Innovative Pivaloyl Fixed 1,3-Thiazole-2-imines as Multitarget Inhibitors: Synthesis, Enzyme Inhibition, Molecular Docking and Structure Activity Relationship (SAR) Studies

Abstract

A small library of Pivaloyl-Fixed 1,3-Thiazole-2-imine pharmacophores (5a-j) was synthesized in three steps, starting with the reaction of pivaloyl chloride with potassium thiocyanate, followed by condensation with p-toluidine. In the final step, the resulting acyl thiourea intermediate was cyclized with α-halo ketone, yielding the target compounds. The structure of newly synthesized compounds was confirmed by spectroscopic and elemental analyses. The overexpression of the urease, α-amylase, and α-glucosidase enzymes causes various physiological conditions, and inhibition of these enzymes plays an essential role in the treatment of numerous urinary and gastrointestinal tract infections. The inhibition of enzymes is an appealing approach to treating bacterial infections. The newly prepared compounds were evaluated for their urease, α-glucosidase, DPPH, and α-amylase inhibitory potential. Among all compounds, 5f and 5b exhibited the highest activity with IC₅₀ values of 40.74 ± 0.09, 35.15 ± 1.12 µm against α-glucosidase, α-amylase respectively. At the same time, for urease, the highest activity with IC₅₀ values of 26.18 ± 0.61 µm was calculated for 5 h. The synthesized compounds were also screened for antioxidant potential using DPPH. Compound 5j displayed the highest antioxidant activity 33.80 ± 0.37 µm, among all the synthesized derivatives. Molecular docking studies were performed with optimized protein structures to evaluate potential interactions between protein and ligand and develop SAR. Docking score fully supported the in vitro studies.