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Discovery of N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)pyrazine-2-carboxamide: a novel, selective, and competitive indole-based lead inhibitor for human monoamine oxidase B.

ABSTRACT: Herein, two new series of N-substituted indole-based analogues were rationally designed, synthesized via microwave heating technology, and evaluated as noteworthy MAO-B potential inhibitors. Compared to the reported indazole-based hits VI and VII, compounds 4b and 4e exhibited higher inhibitory activities over MAO-B with IC₅₀ values of 1.65 and 0.78 µM, respectively. When compared to the modest selectivity index of rasagiline (II, a well-known MAO-B inhibitor, SI > 50), both 4b and 4e also showed better selectivity indices (SI > 60 and 120, respectively). A further kinetic evaluation of the most potent derivative (4e) displayed a competitive mode of inhibition (inhibition constant (K _i)/MAO-B = 94.52 nM). Reasonable explanations of the elicited biological activities were presented via SAR study and molecular docking simulation. Accordingly, the remarkable MAO-B inhibitory activity of 4e (N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)pyrazine-2-carboxamide), with its selectivity and competitive inhibition, advocates its potential role as a promising lead worthy of further optimization.

SUBMITTER: Elkamhawy A

PROVIDER: S-EPMC7470070 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Monoamine oxidase-B (MAO-B) inhibitors are widely used in the treatment of Parkinson's disease. They increase vital monoamine neurotransmitters in the brain. However, there is a need for safer natural reversible MAO inhibitors with MAO-B selectivity. Our previous studies showed that Psoralea corylifolia seeds (PCS) extract contains compounds that inhibit monoamine oxidase-B.In this study, six of PCS constituents sharing a benzopyrone structure were investigated. The compounds Biochanin-A (BIO-A), isopsoralen, 6-prenylnaringenin, neobavaisoflavone, psoralen, and psoralidin, were tested for their ability to inhibit recombinant human MAO-A and B (hMAO-A and hMAO-B) isozymes. The ability of these compounds to inhibit MAO-A and MAO-B were compared to that of PCS ethanolic extract (PCSEE) using spectrophotometric assays and confirmed by luminescence assays. The highly potent and selective MAO-B inhibitor, BIO-A, was further investigated for both isozymes reversibility and enzyme kinetics. Molecular docking studies were used to predict the bioactive conformation and molecular interactions of BIO-A with both isozymes.The data obtained indicate that benzopyrones inhibited hMAO-A and hMAO-B with different degrees as confirmed with the luminescence assay. BIO-A inhibited hMAO-B with high potency and selectivity in the present study (IC50?=?0.003 ?g/mL) and showing 38-fold more selectivity than PCSEE (hMAO-B IC50?=?3.03 ?g/mL, 17-fold selectivity) without affecting hydrogen peroxide. Furthermore, BIO-A reversibly and competitively inhibited both hMAOs with significantly lower inhibitory constant (Ki) in hMAO-B (3.8 nM) than hMAO-A (99.3 nM). Our docking studies indicated that the H-bonds and hydrophobic interactions at the human MAO-A and MAO-B active sites contributed to the reversibility and selectivity of BIO-A.The data obtained indicate that BIO-A is a potent, reversible and selective MAO-B inhibitor and may be recommended for further investigation in its possible use in the therapeutic management of Parkinson's and Alzheimer's diseases.

Project description:Monoamine oxidases (MAOs), specifically MAO-A and MAO-B, play important roles in the breakdown of monoamine neurotransmitters. Therefore, MAO inhibitors are crucial for treating various neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). In this study, we developed a novel cheminformatics pipeline by generating three diverse molecular feature-based machine learning-assisted quantitative structural activity relationship (ML-QSAR) models concerning MAO-B inhibition. PubChem fingerprints, substructure fingerprints, and one-dimensional (1D) and two-dimensional (2D) molecular descriptors were implemented to unravel the structural insights responsible for decoding the origin of MAO-B inhibition in 249 non-reductant molecules. Based on a random forest ML algorithm, the final PubChem fingerprint, substructure fingerprint, and 1D and 2D molecular descriptor prediction models demonstrated significant robustness, with correlation coefficients of 0.9863, 0.9796, and 0.9852, respectively. The significant features of each predictive model responsible for MAO-B inhibition were extracted using a comprehensive variance importance plot (VIP) and correlation matrix analysis. The final predictive models were further developed as a web application, MAO-B-pred ( https://mao-b-pred.streamlit.app/ ), to allow users to predict the bioactivity of molecules against MAO-B. Molecular docking and dynamics studies were conducted to gain insight into the atomic-level molecular interactions between the ligand-receptor complexes. These findings were compared with the structural features obtained from the ML-QSAR models, which supported the mechanistic understanding of the binding phenomena. The presented models have the potential to serve as tools for identifying crucial molecular characteristics for the rational design of MAO-B target inhibitors, which may be used to develop effective drugs for neurodegenerative disorders.

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Discovery of N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)pyrazine-2-carboxamide: a novel, selective, and competitive indole-based lead inhibitor for human monoamine oxidase B.

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