Search

Abstract: As a continuation of efforts to replace the metabolically labile methyl esters of lead alkenyldiarylmethanes (ADAMs) with stable bioisosteres, compounds bearing benzo[d]isoxazole and oxazolidine-2-one rings were designed and evaluated as a new series of potent HIV-1 non-nucleoside reverse transcriptase inhibitors with anti-HIV activity. All of the resulting ADAMs were found to inhibit HIV-1 RT with poly(rC)·oligo(dG) as the template primer. The most promising compound in this series was ADAM 3, with EC50 values of 40nM (vs HIV-1RF) and 20nM (vs HIV-1IIIB). Compound 3 also inhibited HIV-1 reverse transcriptase with an IC50 of 0.91μM. ADAM 4 has an antiviral EC50 of 0.6μM in CEM-SS cells and a plasma half-life of 51.4min. [Copyright &y& Elsevier]

Substituted diarylmethylenepiperidines (DAMPs) were synthesized as conformationally restricted analogues of the alkenyldiarylmethane (ADAM) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Although, like the ADAMs, the DAMPs were found to inhibit the cytopathic effect of HIV-1RF in CEM-SS cells, they were completely inactive as inhibitors of HIV-1 reverse transcriptase. The DAMPs were assessed for inhibition of HIV attachment and fusion. DAMP was active in both assays with IC50 values of 26.5 μM (TI 3.8) and 12.1 μM (TI: >8), respectively. DAMP also inhibited HIV fusion with an IC50 12.8 μM (TI: >6), but not virus attachment. However, attempts to verify inhibition of virus attachment and fusion as antiviral targets using time-of-addition experiments failed to confirm these observations, and instead identified an antiviral target occurring after completion of reverse transcription. DAMPs , , , and were found to inhibit virus replication if added 8 h post virus exposure, and DAMP was equipotent at inhibition of virus replication if added 24 h after virus addition. DAMPs , , and did not inhibit virus replication in TNF-α induced latently infected U1 cells, a model for post-integrative antiviral targets. When tested in both 3′ end-processing and strand-transfer assays in the presence of HIV-1 integrase, none of the DAMPs showed any inhibitory activity, indicating that HIV-1 integrase is not involved in the mechanism of the antiviral action. Thus, the DAMPs are novel conformationally restricted analogues of the previously published ADAM series with an unidentified antiviral target bounded by the completion of reverse transcription and virus integration. [Copyright &y& Elsevier]

Mercaptobenzamide thioesters and thioethers are chemically simple HIV-1 maturation inhibitors with a unique mechanism of action, low toxicity, and a high barrier to viral resistance. A structure-activity relationship (SAR) profile based on 39 mercaptobenzamide prodrug analogs exposed divergent activity/toxicity roles for the internal and terminal amides. To probe the relationship between antiviral activity and toxicity, we generated an improved computational model for the binding of mercaptobenzamide thioesters (SAMTs) to the HIV-1 NCp7 C-terminal zinc finger, revealing the presence of a second low-energy binding orientation, hitherto undisclosed. Finally, using NMR-derived thiol–thioester exchange equilibrium constants, we propose that thermodynamics plays a role in determining the antiviral activity observed in the SAR profile. Image 1 • Synthesis of 39 mercaptobenzamide prodrug analogs. • Generation of improved mercaptobenzamide–NCp7 computational model. • Calculation of an activity limit. [ABSTRACT FROM AUTHOR]

The alkenyldiarylmethanes (ADAMs) are a class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) targeting HIV-1. Four chemically and metabolically stabilized ADAMs incorporating N -methoxyimidoyl halide replacements of the methyl esters of the lead compound were previously reported. In this study, twenty-five new ADAMs were synthesized in order to investigate the biological consequences of installing nine different methyl ester bioisosteres at three different locations. Attempts to define a universal rank order of methyl ester bioisosteres and discover the ‘best’ one in terms of inhibitory activity versus HIV-1 reverse transcriptase (RT) led to the realization that the potencies are critically dependent on the surrounding structure at each location, and therefore the definition of universal rank order is impossible. This investigation produced several new non-nucleoside reverse transcriptase inhibitors in which all three of the three methyl esters of the lead compound were replaced by methyl ester bioisosteres, resulting in compounds that are more potent as HIV-1 RT inhibitors and antiviral agents than the lead compound itself and are expected to also be more metabolically stable than the lead compound. [ABSTRACT FROM AUTHOR]

Abstract: We describe the development of a new type of scaffold to target RNA structures. Multivalent binding oligomers (MBOs) are molecules in which multiple sidechains extend from a polyamine backbone such that favorable RNA binding occurs. We have used this strategy to develop MBO-based inhibitors to prevent the association of a protein–RNA complex, Tat–TAR, that is essential for HIV replication. In vitro binding assays combined with model cell-based assays demonstrate that the optimal MBOs inhibit Tat–TAR binding at low micromolar concentrations. Antiviral studies are also consistent with the in vitro and cell-based assays. MBOs provide a framework for the development of future RNA-targeting molecules. [Copyright &y& Elsevier]

Abstract: The alkenyldiarylmethanes (ADAMs) are currently being investigated as non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) of potential value in the treatment of HIV infection and AIDS. During the course of these studies, a number of ADAM analogues have been identified that protect HIV-infected cells from the cytopathic effects of the virus by an unknown, HIV-1 RT-independent mechanism. Since the phosphodiesterase 4 family is required for HIV infection, the effect of various ADAMs on the activity of PDE4B2 was investigated in an effort to determine if the ADAMs could possibly be targeting phosphodiesterases. Six compounds representative of the ADAM class were tested for inhibition of cAMP hydrolysis by PDE4B2 enzymatic activity. Four ADAMs were found to be weak inhibitors of PDE4B2 and two of them were inactive. The experimental results are consistent with an antiviral mechanism that does not include inhibition of PDE4 isoforms. [Copyright &y& Elsevier]

Abstract: During studies on the alkenyldiarylmethane (ADAM) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), analogues were discovered that exhibit low micromolar and submicromolar cytotoxicities. Since the ADAMs are structurally related to the tubulin polymerization inhibitor CC-5079, a set of 14 ADAMs were tested for inhibition of tubulin polymerization in an attempt to identify the biological target responsible for their cytotoxicity. The results indicate that, overall, the ADAMs are poor inhibitors of tubulin polymerization. However, the two most cytotoxic compounds, 15 and 16, are in fact active as inhibitors of tubulin assembly with IC50 values of 3.7±0.3 and 2.8±0.2μM, respectively, and they both inhibit the binding of colchicine to tubulin. Both compounds were investigated for anticancer activity in the National Cancer Institute’s panel of 60 human cancer cell lines, and both compounds consistently displayed submicromolar cytotoxicities with mean-graph midpoint (MGM) values of 0.31±0.08 and 0.47±0.09μM, respectively. [Copyright &y& Elsevier]

Abstract: The HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) constitute a large and structurally diverse set of compounds, several of which are currently used in the treatment of AIDS. A series of novel alkenyldiarylmethanes (ADAMs) were designed and synthesized as part of an ongoing investigation to replace the metabolically labile methyl ester moieties found in the ADAM pharmacophore with stable modifications that retain the potent anti-HIV activity of the parent compounds. Unsurprisingly, the rat plasma half-lives of the new ADAMs were not improved when compared to the parent compounds, but all of the synthesized ADAMs inhibited the cytopathic effect of HIV-1 in cell culture. The most potent compound identified was (E)-5-[1-(3,7-dimethyl-2-oxo-2,3-dihydro-benzoxazol-5-yl)-5-methoxycarbonyl-pent-1-enyl]-2-methoxy-3-methylbenzoic acid methyl ester (7), which inhibited the cytopathic effects of both HIV-1RF and HIV-1IIIB strains in cell cultures with EC50 values of 30 and 90nM, respectively, and inhibited HIV-1 reverse transcriptase with an IC50 of 20nM. [Copyright &y& Elsevier]

The HIV-1 nucleocapsid protein NCp7, which contains two highly conserved zinc fingers, is being used as a novel target for AIDS therapy due to its pivotal role in viral replication and its mutationally intolerant nature. Herein we report a new class of NCp7 inhibitors that possess good antiviral activity with low cellular toxicity. [Copyright &y& Elsevier]