Structure–activity relationship of 2,4,5-trioxoimidazolidines as inhibitors of thymidine phosphorylase

• Published in: European journal of medicinal chemistry 2011-04, Vol.46 (4), p.1165-1171
• Main Authors: Rajabi, Mehdi, Mansell, David, Freeman, Sally, Bryce, Richard A.
• Format: Article
• Language: English
• Subjects: Anti-angiogenic; Antineoplastic agents; Biological and medical sciences; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General aspects; Humans; Hydantoin; Hydantoins - chemistry; Imidazolidines - chemical synthesis; Imidazolidines - chemistry; Imidazolidines - pharmacology; Medical sciences; Models, Molecular; Molecular modelling; Parabanic acid; Pharmacology. Drug treatments; Protein Conformation; Structure-Activity Relationship; Thymidine phosphorylase; Thymidine Phosphorylase - antagonists & inhibitors; Thymidine Phosphorylase - chemistry; Trioxoimidazolidine
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.01.035

Novel non-nucleobase-derived inhibitors of the angiogenic enzyme, thymidine phosphorylase, have been identified using molecular modelling, synthesis and biological evaluation. These inhibitors are 2,4,5-trioxoimidazolidines bearing N-(substituted)phenylalkyl groups, together with, in most cases, N′-(CH 2) n-carboxylic acid, ester or amide side chains. The best compound from this series is 3-(2,4,5-trioxo-3-phenylethyl-imidazolodin-1-yl)propionamide, with an IC 50 of 40 μM against Escherichia coli TP. Molecular modelling suggests that this ligand, when complexed with closed-cleft human TP, would have the phenylalkyl group in the active site region normally occupied by a thymine-containing structure. A series of parabanic acid derivatives have been synthesised and evaluated against the angiogenic enzyme, thymidine phosphorylase. 3-(2,4,5-Trioxo-3-phenylethyl-imidazolodin-1-yl)propionamide is identified as the most potent. [Display omitted] ► Angiogenic thymidine phosphorylase (TP) is a target for cancer chemotherapy. ► Virtual screening of NCI/ACD databases with TP identified imidazolidine inhibitors. ► A series of imidazolidines were prepared and their TP activity evaluated. ► The lead compound was 3-(2,4,5-trioxo-3-phenylethyl-imidazolidin-1-yl)propionamide.