hMAO-B Inhibitors Research Articles

Identification of 7,8-dihydroxy-3-phenylcoumarin as a reversible monoamine oxidase enzyme inhibitor.

We herein report the biological evaluation of 3-arylcoumarin derivatives (3a-l) as potential human monoamine oxidase-A and -B (hMAO-A and hMAO-B) inhibitors. The result indicated that 7,8-dihydroxy-3-(4-nitrophenyl)coumarin (3j) was most effective against MAO-A (inhibition concentration [IC50 ] = 6.46 ± 0.02 µM) and MAO-B (IC50 = 3.8 ± 0.3 µM) enzymes than other synthesized compounds and reference compounds (pargyline and moclobemide). Furthermore, compound (3j) showed (a) nonselectivity against hMAO enzymes,(b) reversible hMAO enzymes inhibition, and (c) neuroprotection against H2 O2 -treated human neuroblastoma (N2a) cells. Finally, a molecular modeling study revealed that the hMAO enzymes inhibitory activity of the compound (3j) may be due to the orientation where the nitro (NO2 ) group lies deep into the receptor and the phenyl ring directed toward flavin adenosine dinucleotide via hydrogen bond interaction, and possible π-π interaction with various important residues. Thus, the results of the present study demonstrate that compound (3j) can be considered as a promising scaffold for the development of hMAO-A and hMAO-B inhibitors.

7-Amidocoumarins as Multitarget Agents against Neurodegenerative Diseases: Substitution Pattern Modulation.

This study explores the potential of 7-amidocoumarins as multitarget agents against Parkinson's and Alzheimer's diseases, by modulating the substitution patterns within the scaffold. Sixteen compounds were synthesized via 7-amino-4-methylcoumarin acylation, and in vitro evaluation of the molecules against hMAO-A, hMAO-B, hAChE, hBuChE and hBACE1 was performed. Five compounds turned out to be potent and selective hMAO-B inhibitors in the nanomolar range, six displayed inhibitory activity of hMAO-A in the low micromolar range, one showed hAChE inhibitory activity and another one hBACE1 inhibitory activity. MAO-B reversibility profile of 7-(4'-chlorobenzamido)-4-methylcoumarin (10) was investigated, with this compound being a reversible inhibitor. Neurotoxicity on motor cortex neurons and neuroprotection against H2 O2 were also studied, corroborating the safety profile of these molecules. Finally, theoretical ADME properties were also calculated, showing these molecules as good candidates for the optimization of a lead compound. Results suggest that by modulating the substitution pattern at position 7 of the scaffold, selective or multitarget molecules can be achieved.

Design, synthesis and biological evaluation of rasagiline-clorgyline hybrids as novel dual inhibitors of monoamine oxidase-B and amyloid-β aggregation against Alzheimer’s disease

A series of rasagiline-clorgyline hybrids was designed, synthesized and investigated in vitro for their inhibition of monoamine oxidase and amyloid-β aggregation. Most of compounds were found to be selective and highly potent hMAO-B inhibitors showing IC50 values in the nanomolar, and exhibited a moderate inhibition of amyloid-β aggregation. 7-((5-(methyl(prop-2-yn-1-yl)amino) pentyl)oxy)chroman-4-one (6j) was the most interesting compound identified in this research, endowed with higher hMAO-B potency (IC50 = 4 nM) and selectivity (SI > 25000) compared to the reference selective inhibitor rasagiline (IC50 = 141 nM, SI > 355), and exhibited good inhibitory activity against Aβ1-42 aggregation (40.78%, 25 μM). Kinetic and molecular modeling studies revealed that 6j was a competitive reversible inhibitor for hMAO-B. Moreover, compound 6j displayed low toxicity and good neuroprotective effects in SH-SY5Y cell assay, and could penetrate the blood-brain barrier according to the parallel artificial membrane permeability assay. Pharmacokinetics assay revealed that compound 6j possessed good pharmacokinetic profiles after intravenous and oral administrations. Overall, these results highlighted that compound 6j was an effective and promising multitarget agent against Alzheimer’s disease.

Synthesis, molecular modelling and biological activity of some pyridazinone derivatives as selective human monoamine oxidase-B inhibitors.

Since brain neurotransmitter levels are associated with the pathology of various neurodegenerative diseases like Parkinson and Alzheimer, monoamineoxidase (MAO) plays a critical role in balancing these neurotransmitters in the brain. MAO isoforms appear as promising drug targets for the development of central nervous system agents. Pyridazinones have a broad array of biological activities. Here, six pyridazinone derivatives were synthesized and their human monoamine oxidase inhibitory activities were evaluated by molecular docking studies, in silico ADME prediction and in vitro biological screening tests. The compounds were synthesized by the reaction of different piperazine derivatives with 3 (2H)-pyridazinone ring and MAO-inhibitory effects were investigated. Docking studies were conducted with Maestro11.8 software. Most of the synthesized compounds inhibited hMAO-B selectively except compound 4f. Compounds 4a-4e inhibited hMAO-B selectively and reversibly in a competitive mode. Compound 4b was found as the most potent (ki = 0.022 ± 0.001µM) and selective (SI (Ki hMAO-A/hMAO-B) = 206.82) hMAO-B inhibitor in this series. The results of docking studies were found to be consistent with the results of the in vivo activity studies. Compounds 4a-4e were found to be non-toxic to HepG2 cells at 25μM concentration. In silico calculations of ADME properties indicated that the compounds have good pharmacokinetic profiles. It was concluded that 4b is possibly recommended as a promising nominee for the design and development of new pyridazinones which can be used in the treatment of neurological diseases.

Coumarin-Rasagiline Hybrids as Potent and Selective hMAO-B Inhibitors, Antioxidants, and Neuroprotective Agents.

The frequency, complexity and morbidity of neurodegenerative diseases make them a great challenge for nowadays medicine. Most of the treatments currently used for Parkinson's disease - the second most prevalent - are only symptomatic. Therefore, it is urgent to develop drugs that are able to act simultaneously on different targets, being able to stop neuronal death and promote the recovery of neuronal populations already affected. In this work, we studied the activity of a series of hybrid molecules, which combine the structure of both coumarin and an alkynylamine group inspired on rasagiline, as MAO inhibitors, antioxidants and neuroprotective agents. Half of the studied hybrids turned out to be selective monoamine oxidase B (hMAO-B) inhibitors in the low micro/nanomolar range, demonstrating that positions 3 (compounds 1-3) and 7 (compounds 8 and 10) of the coumarin scaffold are the most suitable for the incorporation of the alkynylamine chain. All the studied compounds proved to be capable of neutralizing free radicals (DPPH). Finally, the 4-(but-2-yn-1-ylamino)coumarin (5) showed neuroprotective effects on glial cells and the 4-methyl-7-(pent-2-yn-1-ylamino)coumarin (8) inhibited intraneuronal ROS production as well.

Calycosin and 8-O-methylretusin isolated from Maackia amurensis as potent and selective reversible inhibitors of human monoamine oxidase-B

Nineteen compounds were isolated from the stems of Maackia amurensis by activity-guided screening for new human monoamine oxidase-B (hMAO-B) inhibitors. Among the compounds isolated, flavonoids calycosin (5) and 8-O-methylretusin (6) were found to potently and selectively inhibit hMAO-B (IC50 = 0.24 and 0.23 μM, respectively) but not hMAO-A with high selectivity index (SI) values (SI = 293.8 and 81.3, respectively). In addition, 5 and 6 reversibly and competitively inhibited hMAO-B with Ki values of 0.057 and 0.054 μM, respectively. A pterocarpan (−)-medicarpin (18) was also observed to strongly inhibit hMAO-B (IC50 = 0.30 μM). Most of the compounds weakly inhibited AChE, except isolupalbigenin (13) (IC50 = 20.6 μM), which suggested 13 be considered a potential dual function inhibitor of MAO-B and AChE. Molecular docking simulation revealed that the binding affinities of 5 and 6 for hMAO-B (both −9.3 kcal/mol) were higher than those for hMAO-A (−7.4 and −7.2 kcal/mol, respectively). Compound 5 was found to interact by hydrogen bonding with hMAO-B at Cys172 residue (distance: 3.250 Å); no hydrogen bonding was predicted between 5 and hMAO-A. These findings suggest that compounds 5 and 6 be considered novel potent, selective, and reversible hMAO-B inhibitors and candidates for the treatment of neurological disorders.

Natural based piperine derivatives as potent monoamine oxidase inhibitors: an in silico ADMET analysis and molecular docking studies

Neurodegenerative disorders follow numerous pathological ways concerning overexpression of monoamine oxidase and formation of reactive oxygen species. The computational design of the piperine derivatives has given the significant MAO inhibitors with considerable antioxidant potential. Molecular docking provided the mechanistic insight of the compounds within the hMAO active site. In the current study we have prepared a series of compounds related to piperine and investigated them through monoamine oxidase A and B assay and evaluated the free radical scavenging activity. The synthesized compounds were analyzed by using in silico techniques within the active site of MAO and the ADMET properties were also calculated. The results obtained in this study indicated the interesting therapeutic potential of some compounds such as 7and 17c as most promising hMAO-A inhibitors whereas compounds 15, 5 and 17b were found as hMAO-B inhibitors. Moreover, we assessed the antioxidant potential of the piperine analogues and compounds 5, 17b, and 7 showed very modest antioxidant activity against DPPH and H2O2 radicals. The outcome of the study indicating that the piperine related derivatives are found as considerable MAO inhibitors and antioxidants. Moreover, the SAR structure activity relationships are depicting the structural features required for the MAO inhibition. In case of MAO activity, good correlations were found among the calculated and experimental results.

Design, synthesis, and evaluation of 1, 4-benzodioxan-substituted chalcones as selective and reversible inhibitors of human monoamine oxidase B

The inhibition of monoamine oxidase B (MAO-B) could be an effective approach for the treatment of various neurological disorders. In this study, a series of 1, 4-benzodioxan-substituted chalcone derivatives were designed, synthesised and evaluated for their inhibitory activity against human MAO-B (hMAO-B). The majority of these compounds showed inhibitory activity and high selectivity. The most potent compound, (E)-1-(3-bromo-4-fluorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)prop-2-en-1-one (22), exhibited an IC50 of 0.026 µM with a selectivity index greater than 1538. Kinetics and reversibility studies confirmed that the representative active compounds acted as competitive and reversible inhibitors of hMAO-B. The enzyme-inhibitor interactions were investigated by molecular docking studies and the rationale was provided. As these potent hMAO-B inhibitors exhibited low neurotoxicity and possessed promising drug-like properties, we believe that these active compounds could be further investigated as potential drug candidates for future in vivo studies.

Synthesis, in vitro enzyme activity and molecular docking studies of new benzylamine-sulfonamide derivatives as selective MAO-B inhibitors

Many studies have been conducted on the selective inhibition of human monoamine oxidase B (hMAO-B) enzyme using benzylamine-sulphonamide derivatives. Using various chemical modifications on BB-4h, which was reported previously by our team and showed a significant level of MAO-B inhibition, novel benzylamine-sulphonamide derivatives were designed, synthesised, and their MAO inhibition potentials were evaluated. Among the tested derivatives, compounds 4i and 4t achieved IC50 values of 0.041 ± 0.001 µM and 0.065 ± 0.002 µM, respectively. The mechanism of hMAO-B inhibition by compounds 4i and 4t was studied using Lineweaver–Burk plot. The nature of inhibition was also determined to be non-competitive. Cytotoxicity tests were conducted and compounds 4i and 4t were found to be non-toxic. Molecular docking studies were also carried out for compound 4i, which was found as the most potent agent, within hMAO-B catalytic site.

Ethyl Acetohydroxamate Incorporated Chalcones: Unveiling a Novel Class of Chalcones for Multitarget Monoamine Oxidase-B Inhibitors Against Alzheimer's Disease.

Chalcones are considered as the selective scaffold for the inhibition of MAO-B. A previously synthesized ethyl acetohydroxamate-chalcones (L1-L22) were studied for their inhibitory activities against human recombinant monoamine oxidase A and B (hMAO-A and hMAO-B, respectively) and acetylcholinesterase (AChE) as multi-target directed ligands for the treatment of Alzheimer's Disease (AD). Enzyme inhibition studies of MAO-A, MAO-B and AChE is carried out. Computational studies such as Molecular docking, Molecular Mechanics/Generalized Born Surface Area calculations, ADMET prediction, and protein target prediction are also performed. Among the screened compounds, compound L3 has most potent hMAO-B inhibition with an IC50 value of 0.028 ± 0.0016 µM, and other compounds, L1, L2, L4, L8, L12, and L21 showed significant potent hMAO-B inhibition with IC50 values of 0.051 ± 0.0014, 0.086 ± 0.0035, 0.036 ± 0.0011, 0.096 ± 0.0061, 0.083 ± 0.0016, and 0.038 ± 0.0021 µM, respectively. On the other hand, among the tested compounds, compound L13 showed highest hMAO-A inhibition with an IC50 value of 0.51± 0.051 µM and L9 has a significant value of 1.85 ± 0.045 µM. However, the compounds L3 and L4 only showed high selectivities for hMAO-B with Selectivity Index (SI) values of 621.4 and 416.7, respectively. Among the substituents in ring A of ethyl acetohydroxamate-chalcones (L1-L9), F atom at p-position (L3) showed highest inhibitory effect against hMAO-B. This result supports the uniqness and bizarre behavior of fluorine. Moreover, chalcones L3, L4, L9, L11, and L12 showed potential AChE inhibitory effect with IC50 values of 0.67, 0.85, 0.39, 0.30, and 0.45 µM, respectively. Inhibitions of hMAO-B by L3 or L4 were recovered to the level of the reversible reference (lazabemide), and were competitive with Ki values of 0.0030 ± 0.0002 and 0.0046 ± 0.0005 µM, respectively. Inhibitions of AChE by L3 and L11 were of the competitive and mixed types with Ki values of 0.30 ± 0.044 and 0.14 ± 0.0054 µM, respectively. The studies indicated that L3 and L4 are considered to be promising multitarget drug molecules with potent, selective, and reversible competitive inhibitors of hMAO-B and with highly potent AChE inhibitory effect.

Design of novel monoamine oxidase-B inhibitors based on piperine scaffold: Structure-activity-toxicity, drug-likeness and efflux transport studies

Piperine has been associated with neuroprotective effects and monoamine oxidase (MAO) inhibition, thus being an attractive scaffold to develop new antiparkinsonian agents. Accordingly, we prepared a small library of piperine derivatives and screened the inhibitory activities towards human MAO isoforms (hMAO-A and hMAO-B). Structure-activity relationship (SAR) studies pointed out that the combination of α-cyano and benzyl ester groups increased both potency and selectivity towards hMAO-B. Kinetic experiments with compounds 7, 10 and 15 indicated a competitive hMAO-B inhibition mechanism. Compounds 15 and 16, at 10 μM, caused a small but significant decrease in P-gp efflux activity in Caco-2 cells. Compound 15 stands out as the most potent piperine-based hMAO-B inhibitor (IC50 = 47.4 nM), displaying favourable drug-like properties and a broad safety window. Compound 15 is thus a suitable candidate for lead optimization and the development of multitarget-directed ligands.

In Silico Design, Synthesis of Hybrid Combinations: Quercetin Based MAO Inhibitors with Antioxidant Potential.

Monoamine oxidase (MAO) is a critical target used for the cure of neuropsychological diseases. A series of quercetin based derivatives was designed, synthesized, and evaluated as novel multifunctional agents against monoamine oxidase A and B with antioxidant potential. Hybrid derivatives based on quercetin were synthesized and screened for hMAO inhibition along with antioxidant activity. Molecular docking was performed to explicate the rationale of the different MAO (IC50) values and to explain the presence of inhibitory activity against specificity, respectively. The results of in vitro hMAO inhibition showed that compound 8a, 6c, and 4 were found as potent hMAO-A inhibitors whereas compounds 6b, 6a, and 6d were observed as potent hMAO-B inhibitors. The DPPH radical scavenging activity showed that compounds 6b, 6a, and 4 exhibited a promising antioxidant potential with IC50 values 5.931±0.007, 6.421±0.037, and 8.516±0.098 respectively. Moreover, the compound 6b, 6a, and 4 exhibited remarkable H2O2 scavenging potential with IC50 values 05.80±0.004 µM, 06.20±0.009 µM, and 07.66±0.009 µM respectively. The results of docking studies were found in good correlation with experimental MAO inhibition studies. Moreover, the mechanistic insight into the docking poses was also explored by binding interactions of quercetin based derivatives inside the dynamic site of hMAO-A and hMAO-B. It was also noticed that the potent MAO inhibitors were also acting as better antioxidants as evaluated through DPPH radical scavenging activity and H2O2 radical scavenging assay.

Lead optimization for promising monoamine oxidase inhibitor from eugenol for the treatment of neurological disorder: synthesis and in silico based study

Natural based inhibitors of monoamine oxidase are promising drug candidates for the treatment of several neurodegenerative and neuropsychological disorders including depression, anxiety, Parkinson’s disease and Alzheimer’s disease. In the present study we designed and synthesized the eugenol based derivatives and investigated them for human MAO inhibitory potential as promising candidates for therapeutics of neurological disorders. Moreover, radical scavenging activity of designed derivatives was tested by and H2O2 and DPPH scavenging methods. Eugenol based derivatives were designed and synthesized for human MAO inhibitory action. The in silico and in vitro models were utilized for the evaluation of hMAO inhibition. The insight into molecular interactions among the compounds and both hMAO-A and hMAO-B active site was achieved by molecular docking studies. The two spectrophotometric titrations techniques were used to evaluate antioxidant potential. Compounds 5b and 16 were found as most active hMAO-A inhibitors with IC50 values of 5.989 ± 0.007 µM and 7.348 ± 0.027 µM respectively, through an appreciable selectivity index value of 0.19 and 0.14 respectively. In case of hMAO-B inhibition compounds 13a and 13b were found as most active hMAO-B inhibitors with IC50 values of 7.494 ± 0.014 µM and 9.183 ± 0.034 µM receptively and outstanding value of selectivity index of 5.14 and 5.72 respectively. Radical scavenging assay showed that compounds 5b, 5a, 9b, 9a were active antioxidants. The findings of present study indicated excellent correlation among dry lab and wet lab hMAO inhibitory experiments. Interestingly, the compounds exhibiting better MAO inhibition activity was also appeared as good antioxidant agents.

Design, synthesis and biological evaluation of novel human monoamine oxidase B inhibitors based on a fragment in an X-ray crystal structure

Herein we report our efforts of developing reversible selective hMAO-B inhibitors based on isatin, a fragment in an X-ray crystal structure. Five different scaffolds were designed and many compounds were synthesized. Among them, compound A3 demonstrated very high potency and isoform selectivity against hMAO-B, 11 and 13 times more potent (IC50 = 3 nM) and 23.64 and 6.8 times more selective than the marked drugs, selegiline and safinamide. However, the endeavors to modify the polar 3-one group of isatin, that is in a hydrophobic environment in the binding site of hMAO-B, to small nonpolar hydrophobic groups did not bring about improved hMAO-B inhibitors, which may challenge our understanding of molecular interactions and molecular recognition in biological systems.

Development of piperic acid-based monoamine oxidase inhibitors: Synthesis, structural characterization and biological evaluation

A series of piperic acid esters and amides were synthesized using a two-step strategy. Mass spectrometry and unidimensional (1H NMR, 13C NMR, DEPT) and bidimensional (COSY, HSQC, HMBC) NMR methodologies were used to study the molecular structure of the final compounds, resulting in the assignment of all detected signals.Preliminary biological data of piperine and the derivatives thereof showed that piperic acid 2 and amides 3 and 4 did not display significant inhibitory activity at 10 μM against both hMAO-A and hMAO-B. In contrast, the esters 5 and 6 displayed relevant hMAO inhibitory activities, with IC50 values for hMAO-B lower than piperine and within the nanomolar range (compound 1: IC50 = 1.05 μM; compound 6: IC50 = 169 nM; compound 5: IC50 = 156 nM). Moreover, X-ray crystallographic analyses showed relevant differences between amides 3 and 4 and esters 5 and 6 constituting a valuable information to understand the ligand-target interactions.Additional studies are warranted for a systematic lead optimization process that can lead in the future to a more potent and selective hMAO-B inhibitor based on piperine scaffold.

Exploration of Umbelliferone Based Derivatives as Potent MAO Inhibitors: Dry vs. Wet Lab Evaluation.

Monoamine oxidase inhibitors are potential drug candidates within therapeutics of different neuropsychological and neurodegenerative disorders including anxiety, depression and Parkinson's disease. We investigated the MAO inhibitory effects of the umbelliferone based derivatives for the treatment of neurological disorders. The potential antioxidant effects of the derivatives were evaluated by DPPH and H2O2 scavenging methods. A series of different umbelliferone derivatives was designed and synthesized, and the derivatives were screened for hMAO-A and hMAO-B inhibition. Moreover, the mechanistic insight for enzyme- compound infractions was achieved by docking simulation. The antioxidant potential was dually assessed by two spectrophotometric titrations methods. Compound 5 with bromo 5-bromo-isatin exhibited a remarkable hMAO-A inhibitory potential (7.473±0.035 µM and the selectivity index of 0.14) revealing the impact of hybrid coumarin and 5- bromo-2-oxoindolin-3-yl ring with hydrazine linker on the hMAO-A active site. Compound 13 exhibited significant hMAO-B inhibition with an IC50 value of 10.32±0.044µM with an exceptional selectivity index of 8.55. Incorporation of 2-hydroxy-2-phenylacetate moiety on 2-oxo-2H-chromen ring led the important binding infractions within the hMAO active site. Our findings revealed a good correlation between experimental MAO inhibition and docking score by computational studies. Notably, the compounds with remarkable MAO inhibitory potential were also observed as potential antioxidants.

4-(3-Nitrophenyl)thiazol-2-ylhydrazone derivatives as antioxidants and selective hMAO-B inhibitors: synthesis, biological activity and computational analysis

A new series of 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives were designed, synthesised, and evaluated to assess their inhibitory effect on the human monoamine oxidase (hMAO) A and B isoforms. Different (un)substituted (hetero)aromatic substituents were linked to N1 of the hydrazone in order to establish robust structure–activity relationships. The results of the biological testing demonstrated that the presence of the hydrazothiazole nucleus bearing at C4 a phenyl ring functionalised at the meta position with a nitro group represents an important pharmacophoric feature to obtain selective and reversible human MAO-B inhibition for the treatment of neurodegenerative disorders. In addition, the most potent and selective MAO-B inhibitors were evaluated in silico as potential cholinesterase (AChE/BuChE) inhibitors and in vitro for antioxidant activities. The results obtained from molecular modelling studies provided insight into the multiple interactions and structural requirements for the reported MAO inhibitory properties.

Rhamnocitrin isolated from Prunus padus var. seoulensis: A potent and selective reversible inhibitor of human monoamine oxidase A

Three flavanones and two flavones were isolated from the leaves of Prunus padus var. seoulensis by the activity-guided screening for new monoamine oxidase (MAO) inhibitors. Among the compounds isolated, rhamnocitrin (5) was found to potently and selectively inhibit human MAO-A (hMAO-A, IC50 = 0.051 µM) and effectively inhibit hMAO-B (IC50 = 2.97 µM). The IC50 value of 5 for hMAO-A was the lowest amongst all natural flavonoids reported to date, and the potency was 20.2 times higher than that of toloxatone (1.03 µM), a marketed drug. In addition, 5 reversibly and competitively inhibited hMAO-A and hMAO-B with Ki values of 0.030 and 0.91 µM, respectively. Genkwanin (4) was also observed to strongly inhibit hMAO-A and hMAO-B (IC50 = 0.14 and 0.35 µM, respectively), and competitively inhibit hMAO-A and hMAO-B (Ki = 0.097 and 0.12 µM, respectively). Molecular docking simulation reveals that the binding affinity of 5 with hMAO-A (−18.49 kcal/mol) is higher than that observed with hMAO-B (0.19 kcal/mol). Compound 5 interacts with hMAO-A at four possible residues (Asn181, Gln215, Thr336, and Tyr444), while hMAO-B forms a single hydrogen bond at Glu84. These findings suggest that compound 5 as well as 4 can be considered as novel potent and reversible hMAO-A and/or hMAO-B inhibitors or useful lead compounds for future development of hMAO inhibitors in neurological disorder therapies.

Synthesis and Evaluation of N-[1-(((3,4-Diphenylthiazol-2(3H)-ylidene)amino)methyl)cyclopentyl]acetamide Derivatives for the Treatment of Diseases Belonging to MAOs

A series of N-[1-(((3,4-diphenylthiazol-2(3H)-ylidene)amino)methyl)cyclopentyl]acetamide derivatives (4a-4i) were synthesized in good yield and assayed for their inhibitory potency against monoamine oxidase (MAO) isoforms. Structures of newly synthesized compounds were characterized by IR, 1H-NMR, 13C-NMR, and mass spectroscopic methods. The inhibitory activity of compounds (4a-4i) against hMAO-A and hMAO-B enzymes was elucidated by using in vitro fluorometric method using Amplex Red® reagent. In the hMAO-A inhibition assay, compounds 4a, 4b, 4c, and 4i exhibited similar activity with standard drug moclobemide (IC50 = 6.061 ± 0.262 µM) with IC50 values of 7.06 ± 0.18 µM, 6.56 ± 0.20 µM, 6.78 ± 0.15 µM, and 7.09 ± 0.17 µM, respectively. According to hMAO-B inhibition results, compounds 4a, 4b, and 4c displayed significant activity with IC50 values of 0.42 ± 0.012 µM, 0.36 ± 0.014 µM, and 0.69 ± 0.020 µM, respectively. In the wake of all these results, it was understood that compound 4b was found to be the most potent derivative in the series against both isoforms and selective as MAO-B inhibitor. The cytotoxicity test was performed for compounds 4a, 4b, and 4c, and it was found that these compounds were noncytotoxic at the concentration of their IC50 values. Also, enzyme kinetic and docking studies of compound 4b were performed against MAO-B. It was observed that 4b showed a reversible and noncompetitive inhibition type. The important binding modes of this compound with active site of hMAO-B were shown owing to in silico studies.

Multi-targeted directed ligands for Alzheimer’s disease: design of novel lead coumarin conjugates

Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by central nervous system insults with progressive cognitive (memory, attention) and non-cognitive (anxiety, depression) impairments. Pathophysiological events affect predominantly cholinergic neuronal loss and dysfunctions of the dopaminergic system. The aim of the current study was to design multi-targeted directed lead structures based on the coumarin scaffold with inhibitory properties at two key enzymes in disease relevant systems, i.e. acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Conventional and microwave synthetic methods were utilized to synthesize coumarin scaffold-based novel morpholino, piperidino, thiophene and erucic acid conjugates. Biological assays indicated that the coumarin–morpholine ether conjugate BPR 10 was the most potent hMAO-B inhibitor. The coumarin–piperidine conjugates BPR 13 and BPR 12 were the most potent inhibitors of eeAChE at 100 μM and 1 μM, respectively. Molecular modelling studies were conducted with Accelrys® Discovery Studio® V3.1.1 utilising the published hMAO-B (2V61) and hAChE (4EY7) crystal structures. Compound BPR 10 occupies both the entrance and substrate cavities of the active site of MAO-B. BPR 13 resides in both the peripheral anionic site (PAS) and the catalytic anionic site (CAS) of hAChE. This study demonstrated that the coumarin scaffold serves as a promising pharmacophore for MTDLs design.