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

Abstract

Substituted tetrahydropyrido[3,4-d]pyrimidine derivatives (2a-l) have been synthesized through a series of N-substitution, Suzuki coupling, deprotection and condensation reactions. The structure of new compounds was analysed by interpretations of FTIR,1H NMR, 13C 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.

Keywords

• Pyrido[3,4-d]pyrimidine
• Suzuki coupling
• Anti-leukaemic activity
• Drug resistance
• Molecular docking