scholarly journals Coumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2430
Author(s):  
Guillermo Moya-Alvarado ◽  
Osvaldo Yañez ◽  
Nicole Morales ◽  
Angélica González-González ◽  
Carlos Areche ◽  
...  
Keyword(s):  
Therapeutic Agents ◽  
Monoamine Oxidase B ◽  
Unsaturated Ketone ◽  
Mitochondrial Enzyme ◽  
Computational Docking ◽  
Mao B ◽  
Enzyme Systems ◽  
In Silico Studies ◽  
Inhibition Data

Fourteen coumarin-derived compounds modified at the C3 carbon of coumarin with an α,β-unsaturated ketone were synthesized. These compounds may be designated as chalcocoumarins (3-cinnamoyl-2H-chromen-2-ones). Both chalcones and coumarins are recognized scaffolds in medicinal chemistry, showing diverse biological and pharmacological properties among which neuroprotective activities and multiple enzyme inhibition, including mitochondrial enzyme systems, stand out. The evaluation of monoamine oxidase B (MAO-B) inhibitors has aroused considerable interest as therapeutic agents for neurodegenerative diseases such as Parkinson’s. Of the fourteen chalcocumarins evaluated here against MAO-B, ChC4 showed the strongest activity in vitro, with IC50 = 0.76 ± 0.08 µM. Computational docking, molecular dynamics and MM/GBSA studies, confirm that ChC4 binds very stably to the active rMAO-B site, explaining the experimental inhibition data.

scholarly journals Coumarin analogue 3-methyl-7H-furo[3,2-g] chromen-7-one as a possible antiparkinsonian agent

Biomédica ◽  
2019 ◽  
Vol 39 (3) ◽  
pp. 491-501
Author(s):  
María del Pilar Olaya ◽  
Nadezdha Esperanza Vergel ◽  
José Luis López ◽  
María Dolores Viña ◽  
Mario Francisco Guerrero
Keyword(s):  
Antioxidant Activity ◽  
Monoamine Oxidase ◽  
Mouse Models ◽  
Inhibitory Activity ◽  
Ex Vivo ◽  
Monoamine Oxidase B ◽  
Mao B ◽  
Continue Research ◽  
Substituted Coumarins

Introduction: Parkinson’s disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B.Objective: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity.Materials and methods: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively.Results: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity.Conclusion: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.

scholarly journals Boosting Drug Discovery for Parkinson’s: Enhancement of the Delivery of a Monoamine Oxidase-B Inhibitor by Brain-Targeted PEGylated Polycaprolactone-Based Nanoparticles

Pharmaceutics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 331 ◽  
Author(s):  
Miguel Pinto ◽  
Carlos Fernandes ◽  
Eva Martins ◽  
Renata Silva ◽  
Sofia Benfeito ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Monoamine Oxidase ◽  
Polymeric Nanoparticles ◽  
Symptomatic Relief ◽  
In Vitro Models ◽  
Monoamine Oxidase B ◽  
Mao B ◽  
Drug Candidates ◽  
Poly Caprolactone

The current pharmacological treatments for Parkinson’s disease only offer symptomatic relief to the patients and are based on the administration of levodopa and catechol-O-methyltransferase or monoamine oxidase-B inhibitors (IMAO-B). Since the majority of drug candidates fail in pre- and clinical trials, due largely to bioavailability pitfalls, the use of polymeric nanoparticles (NPs) as drug delivery systems has been reported as an interesting tool to increase the stealth capacity of drugs or help drug candidates to surpass biological barriers, among other benefits. Thus, a novel potent, selective, and reversible IMAO-B (chromone C27, IC50 = 670 ± 130 pM) was encapsulated in poly(caprolactone) (PCL) NPs by a nanoprecipitation process. The resulting C27-loaded PEGylated PCL NPs (~213 nm) showed high stability and no cytotoxic effects in neuronal (SH-SY5Y), epithelial (Caco-2), and endothelial (hCMEC/D3) cells. An accumulation of PEGylated PCL NPs in the cytoplasm of SH-SY5Y and hCMEC/D3 cells was also observed, and their permeation across Caco-2 and hCMEC/D3 cell monolayers, used as in vitro models of the human intestine and blood-brain barrier, respectively, was demonstrated. PEGylated PCL NPs delivered C27 at concentrations higher than the MAO-B IC50 value, which provides evidence of their relevance to solving the drug discovery pitfalls.

The Design and Evaluation of a Novel Monoamine Oxidase B Inhibitor Through in Silico Approach

2019 ◽  
Vol 10 (02) ◽  
Author(s):  
Hasanain Abdulhameed Odhar ◽  
Safaa Muhsen Kareem ◽  
Mohammed Ridha A Alhaideri ◽  
Mohammed Abbas Hasan ◽  
Werner J Geldenhuys
Keyword(s):  
Monoamine Oxidase ◽  
In Silico ◽  
Neuroprotective Effect ◽  
Monoamine Oxidase B ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mao B ◽  
Age Related ◽  
Novel Scaffold

Parkinson’s disease is an age related neurodegenerative disease. Pioglitazone is a Peroxisome proliferator-activated receptor gamma agonist that has been shown to display a neuroprotective effect in parkinsonian models (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated mice). This effect was partially attributed to the ability of thiazolidinedione (TZD) moiety in Pioglitazone to selectively inhibit monoamine oxidase B (MAO-B) enzyme. In the current study, we screened several thiazolidine containing compounds against MAO-B enzyme both in silico and in vitro. Based on the resulted data and information from previous literatures, we were able to design a novel scaffold for MAO-B inhibitors. This scaffold (compound 5482440) was able to inhibit MAO-B enzyme with IC50 value of 1.447 μM. Structure-based virtual analysis showed that this compound was able to participate in water-bridge formation and obtain an extended conformation within MAO-B active site.

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

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4507 ◽  
Author(s):  
Mariagrazia Rullo ◽  
Marco Catto ◽  
Antonio Carrieri ◽  
Modesto de Candia ◽  
Cosimo Damiano Altomare ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Single Point ◽  
Monoamine Oxidase B ◽  
In Vitro Screening ◽  
Binding Modes ◽  
Kinetics Analysis ◽  
Docking Simulations ◽  
Mao B ◽  
Insight Into

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.

scholarly journals Theoretical and Experimental Study of New Dihydroorotate Dehydrogenase and Tryparedoxin Peroxidase Inhibitors: One More Step in the Study of Leishmaniasis Infection

2021 ◽  
Author(s):  
Roger Espinosa-Saez ◽  
Sara M. Robledo ◽  
Tatiana Pineda ◽  
Javier Murillo ◽  
Gilmar Santafé Patiño ◽  
...  
Keyword(s):  
Therapeutic Response ◽  
Md Simulations ◽  
Dihydroorotate Dehydrogenase ◽  
Topical Formulation ◽  
Computational Docking ◽  
In Silico Studies ◽  
Tryparedoxin Peroxidase ◽  
Orally Active

Abstract In this study, the viability of new dihydroorotate dehydrogenase and tryparedoxin peroxidase inhibitors is reported. In vitro antileishmanial activity was evaluated using a Leishmania (V) panamensis strain, and the cytotoxicity of the compounds was assessed using U-937 cells. The in vivo therapeutic response was evaluated in golden hamsters (Mesocricetus auratus) experimentally infected with L. (V) panamensis and treated with a 1% topical formulation of compounds 4a–f. On the other hand, in silico studies considering the synthesized compounds were also carried out. All of the compounds showed promising in vitro activity, with mean EC50 effective concentration values ​​ranging from 3.8 µM to 19.3 µM. Likewise, treatment with compounds 4a–f produced improvement in most of the hamsters and cured some; in particular, those treated with compounds 4b, 4c, 4d, and 4f reacted the best. Molecular dynamics (MD) simulations, computational docking, and MM/GBSA studies indicate the promising bioavailability and absorption characteristics of the studied compounds, which are expected to be orally active. In addition, the studied 2-arylquinolines are absorbable at the blood–brain barrier, but not in the gastrointestinal tract. Finally, ADMET properties suggest that these molecules can be safely used as leishmaniasis inhibitors.

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

2019 ◽  
Vol 27 (7) ◽  
pp. 1195-1210 ◽  
Author(s):  
Michał Załuski ◽  
Jakub Schabikowski ◽  
Miriam Schlenk ◽  
Agnieszka Olejarz-Maciej ◽  
Bartłomiej Kubas ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Adenosine Receptor ◽  
In Silico ◽  
Monoamine Oxidase B ◽  
In Silico Studies

Biological and In silico Studies on Synthetic Analogues of Tyrosine Betaine as Inhibitors of Neprilysin - A Drug Target for the Treatment of Heart Failure

2018 ◽  
Vol 24 (17) ◽  
pp. 1899-1904
Author(s):  
Daniel Fabio Kawano ◽  
Marcelo Rodrigues de Carvalho ◽  
Mauricio Ferreira Marcondes Machado ◽  
Adriana Karaoglanovic Carmona ◽  
Gilberto Ubida Leite Braga ◽  
...  
Keyword(s):  
Heart Failure ◽  
Secondary Metabolites ◽  
Structural Similarity ◽  
Structural Features ◽  
Major Constituent ◽  
Binding Modes ◽  
Starting Point ◽  
In Silico Studies ◽  
Nep Inhibition

Background: Fungal secondary metabolites are important sources for the discovery of new pharmaceuticals, as exemplified by penicillin, lovastatin and cyclosporine. Searching for secondary metabolites of the fungi Metarhizium spp., we previously identified tyrosine betaine as a major constituent. Methods: Because of the structural similarity with other inhibitors of neprilysin (NEP), an enzyme explored for the treatment of heart failure, we devised the synthesis of tyrosine betaine and three analogues to be subjected to in vitro NEP inhibition assays and to molecular modeling studies. Results: In spite of the similar binding modes with other NEP inhibitors, these compounds only displayed moderate inhibitory activities (IC50 ranging from 170.0 to 52.9 µM). However, they enclose structural features required to hinder passive blood brain barrier permeation (BBB). Conclusions: Tyrosine betaine remains as a starting point for the development of NEP inhibitors because of the low probability of BBB permeation and, consequently, of NEP inhibition at the Central Nervous System, which is associated to an increment in the Aβ levels and, accordingly, with a higher risk for the onset of Alzheimer's disease.

Recent In Vitro and In Silico Advances in the Understanding of Intranasal Drug Delivery

2020 ◽  
Vol 26 ◽  
Author(s):  
John Chen ◽  
Andrew Martin ◽  
Warren H. Finlay
Keyword(s):  
Drug Delivery ◽  
In Silico ◽  
Local Drug Delivery ◽  
In Vivo Studies ◽  
Intranasal Drug Delivery ◽  
Nasal Sprays ◽  
In Silico Studies ◽  
Drug Delivery Devices

Background: Many drugs are delivered intranasally for local or systemic effect, typically in the form of droplets or aerosols. Because of the high cost of in vivo studies, drug developers and researchers often turn to in vitro or in silico testing when first evaluating the behavior and properties of intranasal drug delivery devices and formulations. Recent advances in manufacturing and computer technologies have allowed for increasingly realistic and sophisticated in vitro and in silico reconstructions of the human nasal airways. Objective: To perform a summary of advances in understanding of intranasal drug delivery based on recent in vitro and in silico studies. Conclusion: The turbinates are a common target for local drug delivery applications, and while nasal sprays are able to reach this region, there is currently no broad consensus across the in vitro and in silico literature concerning optimal parameters for device design, formulation properties and patient technique which would maximize turbinate deposition. Nebulizers are able to more easily target the turbinates, but come with the disadvantage of significant lung deposition. Targeting of the olfactory region of the nasal cavity has been explored for potential treatment of central nervous system conditions. Conventional intranasal devices, such as nasal sprays and nebulizers, deliver very little dose to the olfactory region. Recent progress in our understanding of intranasal delivery will be useful in the development of the next generation of intranasal drug delivery devices.

In-silico Studies of Isolated Phytoalkaloid Against Lipoxygenase: Study Based on Possible Correlation

2018 ◽  
Vol 21 (3) ◽  
pp. 215-221
Author(s):  
Haroon Khan ◽  
Muhammad Zafar ◽  
Helena Den-Haan ◽  
Horacio Perez-Sanchez ◽  
Mohammad Amjad Kamal
Keyword(s):  
In Silico ◽  
Docking Studies ◽  
In Vivo Studies ◽  
In Vitro Assays ◽  
Chronic Obstructive ◽  
Lipoxygenase Inhibitors ◽  
Lipoxygenase Inhibition ◽  
In Silico Studies

Aim and Objective: Lipoxygenase (LOX) enzymes play an important role in the pathophysiology of several inflammatory and allergic diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis and chronic obstructive pulmonary disease. Inhibitors of the LOX are believed to be an ideal approach in the treatment of diseases caused by its over-expression. In this regard, several synthetic and natural agents are under investigation worldwide. Alkaloids are the most thoroughly investigated class of natural compounds with outstanding past in clinically useful drugs. In this article, we have discussed various alkaloids of plant origin that have already shown lipoxygenase inhibition in-vitro with possible correlation in in silico studies. Materials and Methods: Molecular docking studies were performed using MOE (Molecular Operating Environment) software. Among the ten reported LOX alkaloids inhibitors, derived from plant, compounds 4, 2, 3 and 1 showed excellent docking scores and receptor sensitivity. Result and Conclusion: These compounds already exhibited in vitro lipoxygenase inhibition and the MOE results strongly correlated with the experimental results. On the basis of these in vitro assays and computer aided results, we suggest that these compounds need further detail in vivo studies and clinical trial for the discovery of new more effective and safe lipoxygenase inhibitors. In conclusion, these results might be useful in the design of new and potential lipoxygenase (LOX) inhibitors.

In Vitro, In Silico and Ex Vivo Studies of Dihydroartemisinin Derivatives as Antitubercular Agents

2019 ◽  
Vol 19 (8) ◽  
pp. 633-644 ◽  
Author(s):  
Komal Kalani ◽  
Sarfaraz Alam ◽  
Vinita Chaturvedi ◽  
Shyam Singh ◽  
Feroz Khan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
In Silico ◽  
Ex Vivo ◽  
Virulent Strain ◽  
Infection Model ◽  
Mouse Bone Marrow ◽  
Significant Activity ◽  
Macrophage Infection ◽  
In Silico Studies

Introduction: As a part of our drug discovery program for anti-tubercular agents, dihydroartemisinin (DHA-1) was screened against Mtb H37Rv, which showed moderate anti-tubercular activity (>25.0 µg/mL). These results prompted us to carry out the chemical transformation of DHA-1 into various derivatives and study their antitubercular potential. Materials and Methods: DHA-1 was semi-synthetically converted into four new acyl derivatives (DHA-1A – DHA-1D) and in-vitro evaluated for their anti-tubercular potential against Mycobacterium tuberculosis H37Rv virulent strain. The derivatives, DHA-1C (12-O-(4-nitro) benzoyl; MIC 12.5 µg/mL) and DHA-1D (12-O-chloro acetyl; MIC 3.12µg/mL) showed significant activity against the pathogen. Results: In silico studies of the most active derivative (DHA-1D) showed interaction with ARG448 inhibiting the mycobacterium enzymes. Additionally, it showed no cytotoxicity towards the Vero C1008 cells and Mouse bone marrow derived macrophages. Conclusion: DHA-1D killed 62% intracellular M. tuberculosis in Mouse bone marrow macrophage infection model. To the best of our knowledge, this is the first-ever report on the antitubercular potential of dihydroartemisinin and its derivatives. Since dihydroartemisinin is widely used as an antimalarial drug; these results may be of great help in anti-tubercular drug development from a very common, inexpensive, and non-toxic natural product.

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