Synthesis, characterization and molecular docking studies of thiouracil derivatives as potent thymidylate synthase inhibitors and potential anticancer agents

El-Naggar A.M.; Abou-El-Regal M.M.; El-Metwally S.A.; Sherbiny F.F.; Eissa I.H.

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Synthesis, characterization and molecular docking studies of thiouracil derivatives as potent thymidylate synthase inhibitors and potential anticancer agents

El-Naggar A.M.; Abou-El-Regal M.M.; El-Metwally S.A.; Sherbiny F.F.; Eissa I.H.

Full Text link: https://t.ly/52wBX

Date issued: 2017

Scientific Journal Rankings: Click Here

Doi: https://doi.org/10.1007/s11030-017-9776-1 PubMed ID 28815411

Publisher: Springer International Publishing

Series Info: Molecular Diversity
21

Type: Article

Keywords: 6-Aryl-5-cyano thiouracil , Anticancer , Docking , Thymidylate synthase , 1 benzyl 2 (benzylthio) 4 (4 methoxyphenyl) 6 oxo 1,6 dihydropyrimidine 5 carbonitrile , 2 (allylthio) 4 (4 methoxyphenyl) 6 oxo 1,6 dihydropyrimidine 5 carbonitrile , 2 (allylthio) 6 oxo 4 phenyl 1,6 dihydropyrimidine 5 carbonitrile , 2 (benzylthio) 6 oxo 1,4 diphenyl 1,6 dihydropyrimidine 5 carbonitrile , 2 [[(naphthalen 2 ylamino)methyl]thio] 6 oxo 4 phenyl 1,6 dihydropyrimidine 5 carbonitrile , 2 [[5 cyano 4 (4 methoxyphenyl) 6 oxo 1,6 dihydropyrimidin 2 yl]thio]acetic acid , 2,2' [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 carbonitrile , 3 (4 methoxyphenyl) 6 oxo 8 phenyl 3,4 dihydro 2h,6h pyrimido[2,1 b][1,3,5]thiadiazine 7 carbonitrile , 3 isobutyl 6 oxo 8 phenyl 3,4 dihydro 2h,6h pyrimido [2,1 b][1,3,5]thiadiazine 7 carbonitrile , 3,8 bis(4 methoxyphenyl) 6 oxo 3,4 dihydro 2h,6h pyrimido[2,1 b][1,3,5]thiadiaine 7 carbonitrile , 6 oxo 8 phenyl 3 (4 tolyl) 3,4 dihydro 2h,6h pyrimido [2,1 b][1,3,5]thiadiazine 7 carbonitrile , 6 oxo 8 phenyl 3 (pyrimidin 2 yl) 3,4 dihydro 2h,6h pyrimido[2,1 b][1,3, 5]thiadiazine 7 carbonitrile , 7 (4 methoxyphenyl) 5 oxo 2,3 dihydro 5h thiazolo[3,2 a]pyrimidine 6 carbonitrile , 8 (4 methoxyphenyl) 6 oxo 3 (4 tolyl) 3,4 dihydro 2h, 6h pyrimido[2,1 b][1,3,5]thiadiaine 7 carbonitrile , antineoplastic agent , diethyl2 [[5 cyano 4 (4 methoxyphenyl) 6 oxo 1,6 dihydropyrimidin 2 l]thio]vmalonate , ethyl 2 [[5 cyano 4 (4 methoxyphenyl) 6 oxo 1,6 dihydropyrimidin 2 yl]thio]acetate , ethyl2 [(5 cyano 6 oxo 4 phenyl 1,6 dihydropyrimidin 2 yl)thio]acetate , fluorouracil , pemetrexed , thiouracil derivative , thymidylate synthase , thymidylate synthase inhibitor , unclassified drug , [5 cyano 4 (4 methoxyphenyl) 6 oxo 1,6 dihydropyrimidin 2 yl]propane thioate , antineoplastic agent , enzyme inhibitor , thiouracil , thymidylate synthase , antineoplastic activity , antiproliferative activity , Article , BxPC-3 cell line , controlled study , cytotoxicity , drug design , drug determination , drug screening , drug structure , drug synthesis , enzyme inhibition , Hep-G2 cell line , human , human cell , IC50 , in vitro study , MCF-7 cell line , molecular docking , p53HCT116 cell line , priority journal , antagonists and inhibitors , chemistry , metabolism , protein conformation , structure activity relation , synthesis , tumor cell line , Antineoplastic Agents , Cell Line, Tumor , Chemistry Techniques, Synthetic , Drug Screening Assays, Antitumor , Enzyme Inhibitors , Humans , Molecular Docking Simulation , Protein Conformation , Structure-Activity Relationship , Thiouracil , Thymidylate Synthase

Abstract:

Thymidylate 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.