Dihydroquinazolines enhance 20S proteasome activity and induce degradation of α-synuclein, an intrinsically disordered protein associated with neurodegeneration.

Aggregates or oligomeric forms of many intrinsically disordered proteins (IDPs), including α-synuclein, are hallmarks of neurodegenerative diseases, like Parkinson's and Alzheimer's disease, and key contributors to their pathogenesis. Due to their disordered nature and therefore lack of defined drug-binding pockets, IDPs are difficult targets for traditional small molecule drug design and are often referred to as "undruggable". The 20S proteasome is the main protease that targets IDPs for degradation and therefore small molecule 20S proteasome enhancement presents a novel therapeutic strategy by which these undruggable IDPs could be targeted. The concept of 20S activation is still relatively new, with few potent activators having been identified thus far. Herein, we synthesized and evaluated a library of dihydroquinazoline analogues and discovered several promising new 20S proteasome activators. Further testing of top hits revealed that they can enhance 20S mediated degradation of α-synuclein, the IDP associated with Parkinson's disease.

One-Pot Tandem Assembly of Amides, Amines, and Ketones: Synthesis of C4-Quaternary 3,4- and 1,4-Dihydroquinazolines.

A multicomponent tandem assembly procedure for the synthesis of diverse C4-quaternary 3,4-dihydroquinazolines from amides, amines, and ketones has been developed. The one-pot reaction involves successive triflic anhydride mediated amide dehydration, ketimine addition, and Pictet-Spengler-like cyclization processes and affords products in up to 92% yield. Conversion of 3,4-dihydroquinazolines to the corresponding 1,4-dihydroquinazolines via a two-step N1 dealkylation and regioselective N3 functionalization protocol, including computational rationale for the observed regioselectivity, is also described.

Triflic anhydride mediated synthesis of 3,4-dihydroquinazolines: a three-component one-pot tandem procedure.

A one-pot three-component tandem reaction involving a key Pictet-Spengler-like annulation step has been developed, providing an efficient method for the synthesis of 3,4-dihydroquinazolines in moderate to good yields from amides, aldehydes, and amines. The multicomponent triflic anhydride mediated reaction tolerates the installation of numerous functional groups, affording extensive diversity about the heterocyclic scaffold.