STRUCTURE-ACTIVITY RELATIONSHIP STUDIES WITH SYMMETRICAL NAPHTHALENESULFONIC ACID-DERIVATIVES - SYNTHESIS AND INFLUENCE OF SPACER AND NAPHTHALENESULFONIC ACID MOIETY ON ANTI-HIV-1 ACTIVITY

Symmetric bis(naphthalenesulfonic acid) derivatives containing a varie ty of spacers have been synthesized and evaluated for anti-HIV-1 activ ity in four assay systems. In the assay that measured inhibition of HI V-1-induced cytopathogenicity using a laboratory strain (HTLV-III(B)), a hexamethylene and octamethylene spacer derivative of 4-amino-5-hydr oxy-2,7-naphthalenedisulfonic acid emerged as the most potent derivati ves. The hexamethylene spacer analog exhibited an in vitro therapeutic index that was > 120. Selected derivatives were tested in the giant c ell formation assay. In this assay, the most potent derivative was, ag ain, the hexamethylene compound. Evaluation of selected derivatives ag ainst a clinical isolate of HIV-1 (HE strain) revealed that the hexame thylene derivative was the most potent compound. In the assay that mea sured the inhibition of HIV-1-induced cytopathogenesis in human periph eral blood lymphocytes, the hexamethylene compound emerged as the most active derivative, demonstrating a 50% inhibitory concentration of 1. 3 muM. These studies clearly demonstrate that certain naphthalenesulfo nic acid moieties when coupled to specific spacers were synergistic in producing anti-HIV-1 activity at nontoxic concentrations. In the 4-am ino-5-hydroxy-2,7-naphthalenedisulfonic acid series, shortening of the spacer length, preferably with a flexible polymethylene chain, was hi ghly beneficial for increasing anti-HIV-1 potency.