Synthesis and biological evaluation of 1,3,4-thiadiazole analogues as novel AChE and BuChE inhibitors

In this paper a series of new 1,3,4-thiadiazole derivatives has been designed, synthesized and evaluated as the acetyl- and butyrylcholinesterase inhibitors. Some analogues showed promising inhibition of both enzymes in vitro in the nM range. Generally, inhibitory potency of compounds was stronger against AChE than BuChE, and one of them was 1154-fold more active inhibiting AChE (IC50 = 0.17 μM) than BuChE. The kinetic studies showed that one of the most active analogues 8 (IC50 = 0.09 μM, AChE) acted as a non-competitive AChE inhibitor and was characterized by the high selectivity index (300). The other derivative (1) exhibited a mixed-type of AChE inhibition. Docking simulations enabled the detection of key binding interactions of the compounds with AChE and revealed that they occupied mainly the catalytic active site. The scoring function for the novel compounds was similar or higher than for the reference inhibitor. Additionally, based on Lipinski and other filters, the drug-likeness of compounds was assessed. They revealed that the compounds possess properties which can suggest the favourable pharmacokinetics in the human body after oral admission.

Graphical abstractModified 4-(5-phenyl-1,3,4-thiadiazol-2-yl)benzene-1,3-diols were synthesized and evaluated as the acetyl- and butyrylcholinesterase inhibitors. Some analogues show promising inhibition of both enzymes in vitro in the nM range.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Synthesis of modified 4-(5-phenyl-1,3,4-thiadiazol-2-yl)benzene-1,3-diols. ► Evaluation of acetyl- and butyrylcholinesterase inhibition potency of the obtained compounds. ► Docking simulations of the most active derivatives. ► Virtual screening of pharmacokinetic properties of compounds.