Abstract
Herein is novel 2-morpholino substituted-1,3-benzoxazines compounds were synthesized and introduced as potential potent DNA-PK inhibition. The study revealed that the substituent factors directly affecting activity. The results were promising and resulted in compounds 7c, and 9f with good DNA-PK inhibition activities and might be used as leads after further optimization.
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•DNA-PK enzyme has emerged as an attractive target for drug discovery efforts toward DNA repair pathways.•2D QSAR and pharmacophore modeling processes which in turn were able to predict the activity of proposed structures for saving the time and money.•We e report the design, synthesis, characterization, and modeling studies for novel small molecule DNA-PK inhibitors based upon structure-activity relationship analysis of different reference ligands.•The molecular docking of compound L-27 in the DNA-PK homology model revealed the importance of this side chain which was responsible for its activity.
Drugs of cancer based upon ionizing radiation or chemotherapeutic treatment may affect breaking of DNA double strand in cell. DNA-PK enzyme has emerged as an attractive target for drug discovery efforts toward DNA repair pathways. Hence, the search for potent and selective DNA-PK inhibitors has particularly considered state-of-the art and several series of inhibitors have been designed. In this article, a novel benchmark DNA-PK database of 43 compounds was built and described. Ligand-based approaches including pharmacophore and QSAR modeling were applied and novel models were introduced and analyzed for predicting activity test for DNA-PK drug candidates. Based upon the modeling results, we gave a report of synthesis of fifteen novel 2-((8-methyl-2-morpholino-4-oxo-4H-benzo[e][1,3]oxazin-7-yl)oxy)acetamide derivatives and in vitro evaluation for DNA-PK inhibitory and antiproliferative activities. These fifteen compounds overall are satisfied with Lipinski's rule of five. The biological testing of target compounds showed five promising active compounds 7c, 7d, 7f, 9e and 9f with micromolar DNA-PK activity range from 0.25 to 5µM. In addition, SAR of the compounds activity was investigated and confirmed that the terminal aryl moiety was found to be quite crucial for DNA-PK activity. Moreover flexible docking simulation was done for the potent compounds into the putative binding site of the 3D homology model of DNA-PK enzyme and the probable interaction model between DNA-PK and the ligands was investigated and interpreted.