Insight into <i>in vitro</i> thymidine phosphorylase and <i>in silico</i> molecular docking studies: identification of hybrid thiazole bearing Schiff base derivatives

In pursuit of effective thymidine phosphorylase inhibitors, a series of hybrid analogs of thiazole-hydrazone derivatives (1-15) were synthesized and evaluated for their enzyme inhibitory potential using 7-deazaxanthine as a positive control. The goal was to determine these derivatives' effectiveness in suppressing thymidine phosphorylase activity, a target relevant to antitumor strategies due to the enzyme's role in angiogenesis and tumor growth. Biological evaluations indicated that all synthesized analogs displayed significant to moderate inhibitory activity, with IC₅₀ values between 3.93 ± 0.90 and 25.75 ± 4.30 µM. Particularly, compounds 12, 9, and 28 exhibited superior potency, with IC₅₀ values of 3.93 ± 0.90, 4.10 ± 1.10, and 4.50 ± 1.10 µM, respectively, surpassing the standard inhibitor 7-deazaxanthine (IC₅₀ = 16.8 ± 2.20 µM). Additionally, molecular docking studies were performed to elucidate the binding interactions of the synthesized thiazole-hydrazone derivatives with the active site of thymidine phosphorylase. The docking results aligned well with experimental data, revealing favorable binding conformations and significant interactions that support the observed inhibitory activities, particularly in the most potent compounds. These findings underscore the promise of thiazole-hydrazone derivatives as effective thymidine phosphorylase inhibitors, suggesting that targeted structural modifications could further enhance their activity. Further investigations, including <i>in vivo</i> studies, are warranted to explore their potential applications in anticancer therapies. This study highlights the valuable role of molecular docking in understanding the structure-activity relationship (SAR) of thiazole-hydrazone derivatives, emphasizing the potential of these compounds in advancing thymidine phosphorylase inhibition strategies for therapeutic purposes.