Continuous Flow α-Arylation of N,N-Dialkylhydrazones under Visible-Light Photoredox Catalysis.

The first direct α-arylation of aldehyde-derived N,N-dialkylhydrazones with electron deficient aryl and heteroaryl cyanides under visible-light photoredox catalysis has been developed. Structurally complex α,α'-diaryl-N,N-cycloalkylhydrazones were obtained in moderate yields by repetition of the direct arylation protocol. A continuous-flow procedure for the preparation of α-aryl-N,N-dialkylhydrazones on a multigram scale has also been established.

Acylguanidine Beta Secretase 1 Inhibitors: A Combined Experimental and Free Energy Perturbation Study.

A series of acylguanidine beta secretase 1 (BACE1) inhibitors with modified scaffold and P3 pocket substituent was synthesized and studied with free energy perturbation (FEP) calculations. The resulting molecules showed potencies in enzymatic BACE1 inhibition assays up to 1 nM. The correlation between the predicted activity from the FEP calculations and the experimental activity was good for the P3 pocket substituents.

Application of Free Energy Perturbation for the Design of BACE1 Inhibitors.

Novel spiroaminodihydropyrroles probing for optimized interactions at the P3 pocket of β-secretase 1 (BACE1) were designed with the use of free energy perturbation (FEP) calculations. The resulting molecules showed pIC50 potencies in enzymatic BACE1 inhibition assays ranging from approximately 5 to 7. Good correlation was observed between the predicted activity from the FEP calculations and experimental activity.

A Versatile Approach to CF3 -Containing 2-Pyrrolidones by Tandem Michael Addition-Cyclization: Exemplification in the Synthesis of Amidine Class BACE1 Inhibitors.

The synthesis of new fluorinated pyrrolidones starting from unprotected amino esters and amino nitriles through a Michael addition-lactamization sequence is described. The resulting CF3 -containing building blocks, bearing a quaternary stereogenic center adjacent to the fluorinated group, have been converted into amino pyrrolidines that display potent β-secretase 1 (BACE1) inhibitory activity. This work constitutes an example of selective fluorination as a valid strategy for the modulation of physicochemical and biological properties of lead compounds in drug discovery.