Novel Cyclopropyl Appended 1,3‐Thiazole‐2‐Imines as Multi‐Target Agents: Design, Synthesis, Biological Evaluation and Computational Studies

Abstract In drug development, the 1,3‐thiazole‐2‐imines scaffolds are widely used to discern novel and potential therapies for the elimination of the most challenging diseases. The cyclopropyl motif is found in various medications such as antiviral drug Paxlovid, used to treat COVID‐19. Its presence enhances the metabolic stability and lipophilicity of drugs, making them more effective. Therefore, in the present work, we developed a library of novel cyclopropyl clubbed 1,3‐thiazole‐2‐imines ( 6 a – h ) from the efficient cyclization between multistep synthesized thiourea precursors and ethyl 2‐chloroacetoacetate. Subsequently, the in vitro biological screening including antibacterial, α ‐amylase, and proteinase K inhibition was carried out to assess their inhibition potential. In general, all synthesized compounds revealed moderate to significant potency. The compound ( 6 a ) with no substitution at the phenyl ring exhibited the highest inhibitory activity amongst all, with an IC 50 value of 1.716±0.062 μM against proteinase K. Fortunately, this compound ( 6 a ) also unfolded the most significant antibacterial potential against B. subtilis showing 20 mm zone of inhibition. The compound ( 6 d ) possessing a naphthyl ring was found to be the most potent inhibitor of amylase displaying IC 50 value of 1.634±0.002 μM. Diverse substitution patterns on the framework of 1,3‐thiazole‐2‐imine pharmacophores provided a valuable basis for SAR analysis. Over and above, computational studies including DFT, molecular electrostatic potential, molecular docking, and ADMET were conducted to predict the chemical reactivity, ligand‐protein binding interactions, and drug‐likeness of synthesized compounds. Hence these studies highlighted our synthesized compounds as novel antibacterial, α ‐amylase, and proteinase K inhibitors. Further research could be encouraged by modifying the substituents and their positions on the structure to attain the potent efficacy of these compounds.