ABSTRACT
Targeting host factors is a complementary strategy for the development of new antiviral drugs. We screened a library of isoxazolidine and isoxazole sulfonamides and found four compounds that inhibited HIV-1 infection in human CD4+ lymphocytic T cells with no toxicity at IC(90) concentrations. Structure-activity relationship showed that benzyl sulfonamides and a halo-substituted aromatic ring on the heterocycle scaffold were critical for antiretroviral activity. The size and position of the incorporated halogen had a marked effect on the antiretroviral activity. The sulfonamide derivatives had no significant effect on HIV-1 entry, reverse transcription and integration but impaired a step necessary for activation of viral gene expression. This step was Tat-independent, strongly suggesting that the target is a cell factor. A virus partially resistant to the least potent compounds could be selected but could not be propagated in the long term, consistent with the possibility that HIV-1 may be less likely to develop resistance against drugs targeting some host factors. Here, we provide evidence that novel synthetic methods can be applied to develop small molecules with antiretroviral activity that target host factors important for HIV-1 replication.
Subject(s)
Anti-HIV Agents/chemistry , HIV-1/drug effects , Isoxazoles/chemistry , Sulfonamides/chemistry , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/toxicity , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Cell Line , Drug Resistance, Viral/drug effects , HIV-1/physiology , HeLa Cells , Humans , Isoxazoles/chemical synthesis , Isoxazoles/toxicity , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/toxicity , Virus Replication/drug effectsABSTRACT
A stereoselective one-pot synthesis of substituted 1,2-thiazetidine 1,1-dioxides (beta-sultams) has been achieved from heterocyclic pentafluorophenyl (PFP) sulfonates. Mild N-O bond cleavage of isoxazolidines followed by intramolecular cyclization of the amine onto the PFP demonstrates the potential utility for using the PFP sulfonate as a valuable precursor to sulfonamides. [reaction: see text].
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Sulfonamides/chemical synthesis , Crystallography, X-Ray , Cyclization , Stereoisomerism , Sulfonic Acids/chemistryABSTRACT
A range of pentafluorophenyl (PFP) sulfonate esters derived from the reaction of PFP vinyl sulfonate and various nitrones are shown to have significant inhibitory activity against the bacterial enzymes DDAH and ADI.