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

• Evaluation of in vitro thymidine phosphorylase inhibitory potential.
• Identification of a novel class of thymidine phosphorylase inhibitors.
• Development of anticancer drugs based on quinazoline skeleton.

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 Ki. 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.

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