No abstract

Herein we report the discovery of new modulators of human phenylalanine hydroxylase (hPAH) inspired by the structure of its substrate and regulator l-phenylalanine.

Herein we demonstrate for the first time that a boron promoted one-pot assembly reaction may be used to discover novel enzyme inhibitors. Inhibitors for HNE were simply assembled in excellent yields, high diastereoselectivities and IC50 up to 1.10 μM, based on components like salicylaldehyde, aryl boronic acids and amino acids. The combination of synthetic, biochemical, analytical and theoretical studies allowed the identification of the 4-methoxy or the 4-diethyl amino substituent of the salicylaldehyde as the most important recognition moiety and the imine alkylation, lactone ring opening as key events in the mechanism of inhibition.

The dative N-B bond was used to simply assemble heterocycles with a skeleton akin to the 5-oxofuro[2,3-b]furan motif. Twenty-five new N-B heterocycles were prepared via a highly efficient one-pot four-component reaction in yields and diastereoselectivities up to 95% and >97%, respectively. Several reaction intermediates were discovered using electrospray ionization mass spectroscopy which set the basis for the mechanism elucidation using DFT calculations.