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 IC90 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.

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.Nitric oxide (NO) is an important mediator of intracellular signaling and has attracted interest as a target for therapeutic intervention, as it is widely acknowledged that there are a variety of disease states for which NO is implicated. 1 One of the most significant problems associated with the design of inhibitors, is to target the pathological excess NO production without disrupting essential NO-mediated processes, often by seeking selectivity for a particular NOS isoform. One method for potentially circumventing these problems is the indirect modulation of NO levels by inhibition of the enzyme DDAH which is responsible for controlling levels of N G -methyl-L-arginine (MMA) and N G , N G , dimethyl-L-arginine (ADMA) which are endogeneous inhibitors of NOS. 2,3 Inhibition of bacterial DDAH 4 is also of interest as it offers opportunities for the development of new anti-bacterial agents. The structurally related enzyme arginine deiminase (ADI) is also a possible antibacterial/antiprotozoal target, as various pathogenic organisms utilize ADI to generate ATP under anaerobic conditions. 5aRecently high-resolution structures of a bacterial DDAH 6 and ADI 5 have been disclosed and it has been shown in both enzymes that the active site comprises a catalytic triad containing an acidic residue (Glu / Asp), a basic residue (His) and a cysteine residue (Cys) (Figure 1). Both enzymes are known to catalyze the conversion of the substrate(s) MMA and ADMA to citrulline as shown in figure 1. In a recent communication Knipp et al. described the cysteine modification of DDAH by HcyNO and proposed this as a lead for the possible development of covalent inhibitors of DDAH and ADI. 7 In that work it was proposed that it should be possible to rationally design covalent inhibitors of DDAH based on those findings. That work has prompted us to disclose our own studies, which identify novel small molecule inhibitors of DDAH and ADI. Whilst the development of small molecule inhibitors of both DDAH and ADI is appealing, it is notable that there is only one known inhibitor of bacterial DDAH, which has modest affinity and is an arginine homologue, 8 and there are no known inhibitors of ADI. Herein we disclose our preliminary studies on the use of pentafluorophenyl (PFP) sulfonates as an unprecedented new class of enzyme inhibitors. The biological activity of the PFP-sulfonate group is completely unexplored and is highlighted here by the development of inhibitors of DDAH and ADI As had previously been noted by one of us in the disclosure of the crystal structure of DDAH, the active site resembles that of a cysteine protease with a catalytic triad (Fig 1). 5 The work of Roush et al. on the use of sulfonates and sulfonamides as inhibitors of cysteine proteases, 9 stimulated us to speculate that it may be possible to generate inh...

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].

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.Nitric oxide (NO) is an important mediator of intracellular signaling and has attracted interest as a target for therapeutic intervention, as it is widely acknowledged that there are a variety of disease states for which NO is implicated. 1 One of the most significant problems associated with the design of inhibitors, is to target the pathological excess NO production without disrupting essential NO-mediated processes, often by seeking selectivity for a particular NOS isoform. One method for potentially circumventing these problems is the indirect modulation of NO levels by inhibition of the enzyme DDAH which is responsible for controlling levels of N G -methyl-L-arginine (MMA) and N G , N G , dimethyl-L-arginine (ADMA) which are endogeneous inhibitors of NOS. 2,3 Inhibition of bacterial DDAH 4 is also of interest as it offers opportunities for the development of new anti-bacterial agents. The structurally related enzyme arginine deiminase (ADI) is also a possible antibacterial/antiprotozoal target, as various pathogenic organisms utilize ADI to generate ATP under anaerobic conditions. 5aRecently high-resolution structures of a bacterial DDAH 6 and ADI 5 have been disclosed and it has been shown in both enzymes that the active site comprises a catalytic triad containing an acidic residue (Glu / Asp), a basic residue (His) and a cysteine residue (Cys) (Figure 1). Both enzymes are known to catalyze the conversion of the substrate(s) MMA and ADMA to citrulline as shown in figure 1. In a recent communication Knipp et al. described the cysteine modification of DDAH by HcyNO and proposed this as a lead for the possible development of covalent inhibitors of DDAH and ADI. 7 In that work it was proposed that it should be possible to rationally design covalent inhibitors of DDAH based on those findings. That work has prompted us to disclose our own studies, which identify novel small molecule inhibitors of DDAH and ADI. Whilst the development of small molecule inhibitors of both DDAH and ADI is appealing, it is notable that there is only one known inhibitor of bacterial DDAH, which has modest affinity and is an arginine homologue, 8 and there are no known inhibitors of ADI. Herein we disclose our preliminary studies on the use of pentafluorophenyl (PFP) sulfonates as an unprecedented new class of enzyme inhibitors. The biological activity of the PFP-sulfonate group is completely unexplored and is highlighted here by the development of inhibitors of DDAH and ADI As had previously been noted by one of us in the disclosure of the crystal structure of DDAH, the active site resembles that of a cysteine protease with a catalytic triad (Fig 1). 5 The work of Roush et al. on the use of sulfonates and sulfonamides as inhibitors of cysteine proteases, 9 stimulated us to speculate that it may be possible to generate inh...

No abstract