Arafa R.K.Nour M.S.El-Sayed N.A.Department of Pharmaceutical ChemistryFaculty of PharmacyCairo UniversityKasr El-Aini StreetCairo 11562Egypt; Department of Pharmaceutical ChemistryFaculty of PharmacyMSA University6th October CityCairoEgypt2020-01-092020-01-0920132235234https://doi.org/10.1016/j.ejmech.2013.08.042PubMed ID 24090920https://t.ly/VZKExScopusNovel heterocyclic-fused pyrimidines viz pyrrolo[1,2-c]pyrimidines 4-8, pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines 9-14, pyrimido[4?,5?:4,5] pyrimido[1,6-a]azepines 16-18, pyrrolo[1?,2?:1,6]pyrimido[4,5-d][1, 3]thiazines 19a,b and 1,3-thiazino[4?,5?:4,5]pyrimido[1,6-a]-azepine 19c were designed and synthesized as potential anticancer agents. In this investigation all the newly synthesized compounds were subjected to cytotoxic screening against MCF-7 breast cancer cell line. Moreover, kinase inhibitory assay was done for compounds 5, 7, 9 and 18 against the non-receptor and receptor tyrosine kinases c-Src and VEGFR, respectively. The tested compounds were more potent against c-Src than VEGFR, and the highest activity was observed for 18 showing 81% c-Src activity inhibition. Finally, molecular docking was performed with c-Src and VEGFR in an attempt to simulate and understand the possible binding interactions underlying the association between these small molecules and the kinase enzyme ATP binding pocket essential amino acids. � 2013 Elsevier Masson SAS. All rights reserved.EnglishAntiproliferative agentsc-Src and VEGFR inhibitionFused pyrimidinesMCF-7 breast cancer cell line1 amino 5 phenyl 3 thioxo 3,5,8,9,10,10a hexahydropyrimido[5,4 e]pyrrolo[1,2 c] pyrimidin 6(4h) one1 amino 5 phenyl 3 thioxo 3,5,8,9,10,11,12,12a octahydropyrimido[4',5':4,5] pyrimido[1,6 a]azepin 6(4h) one1 amino 5 phenyl 8,9,10,10a tetrahydropyrimido[5,4 e]pyrrolo[1,2 c]pyrimidine 3,6(4h,5h) dithione1 chloro 5 phenyl 8,9,10,10a tetrahydropyrimido[5,4 e]pyrrolo[1,2 c]pyrimidine 6(5h) one1 hydrazino 5 phenyl 8,9,10,10a tetrahydropyrimido[5,4 e]pyrrolo[1,2 c]pyrimidine 6(5h) one1 imino 2,5 diphenyl 1,5,8,9,10,10a hexahydropyrimido[5,4 e]pyrrolo[1,2 c]pyrimidine 3,6(2h,4h) dione1 oxo 2 phenyl 3 (2,4,5 trioxo 3 phenylimidazolidin 1 yl) 1,2,4a,5,6,7 hexahydro pyrrolo[1,2 c]pyrimidine 4 carbonitrile1 oxo 2 phenyl 3 (2,5 dioxo 3 phenylimidazolidin 1 yl) 1,2,4a,5,6,7 hexahydro pyrrolo[1,2 c]pyrimidine 4 carbonitrile1 oxo 2 phenyl 3 (n p tolylcarbamoylmethyl)amino 1,2,4a,5,6,7 hexahydro pyrrolo[1,2 c]pyrimidine 4 carbonitrile1 oxo 3 (3 phenylthioureido) 1,2,4a,5,6,7 hexahydropyrrolo[1,2 c]pyrimidine 4 carbonitrile1 oxo 3 (3 phenylureido) 1,2,4a,5,6,7 hexahydropyrrolo[1,2 c]pyrimidine 4 carbonitrile1[(4 chlorobenzylidene)amino] 5 phenyl 3 thioxo 3,5,8,9,10,10a hexahydro pyrimido[5,4 e]pyrrolo[1,2 c] pyrimidin 6(4h) one1[(4 chlorobenzylidene)amino] 5 phenyl 3 thioxo 3,5,8,9,10,10a octahydropyrimido[5,4 e]pyrrolo[1,2 c] pyrimidin 6(4h) one2 phenyl 3 (n p tolylcarbamoylmethyl)amino 1,2,4a,5,6,7 hexahydro pyrrolo[1,2 c]pyrimidine 4 carbonitrile3 (2 cyano 1 oxoethyl)amino 1 oxo 2 phenyl 1,2,4a,5,6,7 hexahydropyrrolo[1,2 c]pyrimidine 4 carbonitrile3 (3 phenylureido) 1 thioxo 1,2,4a,5,6,7 hexahydropyrrolo[1,2 c]pyrimidine 4 carbonitrile3 phenylthioureido 1 thioxo 1,2,4a,5,6,7 hexahydropyrrolo[1,2 c]pyrimidine 4 carbonitrile5 phenyl 3 thioxo 3,4,8,9,10,10a hexahydro 1h [1,3] thiazino[4',5':4,5] pyrimido[1,6 a]azepine 1,6(5h) dione5 phenyl 3 thioxo 3,4,8,9,10,10a hexahydro 1h pyrrolo[1',2':1,6] pyrimido[4,5 d][1,3]thiazine 1,6(5h) dione5 phenyl 3,6 dithioxo 3,4,5,6,8,9,10,10a octahydro 1h pyrrolo[1',2':1,6] pyrimido[4,5 d][1,3]thiazine 1 one5 phenyl 6 thioxo 5,6,8,9,10,10a hexahydropyrimido[5,4 e]pyrrolo[1,2 c]pyrimidin 1(2h) one5 phenyl 8,9,10,10a tetrahydropyrimido[5,4 e]pyrrolo[1,2 c]pyrimidine 1,6(2h,5h) dione5 phenyl 8,9,10,11,12,12a tetrahydropyrimido[4',5':4,5]pyrimido[1,6 a]azepine 1,6(2h,5h) dioneantineoplastic agentdoxorubicinpyrimidine derivativeunclassified drugantiproliferative activityarticlebreast cancercancer cell culturecontrolled studydrug cytotoxicitydrug screeningdrug synthesishydrophilicityIC 50molecular dockingmolecular modeloncogene srcstructure activity relationAntiproliferative agentsc-Src and VEGFR inhibitionFused pyrimidinesMCF-7 breast cancer cell lineAntineoplastic AgentsCell ProliferationDose-Response Relationship, DrugDrug DesignDrug Screening Assays, AntitumorHeterocyclic CompoundsHumansMCF-7 CellsModels, MolecularMolecular StructureProtein Kinase InhibitorsPyrimidinesReceptors, Vascular Endothelial Growth Factorsrc-Family KinasesStructure-Activity RelationshipArticlehttps://doi.org/10.1016/j.ejmech.2013.08.042PubMed ID 24090920