Novel 1,3‐oxazine‐tetrazole hybrids as mushroom tyrosinase inhibitors and free radical scavengers: Synthesis,kinetic mechanism,and molecular docking studies

A variety of 5‐(2H‐tetrazol‐5‐yl)‐4‐thioxo‐2‐(substituted phenyl)‐4,5‐dihydro‐1,3‐oxazin‐6‐ones ( 3a–k ) have been synthesized from 1,3‐oxazine‐5‐carbonitriles ( 2a–k ). The protocol represents an efficient, facile, and novel route from easily available precursors to unprecedented structures that share 1,3‐oxazine and tetrazole motifs of utmost value. All the synthesized compounds ( 3a–k ) were evaluated for their inhibitory potential against mushroom tyrosinase. Results revealed that all examined 1,3‐oxazine‐tetrazole hybrids exhibited significant tyrosinase inhibitory activity while compound 3d having 2‐bromophenyl moiety was the most potent among the series with IC₅₀ value 0.0371 ± 0.0018 μM as compared to the reference kojic acid (IC₅₀ = 16.832 ± 0.73 μM). Inhibitory kinetics showed that compound 3d behaves as a competitive inhibitor. The molecular docking analysis was performed against target protein to investigate the binding mode. Moreover, compounds 3j and 3k displayed superior DPPH radical scavenging activity than other analogues.     

Evaluation of Natural and Synthetic 1,4‐naphthoquinones as Inhibitors of Monoamine Oxidase

Previous reports have documented that 1,4‐naphthoquinones act as inhibitors of the monoamine oxidase (MAO) enzymes. In particular, fractionation of the extracts of cured tobacco leafs has led to the characterization of 2,3,6‐trimethyl‐1,4‐naphthoquinone, a non‐selective MAO inhibitor. To derive structure–activity relationships for MAO inhibition by the 1,4‐naphthoquinone class of compounds, this study investigates the human MAO inhibitory activities of fourteen structurally diverse 1,4‐naphthoquinones of natural and synthetic origin. Of these, 5,8‐dihydroxy‐1,4‐naphthoquinone was found to be the most potent inhibitor with an IC₅₀ value of 0.860 μm for the inhibition of MAO‐B. A related compound, shikonin, inhibits both the MAO‐A and MAO‐B isoforms with IC₅₀ values of 1.50 and 1.01 μm , respectively. It is further shown that MAO‐A and MAO‐B inhibition by these compounds is reversible by dialysis. In this respect, kinetic analysis suggests that the modes of MAO inhibition are competitive. This study contributes to the discovery of novel MAO inhibitors, which may be useful in the treatment for disorders such as Parkinson's disease, depressive illness, congestive heart failure and cancer.     

Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors

Monoamine oxidase (MAO) enzymes located in human mitochondria oxidize neurotransmitters and bioactivate the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by oxidation to directly-acting neurotoxic pyridinium cations (MPDP⁺/MPP⁺) that produce Parkinsonism. Antioxidants and MAO inhibitors are useful as neuroprotectants. Naturally-occurring substances, antioxidants and redox agents were assessed as inhibitors of the oxidation (bioactivation) of MPTP by human mitochondria and MAO enzymes. Methylene blue, 5-nitroindazole, norharman (β-carboline), 9-methylnorharman (9-methyl-β-carboline) and menadione (vitamin-K analogue) highly inhibited the oxidation of MPTP to the neurotoxic species, MPDP⁺/MPP⁺, in human mitochondria (IC₅₀ of 0.18, 3.1, 9.9, 7.3, and 12.6 μM, respectively). Inhibition by methylene blue was similar to R-deprenyl (IC₅₀ of 0.15 μM), a known neuroprotectant. The naturally-occurring β-carbolines, harmine, harmaline and tetrahydro-β-carboline, and the antioxidants, melatonin, resveratrol, quercetin and catechin showed little or no inhibition. Oxidation of MPTP in mitochondria was performed by human MAO-B and the above active compounds were also inhibitors of this isozyme. Norharman and 5-nitroindazole were competitive inhibitors of MAO-B whereas methylene blue inhibited MPTP oxidation (IC₅₀ of 50 nM) under a mixed type and predominantly uncompetitive mechanism. Methylene blue, 5-nitroindazole, norharman, 9-methylnorharman and menadione inhibit MAO-B in mitochondria and afford protective effects, as suggested by a reduced conversion of MPTP to neurotoxic species.     

Structure–activity relationship studies of benzyl‐, phenethyl‐, and pyridyl‐substituted tetrahydroacridin‐9‐amines as multitargeting agents to treat Alzheimer's disease

A library of substituted tetrahydroacridin‐9‐amine derivatives were designed, synthesized, and evaluated as dual cholinesterase and amyloid aggregation inhibitors. Compound 8e (N‐(3,4‐dimethoxybenzyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine) was identified as a potent inhibitor of butyrylcholinesterase (BuChE IC₅₀ = 20 nm ; AChE IC₅₀ = 2.2 μm ) and was able to inhibit amyloid aggregation (40% inhibition at 25 μm ). Compounds 9e (6‐chloro‐N‐(3,4‐dimethoxybenzyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine, AChE IC₅₀ = 0.8 μm ; BuChE IC₅₀ = 1.4 μm ; Aβ‐aggregation inhibition = 75.7% inhibition at 25 μm ) and 11b (6‐chloro‐N‐(3,4‐dimethoxyphenethyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine, AChE IC₅₀ = 0.6 μm ; BuChE IC₅₀ = 1.9 μm ; Aβ‐aggregation inhibition = 85.9% inhibition at 25 μm ) were identified as the best compounds with dual cholinesterase and amyloid aggregation inhibition. The picolylamine‐substituted compound 12c (6‐chloro‐N‐(pyridin‐2‐ylmethyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine) was the most potent AChE inhibitor (IC₅₀ = 90 nm ). These investigations demonstrate the utility of 3,4‐dimethoxyphenyl substituent as a novel pharmacophore possessing dual cholinesterase inhibition and anti‐Aβ‐aggregation properties that can be used in the design and development of small molecules with multitargeting ability to treat Alzheimer's disease.     

Evaluation of multifunctional synthetic tetralone derivatives for treatment of Alzheimer's disease

Neurodegeneration, a complex disease state, comprises several pathways that contribute to cell death. Conventional approach of targeting only one of these pathways has not been proven to be entirely successful and has demanded a hypothetical change as to how researchers design and develop new drugs. In this study, effects of a series of α, β‐unsaturated carbonyl‐based tetralone derivatives against Alzheimer's disease (AD) were investigated. Moreover, their activity toward amyloid β‐induced cytotoxicity was also studied. Six compounds including 3f , 3o , 3u , 3ae , 3af , and 3ag were discovered to be most protective against Aβ‐induced neuronal cell death in PC12 cells. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against MAO‐B, AChE, and self‐induced Aβ_1–42 aggregation. The compound 3f exhibited best AChE (IC₅₀ = 0.045 ± 0.02 μm ) inhibitory potential in addition to potent inhibition of MAO‐B (IC₅₀ = 0.88 ± 0.12 μm ). Furthermore, compound 3f disassembled the Aβ fibrils produced by self‐induced Aβ aggregation by 78.2 ± 4.8%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment.     

3D‐quantitative structure‐activity relationship study for the design of novel enterovirus A71 3C protease inhibitors

A three‐dimensional quantitative structure‐activity relationships model of enterovirus A71 3C protease inhibitors was constructed in this study. The protein‐ligand interaction fingerprint was analyzed to generate a pharmacophore model. A predictive and reliable three‐dimensional quantitative structure‐activity relationships model was built based on the Flexible Alignment of AutoGPA. Moreover, three novel compounds ( I – III) were designed and evaluated for their biochemical activity against 3C protease and anti‐enterovirus A71 activity in vitro. III exhibited excellent inhibitory activity (IC₅₀ = 0.031 ± 0.005 μM, EC₅₀ = 0.036 ± 0.007 μM). Thus, this study provides a useful quantitative structure‐activity relationships model to develop potent inhibitors for enterovirus A71 3C protease.     

Synthesis and biological evaluation of novel N‐aryl‐ω‐(benzoazol‐2‐yl)‐sulfanylalkanamides as dual inhibitors of α‐glucosidase and protein tyrosine phosphatase 1B

α‐Glucosidase is known to catalyze the digestion of carbohydrates and release free glucose into the digestive tract. Protein tyrosine phosphatase 1B (PTP1B) is engaged in the dephosphorylation of the insulin receptor and regulation of insulin sensitivity. Therefore, dual antagonists by targeting both α‐glucosidase and PTP1B may be potential candidates for type 2 diabetes therapy. In this work, three series of novel N‐aryl‐ω‐(benzoazol‐2‐yl)‐sulfanylalkanamides were synthesized and assayed for their α‐glucosidase and PTP1B inhibitory activities, respectively. Compound 3l , exhibiting the most effective α‐glucosidase inhibitory activity (IC₅₀ = 10.96 μm ( 3l ), IC₅₀ = 51.32 μm (Acarbose), IC₅₀ = 18.22 μm (Ursolic acid)) and potent PTP1B inhibitory activity (IC₅₀ = 13.46 μm ( 3l ), IC₅₀ = 14.50 μm (Ursolic acid)), was identified as a novel dual inhibitor of α‐glucosidase and PTP1B. Furthermore, 3l is a highly selective PTP1B inhibitor because no inhibition was showed by 3l at 100 μm against PTP‐MEG2, TCPTP, SHP2, or SHP1. Subsequent kinetic analysis revealed 3l inhibited α‐glucosidase in a reversible and mixed manner. Molecular docking study indicated that hydrogen bonds, van der Waals, charge interactions and Pi‐cation interactions all contributed to affinity between 3l and α‐glucosidase/PTP1B.     

Design and synthesis of 4′‐((5‐benzylidene‐2,4‐dioxothiazolidin‐3‐yl)methyl)biphenyl‐2‐carbonitrile analogs as bacterial peptide deformylase inhibitors

Herein, we report the synthesis and screening of 4′‐((5‐benzylidene‐2,4‐dioxothiazolidin‐3‐yl)methyl)biphenyl‐2‐carbonitrile analogs 11(a–j) as bacterial peptide deformylase (PDF) enzyme inhibitors. The compounds 11b (IC₅₀ value = 139.28 μm ), 11g (IC₅₀ value = 136.18 μm ), and 11h (IC₅₀ value = 131.65 μm ) had shown good PDF inhibition activity. The compounds 11b (MIC range = 103.36–167.26 μg/mL), 11g (MIC range = 93.75–145.67 μg/mL), and 11h (MIC range = 63.61–126.63 μg/mL) had also shown potent antibacterial activity when compared with standard ampicillin (MIC range = 100.00–250.00 μg/mL). Thus, the active derivatives were not only PDF inhibitors but also efficient antibacterial agents. To gain more insight on the binding mode of the compounds with PDF enzyme, the synthesized compounds 11(a–j) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. The results suggest that this class of compounds has potential for development and use in future as antibacterial drugs.     

Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors

New synthesized series of 9‐amino‐1,2,3,4‐tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against β‐amyloid aggregation. All novel molecules 3a–3i interacted with both cholinesterases—acetylcholinesterase and butyrylcholinesterase—delivered nanomolar IC₅₀ values. The structure–activity relationship showed that N‐butyl moiety derivatives are stronger inhibitors toward AChE and BuChE than N‐ethyl and N‐propyl moieties compounds. The most potent compound toward acetylcholinesterase was inhibitor 3f (IC₅₀ = 31.2 nm ), and it was more active than reference drug, tacrine (IC₅₀ = 100.2 nm ). Compound 3f showed strong inhibition of butyrylcholinesterase (IC₅₀ = 8.0 nm ), also higher than tacrine (IC₅₀ = 16.3 nm ). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited β‐amyloid aggregation (at the concentration 10 μm —24.96% of inhibition, 25 μm —72%, 50 μm —78.44%, and 100 μm —84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multifunctional agents in the therapy of Alzheimer's disease.     

Synthesis,Biological Evaluation,and Computer‐Aided Drug Designing of New Derivatives of Hyperactive Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitors

The synthesis and biological evaluation of a novel series of compounds based on suberoylanilide hydroxamic acid (SAHA) had been designed as potential histone deacetylase inhibitors (HDACis). Molecular docking studies indicated that our derivatives had better fitting in the binding sites of HDAC8 than SAHA. Compounds 1–5 were synthesized through the synthetic routes. In biological test, compounds also showed good inhibitory activity in HDAC enzyme assay and more potent growth inhibition in human glioma cell lines (MGR2, U251, and U373). A representative compound, N3F, exhibited better inhibitory effect (HDAC, IC₅₀ = 0.1187 μm ; U251, IC₅₀ = 0.8949 μm ) and lower toxicity for human normal cells (LO2, IC₅₀ = 172.5 μm and MRC5, IC₅₀ = 213.6 μm ) compared with SAHA (HDAC, IC₅₀ = 0.8717 μm ; U251, IC₅₀ = 8.938 μm ; LO2, IC₅₀ = 86.52 μm and MRC5, IC₅₀ = 81.02 μm ). In addition, N3F obviously increased Beclin‐1 and Caspase‐3 and 9 as well as inhibited Bcl‐2 in U251 cells. All of our results indicated that these SAHA cap derivatives could serve as potential lead compounds for further optimization. In addition, N3F and N2E both displayed promising profile as antitumor candidates for the treatment of human glioma.     

Rapid synthesis of flavone‐based monoamine oxidase (MAO) inhibitors targeting two active sites using click chemistry

A new library of flavone derivatives targeting two active sites of monoamine oxidases (“aromatic cage” and substrate cavity) were designed and synthesized using click chemistry (CuAAC reaction) between 6‐N₃‐2‐phenyl chromones ( Az1–Az2 ) and a series of alkynes ( k1–k20 ). Their inhibitory activities against MAO isoforms (MAO‐A and MAO‐B) are evaluated. Compounds with fluorine, amide bonds, or amino bonds have shown better inhibition. The most potent flavone MAO inhibitor studied is Az2k19 (1.6 μm for MAO‐A, 2.1 μm for MAO‐B), while Az1k15 and Az2k15 displayed better selectivity toward MAO‐B (SI > 10). Docking studies are in accordance with our hypothesis that these inhibitors are most likely located at both the substrate cavity and the “aromatic cage”. Our results show that it is considerable to develop new MAO inhibitors from C6 substitution of flavone derivatives and that these compounds are also potential for the treatment of diseases associated with MAOs.     

Design,synthesis, and biological evaluation of 4‐aminopyrimidine or 4,6‐diaminopyrimidine derivatives as beta amyloid cleaving enzyme‐1 inhibitors

A series of novel aminopyrimidine and diaminopyrimidine derivatives were designed and optimized to improve their potency and permeability relative to lead compound 1 (IC₅₀ = 37.4 μM), which was discovered in a previous virtual screening. The potency of the optimized compound, 13g (IC₅₀ = 1.4 μM), was 26‐fold greater than that of 1 based on a fluorescence resonance energy transfer assay, and a parallel artificial membrane permeability assay suggested that it could pass through the blood‐brain barrier. Additionally, several compounds containing selenium showed good potencies and deserve further investigation as anti‐Alzheimer's agents.     

The identification and biochemical characterization of drug-like compounds that inhibit botulinum neurotoxin serotype A endopeptidase activity

A robust, high-throughput, two-tiered assay for screening small molecule inhibitors against botulinum neurotoxin serotype A was developed and employed to screen 16,544 compounds. Thirty-four compounds were identified as potent hits employing the first-tier assay. Subsequently, nine were confirmed as actives by our second-tier confirmatory assay. Of these, one displayed potent inhibitory efficacy, possessing an IC₅₀ = 16 μM (±1.6 μM) in our in vitro assay. This inhibitor (0831-1035) is highly water-soluble, and possesses an IC₅₀ = 47 μM (±7.0 μM) in our primary cell culture assay (with virtually no cytotoxicity up to 500 μM), suggesting that this inhibitor is a good candidate for further development as a therapeutic countermeasure to treat botulism resulting from botulinum neurotoxin serotype A intoxication. An enzyme kinetics study indicated that this inhibitor exhibits mixed non-competitive inhibition, with a K_I = 9 μM.     

Synthesis,molecular docking and biological evaluation of 1‐phenylsulphonyl‐2‐(1‐methylindol‐3‐yl)‐benzimidazole derivatives as novel potential tubulin assembling inhibitors

A series of new 1‐phenylsulphonyl‐2‐(1‐methylindol‐3‐yl)‐benzimidazole derivatives were designed, synthesized and evaluated as potential inhibitors of tubulin polymerization and anthropic cancer cell lines. Among them, compound 33 displayed the most potent tubulin polymerization inhibitory activity in vitro (IC₅₀ = 1.41 μM) and strong antiproliferative activities against A549, Hela, HepG2 and MCF‐7 cell lines in vitro with GI₅₀ value of 1.6, 2.7, 2.9 and 4.3 μM, respectively, comparable with the positive control colchicine (GI₅₀ value of 4.1, 7.2, 9.5 and 14.5 μM, respectively) and CA‐4 (GI₅₀ value of 2.2, 4.3, 6.4 and 11.4 μM, respectively). Simultaneously, we evaluated that compound 33 could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Immunofluorescence microscopy also clearly indicated compound 33 a potent antimicrotubule agent. Docking simulation showed that compound 33 could bind tightly with the colchicine‐binding site and act as a tubulin inhibitor. Three‐dimensional‐QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent tubulin assembling inhibitory activity in the future.     

Identification of Novel Selective Lysine‐Specific Demethylase 1 (LSD1) Inhibitors Using a Pharmacophore‐Based Virtual Screening Combined with Docking

Lysine‐specific demethylase 1 (LSD1) plays an important role in regulating the lysine methylation at residues K4 and K9 on histone H3. High levels of LSD1 expression have been observed in several malignant tumors. In this study, we presented a pharmacophore‐based virtual screening of a moderate database of 171 143 small molecules. A pharmacophore of LSD1 inhibitors was constructed for the first time and then used to screen the compound library combined with validated molecular docking tools followed by biochemical assays, led to the identification of 9 novel LSD1 inhibitors, showing their IC₅₀ values in a range of 2.41–101 μm . Furthermore, compound XZ 09 exhibited less inhibition against the homologous monoamine oxidase A (MAO‐A) and B (MAO‐B) displaying its moderate selectivity. Our study provides an effective virtual screening method to identify new LSD1 inhibitors and XZ09 represents a potent and selective lead compound to deserve further optimization for the treatment of LSD1 overexpressing cancers.     

Design,synthesis, and molecular docking studies of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives as xanthine oxidase inhibitors

A series of N‐(9,10‐anthraquinone‐2‐carbonyl)amino acid derivatives ( 1a–j ) was designed and synthesized as novel xanthine oxidase inhibitors. Among them, the L/D‐phenylalanine derivatives ( 1d and 1i ) and the L/D‐tryptophan derivatives ( 1e and 1j ) were effective with micromolar level potency. In particular, the L‐phenylalanine derivative 1d (IC₅₀ = 3.0 μm ) and the D‐phenylalanine derivative 1i (IC₅₀ = 2.9 μm ) presented the highest potency and were both more potent than the positive control allopurinol (IC₅₀ = 8.1 μm ). Preliminary SAR analysis pointed that an aromatic amino acid fragment, for example, phenylalanine or tryptophan, was essential for the inhibition; the D‐amino acid derivative presented equal or greater potency compared to its L‐enantiomer; and the 9,10‐anthraquinone moiety was welcome for the inhibition. Molecular simulations provided rational binding models for compounds 1d and 1i in the xanthine oxidase active pocket. As a result, compounds 1d and 1i could be promising lead compounds for further investigation.     

Inhibitory effects of sulfonylureas and non‐steroidal anti‐inflammatory drugs on in vitro metabolism of canagliflozin in human liver microsomes

Canagliflozin, used to treat type 2 diabetes mellitus (T2DM), is commonly co‐administered with sulfonylureas. The objective of the present study was to evaluate the possible inhibitory effect of sulfonylureas and non‐steroidal anti‐inflammatory drugs (NSAIDs) on canagliflozin metabolism in vitro. Three sulfonylurea derivatives were evaluated as inhibitors: chlorpropamide, glimepiride and gliclazide. Two other NSAIDs were used as positive control inhibitors: niflumic acid and diclofenac. The rate of formation of canagliflozin metabolites was determined by HPLC analysis of in vitro incubations of canagliflozin as a substrate with and without inhibitors, using human liver microsomes (HLMs). Among sulfonylureas, glimepiride showed the most potent inhibitory effect against canagliflozin M7 metabolite formation, with an IC₅₀ value of 88 μm , compared to chlorpropamide and gliclazide with IC₅₀ values of more than 500 μm . Diclofenac inhibited M5 metabolite formation more than M7, with IC₅₀ values of 32 μm for M5 and 80 μm for M7. Niflumic acid showed no inhibition activity against M5 formation, but had relatively selective inhibitory potency against M7 formation, which is catalysed by UGT1A9, with an IC₅₀ value of 1.9 μm and an inhibition constant value of 0.8 μm . A clinical pharmacokinetic interaction between canagliflozin and sulfonylureas is unlikely. However, a possible clinically important drug interaction between niflumic acid and canagliflozin has been identified.     

Cladosporamide A,a new protein tyrosine phosphatase 1B inhibitor,produced by an Indonesian marine sponge-derived Cladosporium sp.

Cladosporamide A (1), a new protein tyrosine phosphatase (PTP) 1B inhibitor, was isolated together with a known prenylated flavanone derivative (2) from the culture broth of an Indonesian marine sponge-derived Cladosporium sp. TPU1507 by solvent extraction, ODS column chromatography, and preparative HPLC (ODS). The structure of 1 was elucidated based on 1D and 2D NMR data. Compound 1 modestly inhibited PTP1B and T-cell PTP (TCPTP) activities with IC₅₀ values of 48 and 54 μM, respectively. The inhibitory activity of 2 against PTP1B (IC₅₀ = 11 μM) was approximately 2-fold stronger than that against TCPTP (IC₅₀ = 27 μM).

     

The Synthesis and Evaluation of C7‐Substituted α‐Tetralone Derivatives as Inhibitors of Monoamine Oxidase

Based on a previous report that α‐tetralone (3,4‐dihydro‐2H‐naphthalen‐1‐one) is a promising scaffold for the design of highly potent inhibitors of the enzyme, monoamine oxidase, the present study investigates the monoamine oxidase inhibitory properties of a synthetic series of fifteen C7‐substituted α‐tetralone derivatives. Arylalkyloxy substitution on C7 of the α‐tetralone moiety yielded compounds with high inhibition potencies toward the human monoamine oxidase‐B isoform with all compounds possessing IC₅₀ values in the submicromolar range (0.00089–0.047 μm ). The C7‐substituted α‐tetralones also were highly potent monoamine oxidase‐A inhibitors with thirteen (of fifteen) compounds possessing IC₅₀ values in the submicromolar range (0.010–0.741 μm ). The α‐tetralones were, however, in each instance selective for monoamine oxidase‐B over the monoamine oxidase‐A isoform. Dialyses of enzyme–inhibitor mixtures show that, while a representative inhibitor acts as a reversible monoamine oxidase‐A inhibitor, inhibition of monoamine oxidase‐B is not readily reversed by dialysis. Using a molecular modeling approach, possible binding orientations and interactions of selected α‐tetralones with the active sites of the monoamine oxidases are also proposed. This study suggests that C7‐substituted α‐tetralones are promising monoamine oxidase inhibitors and may represent lead compounds for the development of therapies for Parkinson's disease and depression.