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.
T10 T11 T12 T13 T14 T1 T2 T3 T4 T5 T6 T7 T8 T9
GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y
AChE AChE AChE AChE BuChE acetyl 1,3,4-thiadiazole 1,3,4-thiadiazole acetyl- and butyrylcholinesterase AChE BuChE AChE BuChE AChE