Correlation between Functionality Preference of Ru Carbenes and <i>exo</i>/<i>endo</i> Product Selectivity for Clarifying the Mechanism of Ring-Closing Enyne Metathesis

Functionality preferences of metathesis Ru carbenes to various alkenes and alkynes with electronic and steric diversity were determined by using time-dependent fluorescence quenching. The functionality preferences depend not only on the properties of multiple bonds but also on the ligands on Ru. There was a good correlation between functionality preference and the metathesis reaction outcome. The correlation between functionality preference and <i>exo</i>/<i>endo</i> product ratio offers a solution to resolve the mechanistic issue related with alkene- vs alkyne-initiated pathway in ring-closing enyne metathesis. The correlation indicates the preference is likely to dictate the reaction pathway and eventually the outcome of the reaction. The Ru catalyst favoring alkyne over alkene provides more <i>endo</i> product, indicating that the reaction mainly initiates at the alkyne. By changing the substitution pattern, the preference can be reversed to give an exclusive <i>exo</i> product

Discovery of Phenylaminopyridine Derivatives as Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

We identified a novel class of aryl-substituted triazine compounds as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) during a high-throughput screening campaign that evaluated more than 200000 compounds for antihuman immunodeficiency virus (HIV) activity using a cell-based full replication assay. Herein, we disclose the optimization of the antiviral activity in a cell-based assay system leading to the discovery of compound <b>27</b>, which possessed excellent potency against wild-type HIV-1 (EC₅₀ = 0.2 nM) as well as viruses bearing Y181C and K103N resistance mutations in the reverse transcriptase gene. The X-ray crystal structure of compound <b>27</b> complexed with wild-type reverse transcriptase confirmed the mode of action of this novel class of NNRTIs. Introduction of a chloro functional group in the pyrazole moiety dramatically improved hERG and CYP inhibition profiles, yielding highly promising leads for further development