'-0 or N4 position of 2',3'-dideoxy-3,-thiacytidine (BCH-189) is described. The anti-HIV-1 activity of 11 analogues which included carboxylic ester or phosphoric ester linkages of PFA or PAA to BCH-189 was determined in MT-4 cells. Of these compounds, the IC50 of analogues 3,4,6, and 7 ranged from 0.2 to 100 µ , while IC50 for BCH-189 in this system was 0.1 µ . In vitro hydrolysis of the various esters or amides in human plasma indicated that these agents were relatively stable in the presence of plasma esterases with Í1/2 values of up to 120 min. Moreover, lipophilicity of these compounds (partition coefficient) was determined in order to establish correlation between lipophilicity and diffusion of BCH-189 analogues into the cells. The active compounds may exert their effects by extracellular or intracellular hydrolysis to the corresponding antiviral agent BCH-189, but intrinsic anti-HIV-1 activity of some of PAA and PFA adducts, themselves, may also be involved.

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Synthetic approaches for new 2,5‐disubstituted‐1,3‐thiazolidines are described. Steric and electronic effects of the N‐substituent of the thiazolidine ring represent the major parameter in the rearrangement process. The nmr studies demonstrate that N‐unsubstituted 2,5‐disubstituted‐1,3‐thiazolidines exist as epimeric mixture, while the corresponding N‐acetylated analogues exist as a conformer mixture.