Urease inhibitory potential of pyridine-containing triazolothiadiazole and triazolothiadiazine scaffolds for the treatment of ulceration and kidney stone: in vitro screening, kinetics mechanism, and in silico computational analysis

Abstract

The hyperactivity of urease enzyme leads to various complications including gastritis and peptic ulcer. A diverse variety of natural and synthetic inhibitors have shown a tremendous potential to inhibit the urease enzyme, thus decreasing the hyperactivity and reducing the risk for the development of urinary calculi and other similar problems. Therefore, we herein report a family of fused heterocycles such as triazolothiadiazoles (4a–h, 5a–f) and triazolothiadiazines (6a–h) as potential antiurease agents with IC50 values in the range 10.41–41.20 µM. Several compounds were identified as potential lead candidates. Among them, compounds 4e and 4f from triazolothiadiazole series showed the highest inhibitory potential with IC50 values of 11.62 ± 0.34 and 10.35 ± 0.14 µM), respectively, whereas 6e from triazolothiadiazine series emerged as the most potent inhibitor with an IC50 value of 10.41 ± 0.13 µM. These compounds exhibited two-fold strong inhibitory efficacy against urease as compared to standard inhibitor, thiourea (IC50 = 22.48 ± 0.67 µM). The mechanistic insights from kinetics experiments for compounds 4e, 4f, and 6e revealed the competitive mode of inhibition with Ki values of 8.65 ± 0.004, 7.04 ± 0.012, and 8.31 ± 0.007 µM, respectively. The in vitro results were further explored through in silico computational docking analysis which reflects that binding of ligands with Ni ions and His492 play a crucial role in urease inhibition. In silico predicted physicochemical properties and ADME profile reflect drug-like nature of these molecules. Communicated by Ramaswamy H. Sarma