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This article describes the design and synthesis of a series of novel amantadine-thiourea conjugates (<b>3a</b>–<b>j</b>) as Jack bean urease inhibitors. The synthesized hybrids were assayed for their in vitro urease inhibition. Accordingly, <i>N</i>-(adamantan-1-ylcarbamothioyl)octanamide (<b>3j</b>) possessing a 7-carbon alkyl chain showed excellent activity with IC₅₀ value 0.0085 ± 0.0011 µM indicating that the long alkyl chain plays a vital role in enzyme inhibition. Whilst <i>N</i>-(adamantan-1-ylcarbamothioyl)-2-chlorobenzamide (<b>3g</b>) possessing a 2-chlorophenyl substitution was the next most efficient compound belonging to the aryl series with IC₅₀ value of 0.0087 ± 0.001 µM. The kinetic mechanism analyzed by Lineweaver–Burk plots revealed the non-competitive mode of inhibition for compound <b>3j</b>. Moreover, in silico molecular docking against target protein (PDBID 4H9M) indicated that most of the synthesized compounds exhibit good binding affinity with protein. The compound <b>3j</b> forms two hydrogen bonds with amino acid residue VAL391 having a binding distance of 1.858 Å and 2.240 Å. The interaction of <b>3j</b> with amino acid residue located outside the catalytic site showed its non-competitive mode of inhibition. Based upon these results, it is anticipated that compound <b>3j</b> may serve as a lead structure for the design of more potent urease inhibitors.