Perspective Design of Chalcones for the Management of CNS Disorders: A Mini-Review.

The development of chalcone-based compounds for CNS disorders has been explored by many research groups. Chalcones are being considered as a potent organic scaffold with widespread applications in the field of drug discovery and medicinal chemistry. The planar or semi-planar geometry of chalcones with various functionalities impinged on the terminal aromatic systems renders the molecule its bio-activity including anti-cancer, anti-malarial, anti-microbial, anti-fungal, antileishmanial, anti-viral, anti-diabetic, anti-hypertensive properties, etc. Moreover, cutting-edge research has been executed in the domain of Central Nervous System (CNS) based scheme, further, their identification and classifications also remain of high interest in the field of medicinal chemistry but the specific reviews are limited. Hence, the present review highlights the significance of chalcones toward their CNS activities (up to 2019), which include anti-depressant activity, anxiolytic activity, activity with GABA receptors, acetylcholinesterase (AChE) and butyryl cholinesterase (BChE) inhibitions, activity as adenosine receptor antagonists anti-Alzheimer's agents, ß-amyloid plaques imaging agents, monoamine oxidase inhibition. To our knowledge, this is the first review exclusively for CNS activity profile of chalcones.

Discovery of potent and reversible MAO-B inhibitors as furanochalcones.

A series of twelve furanochalcones (F1-F12) was synthesized and investigated for their human monoamine oxidase inhibitory activities. Among the series, compound (2E, 4E)-1-(furan-2-yl)-5-phenylpenta-2, 4-dien-1-one (F1), which was analyzed by single-crystal X-ray diffraction, showed potent and selective MAO-B inhibitory activity with an inhibition constant (Ki) value of 0.0041 µM and selectivity index of (SI) 172.4, and exhibited competitive inhibition. Introduction of a cinnamyl group to the furanochalcone significantly increased the inhibitory activity. In the dilution-recovery experiments, the residual activities of MAO-A and MAO-B by F1 under the diluted condition fully recovered as compared with the undiluted condition, indicating F1 is a reversible inhibitor. The Ki value of F1 is the lowest among the values of chalcone derivatives and furthermore lower than that (0.0079 µM) of the reversible MAO-B inhibitor, lazabemide, a marketed drug. Molecular docking study against hMAO-B provided the binding site interactions of the lead compound, including strong π-π stacking between the phenyl system and FAD nucleus.

Monoamine oxidase inhibitory activity of methoxy-substituted chalcones.

The MAO-B inhibitory activity of chalcone (1, 3- diphenyl-2-propen-1-one) based compounds arise from its structural similarity with 1, 4-diphenyl-2-butene, a known MAO-B inhibitor. Based on our previous report, the methoxy-substituted with fluorine containing chalcones are promising reversible MAO-B inhibitors, while in the present study, a series of methoxylated chalcones (C1-C9) bearing substitution on the para position of ring B was synthesized and evaluated for their human monoamine oxidase inhibitory activity. With the exception of (2E)-1-(4-methoxyphenyl)-3-(4-nitrophenyl) prop-2-en-1-one (C7), which is a nonselective inhibitor, the chalcones exhibited competitive, selective, and reversible inhibition of hMAO-B. The most potent compound, (2E)-3-[4-(dimethylamino) phenyl]-1-(4-methoxyphenyl) prop-2-en-1-one (C5), showed the best inhibitory activity towards hMAO-B (IC50=0.29±0.011µM;Ki=0.14±0.001µM). The reversibility of MAO-B inhibition by compound C5 was demonstrated by the recovery of enzyme activity after dialysis of mixtures containing enzyme and inhibitor. The reversiblity of C5 was 25.38±1.40 and 92.00±3.87% before and after dialysis, respectively. PAMPA was carried out to evaluate the blood-brain barrier effects of the designated compounds. Moreover, the most potent MAO-B inhibitor, C5, was found to be nontoxic towards cultured hepatic cells at 5 and 25µM, with 97 and 90% viability. Molecular docking study was performed against hMAO-B to observe the binding site interactions of the lead compound.

Potent and Selective Monoamine Oxidase-B Inhibitory Activity: Fluoro- vs. Trifluoromethyl-4-hydroxylated Chalcone Derivatives.

For various neurodegenerative disorders like Alzheimer's and Parkinson's diseases, selective and reversible MAO-B inhibitors have a great therapeutic value. In our previous study, we have shown that a series of methoxylated chalcones with F functional group exhibited high binding affinity toward human monoamine oxidase-B (hMAO-B). In continuation of our earlier study and to extend the understanding of the structure-activity relationships, a series of five new chalcones were studied for their inhibition of hMAO. The results demonstrated that these compounds are reversible and selective hMAO-B inhibitors with a competitive mode of inhibition. The most active compound, (2E)-1-(4-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one, exhibited a Ki value of 0.33 ± 0.01 µm toward hMAO-B with a selectivity index of 26.36. A molecular docking study revealed that the presence of a H-bond network in hydroxylated chalcone with the N(5) atom of FAD is crucial for MAO-B selectivity and potency.

Ligand based drug design of new heterocyclic imines of GABA analogues: A molecular docking approach for the discovery of new GABA-AT inhibitors.

BACKGROUND: Degradation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) is mainly catalysed by GABA aminotransferase (GABA-AT), excessive activity of which leads to convulsions. Inhibition of GABA-AT increases the concentration of GABA and can terminate the convulsions. Several studies have revealed that GABA analogues could be the outstanding scaffolds for the design of potent inhibitors of GABA-AT. The poor ability of GABA analogues to cross the blood-brain barrier (BBB), always produces low therapeutic index. However, Vigabatrin, a mechanism-based inhibitor of GABA-AT, is currently approved treatment of epilepsy, but it has harmful side effects, leaving a need for improved GABA-AT inactivators. EXPERIMENTAL DESIGN: In our present in silico investigation, AutoDock 4.2,-based on Lamarckian genetic algorithm was employed for virtual screen of a compound library with 35 entries (Schiff's bases of GABA) in search for novel and selective inhibitors of GABA-AT. RESULTS: By means of flexible type of molecular docking, we proposed that these designed molecules could successfully bind into the active pocket of GABA-AT with good predicted affinities in comparison to standard vigabatrin. Among the designed analogues, HIG18, HIG28 and HIG30 showed significant binding free energy of -10.25, -9.88 and -9.31 kcal/mol with predicted inhibitory constant values of 0.03, 0.05 and 0.15 µM respectively. CONCLUSION: Using ligand-based drug design, we proposed that electron withdrawing phenyl substituted heterocyclic imines of GABA could be considered as promising structures for synthesis and testing of new GABA-AT inhibitors from this class. We hypothesize that novel GABA analogues with an azomethine linkage incorporated with heterocyclic system can have increased affinity and more lipophilic character that would provide a probability of having less toxic effect in the therapy of convulsions.

Molecular Docking Studies of Some Novel Antidepressant 5-Substituted Phenyl-3-(Thiophen-2-yl)-4, 5-Dihydro-1h-Pyrazole-1-Carboxamides Against Monoamine Oxidase Isoforms.

Previously we have reported 5-substituted phenyl-3-(thiophen-2-yl)-4, 5-dihydro-1hpyrazole- 1-carboxamides as a novel class of antidepressants. The aim of the current study is to proposing the reason for such biological activities of the molecules by using molecular docking studies using AutoDock4.2. Using molecular docking studies, we propose that most of the antidepressant molecules showed good binding affinity towards MAO-A than MAO-B which is an effective target for the treatment of depression. The R and S form of thiophene based pyrazolines-carboxamides showed a binding energy and inhibition constant between 7.93 to -8.76 and 1.54 to 0.38 µM toward MAO-A and -6.39 to -8.51 and 20.84 to 0.57 µM toward MAO-B respectively.

Pharmacophore Modeling, 3D-QSAR and Molecular Docking of Furanochalcones as Inhibitors of Monoamine Oxidase-B.

Monoamine oxidase B inhibitors are of particular importance in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Herein described is pharmacophore generation and atom-based 3D-QSAR analysis of previously reported furan based MAO-B inhibitors in order to get insight into their structural requirements responsible for high affinity. The best pharmacophore model generated with the five-point hypotheses of ADHRR: hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic (H) and two aromatic rings (R1 & R2). On the basis of generated model, a statistically valid 3D-QSAR with good predictability was developed. Molecular docking of lead compound showed binding energy of -8.66 kcal/mol with a predicted inhibition constant of 0.448 µM towards MAO-B.

Monoamine Oxidase Inhibitory Action of Chalcones: A Mini Review.

INTRODUCTION: Chalcones are one of the major classes of naturally occurring compounds and have a vast significance in medicinal chemistry, presenting with a wide scope of pharmacological actions. DISCUSSION: The present review focused our attention onto the monoamine oxidase inhibitory activity of natural and synthetic chalcones. The review also emphasises the structure-activity relationship studies and molecular recognition of chalcones towards MAO-A and B inhibition. CONCLUSION: Many of the studies clearly revealed that most of the chalcones showed selective, reversible and potent MAO-B inhibition compared to MAO-A. Recent studies also showed that heteroaryl-based chalcones are potent MAO-A inhibitors.

Psychomotor Seizure Screening and in vitro Neuroprotection Assay of Hydrazones Derived from 2-Acetyl Thiophene.

BACKGROUND: Hydrazone core is a versatile structural linker for the development of various classes of antiepileptic agents. The aim of this study was to investigate the anticonvulsant activity of thiophene based hydrazones according to the antiepileptic drug development program protocol. METHODS: The maximal electroshock-induced seizure and 6 Hz "Psychomotor" seizure test models in mice were performed. Additionally, the active compounds in the screening test were subsequently subjected to the maximal electroshock-induced seizure test that allowed determination of their median effective doses and median toxic doses. The most active compound was also subjected to the In vitro Hippocampal slice culture neuroprotection assay. RESULTS: Among the synthesized compounds, 1-(thiophen-2-yl) ethylidene] hydrazine carboxamides (THb) and 1-(thiophen-2-yl) ethylidene] hydrazine carbothioamide (THc) showed a broad-spectrum anticonvulsant activity since they were active in both maximal electroshock-induced seizure and 6Hz-Psychomotor induced seizure models with no neurotoxicity. In the mice maximal electroshock-induced seizure screen, compound THb gave an ED50 of 11.8 mg/kg and a TD50 of 39.47 mg/kg, resulting in a good protection index (PI), that is, TD50/ED50, of 3.3 when compared to Phenobarbital and Valproate. THb (100µM) was also found to be effectively suppressing network hyperexcitability in the in vitro mEC-HC spontaneous bursting model, as determined by effects on spontaneous burst activity and duration. CONCLUSION: The suggested pharmacophore model for lead compounds from thiophene based hydrazones is explained by the hydrophobic domain-thiophene, electron donor-imine and hydrogen bonding domain-carboxamide or carbothioamide unit.

Hydrazones as a privileged structural linker in antitubercular agents: a review.

Hydrazones are a versatile linker of connecting various classes of organic compounds with a unique structural feature of hydrogen bonding donor and the hydrogen bonding acceptor region. An extensive number of research has been carried out on hydrazone derivatives as a potent class of antitubercular agents. The present review focuses on the chemistry, antitubercular activity and structure activity relationship (SAR) of diverse classes of phenyl and heterocyclic based hydrazones.

Development of fluorinated methoxylated chalcones as selective monoamine oxidase-B inhibitors: Synthesis, biochemistry and molecular docking studies.

A series of methoxylated chalcones with fluoro and trifluoromethyl derivatives were synthesized and investigated for their ability to inhibit human monoamine oxidase A and B. The chemical structures of the compounds have been characterized by means of their (1)H NMR, (13)C NMR, Mass spectroscopic datas and elemental analysis. The results demonstrate that these compounds are reversible and selective MAO-B inhibitors with a competitive mode of inhibition. The most potent compound (2E)-1-(4-methoxyphenyl)-3-[4-(trifluoromethyl)phenyl] prop-2-en-1-one showed the best activity and higher selectivity towards hMAO-B with Ki and SI values of 0.22±0.01µM and 0.05 comparable to that standard drug, Selegiline Ki and SI values were found as 0.33±0.03µM and 0.04, respectively. Molecular docking studies were carried out to further explain the in vitro results of the new compounds, and to identify the hypothetical binding mode for the compounds inside the inhibitor binding cavity of hMAO-B.

Plant secondary metabolites- potent inhibitors of monoamine oxidase isoforms.

Target of monoamine oxidase inhibitions are considered as the treatment of depressive states and neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. Many medicinal chemistry research groups are actively working in this area for the development of most promising selective MAO inhibitors. Many plant isolates also showed remarkable MAO inhibition in recent years. The objective of this review is to identify the major MAO inhibitors secondary metabolites from plants like flavonoids, alkaloids and xanthones class of compounds.

Synthesis, preclinical evaluation and antidepressant activity of 5-substituted phenyl-3-(thiophen-2-yl)-4, 5-dihydro-1H-pyrazole-1-carbothioamides.

A series of phenyl-3-(thiophen-2-yl)-4, 5-dihydro-1H-pyrazole-1-carbothioamides (TTa-TTg) were synthesized by the ring closure reaction of phenyl-1-(thiophen-2-yl) prop-2-en-1-ones with thiosemicarbazide in alcoholic basic medium. All the final derivatives were evaluated for their antidepressant and neurotoxicity screening. The structures of the compounds were characterized by IR, 1H NMR, 13C NMR, Mass and elemental analyses. Preclinical evaluation of the compounds were ascertained by in silico toxicity, blood-brain barrier and human oral absorption prediction. In this series, 5-(4-hydroxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1 carbothioamide (TTg) reduced immobility time 61.17 and 62.05 % in both force swimming and tail suspension test respectively at 10 mg/kg dose level when compared to the standard Imipramine without influencing the baseline locomotion. Moreover it was observed that the titled scaffold possessing electron withdrawing chlorine atom in the 4(th) position of aromatic ring of the scaffold also showed good the antidepressant activity. In conclusion, the behavioural investigation revealed that thiophene based pyrazolines having a carbothioamide tail unit in the N1 position may be therapeutically useful as potential antidepressant medications.

Synthesis and PASS-assisted in silico approach of some novel 2-substituted benzimidazole bearing a pyrimidine-2, 4, 6(trione) system as mucomembranous protector.

PURPOSE: The present paper demonstrates the utility of PASS computer-aided program and makes a clear comparison of predicted and observed pharmacological properties of some novel 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-substituted phenylprop-2-en-1-ylidene] pyrimidine-2, 4, 6 (1H, 3H, 5H)-triones (5a-f). MATERIALS AND METHODS: The synthesis of the titled derivatives were achieved by the reaction between 2E)-1-(1H-benzimidazol-2-yl)-3-phenylprop-2-en-1-ones (4a-f) and barbituric acid in the presence of catalytic amount of acetic acid medium. All the final structures were assigned on the basis of IR, (1)HNMR and mass spectra analysis. All the newly synthesized compounds were screened for their antiulcer activity in the pylorus-ligated rats. RESULTS: Compounds 5b, 5e and 5c showed a percentage protection of (69.58, 69.56 and 67.17 at a dose of 50 mg/kg b.w.) when compared to standard omeprazole (77.37%, 2 mg/kg b.w.). CONCLUSION: Scanning of stomach specimens using electron microscope revealed that the mice treated with standard and synthetic derivatives had no injury observed in stomach mucosa, which is identical to that of the control animal.

Hypnotic profile of imines from benzimidazole chalcones: mechanism of synthesis, DFT studies and in silico screening.

A series of 1-(1H-benzimidazol-2-yl)-3-substituted phenylprop-2-en-1-ylidene] amino}-1,3,4-thiadiazole-2- thiols (6a-6f) were synthesized by the acid catalyzed nucleophilic addition reaction between 1-(1H-benzimidazol-2-yl)-3- phenylprop-2-en-1-ones (4a-4f) and 5-amino-1,3,4-thiadiazole-2-thiol. All the synthesized compounds were characterised by IR, (1)HNMR, (13)CNMR, Mass and elemental analyses. A transition state calculation obtained from DFT study to explore the molecular mechanism of action of the synthetic route. The mechanism of synthesis revealed that the imidazole system can make an increase in the electrophilic character of carbonyl carbon in the benzimidazole chalcones. So the electron deficient carbonyl carbon could be efficiently attacked on the amino group of 1,3,4-thiadiazole ring to forms an imine linkage between the two heterocyclic systems. All the titled derivatives at a dose level of 10mg/kg body weight potentiate the hypnotic action of Phenobarbitone (at a dose of 10mg/kg body weight i.p.). The compounds such as 6b, 6a, and 6c showed a significant percentage increase in sleeping time relative to the control experiment 423.8, 387.6 and 329.5 respectively. The preclinical evaluation of the compounds was ascertained by blood-brain barrier, human oral absorption prediction and in silico toxicity assessment.

Pyrazoline: a promising scaffold for the inhibition of monoamine oxidase.

In the five membered nitrogen containing heterocyclic family, pyrazoline could be recognized as a promising scaffold for the inhibition of Monoamine oxidase. Substitution at 1, 3 and 5-position of the pyrazoline nucleus displayed a significant activity towards MAO in the past 15 years. Our study identified the detailed structure activity relationship, the structural requirement for enzyme interaction and the effect of chirality on the pyrazoline nucleus towards MAO-A and MAO-B. We propose that the selectivity of pyrazoline nucleus towards MAO isoenzyme depends up on the bulkiness of the ring in the 1 and 3 position of the scaffold. The current review revealed that the derivatives of pyrazolines have proven to be versatile pharmacophores for the inhibition of MAO on the basis of existing literatures between (1998-2013).