El-Naggar A.M.Abou-El-Regal M.M.El-Metwally S.A.Sherbiny F.F.Eissa I.H.Chemistry DepartmentFaculty of ScienceAin Shams UniversityAbbassiaCairo11566Egypt; Higher Technology Institute10th of Ramadan CityEgypt; Organic Chemistry DepartmentFaculty of Pharmacy (Boys)Al-Azhar UniversityCairo11884Egypt; Organic Chemistry DepartmentFaculty of PharmacyOctober University for Modern Science and Arts (MSA)6th October City11787Egypt; Pharmaceutical Chemistry DepartmentFaculty of Pharmacy (Boys)Al-Azhar UniversityCairo11884Egypt2020-01-092020-01-09201713811991https://doi.org/10.1007/s11030-017-9776-1PubMed ID 28815411https://t.ly/52wBXScopusThymidylate synthase (TS), one of folate-dependent enzymes, is a key and well-recognized target for anticancer agents. In this study, a series of 6-aryl-5-cyano thiouracil derivatives were designed and synthesized in accordance with essential pharmacophoric features of known TS inhibitors. Nineteen compounds were screened in vitro for their anti-proliferative activities toward HePG-2, MCF-7, HCT-116, and PC-3 cell lines. Compounds 21c, 21d, and 24 exhibited high anti-proliferative activity, comparable to that of 5-fluorouracil. Additionally, ten compounds with potent anti-proliferative activities were further evaluated for their ability to inhibit TS enzyme. Six compounds (21b, 21c, 21d, 22, 23 and 24) demonstrated potent dose-related TS inhibition with IC 50 values ranging from 1.57 to 3.89?M. The in vitro TS activity results were consistent with those of the cytotoxicity assay where the most potent anti-proliferative compounds of the series showed good TS inhibitory activity comparable to that of 5-fluorouracil. Furthermore, molecular docking studies were carried out to investigate the binding pattern of the designed compounds with the prospective target, TS (PDB-code: 1JU6). � 2017, Springer International Publishing AG.English6-Aryl-5-cyano thiouracilAnticancerDockingThymidylate synthase1 benzyl 2 (benzylthio) 4 (4 methoxyphenyl) 6 oxo 1,6 dihydropyrimidine 5 carbonitrile2 (allylthio) 4 (4 methoxyphenyl) 6 oxo 1,6 dihydropyrimidine 5 carbonitrile2 (allylthio) 6 oxo 4 phenyl 1,6 dihydropyrimidine 5 carbonitrile2 (benzylthio) 6 oxo 1,4 diphenyl 1,6 dihydropyrimidine 5 carbonitrile2 [[(naphthalen 2 ylamino)methyl]thio] 6 oxo 4 phenyl 1,6 dihydropyrimidine 5 carbonitrile2 [[5 cyano 4 (4 methoxyphenyl) 6 oxo 1,6 dihydropyrimidin 2 yl]thio]acetic acid2,2' [methylenebis(sulfanediyl)]bis[4 (4 methoxyphenyl) 6 oxo 1,6 dihydro pyrimidine 5 carbonitrile]2,5 dioxo 7 phenyl 2,3 dihydro 5h thiazolo[3,2 a]pyrimi dine 6 carbonitrile3 (4 methoxyphenyl) 6 oxo 8 phenyl 3,4 dihydro 2h,6h pyrimido[2,1 b][1,3,5]thiadiazine 7 carbonitrile3 isobutyl 6 oxo 8 phenyl 3,4 dihydro 2h,6h pyrimido [2,1 b][1,3,5]thiadiazine 7 carbonitrile3,8 bis(4 methoxyphenyl) 6 oxo 3,4 dihydro 2h,6h pyrimido[2,1 b][1,3,5]thiadiaine 7 carbonitrile6 oxo 8 phenyl 3 (4 tolyl) 3,4 dihydro 2h,6h pyrimido [2,1 b][1,3,5]thiadiazine 7 carbonitrile6 oxo 8 phenyl 3 (pyrimidin 2 yl) 3,4 dihydro 2h,6h pyrimido[2,1 b][1,3, 5]thiadiazine 7 carbonitrile7 (4 methoxyphenyl) 5 oxo 2,3 dihydro 5h thiazolo[3,2 a]pyrimidine 6 carbonitrile8 (4 methoxyphenyl) 6 oxo 3 (4 tolyl) 3,4 dihydro 2h, 6h pyrimido[2,1 b][1,3,5]thiadiaine 7 carbonitrileantineoplastic agentdiethyl2 [[5 cyano 4 (4 methoxyphenyl) 6 oxo 1,6 dihydropyrimidin 2 l]thio]vmalonateethyl 2 [[5 cyano 4 (4 methoxyphenyl) 6 oxo 1,6 dihydropyrimidin 2 yl]thio]acetateethyl2 [(5 cyano 6 oxo 4 phenyl 1,6 dihydropyrimidin 2 yl)thio]acetatefluorouracilpemetrexedthiouracil derivativethymidylate synthasethymidylate synthase inhibitorunclassified drug[5 cyano 4 (4 methoxyphenyl) 6 oxo 1,6 dihydropyrimidin 2 yl]propane thioateantineoplastic agentenzyme inhibitorthiouracilthymidylate synthaseantineoplastic activityantiproliferative activityArticleBxPC-3 cell linecontrolled studycytotoxicitydrug designdrug determinationdrug screeningdrug structuredrug synthesisenzyme inhibitionHep-G2 cell linehumanhuman cellIC50in vitro studyMCF-7 cell linemolecular dockingp53HCT116 cell linepriority journalantagonists and inhibitorschemistrymetabolismprotein conformationstructure activity relationsynthesistumor cell lineAntineoplastic AgentsCell Line, TumorChemistry Techniques, SyntheticDrug Screening Assays, AntitumorEnzyme InhibitorsHumansMolecular Docking SimulationProtein ConformationStructure-Activity RelationshipThiouracilThymidylate SynthaseArticlehttps://doi.org/10.1007/s11030-017-9776-1PubMed ID 28815411