A set of piperonylic acid derived hydrazones with variable isatin moieties was synthesized and evaluated for their inhibitory activity against the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO‐A/B). The results of in vitro studies revealed IC50 values in the micromolar range, with the majority of the compounds showing selectivity for the MAO‐B isoform. N‐[2‐Oxo‐1‐(prop‐2‐ynyl)indolin‐3‐ylidene]benzo[d][1,3]dioxole‐5‐carbohydrazide (3) was identified as a lead AChE inhibitor with IC50=0.052±0.006 μm. N‐[(3E)‐5‐chloro‐2‐oxo‐2,3‐dihydro‐1H‐indol‐3‐ylidene]‐2H‐1,3‐benzodioxole‐5‐carbohydrazide (2) was the lead MAO‐B inhibitor with IC50=0.034±0.007 μm, and showed 50 times greater selectivity for MAO‐B over MAO‐A. The kinetic studies revealed that compounds 2 and 3 displayed competitive and reversible inhibition of AChE and MAO‐B, respectively. The molecular docking studies revealed the significance of hydrophobic interactions in the active site pocket of the enzymes under investigation. Further optimization studies might lead to the development of potential neurotherapeutic agents.
Several semicarbazones of acetophenone and p-chloroacetophenone Mannich bases were designed and synthesized to meet the pharmacophore requirements essential for anticonvulsant activity. Mannich bases of acetophenone and p-chloroacetophenone were prepared by reacting formaldehyde with various secondary amines and then condensed with several aryl semicarbazides to yield the corresponding semicarbazones. All compounds were evaluated for their anticonvulsant activity by maximal electroshock (MES) and by subcutaneous metrazole (ScMet) and strychnine (ScSty) induced seizure methods, and their neurotoxic effects were determined using the rotorod test. The title compounds were also investigated for antidepressant and sedative-hypnotic potentiation properties. It is established that 3-[3-chlorophenyl(b-dimethylaminopropiophenone)semicarbazone] has excellent anticonvulsant activity in MES, ScSty, and ScMet tests and exhibits a potent antidepressant effect in the absence of sedative-hypnotic potentiation. The present study has proved our earlier hypothesis concerning the pharmacophore model with essential binding sites for semicarbazones. The inclusion of an additional moiety (CH 2 -CH 2 -N<) at the electron donor acceptor group retained the anticonvulsant activity.
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