Design, synthesis, characterization, in vitro and in silico evaluation of novel imidazo[2,1-b][1,3,4]thiadiazoles as highly potent acetylcholinesterase and non-classical carbonic anhydrase inhibitors

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Abstract Glutathione S‐transferases (EC 2.5.1.18, GSTs), consisting of at least seven subfamilies, such as alpha, kappa, mu, pi, theta, zeta, and omega, are the family of cytosolic proteins with many known functions and also are abundant in cells. Moreover, they play significant roles in influencing the efficacy and bioavailability of pharmaceutical agents in humans. It is also known that multiple types of cancer tissue frequently have high levels of GSTs compared to the corresponding healthy tissue. Herein, firstly, the GST was purified from human erythrocytes by rapid and straightforward chromatographic techniques. Subsequently, the active infection medications, the antimycotics (amphotericin B, anidulafungin, and caspofungin), antibacterials (daptomycin, ertapenem, and tigecycline), and antiviral (ganciclovir) were assessed for their inhibitory actions versus GST. All drugs demonstrated micromolar levels of potent inhibitory activity towards GST. Antifungal drugs had K I constants ranging between 20.60±0.05 μM and 50.43±0.12 μM, whilst antibacterial drugs exhibited KIs in the range of 20.92±0.09–114.80±0.41 μM. Daptomycin and ertapenem exhibited competitive inhibition, while other drugs in noncompetitive inhibition. Moreover, amphotericin B exhibited the most potent inhibitory activity ( K I =20.60±0.05 μM), and in contrast, antiviral drug ganciclovir had the highest inhibition constant ( K I =463.10±1.28 μM). Studying both in‐vitro inhibitory activity and molecular docking interactions in silico activities of these infection medications in complex with the GST, an enzyme biologically important, demonstrates was caused significant associations between these drugs and GST were detected. The results here might provide structural guidance to design more potent GST inhibitors.