Design and Synthesis of Novel Heterocyclic Carboxamide Analogues As Potential Urease Enzyme Inhibitors
Year: 2026
Type: article
Abstract: The pathogenic involvement of urease in severe gastrointestinal disorders, particularly Helicobacter pylori infections, as well as its contribution to agricultural inefficiencies, highlights the urgent need for the development of novel, safe, and potent inhibitors. In the present study, a new series of thiazole-2-carboxamide analogues (1a–1c) was rationally designed, synthesized, and structurally characterized using FT-IR, NMR (1H) techniques. The in vitro urease inhibitory activity of the synthesized compounds was assessed against Jack bean urease employing the indophenol colorimetric assay. Among the evaluated analogues, the 4-methoxy-substituted compound 1b exhibited remarkable inhibitory potency, with an IC₅₀ value of 12.45 ± 0.12 μM, significantly surpassing the standard inhibitor thiourea (IC₅₀ = 21.25 ± 0.15 μM). Structure–activity relationship (SAR) analysis indicated that electron-donating substituents enhance inhibitory activity, likely by increasing the electron density and basicity of the carboxamide moiety. Enzyme kinetic studies based on Lineweaver–Burk plots revealed that compound 1b acts as a competitive inhibitor, with a calculated inhibition constant (Kᵢ) of 8.12 μM. Furthermore, molecular docking studies within the urease active site (PDB ID: 3LA4) demonstrated stable bidentate coordination between the ligand and the bimetallic nickel center (Ni301 and Ni302), supporting its strong binding affinity. In addition, SwissADME analysis predicted favorable pharmacokinetic properties, including high gastrointestinal absorption, blood–brain barrier permeability, and full compliance with Lipinski's Rule of Five. Collectively, these findings identify compound 1b as a promising, drug-like lead candidate for the development of urease-targeted therapeutic agents.
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: bronze
OpenAlex ID: W7163173781