MAO-B Inhibitor (2E)-3-(4-Bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one as a Neuroprotective Agent Against Alzheimer's Disease.

Chalcones (trans-1,3-diphenyl-2-propen-1-ones) form simple chemical structures that act as precursors for the biogenesis of flavonoids. These are distributed in plants and have two aromatic or heteroaromatic rings connected by a three-carbon α, ß-unsaturated carbonyl group. Considering the importance of chalcones as monoamine oxidase and acetylcholinesterase inhibitors, the study was designed as a comprehensive and systematic analysis to evaluate the pharmacological activities leading to the formation of drug molecules against Alzheimer's disease (AD). Based on our previous research, 11 indolyl chalcones (IC1-IC11) were synthesised and investigated for MAO-B inhibitory activity. The inhibitory potential was evaluated based on binding and reversibility studies using purified enzymes. The active and most promising molecule, (2E)-3-(4-bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one (IC9), also found predominant acetylcholinesterase inhibition and hence it was found dual acting in vitro. Based on this, the molecule IC9 was further subjected to cell line studies to further explore its role as a neuroprotective agent against neuronal degeneration, one of the main contributing parameters related to AD.

Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations.

Nine compounds (MO1-MO9) containing the morpholine moiety were assessed for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Most of the compounds potently inhibited MAO-B; MO1 most potently inhibited with an IC50 value of 0.030 µM, followed by MO7 (0.25 µM). MO5 most potently inhibited AChE (IC50 = 6.1 µM), followed by MO9 (IC50 = 12.01 µM) and MO7 most potently inhibited MAO-A (IC50 = 7.1 µM). MO1 was a reversible mixed-type inhibitor of MAO-B (Ki = 0.018 µM); MO5 reversibly competitively inhibited AChE (Ki = 2.52 µM); and MO9 reversibly noncompetitively inhibited AChE (Ki = 7.04 µM). MO1, MO5 and MO9 crossed the blood-brain barrier, and were non-toxic to normal VERO cells. These results show that MO1 is a selective inhibitor of MAO-B and that MO5 is a dual-acting inhibitor of AChE and MAO-B, and that both should be considered candidates for the treatment of Alzheimer's disease.

Anti-inflammatory effect of synthesized indole-based chalcone (2E)-3-(4-bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one: an in vitro and in vivo studies.

Purpose: Chalcones are precursors of flavonoids with a wide range of pharmacological activities. This study evaluates the anti-inflammatory effect of indole based chalcone derivative (2E)-3-(4-bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one (IC9) on lipopolysaccharide (LPS) activated murine macrophages RAW264.7 cells and carrageenan-induced acute model in rats.Materials and methods: LPS-treated RAW264.7 cell lines and carrageenan-induced animal model were employed to evaluate the anti-inflammatory activity of IC9. The cell cytotoxicity studies were carried out by MTT assay. Reactive oxygen species (ROS) production and other inflammatory markers such as prostaglandin E2 (PGE2), nitric oxide (NO) as well as cyclooxygenase-2 (COX-2) activity were determined using ELISA. The RT-PCR was performed to determine mRNA expressions in the case of inducible nitric oxide synthase (iNOS), COX-2, Toll-like receptor-4 (TLR-4) and also nuclear translocation of NF-κB activity.Results: LPS-activated RAW264.7 cells showed an increased level of ROS generation and other inflammatory markers such as PGE2, NO level and COX-2 activity. Expression of iNOS, COX- 2 and TLR-4 mRNA expression were also up-regulated along with nuclear translocation of NF-κB. On IC9 supplementation, all the above parameters of LPS-activated cells were found to be reversed, resembling the control group. Moreover, IC9 significantly inhibited paw swelling and exhibited maximum inhibition of 78.45% at low dose of 7.5 mg/kg.bwt.Conclusions: The targeting anti-inflammatory efficacy and profound NF-κB sensitive transcriptional regulatory mechanism of IC9 accounts for its effective anti-inflammatory action.

Identification of Indole-Based Chalcones: Discovery of a Potent, Selective, and Reversible Class of MAO-B Inhibitors.

A series of 11 indole-based chalcones (IC1-11) with various electron donating and withdrawing groups at the para position of the phenyl ring B were synthesized. All the compounds were tested for their human monoamine oxidase (hMAO)-A and hMAO-B inhibitory potencies. Most of the synthesized candidates proved to be potent and selective inhibitors of MAO-B rather than MAO-A, with a reversible and competitive mode. Among them, compound IC9 was found to be a potent inhibitor of hMAO-B with Ki = 0.01 ± 0.005 µM and a selectivity index of 120. It was found to be better than the standard drug, selegiline (hMAO-B with Ki = 0.20 ± 0.020 µM) with a selectivity index of 30.55. PAMPA assays were carried out for all the compounds in order to evaluate the capacity of the compounds to cross the blood-brain barrier. Moreover, the most potent MAO-B inhibitor, IC9, was nontoxic at 5 and 25 µM, with 95.20 and 69.17% viable cells, respectively. The lead compound IC9 has an antioxidant property of 1.18 Trolox equivalents by ABTS assay. Molecular modeling studies were performed against hMAO-B to observe binding site interactions of the lead compound.

Imidazole bearing chalcones as a new class of monoamine oxidase inhibitors.

In the present study, series of eleven (2E)-1-[4-(1H-imidazol-1-yl)substituted phenyl]-3-phenylprop-2-en-1-one (IM1-IM11) derivatives were synthesized and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The results indicate that (2E)-3-[4-(dimethylamino) phenyl]-1-[4-(1H-imidazol-1-yl) phenyl] prop-2-en-1-one (IM5) is a nonselective and reversible competitive inhibitor of MAO-A and MAO-B with IC50 values of 0.30 ±â€¯0.010 and 0.40 ±â€¯0.017 µM, respectively ; those of (2E)-1-[4-(1H-imidazol-1-yl) phenyl]-3-(4-methylphenyl) prop-2-en-1-one (IM4) were 1.06 ±â€¯0.090 and 0.32 ±â€¯0.021 µM, respectively. Kinetic studies document that both IM5 and IM4 are competitive inhibitors of MAO-A and MAO-B with Ki value of 0.11 ±â€¯0.0085 and 0.085 ±â€¯0.0064 µM, respectively. Molecular docking studies of lead compounds further explained the binding modes in the inhibitor binding cavity of both MAO-A and MAO-B.