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

Md Saifuzzaman; Rick Morrison; Zhaohua Zheng; Stephanie Orive; Justin Hamilton; Philip E Thompson; Jasim M A Al-Rawi

doi:10.1016/j.bmc.2017.08.022

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

Bioorg Med Chem. 2017 Oct 15;25(20):5531-5536. doi: 10.1016/j.bmc.2017.08.022. Epub 2017 Aug 15.

Authors

Md Saifuzzaman¹, Rick Morrison², Zhaohua Zheng³, Stephanie Orive⁴, Justin Hamilton⁵, Philip E Thompson⁶, Jasim M A Al-Rawi⁷

Affiliations

¹ Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199 Bendigo, VIC 3552, Australia. Electronic address: M.Saifuzzaman@latrobe.edu.au.
² Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199 Bendigo, VIC 3552, Australia. Electronic address: rmmorrison@students.latrobe.edu.au.
³ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: joyce.zheng@monash.edu.
⁴ Australian Centre for Blood Diseases and Department of Clinical Haematology, Monash University, 99 Commercial Road, Melbourne, Victoria 3004, Australia. Electronic address: Stephanie.orive@gmail.com.
⁵ Australian Centre for Blood Diseases and Department of Clinical Haematology, Monash University, 99 Commercial Road, Melbourne, Victoria 3004, Australia. Electronic address: Justin.Hamiltom@monash.edu.
⁶ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: Philip.Thompson@monash.edu.
⁷ Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199 Bendigo, VIC 3552, Australia. Electronic address: j.al-rawi@latrobe.edu.au.

PMID: 28838830
DOI: 10.1016/j.bmc.2017.08.022

Abstract

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.

Keywords: Antiplatelet activity; DNA-PK; PDE3A; PI3K; Synthesis of O-substituted-2-morpholino-8-aryl-benzo-oxazin-4-one.

MeSH terms

Benzoxazines / chemical synthesis
Benzoxazines / chemistry
Benzoxazines / pharmacology*
Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
DNA-Activated Protein Kinase / antagonists & inhibitors*
DNA-Activated Protein Kinase / metabolism
Dose-Response Relationship, Drug
Humans
Molecular Structure
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Platelet Aggregation / drug effects
Platelet Aggregation Inhibitors / chemical synthesis
Platelet Aggregation Inhibitors / chemistry
Platelet Aggregation Inhibitors / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Benzoxazines
Phosphoinositide-3 Kinase Inhibitors
Platelet Aggregation Inhibitors
Protein Kinase Inhibitors
benzo(e)(1,3)oxazin-4-one
DNA-Activated Protein Kinase
Cyclic Nucleotide Phosphodiesterases, Type 3
PDE3A protein, human