Githa Elizabeth Mathew

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.

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).

Exploration of chlorinated thienyl chalcones: A new class of monoamine oxidase-B inhibitors

Chalcone has been reported to be a valid scaffold for the design of monoamine oxidase (MAO) inhibitors. This scenario has amplified the momentum for the discovery of heteroaryl based chalcone MAO inhibitors. In the present study, we have synthesized a series of eleven chlorinated thienyl chalcone derivatives substituted with a different functional groups at the para- position on the ring B and investigated for their ability to inhibit human MAO-A and -B. With the exception of compound (2E)-1-(4-chlorocyclopenta-1,3-dien-1-yl)-3-(4-nitrophenyl)prop-2-en-1-one (TC7), which was a selective MAO-A inhibitor, all the other derivatives inhibited hMAO-B potently and selectively with competitive mode of inhibition. The most potent compound (2E)-1-(4-chlorocyclopenta-1,3-dien-1-yl)-3-(4-ethylphenyl)prop-2-en-1-one (TC6) was found to be the best activity and higher selectivity towards hMAO-B with Ki and SI values of 0.31±0.02μM and 16.84, respectively. All the compounds presented in the current study are completely non-toxic with 74-88% viable cells to hepatic cells at 100μM concentration. Molecular docking and molecular dynamics simulation studies were carried out using Autodock-4.2 and Amber 14 to understand the molecular level interaction and energy relation of MAO isoforms with selective MAO-B inhibitor TC6.

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.

Synthesis, Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO-B Inhibitors.

A series of (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(para‐substituted phenyl)prop‐2‐en‐1‐ones (TB1–TB11) was synthesized and tested for inhibitory activity toward human monoamine oxidase (hMAO). All compounds were found to be competitive, selective, and reversible toward hMAO‐B except (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one (TB7) and (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐chlorophenyl)prop‐2‐en‐1‐one (TB8), which were selective inhibitors of hMAO‐A. The most potent compound, (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐[4‐(dimethylamino)phenyl]prop‐2‐en‐1‐one (TB5), showed the best inhibitory activity and higher selectivity toward hMAO‐B, with Ki and SI values of 0.11±0.01 μm and 13.18, respectively. PAMPA assays for all compounds were carried out in order to evaluate the capacity of the compounds to cross the blood–brain barrier. Moreover, the most potent MAO‐B inhibitor, TB5, was found to be nontoxic at 5 and 25 μm, with 95.75 and 84.59 % viability among cells, respectively. Molecular docking simulations were carried out to understand the crucial interactions responsible for selectivity and potency.

Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives

Numerous studies have shown that chalcones are promising scaffolds for the development of new monoamine oxidase‐B (MAO‐B) inhibitors. As a continuation of our ongoing research into the development of reversible human MAO‐B (hMAO‐B) inhibitors, two series of twenty chalcones containing electron‐donating and electron‐withdrawing substituents were synthesized. All compounds were found to be competitive, selective, and reversible inhibitors of hMAO‐B except (2E)‐1‐(4‐methylphenyl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one (P7) and (2E)‐1‐(4‐chlorophenyl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one (P17), which were found to be selective inhibitors of hMAO‐A. The most potent hMAO‐B inhibitor, (2E)‐1‐(4‐chlorophenyl)‐3‐(4‐ethylphenyl)prop‐2‐en‐1‐one (P16), showed a Ki value of 0.11±0.01 μm. Molecular docking simulations were carried out to identify the hypothetical binding mode for the most potent compounds in the active sites of hMAO‐A and B. The ability of the compounds to cross the blood–brain barrier was assessed by parallel artificial membrane permeability assay (PAMPA). Additionally, the most potent hMAO‐B inhibitor P16 showed no toxicity in cultured hepatic cells at concentrations of 5 and 25 μm.

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.

Pharmacophore-Based 3D-QSAR Analysis of Thienyl Chalcones as a New Class of Human MAO-B Inhibitors: Investigation of Combined Quantum Chemical and Molecular Dynamics Approach

Selective monoamine oxidase-B (MAO-B) inhibitors are imperative in the treatment of various neurodegenerative disorders. Herein, we describe the pharmacophore generation and atom-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of previously reported thiophene-based hMAO-B inhibitors by our research group. The aim of this study was to identify the principal structural features that could potentially be responsible for the inhibitory activity of hMAO-B inhibitors. The best pharmacophore model generated was the four-point assay of AHRR.8. The pharmacophore model exhibited good correlation with its predictability of the statistically valid 3D-QSAR analyses. Density functional theory calculations were further employed on the lead molecule (2E)-1-(5-bromothiophen-2-yl)-3-[4-(dimethylamino) phenyl] prop-2-en-1-one (Tb5) to investigate the electrostatic potential surface and analyze the natural bond orbital toward the binding characteristics. Molecular dynamics simulations were performed to characterize the molecular level interactions and relative energies of the hMAO isoforms: hMAO-A and hMAO-B with three potent and selective hMAO-B inhibitors (Tb5, Tb6, and Tb9). The results of both continuous and accelerated molecular dynamics simulations demonstrate a distinct preference of the three ligands to bind to hMAO-B rather than hMAO-A.

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

For various neurodegenerative disorders like Alzheimers 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.

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.