Iminothiazoline-Sulfonamide Hybrids as Jack Bean Urease Inhibitors; Synthesis, Kinetic Mechanism and Computational Molecular Modeling

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Abstract

The present work reports the synthesis of several 2-iminothiazoline derivatives of sulfanilamide (3a–j) as inhibitors of jack bean ureases. The title compounds were synthesized by the heterocyclization of sulfanilamide thioureas with propragyl bromide in dry ethanol in the presence of 1,8-Diazabicyclo[5.4.0]undec-7-ene as a base. All of the compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (3h) and (3i) exhibited excellent enzyme inhibitory activity with IC50 0.064 and 0.058μm, respectively, while IC50 of thiourea is 20.9μm. The kinetic mechanism analyzed by Dixon plot showed that compound (3h) is a mixed-type inhibitor while (3i) is a competitive one. Docking studies suggested that Asp633, Ala636, His492, Ala440, Lue523, Asp494 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. 2-iminothiazoline analogues (3a–j) showed good docking score (−10.6466 to −8.7215 Kcal/mol) and binding energy (London dG ranging from −14.4825 to −10.4087 Kcal/mol) which is far better than the standard thiourea (binding score in S field −4.5790 Kcal/mol London dG −4.7726 Kcal/mol). Our results inferred compound (3i) may serve as a structural model for the design of most potent urease inhibitors.

2-iminothiazoline-sulfonamide hybrids (3a–j) were synthesized by the heterocyclization of sulfanilamide thioureas with propragyl bromide. The compounds (3h) and (3i) exhibited excellent activity with IC50 0.064 and 0.058 μm respectively while IC50 of thiourea is 20.9 μm. Docking score (−10.6466 to −8.7215 Kcal/mol) and binding energy (London dG ranging from −14.4825 to −10.4087 Kcal/mol) are good.

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