One Pot Synthesis of Micromolar BACE-1 Inhibitors Based on the Dihydropyrimidinone Scaffold and Their Thia and Imino Analogues

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-09, Vol.25 (18), p.4152
• Main Authors: Bais, Jessica, Benedetti, Fabio, Berti, Federico, Cerminara, Iole, Drioli, Sara, Funicello, Maria, Regini, Giorgia, Vidali, Mattia, Felluga, Fulvia
• Format: Article
• Language: English
• Subjects: Aldehydes; Alzheimer’s disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - chemistry; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; BACE-1 inhibitors; Biginelli reaction; Binding sites; Carbonyl compounds; Chemistry Techniques, Synthetic; dihydropyrimidinones; Enzymes; Guanidine hydrochloride; Hydrogen bonds; Models, Molecular; Molecular Conformation; Molecular Structure; Peptides; Proteins; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Secretase; Structure-Activity Relationship; Sulfur; Thiourea; Urea; β-secretase; β-Site APP-cleaving enzyme 1; β-Site APP-cleaving enzymes
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25184152

A library of dihydropyrimidinones was synthesized via a "one-pot" three component Biginelli reaction using different aldehydes in combination with β-dicarbonyl compounds and urea. Selected 2-thiooxo and 2-imino analogs were also obtained with the Biginelli reaction from thiourea and guanidine hydrochloride, respectively. The products were screened in vitro for their β-secretase inhibitory activity. The majority of the compounds resulted to be active, with IC in the range 100 nM-50 μM.