Synthesis and Antiinfluenza Evaluation of Orally Active Bicyclic Ether Derivatives Related to Zanamivir.

Masuda, Takeshi; Shibuya, Satoshi; Arai, Masami; Yoshida, Shuku; Tomozawa, Takanori; Ohno, Akiko; Yamashita, Makoto; Honda, Takeshi

doi:10.1002/chin.200324109

Cited by 2 publications

(3 citation statements)

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“…The fact that antiviral activities are generally higher than purified enzyme activity is not particularly alarming because similar observations have been reported for viral neuraminadase activity. 37 However, we did take note of the discrepancy between antiviral activity of 5 and 6 and its lack of correlation with purified enzyme activity because this result could be indicative of an alternative mode of action such as entry. To address this critical issue, we next looked for evidence of early stage inhibition.…”

Section: Resultsmentioning

confidence: 97%

Synthesis and Biological Evaluation of Geminal Disulfones as HIV-1 Integrase Inhibitors

et al. 2005

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Integration of HIV-1 viral DNA into the host genome is carried out by HIV-integrase (IN) and is a critical step in viral replication. Although several classes of compounds have been reported to inhibit IN in enzymatic assays, inhibition is not always correlated with antiviral activity. Moreover, potent antiviral IN inhibitors such as the chicoric acids do not act upon the intended enzymatic target but behave as entry inhibitors instead. The charged nature of the chicoric acids contributes to poor cellular uptake, and these compounds are further plagued by rapid ester hydrolysis in vivo. To address these critical deficiencies, we designed neutral, nonhydrolyzable analogues of the chicoric acids. Herein, we report the synthesis, enzyme inhibition studies, and cellular antiviral data for a series of geminal disulfones. Of the 10 compounds evaluated, 8 showed moderate to high inhibition of IN in purified enzyme assays. The purified enzyme data correlated with antiviral assays for all but two compounds, suggesting alternative modes of inhibition. Time-of-addition studies were performed on these analogues, and the results indicate that they inhibit an early stage in the replication process, perhaps entry. In contrast, the most potent member of the correlative group shows behavior consistent with IN being the cellular target.

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Section: Resultsmentioning

confidence: 97%

Synthesis and Biological Evaluation of Geminal Disulfones as HIV-1 Integrase Inhibitors

et al. 2005

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“…The positioning and the relative orientation of the hydroxy groups on the cyclic ethers was found to affect the inhibitory activity significantly. Reportedly, this is the first orally efficacious zanamivir-related derivative [114]. Importantly, evaluation of the in vivo efficacy of this compound by oral administration in a mouse model of influenza A (N1) virus infection showed an efficacy similar to that of oseltamivir (11), based on median survival time [114].…”

Section: Glycerol Side Chain Modificationsmentioning

confidence: 95%

“…Work on C-7-substituted 4-deoxy-4-guanidino-Neu5Ac2en derivatives was further extended to the synthesis of compounds in which the glycerol side chain was replaced by cyclic ether moieties, such as the dihydroxylated tetrahydrofuran-2-yl (53) and tetrahydropyran-2-yl (54 and 55) moieties incorporating the C-7 oxygen atom in the cyclic ether [114]. The positioning and the relative orientation of the hydroxy groups on the cyclic ethers was found to affect the inhibitory activity significantly.…”

Section: Glycerol Side Chain Modificationsmentioning

confidence: 99%