Novel haloalkyl phosphate derivatives of the anti-HIV nucleoside analogue AZT were prepared by phosphorochloridate chemistry. These materials were designed to act as labile membrane-soluble prodrugs of the bio-active free nucleotides. In vitro evaluation revealed the compounds to have a pronounced and selective antiviral action, which varied greatly with the structure of the phosphate moiety. By comparison to simple dialkyl phosphates, which are inactive against HIV-1, the introduction of halogen atoms into the alkyl (phosphate) chains led to anti-HIV activity. Although halogen substitution in just one alkyl chain was sufficient for biological activity, substitution in the second alkyl chain further enhanced activity. Conversely, stabilization of the second chain, by conversion to a phosphonate, led to a reduction in activity. In one case, the diastereo-isomers resulting from mixed stereochemistry at the phosphate centre were separated, and found to differ in activity by one order of magnitude. Lastly, the bis(mono- and di-chloroethyl) phosphates were prepared and found to display moderate anti-HIV activity.
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