Design, Synthesis and Biological Evaluation of Novel Urea and Thiourea Bearing thieno[3,2-d]-pyrimidines as PI3 Kinase Inhibitors

Background: Phosphatidylinositol-3-kinase a (PI3K alpha) is a ubiquitous intracellular enzyme, mainly involved in intracellular signaling pathways, promotes cellular growth, proliferation, and differentiation. Therefore, inhibition of PI3K can be a hotspot in molecular targeted therapy for the treatment of cancer. Methods: The present research work involves molecular docking studies performed to screen derivatives of urea and thiourea bearing thieno [3,2-d]-pyrimidines against the active site of PI3K enzyme using MOE.2008.10. The designed structures (6a-f) and (7a-j) were synthesized by the facile synthetic methods and evaluated for their anticancer activity against HT-29 and MCF-7 cell lines and inhibitory activity against PI3K alpha enzyme. Results: Among the tested compounds, 4-(4-(2-(3-(pyrimidin-2-yl)thioureido)ethyl)piperazin-1-yl)thieno[3,2-d]pyrimidine-6-carboxamide (70 showed the highest anticancer activity against HT-29 and MCF-7 cell lines with IC50 values of 2.18 mu M and 4.25 mu M, respectively. Further, the same compound also exhibited potent PI3K alpha inhibitory activity with IC50 value of 1.26 mu M. Conclusion: Docking studies supported the initial pharmacophoric hypothesis and suggested a mode of interaction at the active binding site of PI3K alpha, demonstrating that the target compounds were potential inhibitory agents for cancer therapy.