Identification of bis-thiazole linked oxazine Schiff bases: synthesis, in-vitro biological evaluation and computational insights toward potent urease and thymidine phosphorylase inhibitors
Yousaf Khan, Mujeeb UL Naeem, Syeda Farwa Naqvi, Samina Aslam, Rubina Adnan, Marukh Naseem, Syeda Briha Fatima, Azmatullah, Urooba Gulshan, Syed Aminullah
Abstract
Abstract Recent advances in molecular therapeutics underscore the central role of dysregulated endogenous enzymes in the onset and progression of non-infectious diseases. Urease and thymidine phosphorylase are two clinically relevant enzymes implicated in microbial virulence, inflammation, and cancer biology, yet potent dual modulators remain limited. Here, we report the design and synthesis of a novel library of bis-thiazole linked oxazine Schiff base hybrids ( 1–10 ) as candidate dual-enzyme inhibitors. Structural elucidation using FT-IR, 1 HNMR, 13 C NMR spectroscopy, and HRMS confirmed the structural integrity of the synthesized scaffolds. Biological evaluation revealed potent inhibitory activity across the series, with compounds 1, 2, 5 and 8 demonstrating superior efficacy compared with the standard inhibitors thiourea and 7-deazaxanthine. Notably, compound- 1 acted as the most effective dual inhibitor, achieving IC 50 values of 4.30 ± 0.73 µM (thymidine phosphorylase) and 3.90 ± 0.84 µM (urease). Molecular docking analyses further identify stable binding conformations and extensive interaction networks within the catalytic sites of both targets, providing a structural rationale for the observed potencies. These findings position the bis-thiazole linked oxazine Schiff base scaffold as a compelling chemotype for next-generation enzyme-directed therapeutics. The strong inhibitory profiles and well-defined molecular interactions provide a clear rationale for further structure-guided optimization. Together, these results lay the groundwork for advancing this scaffold toward translational development.