Nineteen tosylated acyl hydrazone derivatives were synthesized, and their inhibitory activities against monoamine oxidases (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-secretase (BACE-1) were evaluated. Compound 3o was the most potent inhibitor of MAO-A, with an IC₅₀ value of 1.54 µM, followed by 3a (IC₅₀ = 3.35 µM). A structural comparison with 3a indicated that the 3-F group in 3o increased its inhibitory activity against MAO-A. Compound 3s was the most potent inhibitor of MAO-B, with an IC₅₀ value of 3.64 µM, followed by 3t (IC₅₀ = 5.69 µM). The MAO-B inhibitory activity increased in the order of 3- > 4- > 2-NO₂ groups in 3s, 3t, and 3r, respectively. All the compounds weakly inhibited AChE and BChE, which retained >50% residual activity at 10 µM, except for 3a, which inhibited BChE with an IC₅₀ value of 16.1 µM. Interestingly, 3e, 3f, and 3n inhibited BACE-1 with IC₅₀ values of 8.63, 9.92, and 8.47 µM, respectively, which were lower than the IC₅₀ of the quercetin reference. Compounds 3o and 3s were found to be reversible competitive inhibitors of MAO-A and MAO-B, respectively, with K_i values of 0.35 ± 0.074 and 1.97 ± 0.65 µM, respectively. Moreover, compounds 3e, 3f, and 3n were effective BACE-1 inhibitors. The lead molecules were further investigated by molecular docking studies to elucidate the binding interactions with the target enzymes.

SIRT2, the cytoplasmic member of the sirtuin family, is generally acknowledged to promote cancer and contribute to the progression of various pathologies, including neurodegeneration, inflammation, obesity, and bacterial infection through the deacetylation of target substrates. In our previous efforts we identified potent and highly selective SIRT2 inhibitors with IC ₅₀ values in the micromolar range. To further optimize their activity, we performed molecular docking‐guided design and subsequent synthesis of a series of novel 1,3,4‐thiadiazole derivatives. SIRT inhibitory screening identified that ST131 and ST132 achieved moderate inhibitory effects against SIRT2 with IC ₅₀ values of 8.95 and 6.62 µM, respectively. Moreover, cellular assays in MCF‐7 breast cancer cells revealed that ST132 has shown an antiproliferative effect, as well as increased acetylated α‐tubulin expression levels, which is typically consistent with SIRT2 inhibition. In addition, docking studies were performed to analyze and rationalize the structural differences responsible for SIRT2 activity, shedding light on the importance of the interactions occurring at the entrance of the binding site. Finally, molecular mechanics‐generalized born surface area (MM‐GBSA) and molecular dynamics (MD) simulation approaches were conducted to verify the stability of ST132 in the complex with SIRT2.

Monoamine oxidase (MAO) catalyzes the breakdown of neurotransmitters, including serotonin, dopamine, and norepinephrine. There are two isoforms of this enzyme: MAO‐A and MAO‐B. MAO efficacy is widely investigated in neurodegenerative (MAO‐B) and depressive (MAO‐A) disorders. Upon examining the structures of known inhibitors, it becomes evident that many share an aliphatic amine structure. Furthermore, the literature suggests that compounds with naphthalene skeletons, phenolic structures, and hydrazone moieties exhibit MAO inhibitory activity. In this study, 12 N ‐acylhydrazone derivatives ( 5a–f , 6a–f ) were designed using ligand‐based design methods. Based on biological activity studies, the MAO‐A inhibition of the compounds was calculated to be 0.073–2.54 µM, and the MAO‐B inhibition was 0.064–3.147 µM. Among all compounds, the derivatives bearing a naphthalene ring ( 5d – f , 6d – f ) exhibited MAO enzyme inhibition at levels comparable to those of the reference compounds. The compound with the highest activity, 6e , had IC ₅₀ values of 0.073 ± 0.002 and 0.064 ± 0.002 µM against MAO‐A and MAO‐B, respectively. Due to its superior potency against human MAO‐B, enzyme kinetic studies were further conducted on compound 6e . Consequently, the pronounced inhibitory potency, reversible competitive kinetics, and favorable pharmacokinetic profile of compound 6e designate it as a strong lead candidate for advanced preclinical evaluation.