La Trobe
42666_SOURCE01_2_A.pdf (1.37 MB)

Synthesis of 7-O, 8-aryl- and 8-aryl-substituted 2-morpholino-benzoxazin-4-ones as DNA-PK, PI3K and PDE3A Inhibitors

Download (1.37 MB)
posted on 2023-01-18, 17:53 authored by Md Saifuzzaman
Compounds comprising a 2-morpholino-1,3-benzoxazine scaffold have been proven to possess important biological activities, especially with substitution at 7 and/or 8 positions and were reported in the literature however, extensive study of this particular substitution has not been done. So, a series of 8-aryl-7-(O-substituted)-2-morpholino-4H-benzo[1,3]oxazin-4-ones was synthesized via a key precursor, 8-bromo-7-hydroxy-2-morpholino-4H-benzo[1,3]oxazin-4- one 107 which was amenable to ether synthesis at the 7-position and Suzuki coupling at the 8- position. Another series of analogues of 8-(dibenzothiophen-4-yl)-2- morpholino‑4H‑benzo[1,3]oxazin-4-ones was also synthesized where various primary or secondary amines were placed at the 1-position of dibenzothiophene through an acetamido/propanamido- linkage. All new compounds were evaluated for their inhibitory activities against DNA-PK, PI3K isoforms and PDE3A enzymes. It was shown that 7, 8- disubstitution has no promising inhibitory effect on DNA-PK and PI3K isoforms except for PI3Kδ which was somewhat more tolerant of this substitution particularly where 8-(4- methoxylphenyl) substituents (114c, 115c, 116c and 118c) were present (IC50 ~ 2-3 μM). Good activities against PDE3A were obtained for this series of compounds, with particular members of the 7-(2-pyridinyl)methoxy series (114a, 114e, 114f and 114g) showing good inhibition (IC50 ~ 2-3 μM). In the case of 8-(dibenzothiophen-1-yl)-substitution series (134a-p), a number of compounds with a significant DNA-PK inhibition at sub-nanomolar range with excellent selectivity over the PI3K isoforms was obtained, such as the compound with 2,6- dimethylmorpholino-acetamido substitution at 1-dibenzothiophene (134d) had IC50 = 0.48 nM (at least 250 times more active against DNA-PK than PI3K isoforms). Several compounds also showed potent inhibition of specific PI3K isoforms. For example, the compound with 2- morpholinoacetamido substitution (134c) showed the most potent PI3Kδ isoform activity of all the compounds tested with IC50 = 50 nM and moderate PI3Kβ isoform inhibition (IC50 =100 nM). Other compounds had a potency in the low micromolar range in certain isoforms, and showed some diverse selectivity profiles. DNA-PK activity of N-(4-(2-morpholino-4-oxo-4Hbenzo[e][1,3]oxazin-8-yl)dibenzo[b,d]thiophen-1-yl)acrylamide 135 and 3-substituted-N-(4- (2-morpholino-4-oxo-4H-benzo[e][1,3]oxazin-8-yl)dibenzo[b,d]thiophen-1-yl)propanamide 136a-d was lower than that for acetamido-analogues 134a-p and the IC50 values were found to be 65.31-221.8 nM. The results indicate that 7, 8-disubstituted compounds have strong activity against PDE3A and PI3Kδ, whereas 8-(dibenzothiophen-1-yl)-substituted products have very high activity against DNA-PK and PI3K (β and δ) with good specificity.

Submission note: A thesis submitted in total fulfilment of the requirements for the degree of Doctor of Philosophy to the Department of Pharmacy & Applied Science, College of Science, Health and Engineering, La Trobe University, Bendigo, Victoria.


Center or Department

College of Science, Health and Engineering. Department of Pharmacy & Applied Science.

Thesis type

  • Ph. D.

Awarding institution

La Trobe University

Year Awarded


Rights Statement

This thesis contains third party copyright material which has been reproduced here with permission. Any further use requires permission of the copyright owner. The thesis author retains all proprietary rights (such as copyright and patent rights) over all other content of this thesis, and has granted La Trobe University permission to reproduce and communicate this version of the thesis. The author has declared that any third party copyright material contained within the thesis made available here is reproduced and communicated with permission. If you believe that any material has been made available without permission of the copyright owner please contact us with the details.

Data source

arrow migration 2023-01-10 00:15. Ref: latrobe:42666 (9e0739)

Usage metrics

    Open Theses


    No categories selected



    Ref. manager