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A series of novel 3-(substituted phenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]isoxazole analogues were synthesized by the reaction of 5,6-dimethoxy-2-[(E)-1-phenylmethylidene]-1-indanone with hydroxylamine hydrochloride. The title compounds were tested for their in vitro anti-HIV activity. Among the compounds, (4g) showed a promising anti-HIV activity in the in vitro testing against IIIB and ROD strains. The IC50 of both IIIB and ROD were found to be 9.05 microM and > 125 microM, respectively.

HIV-1 capsid (CA) performs multiple roles in the viral life cycle and is a promising target for antiviral development. In this work, we describe the design, synthesis, assessment of antiviral activity, and mechanistic investigation of 20 piperazinone phenylalanine derivatives with a terminal indole or benzene ring. Among them, <b>F₂-7f</b> exhibited moderate anti-HIV-1 activity with an EC₅₀ value of 5.89 μM, which was slightly weaker than the lead compound <b>PF74</b> (EC₅₀ = 0.75 μM). Interestingly, several compounds showed a preference for HIV-2 inhibitory activity, represented by <b>7f</b> with an HIV-2 EC₅₀ value of 4.52 μM and nearly 5-fold increased potency over anti-HIV-1 (EC₅₀ = 21.81 μM), equivalent to <b>PF74</b> (EC₅₀ = 4.16 μM). Furthermore, <b>F₂-7f</b> preferred to bind to the CA hexamer rather than to the monomer, similar to <b>PF74</b>, according to surface plasmon resonance results. Molecular dynamics simulation indicated that <b>F₂-7f</b> and <b>PF74</b> bound at the same site. Additionally, we computationally analyzed the ADMET properties for <b>7f</b> and <b>F₂-7f</b>. Based on this analysis, <b>7f</b> and <b>F₂-7f</b> were predicted to have improved drug-like properties and metabolic stability over <b>PF74</b>, and no toxicities were predicted based on the chemotype of <b>7f</b> and <b>F₂-7f</b>. Finally, the experimental metabolic stability results of <b>F₂-7f</b> in human liver microsomes and human plasma moderately correlated with our computational prediction. Our findings show that <b>F₂-7f</b> is a promising small molecule targeting the HIV-1 CA protein with considerable development potential.

No abstract is provided for this article.

A series of novel 2'-C-methylribonucleosides, involving 5-iodo and 5-alkynyl uridine analogues as well as related bicyclic furano- and pyrrolo[2,3-d]pyrimidinone compounds, has been synthesized and evaluated for their inhibitory effect on replication of the hepatitis C virus (HCV). The new nucleoside analogues did not show meaningful anti-HCV activity.

A series of oligopeptides have been synthesized that are structurally related to the natural agent netropsin. The binding constants to double-stranded polynucleotides as well as the cytostatic activity against both murine human tumor cell lines and the in vitro activity against a range of DNA and RNA viruses have been determined for these novel compounds and some of their synthetic precursors. 1-Methyl-5-nitropyrrole-2-carboxylic acid methyl ester (4), N-[[1-methyl-4-(1-methyl-4-nitropyrrole-2-carboxamido)pyrrol-2- yl]carbonyl]-L-alanine tert-butyl ester (28), and N-[[1-methyl-4-(1-methyl-4-nitropyrrole-2-carboxamido)pyrrol-2- yl]carbonyl]-L-alanyl-L-alanine tert-butyl ester (29) showed modest inhibitory effect on tumor cell proliferation (CD50 = 26-85 micrograms/mL). Of all the compounds that were evaluated, 28 proved the most potent antiviral agent. It was inhibitory to parainfluenza-3 virus and Coxsackie virus B4 in Vero cells at a concentration of 20 micrograms/mL.

A series of new substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble nucleotide prodrugs, to extend and quantify the SAR observed for an earlier series of related derivatives. All of the compounds were found to be significantly more potent against HIV in cell culture than the nucleoside analogue d4T, and most were also found to be significantly more potent than the parent phosphoramidate. A Hansch type QSAR analysis was applied to the combined series of 21 compounds. The results of this analysis revealed anti-HIV activity to be principally dependent on lipophilicity in a quadratic manner, with terms representing substituent steric bulk and electronic effects having a minimal significance.

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