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Over-expression of thymidine phosphorylase (TP) plays a key role in many pathological complications, including angiogenesis which leads to cancer cells proliferation. Thus in search of new anticancer agents, a series of 4-hydroxybenzohydrazides ( 1–29 ) was synthesized, and evaluated for  in vitro  thymidine phosphorylase inhibitory activity. Twenty compounds  1 – 3 ,  6 – 14 ,  16 ,  19 ,  22 – 24 , and  27 – 29  showed potent to weak TP inhibitory activities with IC 50  values in the range of 6.8 to 229.5  μ M, in comparison to the standards  i . e . tipiracil (IC 50  = 0.014 ± 0.002  μ M) and 7-deazaxanthine (IC 50  = 41.0 ± 1.63  μ M). Kinetic studies on selected inhibitors  3 ,  9 ,  14 ,  22 ,  27 , and  29  revealed uncompetitive and non-competitive modes of inhibition. Molecular docking studies of these inhibitors indicated that they were able to interact with the amino acid residues present in allosteric site of TP, including Asp391, Arg388, and Leu389. Antiproliferative (cytotoxic) activities of active compounds were also evaluated against mouse fibroblast (3T3) and prostate cancer (PC3) cell lines. Compounds  1 ,  2 ,  19 , and  22 – 24  exhibited anti-proliferative activities against PC3 cells with IC 50  values between 6.5 to 10.5  μ M, while they were largely non-cytotoxic to 3T3 (mouse fibroblast) cells proliferation. Present study thus identifies a new class of dual inhibitors of TP and cancer cell proliferation, which deserves to be further investigated for anti-cancer drug development.

plos one

Thymidine phosphorylase and prostrate cancer cell proliferation inhibitory activities of synthetic 4-hydroxybenzohydrazides: In vitro, kinetic, and in silico studies