Synthesis and biological evaluation of 8-aryl-2-morpholino-7-O-substituted benzo[ e ][1,3]oxazin-4-ones against DNA-PK, PI3K, PDE3A enzymes and platelet aggregation Academic Article uri icon


  • A series of 40 7-(O-substituted)-2-morpholino-8-aryl-4H-benzo[e][1,3]oxazin-4-one derivatives was synthesized. They were prepared via synthesis of a key precursor, 8-bromo-7-hydroxy-2-morpholino-4H-benzo[e][1,3]oxazin-4-one 13 which was amenable to ether synthesis at the 7-position and Suzuki coupling at the 8-position. The 2 protons of 7-OCH2 in compounds 18g, 18h, 18i, 18l and 18m prove to be magnetically non-equivalent, atropisomerism (axial chirality), as result of sterically hindered rotation of the bulky 8-aryl-substituent. The products were evaluated for their activities against PI3K isoforms, DNA-PK and PDE3. The results showed that this substitution pattern has a deleterious effect on PI3K activities, which may arise from steric hindrance in the active site. PI3Kδ was somewhat more tolerant of this substitution particularly where 8-(4-methoxylphenyl) substituents were present (IC50s∼2-3μM). Good activities against PDE3 were also obtained for compounds, with particular members of the 7-(2-pyridinyl) methoxy series 19 showing good inhibition (IC50s∼2-3μM), comparable to previously described analogues. A piperazinyl derivative 26a effectively inhibited ADP-induced platelet aggregation with an IC50 of 8μM.


  • Saifuzzaman, Md
  • Morrison, Rick
  • Zheng, Zhaohua
  • Orive, Stephanie
  • Hamilton, Justin
  • Thompson, Philip E
  • Al-Rawi, Jasim MA

publication date

  • 2017