High-throughput discovery of highly selective reversible hMAO-B inhibitors based on at-line nanofractionation.

Human monoamine oxidase B (hMAO-B) has emerged as a pivotal therapeutic target for Parkinson's disease. Due to adverse effects and shortage of commercial drugs, there is a need for novel, highly selective, and reversible hMAO-B inhibitors with good blood-brain barrier permeability. In this study, a high-throughput at-line nanofractionation screening platform was established with extracts from Chuanxiong Rhizoma, which resulted in the discovery of 75 active compounds, including phenolic acids, volatile oils, and phthalides, two of which were highly selective novel natural phthalide hMAO-B inhibitors that were potent, selective, reversible and had good blood‒brain permeability. Molecular docking and molecular dynamics simulations elucidated the inhibition mechanism. Sedanolide (IC50 = 103 nmol/L; SI = 645) and neocnidilide (IC50 = 131 nmol/L; SI = 207) demonstrated their excellent potential as hMAO-B inhibitors. They offset the limitations of deactivating enzymes associated with irreversible hMAO-B inhibitors such as rasagiline. In SH-SY5Y cell assays, sedanolide (EC50 = 0.962 µmol/L) and neocnidilide (EC50 = 1.161 µmol/L) exhibited significant neuroprotective effects, comparable to the positive drugs rasagiline (EC50 = 0.896 µmol/L) and safinamide (EC50 = 1.079 µmol/L). These findings underscore the potential of sedanolide as a novel natural hMAO-B inhibitor that warrants further development as a promising drug candidate.

Correlation intensity index-index of ideality of correlation: A hyphenated target function for furtherance of MAO-B inhibitory activity assessment.

Monoamine oxidases are the enzymes involved in the management of brain homeostasis through oxidative deamination of monoamines such as neurotransmitters, tyramine etc. The excessive production of monoamine oxidase-B specifically results in numerous neurodegenerative disorders like Alzheimer's and Parkinson's diseases. Inhibitors of monoamine oxidase-B are applied in the management of these disorders. Here in this article we have developed robust hybrid descriptor based QSAR models related to 123 monoamine oxidase-B inhibitors through CORAL software by means of Monte Carlo optimization method. Three target functions were applied to prepare QSAR models and three splits were made for each target function. The most reliable, robust and better predictive QSAR models were developed with TF3 (correlation intensity index -index of ideality of correlation). Correlation intensity index showed positive effect on QSAR models. The structural features obtained from the QSAR modeling were incorporated in newly designed molecules and exhibited positive effect on their endpoint. Significant binding interactions were represented by these molecules in docking studies. Molecule B5 displayed prominent pIC50 (8.3) and binding affinity (-11.5 kcal mol-1) towards monoamine oxidase-B.

Xanthine-Dopamine Hybrid Molecules as Multitarget Drugs with Potential for the Treatment of Neurodegenerative Diseases.

Multitarget drugs based on a hybrid dopamine-xanthine core were designed as potential drug candidates for the treatment of neurodegenerative diseases. Monoamine oxidase B (MAO-B) inhibitors with significant ancillary A2A adenosine receptor (A2AAR) antagonistic properties were further developed to exhibit additional phosphodiesterase-4 and -10 (PDE4/10) inhibition and/or dopamine D2 receptor (D2R) agonistic activity. While all of the designed compounds showed MAO-B inhibition in the nanomolar range mostly combined with submicromolar A2AAR affinity, significant enhancement of PDE-inhibitory and D2R-agonistic activity was additionally reached for some compounds through various structural modifications. The final multitarget drugs also showed promising antioxidant properties in vitro. In order to evaluate their potential neuroprotective effect, representative ligands were tested in a cellular model of toxin-induced neurotoxicity. As a result, protective effects against oxidative stress in neuroblastoma cells were observed, confirming the utility of the applied strategy. Further evaluation of the newly developed multitarget ligands in preclinical models of Alzheimer's and Parkinson's diseases is warranted.

Design, synthesis and evaluation of novel monoamine oxidase B (MAO-B) inhibitors with improved pharmacokinetic properties for Parkinson's disease.

A series of novel ((benzofuran-5-yl)methyl)pyrrolidine-2-carboxamide derivatives were designed, synthesized and evaluated as MAO-B inhibitors. SAR studies indicated that cyclizing benzyl ether into benzofuran ring resulted in the most potent MAO-B inhibitor (IC50 = 0.037 µM), (2S,4S)-4-fluoro-1-((2-(4-fluorophenyl) benzofuran-5-yl)methyl)pyrrolidine-2-carboxamide (C14). PK properties of C14 in rats and mice were significantly improved compared to our previous candidate and safinamide, indicating that benzofuran moiety is essential for improving PK properties. Moreover, C14 displayed good metabolic stability and brain-blood barrier permeability, as well as favorable in vitro properties. Finally, C14 significantly inhibited MAO-B in the mouse brain. C14 exhibited a potential efficacy for DA deficits in the MPTP-induced mouse model and significantly increased DA concentration in the striatum. Thus, we identified that C14 may be a promising drug candidate for PD treatment.

Polyphenolic Glycosides from the Fruits Extract of Lycium ruthenicum Murr and Their Monoamine Oxidase B Inhibitory and Neuroprotective Activities.

The fruits ofLycium ruthenicum Murr have long been consumed as health food and used in folk medicine in China. Apart from the well-known polysaccharides, the active small molecular constituents in this fruit have not been fully studied. In this work, a systematic phytochemical study was carried out to investigate the small molecules and their potential health benefits. Nine new polyphenolic glycosides, lyciumserin A-I (1-9), together with 16 known compounds (10-25), were isolated and elucidated by high-resolution electrospray ionization mass spectrometry and comprehensive NMR analyses in combination with chemical hydrolysis. Compounds 1, 2, and 16 exhibited moderate inhibitory activity of monoamine oxidase B (MAO-B), while compounds 1 (50 µM) and 2 (100 µM) displayed significant neuroprotective effects (69.22 and 72.38% of cell viability, respectively) in the 6-hydroxydopamine-induced injury of the PC12 cell model (54.41%), comparable to the positive drug rasagiline (70.45%). The neuroprotective effect of 1 and 2 was further evidenced by the observation of the morphological change and fluorescein diacetate/propidium iodide staining. In addition, the levels of the major active compounds (1, 3, 5/6, and 16-18) vary from 21.5 to 892.3 µg/g. This is the first report on phenolic glycosides from the fruits ofL. ruthenicum Murr that possess both significant MAO-B inhibitory and neuroprotective effects, indicating the promising potential of the fruits for the development of health care products and even therapeutic agents for the treatment of Parkinson's disease and other neurodegenerative diseases.

Discovery of novel 3-butyl-6-benzyloxyphthalide Mannich base derivatives as multifunctional agents against Alzheimer's disease.

Based on the multitarget-directed ligands strategy, a series of 3-butyl-6-benzyloxyphthalide Mannich base derivatives were designed, synthesized and identified for Alzheimer's disease (AD). Biological activity studies demonstrated that the designed hybrids showed multitarget activities toward AD. Among them, compound 7d was the most potent agent with excellent inhibitory activities on EeAChE (IC50 = 0.087 µM), HuAChE (IC50 = 0.041 µM) and MAO-B (IC50 = 0.30 µM). Furthermore, molecular docking studies were conducted to investigate the interaction mode with enzymes. Besides, 7d also possessed good effects of Cu2+ chelation, ameliorate oxidative stress, and anti-neuroinflammation, desirable BBB permeability and eligible drug-like properties. Altogether, the multifunctional profiles of 7d prove that it deserves further investigation as a novel drug candidate for AD treatment.

Coumarin-Resveratrol-Inspired Hybrids as Monoamine Oxidase B Inhibitors: 3-Phenylcoumarin versus trans-6-Styrylcoumarin.

Monoamine oxidases (MAOs) are attractive targets in drug design. The inhibition of one of the isoforms (A or B) is responsible for modulating the levels of different neurotransmitters in the central nervous system, as well as the production of reactive oxygen species. Molecules that act selectively on one of the MAO isoforms have been studied deeply, and coumarin has been described as a promising scaffold. In the current manuscript we describe a comparative study between 3-phenylcoumarin (endo coumarin-resveratrol-inspired hybrid) and trans-6-styrylcoumarin (exo coumarin-resveratrol-inspired hybrid). Crystallographic structures of both compounds were obtained and analyzed. 3D-QSAR models, in particular CoMFA and CoMSIA, docking simulations and molecular dynamics simulations have been performed to support and better understand the interaction of these molecules with both MAO isoforms. Both molecules proved to inhibit MAO-B, with trans-6-styrylcoumarin being 107 times more active than 3-phenylcoumarin, and 267 times more active than trans-resveratrol.

6-Benzyloxyphthalides as selective and reversible monoamine oxidase B inhibitors with antioxidant and anti-neuroinflammatory activities for Parkinson's disease treatment.

A series of 6-benzyloxyphthalides were designed and synthesized as potent monoamine oxidase B inhibitors with antioxidant and anti-neuroinflammatory activities. The representative compounds 8f and 14a exhibited excellent selective MAO-B inhibition activity (IC50 = 1.33 nM, SI = 865; IC50 = 0.02 nM, SI = 40250, respectively) and moderate antioxidant activity (0.34 and 0.36 Trolox equivalent, respectively). Further studies showed that they were competitive and quasi-reversible MAO-B inhibitors. In cellular experiments, they could significantly decrease the production of NO and TNF-α in LPS-stimulated BV-2 cells to perform their in vitro anti-neuroinflammatory activities. Moreover, BBB permeability study and the predicted physicochemical properties indicated they were suitable for the CNS. Finally, in in vivo acute and subacute MPTP-induced mice model of PD, 8f and 14a could significantly improve most behavioral disorders, restore the DA content and decrease the MDA content in the mice striatum, exhibiting better anti-PD effects than clinically used safinamide. Hence, compounds 8f and 14a are identified in our studies as prospective prototype in the research of innovative multifunctional drugs for Parkinson's disease treatment.

Indoles and 1-(3-(benzyloxy)benzyl)piperazines: Reversible and selective monoamine oxidase B inhibitors identified by screening an in-house compound library.

The therapeutic indications for monoamine oxidases A and B (MAO-A and MAO-B) inhibitors that have emerged from biological studies on animal and cellular models of neurological and oncological diseases have focused drug discovery projects upon identifying reversible MAO inhibitors. Screening of our in-house academic compound library identified two hit compounds that inhibit MAO-B with IC50 values in micromolar range. Two series of indole (23 analogues) and 3-(benzyloxy)benzyl)piperazine (16 analogues) MAO-B inhibitors were derived from hits, and screened for their structure-activity relationships. Both series yielded low micromolar selective inhibitors of human MAO-B, namely indole 2 (IC50 = 12.63 ± 1.21 µM) and piperazine 39 (IC50 = 19.25 ± 4.89 µM), which is comparable to selective MAO-B inhibitor isatin (IC50 = 6.10 ± 2.81 µM), yet less potent in comparison to safinamide (IC50 = 0.029 ± 0.002 µM). Selective MAO-B inhibitors 2, 14, 38 and 39 exhibited favourable permeation of the blood-brain barrier and low cytotoxicity in the human neuroblastoma cell line SH-SY5Y.

Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson's Disease: Past, Present, and Future.

Monoamine oxidase-B (MAO-B) inhibitors are commonly used for the symptomatic treatment of Parkinson's disease (PD). MAO-B inhibitor monotherapy has been shown to be effective and safe for the treatment of early-stage PD, while MAO-B inhibitors as adjuvant drugs have been widely applied for the treatment of the advanced stages of the illness. MAO-B inhibitors can effectively improve patients' motor and non-motor symptoms, reduce "OFF" time, and may potentially prevent/delay disease progression. In this review, we discuss the effects of MAO-B inhibitors on motor and non-motor symptoms in PD patients, their mechanism of action, and the future development of MAO-B inhibitor therapy.

Cyanobiphenyls: Novel H3 receptor ligands with cholinesterase and MAO B inhibitory activity as multitarget compounds for potential treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a complex and incurable illness that requires the urgent approval of new effective drugs. However, since 2003, no new molecules have shown successful results in clinical trials, thereby making the common "one compound - one target" paradigm questionable. Recently, the multitarget-directed ligand (MTDL) approach has gained popularity, as compounds targeting at least two biological targets may be potentially more effective in treating AD. On the basis of these findings, we designed, synthesized, and evaluated through biological assays a series of derivatives of alicyclic amines linked by an alkoxy bridge to an aromatic lipophilic moiety of [1,1'-biphenyl]-4-carbonitrile. The research results revealed promising biological activity of the obtained compounds toward the chosen targets involved in AD pathophysiology; the compounds showed high affinity (mostly low nanomolar range of Ki values) for human histamine H3 receptors (hH3R) and good nonselective inhibitory potency (micromolar range of IC50 values) against acetylcholinesterase from electric eel (eeAChE) and equine serum butyrylcholinesterase (eqBuChE). Moreover, micromolar/submicromolar potency against human monoamine oxidase B (hMAO B) was detected for some compounds. The study identified compound 5 as a multiple hH3R/eeAChE/eqBuChE/hMAO B ligand (5: hH3R Ki = 9.2 nM; eeAChE IC50 = 2.63 µM; eqBuChE IC50 = 1.30 µM; hMAO B IC50 = 0.60 µM). Further in vitro studies revealed that compound 5 exhibits a mixed type of eeAChE and eqBuChE inhibition, good metabolic stability, and moderate hepatotoxicity effect on HepG2 cells. Finally, compound 5 showed a beneficial effect on scopolamine-induced memory impairments, as assessed by the passive avoidance test, thus revealing the potential of this compound as a promising agent for further optimization for AD treatment.

Cost-Effectiveness of Dopamine Agonists and Monoamine Oxidase B Inhibitors in Early Parkinson's Disease.

BACKGROUND: The PD MED study reported small but persistent benefits in patient-rated mobility scores and quality of life from initiating therapy with levodopa compared with levodopa-sparing therapies in early Parkinson's disease (PD). OBJECTIVES: The objective was to estimate the cost-effectiveness of levodopa-sparing therapy (dopamine agonists or monoamine oxidase type B inhibitors compared with levodopa alone. METHODS: PD MED is a pragmatic, open-label randomized, controlled trial in which patients newly diagnosed with PD were randomly assigned between levodopa-sparing therapy (dopamine agonists or monoamine oxidase type B inhibitors ) and levodopa alone. Mean quality-adjusted life-years and costs were calculated for each participant. Differences in mean quality-adjusted life-years and costs between levodopa and levodopa-sparing therapies and between dopamine agonists and monoamine oxidase type B inhibitors were estimated using linear regression. RESULTS: Over a mean observation period of 4 years, levodopa was associated with significantly higher quality-adjusted life-years (difference, 0.18; 95% CI, 0.05-0.30; P < 0.01) and lower mean costs (£3390; £2671-£4109; P < 0.01) than levodopa-sparing therapies, the difference in costs driven by the higher costs of levodopa-sparing therapies. There were no significant differences in the costs of inpatient, social care, and institutional care between arms. There was no significant difference in quality-adjusted life-years between those allocated dopamine agonists and monoamine oxidase type B inhibitors (0.02; -0.17 to 0.13 in favor of dopamine agonists; P = 0.81); however costs were significantly lower for those allocated monoamine oxidase type B inhibitors (£2321; £1628-£3015; P < 0.01) because of the higher costs of dopamine agonists. There were no significant differences between arms for other costs. CONCLUSIONS: Initial treatment with levodopa is highly cost-effective compared with levodopa-sparing therapies. Monoamine oxidase type B inhibitors, as initial levodopa-sparing therapy was more cost-effective, with similar quality-adjusted life-years but lower costs than dopamine agonists. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The effect of monoamine oxidase-B inhibitors on the alleviation of depressive symptoms in Parkinson's disease: meta-analysis of randomized controlled trials.

BACKGROUND: Depression is a major nonmotor symptom of Parkinson's disease (PD). However, few treatments exist for PD depression. Monoamine oxidase-B inhibitors (MAOB-Is) provide symptomatic relief for the motor symptoms of PD and exert antidepressive effects. The present meta-analysis of randomized controlled trials (RCTs) investigated the effects of MAOB-Is on depressive symptoms in patients with PD. METHODS: Articles on PD-management-related RCTs using one of three MAOB-Is approved by the US Food and Drug Administration, that is, selegiline, rasagiline, and safinamide, were identified. The primary outcomes were the benefits of MAOB-Is for depressive symptoms. Subgroup analysis included the effects of MAOB-Is on patients in the early versus middle-to-late stages of PD and the effect of short-term versus long-term treatment. RESULTS: Overall, six studies were included, four of which were conducted on patients with early stage PD. Overall, MAOB-Is significantly reduced the severity of depressive symptoms [standardized mean difference (SMD): -0.14, 95% confidence interval (CI): -0.21 to -0.06, p < 0.001]. Subgroup analysis indicated that the positive effect of MAOB-Is was significant in patients with early stage PD (SMD: -0.20, 95% CI: -0.31 to -0.09, p < 0.001), but not in those with middle-to-late-stage PD (SMD: -0.07, 95% CI: -0.17 to 0.03, p = 0.18). The antidepressive effect was significant for short-term treatment, that is, 90-120 days (SMD: -0.23, 95% CI: -0.35 to -0.10, p < 0.001), but not long-term treatment, that is, 24 weeks to 18 months (SMD: -0.08, 95% CI: -0.18 to 0.01, p = 0.09). CONCLUSION: In addition to the treatment of PD motor symptoms, MAOB-Is may help reduce the severity of depressive symptoms in PD, especially in patients with early stage PD. Considering the tolerability and simultaneous benefits of MAOB-Is, further RCTs are warranted to confirm their therapeutic effects in moderate-to-severe PD depression.

Combined 3D-QSAR and docking analysis for the design and synthesis of chalcones as potent and selective monoamine oxidase B inhibitors.

Monoamine oxidases (MAOs) are important targets in medicinal chemistry, as their inhibition may change the levels of different neurotransmitters in the brain, and also the production of oxidative stress species. New chemical entities able to interact selectively with one of the MAO isoforms are being extensively studied, and chalcones proved to be promising molecules. In the current work, we focused our attention on the understanding of theoretical models that may predict the MAO-B activity and selectivity of new chalcones. 3D-QSAR models, in particular CoMFA and CoMSIA, and docking simulations analysis have been carried out, and their successful implementation was corroborated by studying twenty-three synthetized chalcones (151-173) based on the generated information. All the synthetized molecules proved to inhibit MAO-B, being ten out of them MAO-B potent and selective inhibitors, with IC50 against this isoform in the nanomolar range, being (E)-3-(4-hydroxyphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-en-1-one (152) the best MAO-B inhibitor (IC50 of 170 nM). Docking simulations on both MAO-A and MAO-B binding pockets, using compound 152, were carried out. Calculated affinity energy for the MAO-A was +2.3 Kcal/mol, and for the MAO-B was -10.3 Kcal/mol, justifying the MAO-B high selectivity of these compounds. Both theoretical and experimental structure-activity relationship studies were performed, and substitution patterns were established to increase MAO-B selectivity and inhibitory efficacy. Therefore, we proved that both 3D-QSAR models and molecular docking approaches enhance the probability of finding new potent and selective MAO-B inhibitors, avoiding time-consuming and costly synthesis and biological evaluations.

Discovery and optimization of 3-thiophenylcoumarins as novel agents against Parkinson's disease: Synthesis, in vitro and in vivo studies.

Monoamine oxidase B (MAO-B) inhibitors are still receiving great attention as promising therapeutic agents for central nervous system disorders. This study explores, for the first time, the potential of 3-thiophenylcoumarins as in vitro and in vivo agents against Parkinsons disease. Twelve compounds were synthesized via Perkin-Oglialoro reaction, and in vitro evaluation of six hydroxylated molecules was performed. MAO-A and MAO-B inhibition, DPPH scavenging and inhibition of ROS formation, neurotoxicity on motor cortex neurons and neuroprotection against H2O2, were studied. In vivo effect on locomotor activity using the open field test was also evaluated for the best candidate [3-(4'-bromothiophen-2'-yl)-7-hydroxycoumarin, 5], a potent, selective and reversible MAO-B inhibitor (IC50 = 140 nM). This compound proved to have a slightly better in vivo profile than selegiline, one of the currently treatments for Parkinson's disease, in reserpinized mice pretreated with levodopa and benserazide. Results suggested that, comparing positions 7 and 8, substitution at position 7 of the coumarin scaffold is better for the enzymatic inhibition. However, the presence of a catechol at positions 7 and 8 exponentially increases the antioxidant potential and the neuroprotective properties. Finally, all the molecules present good theoretical physicochemical properties that make them excellent candidates for the optimization of a lead compound.

3-Arylcoumarins as highly potent and selective monoamine oxidase B inhibitors: Which chemical features matter?

Monoamine oxidase B inhibitory activity is closely regulated by the interaction of the small molecules with the enzyme. It is therefore desirable to use theoretical approaches to design rational methods to develop new molecules to modulate specific interactions with the protein. Here, we report such methods, and we illustrate their successful implementation by studying six synthetized 3-arylcoumarins (71-76) based on them. Monoamine oxidase B inhibition is essential to maintain the balance of dopamine, and one of its major functions is to combat dopamine degradation, a phenomenon linked to Parkinson's disease. In this work, we study small-molecule inhibitors based on the 3-arylcoumarin scaffold and their monoamine oxidase B selective inhibition. We show that 3D-QSAR models, in particular CoMFA and CoMSIA, and molecular docking approaches, enhance the probability to find new interesting inhibitors, avoiding very costly and time-consuming synthesis and biological evaluations.

Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones.

A series of 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor (3), we studied single-point modifications at the benzyloxy or at the basic moiety. The in vitro screening highlighted triple-acting compounds (6, 8, 9, 16, 20) showing nanomolar and selective MAO B inhibition along with IC50 against ChEs at the low micromolar level. Enzyme kinetics analysis toward AChE and docking simulations on the target enzymes were run in order to get insight into the mechanism of action and plausible binding modes.

Novel approaches to the discovery of selective human monoamine oxidase-B inhibitors: is there room for improvement?

Introduction: Selective monoamine oxidase-B (MAO-B) inhibitors are currently used as coadjuvants for the treatment of early motor symptoms in Parkinson's disease. They can, based on their chemical structure and mechanism of inhibition, be categorized into reversible and irreversible agents. Areas covered: This review provides a comprehensive update on the development state of selective MAO-B inhibitors describing the results, structures, structure-activity relationships (SARs) and Medicinal chemistry strategies as well as the related shortcomings over the past five years. Expert opinion: Researchers have explored and implemented new and old chemical scaffolds achieving high inhibitory potencies and isoform selectivity. Most of them were characterized and proposed as multitarget agents able to act at different levels (including AChE inhibition, H3R or A2AR antagonism, antioxidant and chelating properties, Aß1-42 aggregation reduction) in the network of aetiologies of neurodegenerative disorders. These results can also be used to avoid 'cheese-reaction' effects and the occurrence of serotonergic syndrome in patients.

Novel multi-target directed ligands based on annelated xanthine scaffold with aromatic substituents acting on adenosine receptor and monoamine oxidase B. Synthesis, in vitro and in silico studies.

N9-Benzyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones were designed as dual-target-directed ligands combining A2A adenosine receptor (AR) antagonistic activity with blockade of monoamine oxidase B (MAO-B). A library of 37 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO-B. A systematic modification of the tricyclic structures based on a xanthine core by enlargement of the third heterocyclic ring or attachment of various substituted benzyl moieties resulted in the development of 9-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione (9u; Ki human A2AAR: 189 nM and IC50 human MAO-B: 570 nM) as the most potent dual acting ligand of the series displaying high selectivity versus related targets. Moreover, some potent, selective MAO-B inhibitors were identified in the group of pyrimido- and 1,3-diazepino[2,1-f]purinediones. Compound 10d (10-(3,4-dichlorobenzyl)-1,3-dimethyl-7,8,9,10-tetrahydro-1H-[1,3]diazepino[2,1-f]purine-2,4(3H,6H)-dione) displayed an IC50 value at human MAO-B of 83 nM. Analysis of structure-activity relationships was complemented by molecular docking studies based on previously published X-ray structures of the protein targets. An extended biological profile was determined for selected compounds including in vitro evaluation of potential hepatotoxicity calculated in silico and antioxidant properties as an additional desirable activity. The new molecules acting as dual target drugs may provide symptomatic relief as well as disease-modifying effects for neurodegenerative diseases, in particular Parkinson's disease.

Monoamine oxidase-B inhibitors as potential neurotherapeutic agents: An overview and update.

Monoamine oxidase (MAO) inhibitors have made significant contributions and remain an indispensable approach of molecular and mechanistic diversity for the discovery of antineurodegenerative drugs. However, their usage has been hampered by nonselective and/or irreversible action which resulted in drawbacks like liver toxicity, cheese effect, and so forth. Hence, the search for selective MAO inhibitors (MAOIs) has become a substantial focus in current drug discovery. This review summarizes our current understanding on MAO-A/MAO-B including their structure, catalytic mechanism, and biological functions with emphases on the role of MAO-B as a potential therapeutic target for the development of medications treating neurodegenerative disorders. It also highlights the recent developments in the discovery of potential MAO-B inhibitors (MAO-BIs) belonging to diverse chemical scaffolds, arising from intensive chemical-mechanistic and computational studies documented during past 3 years (2015-2018), with emphases on their potency and selectivity. Importantly, readers will gain knowledge of various newly established MAO-BI scaffolds and their development potentials. The comprehensive information provided herein will hopefully accelerate ideas for designing novel selective MAO-BIs with superior activity profiles and critical discussions will inflict more caution in the decision-making process in the MAOIs discovery.