"Click Chemistry": An Emerging Tool for Developing a New Class of Structural Motifs against Various Neurodegenerative Disorders.

Click chemistry is a set of easy, atom-economical reactions that are often utilized to combine two desired chemical entities. Click chemistry accelerates lead identification and optimization, reduces the complexity of chemical synthesis, and delivers extremely high yields without undesirable byproducts. The most well-known click chemistry reaction is the 1,3-dipolar cycloaddition of azides and alkynes to form 1,2,3-triazoles. The resulting 1,2,3-triazoles can serve as both bioisosteres and linkers, leading to an increase in their use in the field of drug discovery. The current Review focuses on the use of click chemistry to identify new molecules for treating neurodegenerative diseases and in other areas such as peptide targeting and the quantification of biomolecules.

An efficient method to access spiro pseudoindoxyl ketones: evaluation of indoxyl and their N-benzylated derivatives for inhibition of the activity of monoamine oxidases.

A simple, metal-free approach was developed to obtain novel pseudoindoxyl derivatives. The reaction was mediated by tBuOK on tetrahydrocarbazole 8 in dimethyl sulfoxide (DMSO) at room temperature through the hydroxylation of the indole double bond and a subsequent pinacol-type rearrangement. Spiro pseudoindoxyl compounds and their N-benzylated derivatives were assessed for their inhibitory activities against monoamine oxidase (MAO) enzymes. Based on half-maximal inhibitory concentration (IC50) values, 13 compounds were found to have higher inhibitory activity against MAO-B than against MAO-A. With regard to MAO-B inhibition, 11f showed the best inhibitory activity, with an IC50 value of 1.44 µM, followed by 11h (IC50 = 1.60 µM), 11j (IC50 = 2.78 µM), 11d (IC50 = 2.81 µM), and 11i (IC50 = 3.02 µM). Compound 11f was a competitive inhibitor with a Ki value of 0.51 ± 0.023 µM. In a reversibility experiment using dialysis, 11f showed effective recovery of MAO-B inhibition similar to that of safinamide. These experiments suggested that 11f was a potent, reversible, and competitive inhibitor of MAO-B activity.

A comprehensive review of the docking studies of chalcone for the development of selective MAO-B inhibitors.

Monoamine oxidase B is a crucial therapeutic target for neurodegenerative disorders like Alzheimer's and Parkinson's since they assist in disintegrating neurotransmitters such as dopamine in the brain. Pursuing efficacious monoamine oxidase B inhibitors is a hot topic, as contemporary therapeutic interventions have many shortcomings. Currently available FDA-approved monoamine oxidase inhibitors like safinamide, selegiline and rasagiline also have a variety of side effects like depression and insomnia. In the quest for a potent monoamine oxidase B inhibitor, sizeable, diverse chemical entities have been uncovered, including chalcones. Chalcone is a renowned structural framework that has been intensively explored for its monoamine oxidase B inhibitory activity.The structural resemblance of chalcone (1,3-diphenyl-2-propen-1-one) based compounds and 1,4-diphenyl-2-butene, a recognized MAO-B inhibitor, accounts for their MAO-B inhibitory activity. Therefore, multiple revisions to the chalcone scaffold have been attempted by the researchers to scrutinize the implications of substitutions onthe molecule's potency. In this work, we outline the docking investigation results of various chalcone analogues with monoamine oxidase B available in the literature until now to understand the interaction modes and influence of substituents. Here we focused on the interactions between reported chalcone derivatives and the active site of monoamine oxidase B and the influence of substitutions on those interactions. Detailed images illustrating the interactions and impact of the substituents or structural modifications on these interactions were used to support the docking results.

Exploration of a new class of monoamine oxidase B inhibitors by assembling benzyloxy pharmacophore on halogenated chalcones.

Eight derivatives of benzyloxy-derived halogenated chalcones (BB1-BB8) were synthesized and tested for their ability to inhibit monoamine oxidases (MAOs). MAO-A was less efficiently inhibited by all compounds than MAO-B. Additionally, the majority of the compounds displayed significant MAO-B inhibitory activities at 1 µM with residual activities of less than 50%. With an IC50 value of 0.062 µM, compound BB4 was the most effective in inhibiting MAO-B, followed by compound BB2 (IC50 = 0.093 µM). The lead molecules showed good activity than the reference MAO-B inhibitors (Lazabemide IC50 = 0.11 µM and Pargyline Pargyline IC50 = 0.14). The high selectivity index (SI) values for MAO-B were observed in compounds BB2 and BB4 (430.108 and 645.161, respectively). Kinetics and reversibility experiments revealed that BB2 and BB4 were reversible competitive MAO-B inhibitors with Ki values of 0.030 ± 0.014 and 0.011 ± 0.005 µM, respectively. Swiss target prediction confirmed the high probability in the targets of MAO-B for both compounds. Hypothetical binding mode revealed that the BB2 or BB4 is similarly oriented to the binding cavity of MAO-B. Based on the modelling results, BB4 showed a stable confirmation during the dynamic simulation. From these results, it was concluded that BB2 and BB4 were potent selective reversible MAO-B inhibitors and they can be considered drug candidates for treating related neurodegenerative diseases such as Parkinson's disease.

Two dimensional-QSAR and molecular dynamics studies of a selected class of aldoxime- and hydroxy-functionalized chalcones as monoamine oxidase-B inhibitors.

Candidates generated from unsaturated ketone (chalcone) demonstrated as strong, reversible and specific monoamine oxidase-B (MAO-B) inhibitory activity. For the research on MAO-B inhibition, our team has synthesized and evaluated a panel of aldoxime-chalcone ethers (ACE) and hydroxylchalcones (HC). The MAO-B inhibitory activity of several candidates is in the micro- to nanomolar range in these series. The purpose of this research was to develop predictive QSAR models and look into the relation between MAO-B inhibition by aldoxime and hydroxyl-functionalized chalcones. It was shown that the molecular descriptors ETA Shape P, MDEO-12, ETA dBetaP, SpMax1 Bhi and ETA EtaP B are significant in the inhibitory action of the MAO-B target. Using the current 2D QSAR models, potential chalcone-based MAO-B inhibitors might be created. The lead molecules were further analyzed by the detailed molecular dynamics study to establish the stability of the ligand-enzyme complex.Communicated by Ramaswamy H. Sarma.

Introduction of benzyloxy pharmacophore into aryl/heteroaryl chalcone motifs as a new class of monoamine oxidase B inhibitors.

The inhibitory action of fifteen benzyloxy ortho/para-substituted chalcones (B1-B15) was evaluated against human monoamine oxidases (hMAOs). All the molecules inhibited hMAO-B isoform more potently than hMAO-A. Furthermore, the majority of the molecules showed strong inhibitory actions against hMAO-B at 10 µM level with residual activities of less than 50%. Compound B10 has an IC50 value of 0.067 µM, making it the most potent inhibitor of hMAO-B, trailed by compound B15 (IC50 = 0.12 µM). The thiophene substituent (B10) in the A-ring exhibited the strongest hMAO-B inhibition structurally, however, increased residue synthesis did not result in a rise in hMAO-B inhibition. In contrast, the benzyl group at the para position of the B-ring displayed more hMAO-B inhibition than the other positions. Compounds B10 and B15 had relatively high selectivity index (SI) values for hMAO-B (504.791 and 287.600, respectively). Ki values of B10 and B15 were 0.030 ± 0.001 and 0.033 ± 0.001 µM, respectively. The reversibility study showed that B10 and B15 were reversible inhibitors of hMAO-B. PAMPA assay manifested that the benzyloxy chalcones (B10 and B15) had a significant permeability and CNS bioavailability with Pe value higher than 4.0 × 10-6 cm/s. Both compounds were stabilized in protein-ligand complexes by the π-π stacking, which enabled them to bind to the hMAO-B enzyme's active site incredibly effectively. The hMAO-B was stabilized by B10- and B15-hMAO-B complexes, with binding energies of - 74.57 and - 87.72 kcal/mol, respectively. Using a genetic algorithm and multiple linear regression, the QSAR model was created. Based on the best 2D and 3D descriptor-based QSAR model, the following statistics were displayed: R2 = 0.9125, Q2loo = 0.8347. These findings imply that B10 and B15 are effective, selective, and reversible hMAO-B inhibitors.

Revealing the role of the benzyloxy pharmacophore in the design of a new class of monoamine oxidase-B inhibitors.

The conceptual layout of monoamine oxidase (MAO) inhibitors has been modified to explore their potential biological application in the case of neurological disorders for the time being. The current review article is an effort to display the summation of innovative conceptual prospects of MAO inhibitors and their intriguing chemistry and bioactivity. Based on this scenario, we emphasize the pivotal role of the benzyloxy moiety attached to scaffolds like oxadiazolones, indolalkylamines, safinamide, caffeine, benzofurans, α-tetralones, ß-nitrostyrene, benzoquinones, coumarins, indoles, chromones, and chromanone analogs, while acting as an MAO inhibitor.

Development of 2D, 3D-QSAR and Pharmacophore Modeling of Chalcones for the Inhibition of Monoamine Oxidase B.

BACKGROUND: Selective and reversible types of MAO-B inhibitors have emerged as promising candidates for the management of neurodegenerative diseases. Several functionalized chalcone derivatives were shown to have potential reversible MAO-B inhibitory activity, which have recently been reported from our laboratory. METHODS: With the experimental results of about 70 chalcone derivatives, we further developed a pharmacophore modelling, and 2D and 3D- QSAR analyses of these reported chalcones for MAOB inhibition. RESULTS: The 2D-QSAR model presented four variables (MATS7v, GATS 1i and 3i, and C-006) from 143 Dragon 7 molecular descriptors, with a r2 value of 0.76 and a Q2 cv for cross-validation equal to 0.72. An external validation also was performed using 11 chalcones, obtaining a Q2 ext value of 0.74. The second 3D-QSAR model using MLR (multiple linear regression) was built starting from 128 Volsurf+ molecular descriptors, being identified as 4 variables (Molecular descriptors): D3, CW1 and LgS11, and L2LGS. Adetermination coefficient (r2) value of 0.76 and a Q2 cv for cross-validation equal to 0.72 were obtained for this model. An external validation also was performed using 11 chalcones and a Q2 ext value of 0.74 was found. CONCLUSION: This report exhibited a good correlation and satisfactory agreement between experiment and theory.

Replacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions.

To develop new potent and highly selective MAO-B inhibitors from chalcone-thioethers, eleven chalcones-thioethers were synthesized and their monoamine oxidase (MAO) inhibition, kinetics, reversibility, and cytotoxicity of lead compounds were analyzed. Molecular dynamics were carried out to investigate the interactions. Compound TM8 showed potent inhibitory activity against MAO-B, with an IC50 value of 0.010 µM, followed by TM1, TM2, TM7, and TM10 (IC50 = 0.017, 0.021, 0.023, and 0.026 µM, respectively). Interestingly, TM8 had an extremely high selectivity index (SI; 4860) for MAO-B. Reversibility and kinetic experiments showed that TM8 and TM1 were reversible and competitive inhibitors of MAO-B with Ki values of 0.0031 ± 0.0013 and 0.011± 0.001 µM, respectively. Both TM1 and TM8 were non-toxic to Vero cells with IC50 values of 241.8 and 116.3 µg/mL (i.e., 947.7 and 402.4 µM), respectively, and at these IC50 values, both significantly reduced reactive oxygen species (ROS) levels. TM1 and TM8 showed high blood-brain barrier permeabilities in the parallel artificial membrane permeability assay. Molecular dynamics studies were conducted to investigate interactions between TM1 and TM8 and the active site of MAO-B. Conclusively, TM8 and TM1 are potent and highly selective MAO-B inhibitors with little toxicity and good ROS scavenging abilities and it is suggested that both are attractive prospective candidates for the treatment of neurological disorders.

Recent Updates on Pyrazoline Derivatives as Promising Candidates for Neuropsychiatric and Neurodegenerative Disorders.

Pyrazolines are five-membered heterocyclic compounds containing two nitrogen atoms that represent a privileged scaffold for various bioactive compounds with diverse pharmacological activities. Chalcones and hydrazine derivatives are excellent precursors for pyrazolines, which provide easy access for fabricating the pyrazoline ring at N1, C3 and C5 positions that give rise to a wide range of pyrazoline designs. In addition, this method institutes a new asymmetric center at C5 position and extent of the conjugation between phenyl group at C3 position to N1 that could greatly enhance the physicochemical and pharmacological properties towards the target enzymes and hence they are reported to have a wide spectrum of biological activities such as anti-cancer, antiinflammatory, etc. Most importantly, they have remarkable effects on the central nervous system (CNS). Several reports show that the pyrazoline derivatives have a significant inhibitory effect towards the monoamine oxidase enzymes (MAOs), which are known to be responsible for neurodegenerative disorders. These enzymes have two isoforms, namely MAO-A and MAO-B which are, in particular, responsible for psychiatric and neurological disorders, respectively. Chalcones are generally potential and more selective inhibitors towards MAO-B isoform whereas pyrazolines derived from chalcones mostly turned into selective inhibitors of MAO-A isoform may be due to the presence of two nitrogen heteroatoms. Therefore, these two derivatives have received much attention from medicinal chemists as they could solve entire CNS-related issues; however pyrazolines have not been studied as much as chalcones. Our group already documented the importance of pyrazolines towards MAO-A inhibition in 2013. With their growing importance, several studies on pyrazolines have constantly been reported for their MAO inhibitions. Therefore, in this review, we report up-to-date developments (after 2014) on pyrazolines as potential MAO inhibitors.

Deciphering the detailed structure-activity relationship of coumarins as Monoamine oxidase enzyme inhibitors-An updated review.

In the last few years, Monoamine oxidase (MAO) have emerged as a target for the treatment of many neurodegenerative diseases including anxiety, depression, Alzheimer's, and Parkinson's diseases. The MAO inhibitors especially selective and reversible inhibitors of either of the isoenzymes (MAO-A & MAO-B) have been given more attention as both the form have different therapeutic properties and hence can be used for different neurological disorders. The lack of selective and reversible inhibitors available for both the enzymes and severity of the neuronal disorder in society have opened a new door to the researchers to carry out large and dedicated researches in this field. Among the several classes of the molecule as the inhibitors, coumarins hold a rank as a potent scaffold with its ease of synthesis, high therapeutic potential, and reversibility in inhibiting MAOs. The current review is an update of the research in the field that covers the works during the last six years (2014-2020) with a major focus on the SAR of the coumarin derivatives including synthetic, natural, and hybrids of coumarins with FDA-approved drugs.

(Hetero-)(arylidene)arylhydrazides as Multitarget-Directed Monoamine Oxidase Inhibitors.

Fourteen (hetero-)(arylidene)arylhydrazide derivatives (ABH1-ABH14) were synthesized, and their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE) were evaluated. Compound ABH5 most potently inhibited MAO-B with an IC50 value of 0.025 ± 0.0019 µM; ABH2 and ABH3 exhibited high IC50 values as well. Most of the compounds weakly inhibited MAO-A, except ABH5 (IC50 = 3.31 ± 0.41 µM). Among the active compounds, ABH2 showed the highest selectivity index (SI) of 174 for MAO-B, followed by ABH5 (SI = 132). ABH3 and ABH5 effectively inhibited AChE with IC50 values of 15.7 ± 6.52 and 16.5 ± 7.29 µM, respectively, whereas the other compounds were weak inhibitors of AChE. ABH5 was shown to be a reversible competitive inhibitor for MAO-A and MAO-B with Ki values of 0.96 ± 0.19 and 0.024 ± 0.0077 µM, respectively, suggesting that this molecule can be considered as an interesting candidate for further development as a multitarget inhibitor relating to neurodegenerative disorders.

Novel Class of Chalcone Oxime Ethers as Potent Monoamine Oxidase-B and Acetylcholinesterase Inhibitors.

Previously synthesized novel chalcone oxime ethers (COEs) were evaluated for inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Twenty-two of the 24 COEs synthesized, except COE-17 and COE-24, had potent and/or significant selective inhibitory effects on MAO-B. COE-6 potently inhibited MAO-B with an IC50 value of 0.018 µM, which was 105, 2.3, and 1.1 times more potent than clorgyline, lazabemide, and pargyline (reference drugs), respectively. COE-7, and COE-22 were also active against MAO-B, both had an IC50 value of 0.028 µM, which was 67 and 1.5 times lower than those of clorgyline and lazabemide, respectively. Most of the COEs exhibited weak inhibitory effects on MAO-A and AChE. COE-13 most potently inhibited MAO-A (IC50 = 0.88 µM) and also significantly inhibited MAO-B (IC50 = 0.13 µM), and it could be considered as a potential nonselective MAO inhibitor. COE-19 and COE-22 inhibited AChE with IC50 values of 5.35 and 4.39 µM, respectively. The selectivity index (SI) of COE-22 for MAO-B was higher than that of COE-6 (SI = 778.6 vs. 222.2), but the IC50 value (0.028 µM) was slightly lower than that of COE-6 (0.018 µM). In reversibility experiments, inhibitions of MAO-B by COE-6 and COE-22 were recovered to the levels of reference reversible inhibitors and both competitively inhibited MAO-B, with Ki values of 0.0075 and 0.010 µM, respectively. Our results show that COE-6 and COE-22 are potent, selective MAO-B inhibitors, and COE-22 is a candidate of dual-targeting molecule for MAO-B and AChE.

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

BACKGROUND: Chalcones are considered as the selective scaffold for the inhibition of MAO-B. OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Synthesis of novel chalcones through palladium-catalyzed CO cross-coupling reaction of bromo-chalcones with ethyl acetohydroxamate and their antiplasmodial evaluation against Plasmodium falcipuram in vitro.

An efficient method for palladium-catalyzed CO cross-coupling of ethyl acetohydroxamate (EAcHO) with 4-bromo-chalcones has been developed to synthesize novel chalcones. The two supporting ligands, namely tBuXPhos (L7), and cataCXium®PIntB (L16) were found to be effective ligands towards the Pd-catalyzed CO cross-coupling reaction to afford the desired product in moderate to excellent yields (50-99%). The coupled products were screened for in vitro blood stage antiplasmodial activity against Plasmodium falciparum (3D7) using the [3H] hypoxanthine incorporation inhibition assay. Of the twenty two compounds screened, eleven showed good antiplasmodial activity with IC50 values ranging from 6-16 µg/mL. The selected active molecules 11, 16, 22, (IC50 12 µg/mL) and 19 (IC50 6 µg/mL) were studied for their cytotoxic effect against HepG2 Cells (human hepatocellular liver carcinoma cell lines), showing the selectivity index (SI) values are greater than 4 except chalcone 22. Our result demonstrates a methodology for synthesizing novel chalcones as a new class of antiplasmodial agent.

Synthesis and Evaluation of Antiplasmodial Activity of 2,2,2-Trifluoroethoxychalcones and 2-Fluoroethoxy Chalcones against Plasmodium falciparum in Culture.

A new class of compounds comprising two series of chalcones with 2,2,2-trifluoroethoxy group and 2-fluoroethoxy groups were synthesized and screened for in vitro antiplasmodial activity against Plasmodium falciparum (3D7) using the [³H] hypoxanthine incorporation inhibition assay. Chalcones with 2,2,2-trifluoroethoxy groups substituted on the p- and m-positions of the 1-phenyl ring showed weak antiplasmodial activity, while compounds substituted on the o-position of the 1-phenyl ring displayed enhanced antiplasmodial activity, thus indicating that 2,2,2-trifluoroethoxy groups on the 1-phenyl ring of chalcones show position-dependent antiplasmodial activity. Of the 34 compounds synthesized, chalcones 3a and 3f exhibited significant inhibitory effects, with IC50 values of 3.0 µg/mL and 2.2 µg/mL, respectively. Moreover, these compounds 3a and 3f showed profound antiplasmodial activity in combination with artemisinin in vitro. The most active molecules, 3a, and 3f, were further assessed for their cytotoxicity towards mammalian Vero cells and the selectivity index (SI) values are 8.6, and 8.2 respectively, being considered non-toxic. We also studied the antiplasmodial activity of 2-fluoroethoxychalcones to discern the effect of the number of fluorine atoms in the fluoroethoxy group. Our results showed that chalcones with 2-fluoroethoxy group on the 1-phenyl ring exhibited more enhanced inhibitory effects on the growth of parasites than their trifluoro analogues, which reveals that monofluoroethoxy group is generally more effective than trifluoroethoxy group in the inhibition of parasite growth. Thus o-2,2,2-trifluoroethoxychalcones (Series 3) and 2-fluoroethoxychalcones may serve as good antiplasmodial candidates for future further development.

BrettPhos ligand supported palladium-catalyzed C-O bond formation through an electronic pathway of reductive elimination: fluoroalkoxylation of activated aryl halides.

We report an unprecedented BrettPhos ligand supported Pd-catalyzed CO bond-forming reaction of activated aryl halides with primary fluoroalkyl alcohols. We demonstrate that the Phosphine ligand (BrettPhos) possesses the property of altering the mechanistic pathway of reductive elimination from nucleophile to nucleophile. The Pd/BrettPhos catalyst system facilitates the reductive elimination of the oxygen nucleophile through an electronic pathway.