The concept of a nonresonant microwave applicator for continuous-flow organic chemistry is introduced and evaluated. The frequency of the incident microwave radiation can be adjusted between 2.4 and 2.5 GHz to optimize the energy absorbance. The temperature of the reaction is monitored by five IR sensors, and their signals can be used to automatically adjust the power output from the microwave generator. The heating of several different solvents up to 20°C above the standard boiling point has been explored. Several different organic reactions have been successfully carried out using a 200 mm × ⌽ 3 mm tubular borosilicate reactor and a flow between 47 and 2120 μL/min. The microwave heating pattern was visualized with an IR camera. The transformations include palladium-catalyzed coupling reactions (oxidative Heck and Suzuki reactions), heterocyclic chemistry (oxathiazolone and Fischer indole synthesis), rearrangement (Claisen), and a Diels−Alder cycloaddition reaction. A scale-out to 57 mmol/h was performed with the Fischer indole reaction.
A new generation of HIV-1 protease inhibitors encompassing a tertiary-alcohol-based transition-state mimic has been developed. By elongation of the core structure of recently reported inhibitors with two carbon atoms and by varying the P1' group of the compounds, efficient inhibitors were obtained with Ki down to 2.3 nM and EC50 down to 0.17 microM. Two inhibitor-enzyme X-ray structures are reported.
Two series, including in total 18 novel HIV-1 protease inhibitors, comprising a tertiary alcohol as the transition-state mimic have been synthesised and evaluated. Replacement of the previously used, but metabolically unstable, indanol amide group with amino acid derived aliphatic P2-P3 moieties provided potent inhibitors with low K i -and EC 50 -values (2.7 nM and 2.0 mM, respectively). The P1 0 subunit was varied using 10 different aromatic and heteroaromatic substituents furnishing the corresponding inhibitors with retained activity. Permeability and stability studies showed examples in the same range as Atazanavir. X-Ray crystallographic analysis of two selected inhibitor enzyme cocomplexes (9a and 9d) supplied detailed structural information. The binding modes were compared to those of Atazanavir and a previously reported indanol amide containing inhibitor ( 14). The novel inhibitors with an elongated P1 0 side chain enabled a previously unexploited edge-on interaction with Phe53/153. Exchange of the previously used indanol amide P2 moiety, with a tert-leucine derived P2-P3 side chain, furnished small main chain displacements in the S2-S3 pocket. The methyl amide in the P3 position caused a 2 A shift of the Arg8/108 in comparison to 14, indicating the flexibility of the protease active site.
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