Synthesis, biological evaluation and molecular docking studies of tetrahydropyrido[3, 4- d ]pyrimidine derivatives as anti-leukemic agents

Substituted tetrahydropyrido[3,4- d ]pyrimidine derivatives ( 2a -l ) have been synthesized through a series of Nsubstitution, Suzuki coupling, deprotection and condensation reactions. The structure of new compounds was analysed by interpretations of FTIR, 1 H NMR, 13 C NMR, and mass spectral data. The synthesised compounds were tested for their anti-leukaemic activity on wild type K562 (K562 -WT) and IR1 and IR2 cell lines that are imatinib resistant due to clonal evolution. The compounds 2b , 2c , 2i , 2k and 8 showed were high HEK293 cells. Molecular docking studies using crystal structure of drug -resistant ABL-T315I mutant revealed the ability of these molecules to overcome resistance due to mutations in the ABL kinase. Notably, experimental and computational analyses identified that compound 8 exhibited highest anti -leukemic activity and potential to overcome drug resistance arising due to multiple molecular mechanisms.