2-Arylquinazolin-4(3H)-ones: A novel class of thymidine phosphorylase inhibitors

Article abstract of DOI:10.1016/j.bioorg.2015.10.006

Thymidine phosphorylase (TP) over expression plays an important role in several pathological conditions, such as rheumatoid arthritis, chronic inflammatory diseases, psoriasis, and tumor angiogenesis. In this regard, a series of twenty-five 2-arylquinazolin-4(3H)-one derivatives 1-25 were evaluated for thymidine phosphorylase inhibitory activity. Six compounds 5, 6, 20, 2, 23, and 3 were found to be active against thymidine phosphorylase enzyme with IC₅₀ values in the range of 42.9-294.6 μM. 7-Deazaxanthine (IC₅₀ = 41.0 ± 1.63 μM) was used as a standard inhibitor. Compound 5 showed a significant activity (IC₅₀ = 42.9 ± 1.0 μM), comparable to the standard. The enzyme kinetic studies on the most active compounds 5, 6, and 20 were performed for the determination of their modes of inhibition, and dissociation constants K_i. All active compounds were found to be largely non-cytotoxic against the mouse fibroblast 3T3 cell line. This study identifies a novel class of thymidine phosphorylase inhibitors which may be further investigated as leads to develop therapeutic agents.