MyMedR

Displaying all 7 publications

Abstract:

Sort:

Cholinesterase Inhibitory Activities of Selected Halogenated Thiophene Chalcones

Parambi DGT, Aljoufi F, Murugaiyah V, Mathew GE, Dev S, Lakshminarayanan B, et al.

Cent Nerv Syst Agents Med Chem, 2019;19(1):67-71.
PMID: 30451121 DOI: 10.2174/1871524918666181119114016

BACKGROUND: Dual-acting human monoamine oxidase B (hMAO-B) and cholinesterase (ChE) inhibitors are more effective than the classic one-drug one-target therapy for Alzheimer's disease (AD).
METHODS: The ChE inhibitory ability of some halogenated thiophene chalcone-based molecules known to be selective hMAO-B inhibitors was evaluated.
RESULTS: Based on the IC50 values, the selected compounds were found to moderately inhibit ChE, with IC50 values in the range of 14-70 µM. Among the synthesised molecules, T8 and T6 showed the most potent inhibitory activity against AChE and BChE, respectively.
CONCLUSION: Taken together, the data revealed that T8 could be further optimized to enhance its AChE inhibitory activity.

Matched MeSH terms: Monoamine Oxidase Inhibitors/chemistry*
Quantitative Structure-Activity Relationship (QSAR) Studies for the Inhibition of MAOs

Ramesh M, Muthuraman A

Comb Chem High Throughput Screen, 2020;23(9):887-897.
PMID: 32208114 DOI: 10.2174/1386207323666200324173231

Monoamine oxidases are the crucial drug targets for the treatment of neurodegenerative disorders like depression, Parkinson's disease, and Alzheimer's disease. The enzymes catalyze the oxidative deamination of several monoamine containing neurotransmitters, i.e. serotonin (5-HT), melatonin, epinephrine, norepinephrine, phenylethylamine, benzylamine, dopamine, tyramine, etc. The oxidative reaction of monoamine oxidases results in the production of hydrogen peroxide that leads to the neurodegeneration process. Therefore, the inhibition of monoamine oxidases has shown a profound effect against neurodegenerative diseases. At present, the design and development of newer lead molecules for the inhibition of monoamine oxidases are under intensive research in the field of medicinal chemistry. Recently, the advancement in QSAR methodologies has shown considerable interest in the development of monoamine oxidase inhibitors. The present review describes the development of QSAR methodologies, and their role in the design of newer monoamine oxidase inhibitors. It will assist the medicinal chemist in the identification of selective and potent monoamine oxidase inhibitors from various chemical scaffolds.

Matched MeSH terms: Monoamine Oxidase Inhibitors/chemistry*
Semicarbazones, thiosemicarbazone, thiazole and oxazole analogues as monoamine oxidase inhibitors: Synthesis, characterization, biological evaluation, molecular docking, and kinetic studies

Qazi SU, Naz A, Hameed A, Osra FA, Jalil S, Iqbal J, et al.

Bioorg Chem, 2021 10;115:105209.
PMID: 34364054 DOI: 10.1016/j.bioorg.2021.105209

A series of semicarbazone, thiosemicarbazone, thiazole, and oxazole derivatives were designed, synthesized, and examined for monoamine oxidase inhibition using two isoforms, i.e., MAO-A and MAO-B. Among all the analogues, 3c and 3j possessed substantial activity against MAO-A with IC50 values of 5.619 ± 1.04 µM and 0.5781 ± 0.1674 µM, respectively. Whereas 3d and 3j were active against monoamine oxidase B with the IC50 values of 9.952 ± 1.831 µM and 3.5 ± 0.7 µM, respectively. Other derivatives active against MAO-B were 3c and 3g with the IC50 values of 17.67 ± 5.6 µM and 37.18 ± 2.485 µM. Moreover, molecular docking studies were achieved for the most potent compound (3j) contrary to human MAO-A and MAO-B. Kinetic studies were also performed for the most potent analogue to evaluate its mode of interaction with MAO-A and MAO-B.

Matched MeSH terms: Monoamine Oxidase Inhibitors/chemistry
Fulltext Multi-targeting aurones with monoamine oxidase and amyloid-beta inhibitory activities: Structure-activity relationship and translating multi-potency to neuroprotection

Liew KF, Lee EH, Chan KL, Lee CY

Biomed Pharmacother, 2019 Feb;110:118-128.
PMID: 30466001 DOI: 10.1016/j.biopha.2018.11.054

Previously, a series of aurones bearing amine and carbamate functionalities was synthesized and evaluated for their cholinesterase inhibitory activity and drug-like attributes. In the present study, these aurones were evaluated for their multi-targeting properties in two Alzheimer's disease (AD)-related activities namely, monoamine oxidase (MAO) and amyloid-beta (Aβ) inhibition. Evaluation of the aurones for MAO inhibitory activity disclosed several potent selective inhibitors of MAO-B, particularly those with 6-methoxyl group attached at ring A. Of the different amine moieties attached as side chains, pyrrolidine-bearing aurones were prominent as represented by 2-2, the most potent inhibitor. Evaluation on the Aβ aggregation inhibition identified 4-3 as the best inhibitor with a percentage inhibition comparable to that of a known Aβ inhibitor curcumin. Examination on the neuroprotective ability of the more drug-like aurone 4-3 in two Caenorhabditis elegans neurodegeneration models showed 4-3 to protect the nematodes against both Aβ- and 6-hydroxydopamine-induced toxicities. These new activities further support 4-3 as a promising lead to develop the aurones as potential multipotent agents for neurodegenerative diseases.

Matched MeSH terms: Monoamine Oxidase Inhibitors/chemistry
Deep eutectic solvent mediated synthesis of 3,4-dihydropyrimidin-2(1H)-ones and evaluation of biological activities targeting neurodegenerative disorders

Saleem Khan M, Asif Nawaz M, Jalil S, Rashid F, Hameed A, Asari A, et al.

Bioorg Chem, 2022 01;118:105457.
PMID: 34798458 DOI: 10.1016/j.bioorg.2021.105457

Substitution of hazardous and often harmful organic solvents with "green" and "sustainable" alternative reaction media is always desirous. Ionic liquids (IL) have emerged as valuable and versatile liquids that can replace most organic solvents in a variety of syntheses. However, recently new types of low melting mixtures termed as Deep Eutectic Solvents (DES) have been utilized in organic syntheses. DES are non-volatile in nature, have sufficient thermal stability, and also have the ability to be recycled and reused. Hence DES have been used as alternative reaction media to perform different organic reactions. The availability of green, inexpensive and easy to handle alternative solvents for organic synthesis is still scarce, hence our interest in DES mediated syntheses. Herein we have investigated Biginelli reaction in different DES for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Monoamine oxidases and cholinesterases are important drug targets for the treatment of various neurological disorders such as Alzheimer's disease, Parkinson's disease, depression and anxiety. The compounds synthesized herein were evaluated for their inhibitory potential against these enzymes. Some of the compounds were found to be highly potent and selective inhibitors. Compounds 1 h and 1c were the most active monoamine oxidase A (MAO A) (IC50 = 0.31 ± 0.11 µM) and monoamine oxidase B (MAO B) (IC50 = 0.34 ± 0.04 µM) inhibitors respectively. All compounds were selective AChE inhibitors and did not inhibit BChE (<29% inhibition). Compound 1 k (IC50 = 0.13 ± 0.09 µM) was the most active AChE inhibitor.

Matched MeSH terms: Monoamine Oxidase Inhibitors/chemistry
Synthesis, monoamine oxidase inhibition activity and molecular docking studies of novel 4-hydroxy-N'-[benzylidene or 1-phenylethylidene]-2-H/methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides

Saddique FA, Zaib S, Jalil S, Aslam S, Ahmad M, Sultan S, et al.

Eur J Med Chem, 2018 Jan 01;143:1373-1386.
PMID: 29126721 DOI: 10.1016/j.ejmech.2017.10.036

Three series of 4-hydroxy-N'-[benzylidene/1-phenylethylidene]-2-H/methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides (9-11)a-l were synthesized and unraveled to be highly potent dual inhibitors of monoamine oxidases (MAO-A and MAO-B). All the examined compounds demonstrated IC50 values in lower micro-molar range for both MAO-A as well as MAO-B. The most active MAO-A inhibitor was 4-hydroxy-N'-(1-phenylethylidene)-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxide (9i) with an IC50 value of 0.11 ± 0.005 μM, whereas, methyl 4-hydroxy-2H-benzo[e][1,2]thiazine-3-carboxylate 1,1-dioxide (3) was the most active MAO-B inhibitor with an IC50 value of 0.21 ± 0.01 μM. Enzyme kinetics studies revealed that the most potent compounds inhibited both MAO enzymes (A & B) in a competitive fashion. Molecular docking studies were also performed to obtain an intuitive picture of inhibition potential for potent inhibitors. The high potency of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability.

Matched MeSH terms: Monoamine Oxidase Inhibitors/chemistry
New isatin derivative inhibits neurodegeneration by restoring insulin signaling in brain

Aftab MF, Afridi SK, Mughal UR, Karim A, Haleem DJ, Kabir N, et al.

J. Chem. Neuroanat., 2017 04;81:1-9.
PMID: 28093241 DOI: 10.1016/j.jchemneu.2017.01.001

Diabetes is associated with neurodegeneration. Glycation ensues in diabetes and glycated proteins cause insulin resistance in brain resulting in amyloid plaques and NFTs. Also glycation enhances gliosis by promoting neuroinflammation. Currently there is no therapy available to target neurodegenration in brain therefore, development of new therapy that offers neuroprotection is critical. The objective of this study was to evaluate mechanistic effect of isatin derivative URM-II-81, an anti-glycation agent for improvement of insulin action in brain and inhibition of neurodegenration. Methylglyoxal induced stress was inhibited by treatment with URM-II-81. Also, Ser473 and Ser9 phosphorylation of Akt and GSK-3β respectively were restored by URM-II-81. Effect of URM-II-81 on axonal integrity was studied by differentiating Neuro2A using retinoic acid. URM-II-81 restored axonal length in MGO treated cells. Its effects were also studied in high fat and low dose streptozotocin induced diabetic mice where it reduced RBG levels and inhibited glycative stress by reducing HbA1c. URM-II-81 treatment also showed inhibition of gliosis in hippocampus. Histological analysis showed reduced NFTs in CA3 hippocampal region and restoration of insulin signaling in hippocampii of diabetic mice. Our findings suggest that URM-II-81 can be developed as a new therapeutic agent for treatment of neurodegenration.

Matched MeSH terms: Monoamine Oxidase Inhibitors/chemistry