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Previous efforts in our lab have led to the development of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) thiophene[3,2-<i>d</i>]pyrimidine compound <b>1</b> (<b>K-5a2</b>) with promising activity against wild-type and mutant HIV-1 strains. In this work, a series of novel diarylpyrimidines derivatives carrying a structurally diverse motif at the right wing of the lead <b>K-5a2</b> was designed and synthesized as potential anti-HIV-1 agents. The results demonstrated that <b>8a</b> yielded exceptionally potent activity against HIV-1 wild-type (50% effective concentration (EC₅₀) = 3.30 nM) and mutant strain RES056 (EC₅₀ = 22.6 nM) in MT-4 cells; in the reverse transcriptase inhibitory assay, <b>8a</b> (half maximal inhibitory concentration (IC₅₀) = 0.028 μM) was remarkably superior to that of <b>K-5a2</b> (IC₅₀ = 0.300 μM) and comparable to that of etravirine (ETR; IC₅₀ = 0.011 μM). Notably, <b>8a</b> exhibited better druggability than that of <b>K-5a2</b>, including significantly reduced CYP enzymatic inhibitory activity (IC₅₀ > 50 μM), lower human ether-à-go-go related gene (hERG) inhibition (IC₅₀ > 30 μM), and improved metabolic stability (short half-life, <i>T</i>_1/2 = 77.5 min) <i>in vitro</i>.

N-(adamantyl-1)methyl, N-(adamantyl-2), and N-(omega-aminodecyl) amides of vancomycin, eremomycin, and dechloroeremomycin aglycons and their des-(N-Me-D-Leu) derivatives were synthesized and their antibacterial and anti-HIV activities were investigated. Carboxamides with an intact peptide core demonstrated activity against glycopeptide-susceptible and -resistant bacteria (1-32 microM). N-(adamantyl-1)methylcarboxamide of eremomycin aglycons had good antiretroviral activity (1.6 microM against HIV-1). Compounds with destroyed peptide core [des-(N-Me-D-Leu)-aglycon amides] were inactive against both glycopeptide-sensitive and -resistant bacteria. (Adamantyl-1)methylamide of des-(N-Me-D-Leu)-eremomycin aglycon had good antiretroviral activity (EC50 of 5.5 microM for HIV-1 and 3.5 microM for HIV-2). (Adamantyl-1)methylamides of eremomycin aglycon and its des-(N-Me-d-Leu)-derivative are the most promising and selective antiretroviral agents. Their ability to induce bacterial resistance to glycopeptide antibiotics during prolonged administration may be expected to be very low or absent. This might make the use of these derivatives feasible in the prolonged therapy or prophylaxis of HIV infections.

No abstract is provided for this article.

Negatively charged albumins (NCAs, with the prototypes Suc-HSA and Aco-HSA), modified proteins with a potent anti-HIV-1 activity in the nanomolar concentration range, were studied for several aspects of their antiviral mechanism. In addition we investigated the antiviral activity of combinations and covalent conjugates of these NCAs and the reverse transcriptase inhibitor AZT. Addition of NCAs to HIV-1-infected target cells in time-of-addition experiments could be delayed for 30 min after infection before significant loss of activity occurred. Syncytium formation of HIV-infected and uninfected T-cells was inhibited by the NCAs at concentrations of 1-4 microg/ml. The gp120-mediated virus/cell binding, however, was only inhibited by the NCAs at a 10-fold higher concentrations. The combined data are compatible with a preferential influence on virus/cell fusion. A subsynergistic activity against HIV-1 was observed with the non-covalent mixture of Aco-HSA and AZT. When AZT was covalently coupled to the NCAs, and added one hour after infection of the target cells, the anti-HIV-1 activity of NCA-AZTMP was diminished by only 2-6-fold, while this was diminished at least 120-fold for the NCAs. Furthermore the addition of NCA-AZTMP could be delayed up to at least 3 h after infection without loss of antiviral activity. It is concluded that AZT that was coupled to the NCAs significantly contributes to the overall antiviral activity of the conjugates leading to complementary effects. These results highlight the potential of using NCA-AZTMP as dual-targeting preparations against HIV-1 in which both the carrier and the coupled drug contribute to the therapeutic efficacy acting at a different level in the replication cycle.