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Bis-cycloSal-d4T-monophosphates have been synthesized as potentially anti-HIV active “dimeric” prodrugs of 2‘,3‘-dideoxy-2‘,3‘-didehydrothymidine monophosphate (d4TMP). These pronucleotides display a mask−drug ratio of 1:2, a novelty in the field of pronucleotides. Both bis-cycloSal-d4TMP 6and bis-5-methyl-cycloSal-d4TMP 7showed increased hydrolytic stability as compared to their “monomeric” counterparts and a completely selective hydrolytic release of d4TMP. The hydrolysis pathway was investigated via31P NMR spectroscopy. Moreover, due to the steric bulkiness, compound 6already displayed strongly reduced inhibitor potency toward human butyrylcholinesterase (BChE), while compound 7turned out to be devoid of any inhibitory activity against BChE. Partial separation of the diastereomeric mixture of 6revealed strong dependence of the pronucleotides' properties on the stereochemistry at the phosphorus centers. Both 6and 7showed good activity against HIV-1 and HIV-2 in wild-type CEM cells in vitro. These compounds were significantly more potent than the parent nucleoside d4T 1in HIV-2-infected TK-deficient CEM cells, indicating an efficient TK-bypass. [ABSTRACT FROM AUTHOR]