Several naphthalenedi-and trisulfonic acids have been synthesized and evaluated for inhibitory potential against cytopathogenesis and purified recombinanthuman immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) reverse transcriptase (RT). The most potent derivative that emerged from the anti-RT study was a small molecule 6 (MW= 840), a dipalmitoylated derivative of 2, 7-naphthalenedisulfonic acid. Analog 6 demonstrated 50% inhibitory concentration (ICso) values of 2.42 and 0.86 ĩ for HIV-1 and HIV-2 RT, respectively. The second most active compound was also a derivative of the same naphthalenedisulfonic acid but contained only one palmitoyl moiety. This compound 9 displayed ICso values of 4.8 and 3.7 ĩ for HIV-1 and HIV-2 RT, respectively. Both analogs 6 and 9 are active at noncytotoxic doses, exhibit slightly higher potencies for the RT of HIV-2 over HIV-1, and demonstrate activities superior to the hexasulfonic acid derivative suramin (ICso values of 9.4 and 15.5 ĩ for HIV-1 and HIV-2 RT, respectively). In the cytopathogenesis assay, the most active compound is a bis naphthalenedisulfonic acid derivative 17, containing a flexible octamethylenespacer and exhibiting an in vitro therapeuticindex of 29.7. Most striking, however, is the influence of the palmitoyl functionality in the naphthalenedisulfonic acid series to confer activity against both HIV-1 and HIV-2 RT.

The human immunodeficiency virus (HIV) reverse transcriptase (RT) is a viral encoded enzyme that is vital for viral replication. The RT from the AIDS virus type 1 (HIV-1) is a heterodimer consisting of two chains of 66 and 51 kD, 1whereas the RT from the AIDS virus type 2 (HIV-2) has two comparable chains of 68 and 55 kD. 2 Both RTs share a high degree of homology in their amino acid sequences, and possess RNA-dependent DNA polym-erase, DNA-dependent DNA polymerase, and ribonuclease H (RNase H) activities. However, they demonstrate differences in their Km values for the DNA polymerizing activity, the RNase activity and other properties. 3 The