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

• Published in: Journal of biomolecular structure & dynamics 2023-12, p.1-10
• Main Authors: Ullah, Saeed, Halim, Sobia Ahsan, Ibrar, Aliya, Khan, Imtiaz, Ataya, Farid Shokry, Fouad, Dalia, Batiha, Gaber El-Saber, Khan, Ajmal, Al-Harrasi, Ahmed
• Format: Article
• Language: English
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2023.2291542

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 ( - , - ) and triazolothiadiazines ( - ) as potential antiurease agents with IC values in the range 10.41-41.20 µM. Several compounds were identified as potential lead candidates. Among them, compounds and from triazolothiadiazole series showed the highest inhibitory potential with IC values of 11.62 ± 0.34 and 10.35 ± 0.14 µM), respectively, whereas from triazolothiadiazine series emerged as the most potent inhibitor with an IC value of 10.41 ± 0.13 µM. These compounds exhibited two-fold strong inhibitory efficacy against urease as compared to standard inhibitor, thiourea (IC = 22.48 ± 0.67 µM). The mechanistic insights from kinetics experiments for compounds , , and revealed the competitive mode of inhibition with K values of 8.65 ± 0.004, 7.04 ± 0.012, and 8.31 ± 0.007 µM, respectively. The results were further explored through computational docking analysis which reflects that binding of ligands with Ni ions and His492 play a crucial role in urease inhibition. predicted physicochemical properties and ADME profile reflect drug-like nature of these molecules.Communicated by Ramaswamy H. Sarma.