HALOALKYL PHOSPHATE DERIVATIVES OF AZT AS INHIBITORS OF HIV - STUDIESIN THE PHOSPHATE REGION

Novel haloalkyl phosphate derivatives of the anti-HIV nucleoside analo gue AZT were prepared by phosphorochloridate chemistry. These material s 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 greatl y 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 ac tivity. Although halogen substitution in just one alkyl chain was suff icient for biological activity, substitution in the second alkyl chain further enhanced activity. Conversely, stabilization of the second ch ain, by conversion to a phosphonate, led to a reduction in activity. I n one case, the diastereoisomers resulting from mixed stereochemistry at the phosphate centre were separated, and found to differ in activit y by one order of magnitude. Lastly, the bis(mono- and di-chloroethyl) phosphates were prepared and found to display moderate anti-HIV activ ity.