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

Figures & data

Figure 1. Several biologically active coumarin molecules (2H-1-benzopyran-2-one).

Figure 2. Some benzoxazine structures of ADP and/or collagen-induced platelet aggregation, DNA-PK and PI3K inhibitors.

Table 1. PI3K inhibition IC₅₀ of product 12b, 13b, 15a and 17b,c.

Name	Structure	PI3Kα IC50 (μM)	PI3Kβ IC50 (μM)	PI3Kγ IC50 (μM)	PI3Kδ IC50 (μM)
12b		>100	49.10	69.70	81.00
13b		14.7	>100	5.56	>100
15a		>100	23.10	>100	28.26
17a		>100	>100	>100	5.08
17b		>100	>100	>100	>100

Scheme 1. Synthesis of substituted-7-hydroxy-2-oxo-2H-chromene-6-carboxylic acid 10a–f, 11a–c and chromene-8-carboxylic acids 12a–c & 13a,b.

Scheme 2. Synthesis of substituted-2-thioxo-chromen-1,3-oxazine linear compounds 14, angular compounds 16, 2-morpholino-substituted-chromen[6,7-e][1,3]oxazine-4,8-dione 15 and 8-morpholino-substituted-chromen[8,7-e][1,3]oxazine-2,10-dione 17. Reaction conditions: (i) freshly prepared Ph₃P(SCN)₂; (ii) morpholine in dioxane/reflux.

Scheme 3. Synthesis of mono- and di-bromo-2-morpholino-substituted-benzoxazines 19a–c. Reaction condition: (i) NaHCO₃\in water/2-propanol/MeI; (ii) morpholine/RT.

Scheme 4. Outline the reactions of substituted-2-thioxo and 2-methyl thio-chromen-1,3-oxazine linear compounds 14a,b and 22a,b with benzylamine and 2-(pyrdin-3-yl-amino) respectively. Reaction conditions: (i) NaHCO₃/benzylamine in water/2-propanol; (ii) NaHCO₃ in water/2-propanol/MeI; (iii) 3-aminopyridine; (iv) benzylamine.