Computer Modelling Studies Of Quinazolinone Derivatives As Novel PI3K? Inhibitors And Design,Synthesis Studies Of Dabigatran Derivatives

The phosphoinositide 3-kinase??PI3K??was over-expressed in some malignant cells,rendering it a key drug target for chronic lymphocytic leukaemia.Dabigatran has gained wide attention as a landmark cardiovascular drug,but it has some defects.It is necessary to make structural modification and synthesis study.In the first section,the interaction mechanism of 37 novel quinazolinone scaffold-based derivatives as PI3K?inhibitors was systemically explored by using 3D-QSAR,molecular docking,pharmacophore model and molecular dynamics?MD?simulations.The 3D-QSAR models with high predictability and reliability were established.Contour maps indicated that the bioactivity of PI3K?inhibitor was mainly affected by electrostatic and hydrophobic fields.Surflex-dock and pharmacophore model result showed that enhancing the H-bond interaction of the key substituents around the 2-and 4-positions of pyrimidine with Glu826,Val828 and Asp911,as well as the electrostatic interactions of substituents around the 3-position of benzene with Ser831,Asp832 and Asn836,significantly improve the binding stability of the inhibitor.10 novel PI3K?inhibitors?D1-D10?with higher predicted activity and binding affinity were designed.MD simulations indicated that the newly designed compounds have better binding affinity with the PI3K?proteins.In the second section,computer modelling study of novel dabigatran derivatives was performed to study the structure-activity relationship and interaction mode of novel dabigatran derivatives.The compounds with higher docking scores were screened by molecular docking.Finally the compounds 14a-14c were synthesized,and the synthetic route was optimized.The structures were characterized by ¹H NMR,¹³C NMR and HR-MS.In summary,newly synthesized compounds can be further studied as potential anticoagulant inhibitors.These research results provided strong theoretical guidance for the development of novel PI3K?selective inhibitors,and offer important reference value for the further study of dabigatran derivatives.