Structure-activity relationship studies with symmetric naphthalenesulfonic acid derivatives. Synthesis and influence of spacer and naphthalenesulfonic acid moiety on anti-HIV-1 activity.
Symmetric bis(naphthalenesulfonic acid) derivatives containing a variety of spacers have been synthesized and evaluated for anti-HIV-1 activity in four assay systems. In the assay that measured inhibition of HIV-1-induced cytopathogenicity using a laboratory strain (HTLV-IIIB), a hexamethylene and octamethylene spacer derivative of 4-amino-5-hydroxy-2,7-naphthalenedisulfonic acid emerged as the most potent derivatives. The hexamethylene spacer analog exhibited an in vitro therapeutic index that was > 120. Selected derivatives were tested in the giant cell formation assay. In this assay, the most potent derivative was, again, the hexamethylene compound. Evaluation of selected derivatives against a clinical isolate of HIV-1 (HE strain) revealed that the hexamethylene derivative was the most potent compound. In the assay that measured the inhibition of HIV-1-induced cytopathogenesis in human peripheral blood lymphocytes, the hexamethylene compound emerged as the most active derivative, demonstrating a 50% inhibitory concentration of 1.3 microM. These studies clearly demonstrate that certain naphthalenesulfonic acid moieties when coupled to specific spacers were synergistic in producing anti-HIV-1 activity at nontoxic concentrations. In the 4-amino-5-hydroxy-2,7-naphthalenedisulfonic acid series, shortening of the spacer length, preferably with a flexible polymethylene chain, was highly beneficial for increasing anti-HIV-1 potency.
Mohan
P
P
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago 60680.
Wong
M F
MF
Verma
S
S
Huang
P P
PP
Wickramasinghe
A
A
Baba
M
M
D000998:Antiviral Agents / Q000138:chemical synthesis*; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009282:Naphthalenesulfonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D001713:Biphenyl Compounds; D009282:Naphthalenesulfonates; C082306:4,4'-(4,4'-biphenyldiylbis(sulfonylamino))bis(5-hydroxy-2,7-naphthalenedisulfonic acid); C082305:4,4'-(1,6-hexanediylbis(carbonylamino))bis(5-hydroxy-2,7-naphthalenedisulfonic acid)