Design, synthesis, molecular modelling and biological evaluation of novel 6-amino-5-cyano-2-thiopyrimidine derivatives as potent anticancer agents against leukemia and apoptotic inducers.

Herein, a novel series of 6-amino-5-cyano-2-thiopyrimidines and condensed pyrimidines analogues were prepared. All the synthesized compounds and were evaluated for anticancer activity by the National Cancer Institute (NCI; MD, USA) against 60 cell lines. Compound showed promising anticancer activity and was selected for the five-dose testing. Results demonstrated that compound possessed broad spectrum anti-cancer activity against the nine cancerous subpanels tested with selectivity ratio ranging from 0.7 to 39 at the GI level with high selectivity towards leukaemia. Mechanistic studies showed that Compound showed comparable activity to Duvelisib against PI3Kδ (IC = 0.0034 and 0.0025 μM, respectively) and arrested cell cycle at the S phase and displayed significant increase in the early and late apoptosis in HL60 and leukaemia SR cells. The necrosis percentage showed a significant increase from 1.13% to 3.41% in compound treated HL60 cells as well as from 1.51% to 4.72% in compound treated leukaemia SR cells. Also, compound triggered apoptosis by activating caspase 3, Bax, P53 and suppressing Bcl. Moreover, revealed a good safety profile against human normal lung fibroblast cell line (WI-38 cells). Molecular analysis of Duvelisib and compound in PI3K was performed. Finally, these results suggest that 2-thiopyrimidine derivative might serve as a model for designing novel anticancer drugs in the future.