Synthesis of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide and 3-oxo-3,4-dihydrobenzo[b][1,4]oxazine-8-carboxamide derivatives as PARP1 inhibitors

  • Bioorg Chem. 2020 Sep;102:104075. doi: 10.1016/j.bioorg.2020.104075.
Xuwei Shao  1 ,  Steven Pak  1 ,  Uday Kiran Velagapudi  1 ,  Shruthi Gobbooru  1 ,  Sai Shilpa Kommaraju  1 ,  Woon-Kai Low  1 ,  Gopal Subramaniam  2 ,  Sanjai Kumar Pathak  3 ,  Tanaji T Talele  4
Affiliations
  • 1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
  • 2. Chemistry and Biochemistry Department, Queens College of the City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA.
  • 3. Chemistry and Biochemistry Department, Queens College of the City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA; Chemistry Doctoral Program, Biochemistry Doctoral Program, The Graduate Center of the City University of New York, 365 5th Ave, New York, NY 10016, USA. Electronic address: [email protected].
  • 4. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA. Electronic address: [email protected].
PMID: 32777641 DOI: 10.1016/j.bioorg.2020.104075
Abstract

Poly(ADP-ribose) polymerase 1 (PARP1), a widely explored Anticancer drug target, plays an important role in single-strand DNA break repair processes. High-throughput virtual screening (HTVS) of a Maybridge small molecule library using the PARP1-benzimidazole-4-carboxamide co-crystal structure and pharmacophore model led to the identification of eleven compounds. These compounds were evaluated using recombinant PARP1 enzyme assay that resulted in the acquisition of three PARP1 inhibitors: 3 (IC50 = 12 μM), 4 (IC50 = 5.8 μM), and 10 (IC50 = 0.88 μM). Compound 4 (2,3-dihydro-1,4-benzodioxine-5-carboxamide) was selected as a lead and was subjected to further chemical modifications, involving analogue synthesis and scaffold hopping. These efforts led to the identification of (Z)-2-(4-hydroxybenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (49, IC50 = 0.082 μM) as the most potent inhibitor of PARP1 from the series.

Keywords
1,4-benzodioxine; 1,4-benzoxazin-3-one; Knoevenagel condensation; PARP1; Virtual screening.
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