title: Synthesis, structure elucidation, DNA-PK, PI3K, anti-platelet and anti-bacteria activity of linear 5, 6, and 10-substituted-2-morpholino-chromen-oxazine-dione and angular 3, 4, 6-substituted-8-morpholino-chromen-oxazine-2,10-dione.
abstract: Coumarin, a naturally occurring or synthesised phytochemical, displays a wide range of biological activities. However, chromen-2-ones fused with 1,3-benzoxazine rings is not well documented and there is a gap in the literature which required engaging. The substituted-2-thioxo-chromen-oxazine linear compounds 14a-i and angular compounds 16a-e were synthesised from the reaction of hydroxy-substituted-chromene-carboxylic 10-13 with freshly prepared Ph3P(SCN)2. 2-Morpholino-substituted-chromen-oxazine-4,8-dione and 8-morpholino-substituted-chromen-oxazine-2,10-dione 15a-f and 17 were synthesised from the reaction of the corresponding oxazines 14 and 16 with morpholine. PI3K activity was observed for the hydroxy-substituted-chromene-carboxylic acid of which compound 13b showed moderate PI3Kγ (IC50=5.56 μM) and PI3Kα (IC50=14.7 μM) activity. Additionally, 8-morpholino-chromen-oxazine-2,10-dione 17a showed isoform selective PI3Kδ activity with IC50=5.08 μM with non-DNA-PK ≥ 100 μM. Consequently compound 17a can be considered as a selective PI3Kδ inhibitor with non-DNA-PK at compound concentrations ≥100 μM.
authors.affiliation: a Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University , Bendigo , VIC , Australia.
authors.forename: Rick
authors.initials: R
authors.lastname: Morrison
authors.affiliation: a Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University , Bendigo , VIC , Australia.
authors.forename: Jasim M A
authors.initials: JM
authors.lastname: Al-Rawi
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects*; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D013293:Enterococcus faecalis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D051747:DNA-Activated Protein Kinase; D009025:Morpholines; D010078:Oxazines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010975:Platelet Aggregation Inhibitors; D047428:Protein Kinase Inhibitors; C000614128:2-morpholino-chromen-oxazine-dione; C000614127:8-morpholino-chromen-oxazine-2,10-dione
keywords: Anti-bacterial activity; DNA-PK; PI3K; anti-platelet; morpholino-chromen[1,3]oxazines