A series of 6-halo-(F-, Cl-, Br-, I-) and 6-alkoxy-(OMe-, OEt-) 9-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl) purines (F-ddN) have been synthesized and characterized with the objective of finding compounds which might be superior to existing drugs for the treatment of HIV in the central nervous system. These compounds, which contain lipophilic 6-substituents, were chosen as acid-stable prodrugs for the anti-HIV-active F-ddN, 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl) hypoxanthine (F-ddI), because of their potential to increase blood-brain-barrier penetration relative to F-ddI. All the new compounds were more lipophilic than the currently approved anti-AIDS drugs. Partition coefficient increases of 30- and 110-fold were achieved, relative to didanosine (ddI), for the 6-chloro- and 6-ethoxy analogues. 2'-Fluoro substitution abolished the pH 1, acid-catalyzed cleavage of the nucleoside glycosylic bond. However, pH 1, acid-catalyzed hydrolysis of the 6-fluoro substituent to produce F-ddI was observed to occur at a rate (t1/2 0.54 h) which was ca. 40-170 times faster than that of the other prodrugs. The utility of the F-ddNs as prodrugs for F-ddI depends upon their ability to act as substrates for adenosine deaminase. The relative rates of adenosine deaminase-catalyzed prodrug hydrolysis to F-ddI varied by a factor of > 25,000 with the 6-fluoro- and 6-ethoxy analogues reacting the fastest and slowest, respectively. All of the prodrugs possessed anti-HIV activity in the phytohemagglutinin-stimulated peripheral blood mononuclear cell test system and a qualitative correlation exists between prodrug anti-HIV activity and adenosine deaminase hydrolysis rates.