Novel PARP-1 inhibitors based on a 2-propanoyl-3H-quinazolin-4-one scaffold

  • Bioorg Med Chem Lett. 2014 Jan 15;24(2):462-6. doi: 10.1016/j.bmcl.2013.12.048.
Giuseppe Giannini  1 ,  Gianfranco Battistuzzi  2 ,  Loredana Vesci  2 ,  Ferdinando M Milazzo  2 ,  Francesca De Paolis  2 ,  Marcella Barbarino  2 ,  Mario Berardino Guglielmi  2 ,  Valeria Carollo  2 ,  Grazia Gallo  2 ,  Roberto Artali  3 ,  Sabrina Dallavalle  4
Affiliations
  • 1. R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy. Electronic address: [email protected].
  • 2. R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
  • 3. Scientia Advice di Roberto Artali, 20832 Desio (MB), Italy.
  • 4. Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
PMID: 24388690 DOI: 10.1016/j.bmcl.2013.12.048
Abstract

Poly(ADP-ribose)polymerase-I (PARP-1) enzyme is involved in maintaining DNA integrity and programmed cell death. A virtual screening of commercial libraries led to the identification of five novel scaffolds with inhibitory profile in the low nanomolar range. A hit-to-lead optimization led to the identification of a group of new potent PARP-1 inhibitors, acyl-piperazinylamides of 3-(4-oxo-3,4-dihydro-quinazolin-2-yl)-propionic acid. Molecular modeling studies highlighted the preponderant role of the propanoyl side chain.

Keywords
3-(4-Oxo-3,4-dihydro-quinazolin-2-yl)-propionamides; Anticancer; Hit-to-lead optimization; Molecular modeling; PARP-1 inhibitors; Virtual screening of commercial libraries.