Title:Design, Synthesis and Biological Evaluation of Novel Urea and Thiourea Bearing thieno[3,2-d]-pyrimidines as PI3 Kinase Inhibitors
VOLUME: 18 ISSUE: 6
Author(s):Srinu Bodige, Parameshwar Ravula, Kali Charan Gulipalli, Srinivas Endoori, J.N. Narendra Sharath Chandra, Purna Koteswara Rao Cherukumalli, Vanaja.G.R and Nareshvarma Seelam*
Affiliation:Department of Chemistry, Koneru Lakshmaiah Education Foundation, Green Fields, Vaddeswaram, Guntur, 522502, Department of Pharmaceutical Chemistry, Gurunanak Institutions Technical Campus, School of Pharmacy, Hyderabad, 501506, Department of Chemistry, Koneru Lakshmaiah Education Foundation, Green Fields, Vaddeswaram, Guntur, 522502, Department of Chemistry, Koneru Lakshmaiah Education Foundation, Green Fields, Vaddeswaram, Guntur, 522502, Department of Pharmaceutical Chemistry,Bharath Institute of Technology-Pharmacy, Hyderabad, 501506, Department of Chemistry, Koneru Lakshmaiah Education Foundation, Green Fields, Vaddeswaram, Guntur, 522502, Department of Animal Biology, University of Hyderabad, Hyderabad, 500046, Department of Chemistry, Koneru Lakshmaiah Education Foundation, Green Fields, Vaddeswaram, Guntur, 522502
Keywords:Thieno [3, 2-d]-pyrimidines, anticancer agents, molecular docking, PI3K inhibitors, novel urea, facile synthetic methods.
Abstract:Background: Phosphatidylinositol-3-kinase α (PI3Kα) 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 PI3Kα 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 (7f) showed the highest anticancer activity against HT-29 and MCF-7 cell lines
with IC50 values of 2.18 µM and 4.25 µM, respectively. Further, the same compound also exhibited potent
PI3Kα inhibitory activity with IC50 value of 1.26 µM.
Conclusion: Docking studies supported the initial pharmacophoric hypothesis and suggested a mode of interaction
at the active binding site of PI3Kα, demonstrating that the target compounds were potential inhibitory
agents for cancer therapy.
