Design, synthesis and biological profiling of bis-thiazole linked Schiff bases as effective enzyme inhibitors for targeting urease and thymidine phosphorylase proteins

Earlier therapeutic strategies primarily focused on combating diseases caused by external pathogens; recent advancements have highlighted the pivotal role of endogenous Enzymes in the progression of non-infectious disorders. Enzymes such as Urease and thymidine Phosphorylase have been implicated in various pathological conditions, prompting the need for effective enzyme-targeted inhibitors. In this study, a novel series of bis-thiazole linked linked Schiff Bases (1-10) was designed and synthesized as potential dual enzyme inhibitors. The structural integrity of the synthesized compounds was confirmed by FTIR, ¹H-NMR, ¹³C-NMR and HRMS analyses. The derivatives were screened for their inhibitory activity against Urease and thymidine Phosphorylase. Among them, the synthesized analogues 4, 5, 7, and 8 exhibited significant activity, surpassing the reference inhibitors thiourea (IC₅₀ = 13.45 ± 0.95 µM) and 7-deazaxanthine (IC₅₀ = 17.61 ± 0.92 µM). In particular, compound-8 emerged as the most potent dual inhibitor, with IC₅₀ values of 8.20 ± 0.98 M and 9.29 ± 0.51 µM against Urease and thymidine Phosphorylase, respectively. To elucidate the binding mechanism, molecular docking studies were conducted, revealing favorable interactions between the active compounds and key residues within the active sites of the target Enzymes. These findings suggest that the bis-thiazole linked Schiff Bases scaffold holds strong potential as a promising chemotype for the development of future enzyme-inhibiting therapeutics.

Helicobacter pylori; Human thymidine phosphorylase; Molecular docking; Proteus mirabilis; SAR; Schiff Base; Thiazole; Urease.