Design and synthesis of thiobarbituric acid analogues as potent urease inhibitors

•Twenty analogues of thiobarbiturate and bis-thiobarbiturate were synthesized in good yields and found good urease inhibitors.•Out of these twenty analogues, ten analogues 5a–5k exhibited potent inhibitory activity.•Compounds 5j and 5k having o-fluoro (IC50 8.42 ± 0.32 µM) and p-fluoro (IC50 9.81 ± 0.32 µM) were found the most potent urease inhibitors.•Docking studies revealed the best binding scores for 5e (–12.20 kcal/mol), 5f (–17.49 kcal/mol), 5 h (–17.86 kcal/mol), 5i (–16.83 kcal/mol) and 5j (–15.87 kcal/mol). A series of thiobarbiturates 4a–4e and bis-thiobarbiturates analogues 5a–5o has been synthesized by condensing 1,3-diethylthiobarbituric acid 3 with a variety of aromatic aldehydes with varied structural features and substitution at active methylene position of thiobarbituric acid. Afterward, chemical structures of newly synthesized analogues of thiobarbituric acid were characterized through FT-IR, NMR spectroscopy and mass spectrometry. Subsequently, the inhibitory potential of thiobarbiturates 4a–4e and bis-thiobarbiturates analogues 5a–5o against urease enzyme was evaluated. The inhibitory potential of all synthesized analogues in terms of IC50 value was observed in the range of 8.42 ± 0.32 to 79.34 ± 0.52 μM by comparing with thiourea (IC50 21.25 ± 0.15 μM) as a standard urease inhibitor. Out of these twenty analogues, most of the analogues exhibited potent inhibitory activity against urease. After interesting findings, structure activity relationship (SAR) has been established for all analogues. Docking studies revealed that synthesized analogues interacted with active site residues of bimetallic nickel center of the urease enzyme through, thiolate, π-π stacking and hydrogen bonding interactions. [Display omitted]