Long chain 1-acyl-3-arylthioureas as jack bean urease inhibitors, synthesis, kinetic mechanism and molecular docking studies

Abstract

Abstract The current research work reports the synthesis of novel long chain acyl thiourea derivatives as inhibitors of jack bean ureas. The title compounds were synthesized by the conversion of long chain carboxylic acids into corresponding acid chlorides followed by reaction with potassium thiocyanate to obtain a key reactive intermediate isothiocyanate, the latter was treated with suitably substituted aromatic anilines to afford the title 1-(substituted)phenyl-3-tetradecanoylthioureas. All of the compounds showed higher urease inhibitory activity than the standard thiourea. The compound 5f exhibited excellent enzyme inhibitory activity with IC50 0.0391 ± 0.0028 µM while IC50 of thiourea is 18.195 ± 0.382 µM. The kinetic mechanism analyzed by Lineweaver–Burk plots showed that compound 5f is a non-competitive type inhibitor. Docking studies suggested that Asp494, Ala636, His593, Ala636, Lue494, Asp521 and Arg439 are the major interacting residues in the binding site of the protein and may have an instrumental role in the inhibition of enzyme's function. Synthesized acyl thioureas 5a–5k showed good docking score (−8.2 to −6.9 Kcal/mol) and efficacy of lead molecules was investigated by carrying out pharmacokinetic studies, Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) assessment justified that these novel synthesized compounds showed good lead like potential with little hepatotoxic and skin sensitive effects. Chemo-informatics properties were evaluated by computational approaches and it was found that synthesized compounds mostly obeyed the Lipinski's rule.