3D-QSAR Study Of T315I Mutant Dual Inhibitors And Synthesis Of Chiral Nilotinib Derivative

At present,the clinical application of tyrosine kinase inhibitors is the main treatment of chronic myeloid leukemia.The recommended drug is nilotinib,which is resistant to drug resistance caused by imatinib drugs.Howener,it is difficult to overcome the mutations targeting T3151.According to computer-aided drug design method,a 3D-QSAR analysis of the double function inhibitor of benzothiazole for T315I mutation was complied,and highpredictive models were constructed,providing the theoretical basis for the further design of efficient tyrosine kinase inhibitors.Meanwhile,a new chiral derivative of nilotinibintroducing a novel chiral heterocyclic group of bafutinibwassynthesized.It is hope to be active on T315I mutation.The main research contents are:First?Three-Dimensional Quantitative Structure-Activity Relationships of Benzothiazole Dual functional Inhibitors for T315I MutationIn this paper,a group of 49 compounds with dual functional inhibitors of small molecular ligands were studied to obtaine some useful information for further research,by using three-dimensional quantitative structure-activity relationship study belong to ligand-based drug design method in computer aided drug design,and molecular docking based on the receptor structure.Each method has been a better highly predictive model with SOMFA model(q2 = 0.720,r2 = 0.748,F value = 124.9,and SEE = 0.761),CoMFA model(q2?0.586,r2 = 0.951,F value = 118.9,and SEE = 0.359),and CoMSIA model(q2=0.673,r2 = 0.88,F value = 45.2,and SEE = 0.560)were obtained.In addition,molecular docking studies applied to locate the binding orientations and conformations of these derivatives with Ab1 WT and Ab1 T315I.These results from 3D-QSAR and docking studies have great significance for designing novel Tyrosine kinase inhibitors in the future.Second?The Synthesis of Novel Chiral Nilotinib DerivativesAccording to the synthesis of nilotinib and the introduction of chiral heterocyclic group(R)-N-(3-(3-(dimethylamino)pyrrolidine,a derivative of nilotinib,called(R)-N-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)-5-(trifluoromethyl)pheyl)-4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)be nzamide was synthesized.Then,a new imatinib intermediate called 3-bromo-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-5-(tri fluoromethyl)benzamide was synthesizedSome of these steps have been improved and optimized for higher yields.Thestructures ofsome compounds are characterized by NMR,IR,and HRMS.