Synthesis, in vitro urease inhibition, ADMET profiling, and molecular docking of anthranilamide-linked benzamides

Urease is a nickel-containing metalloenzyme implicated in various gastrointestinal and urinary tract diseases, primarily through its role in the pathogenesis of Helicobacter pylori. Inhibition of urease is thus a promising strategy for developing antiulcer agents. In the present study, a set of twenty-two (22) anthranilamide-based compounds (1-22) was strategically designed and synthesized via a two-step protocol involving the formation of benzoxazinone intermediates followed by condensation with 3-aminoacetophenone. The synthesized derivatives were analyzed and characterized through spectroscopic techniques such as ¹H NMR, ¹³C-NMR, LR-, and HR-EIMS. The inhibitory potential of these compounds against jack bean urease was assessed in vitro. Several compounds, including 3, 4, 6, 7, 8, 12, 13, 15, 16, and 18-22, exhibited superior inhibitory activity in the range of IC₅₀ = 0.07 - 6.44 µM, compared to the standard thiourea (IC₅₀ = 19.43 µM), with compound 18 displaying the most potent inhibition (IC₅₀ = 0.07 µM). A detailed structure-activity relationship (SAR) analysis indicated that para-substituted halogenated phenyl groups significantly enhanced urease inhibition. Both electron-withdrawing and electron-donating groups influenced activity depending on their position. These findings highlight substituted benzamides as promising scaffolds for urease inhibition and warrant further in vivo exploration.