Selected Class of Enamides Bearing Nitro Functionality as Dual-Acting with Highly Selective Monoamine Oxidase-B and BACE1 Inhibitors
| Autor: | Sanal Dev, Anusree Venkidath, Bijo Mathew, Shebina P Rasheed, Nicola Gambacorta, Jong Min Oh, Ginson George, Hoon Kim, Ajeesh Vengamthodi, Ahmed Khames, Orazio Nicolotti, Mohamed A. Abdelgawad, Elham Amin |
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| Rok vydání: | 2021 |
| Předmět: |
Monoamine Oxidase Inhibitors
Monoamine oxidase Stereochemistry Pharmaceutical Science Article Analytical Chemistry chemistry.chemical_compound QD241-441 Drug Discovery dual-acting inhibitor medicine β-secretase Protease Inhibitors monoamine oxidase Physical and Theoretical Chemistry IC50 Molecular Structure potent reversible inhibitor Organic Chemistry Membranes Artificial molecular docking Pargyline Amides Monoamine neurotransmitter chemistry nitro group-bearing enamides Chemistry (miscellaneous) Docking (molecular) Blood-Brain Barrier Nitro Molecular Medicine Lazabemide Monoamine oxidase B Amyloid Precursor Protein Secretases medicine.drug |
| Zdroj: | Molecules Volume 26 Issue 19 Molecules, Vol 26, Iss 6004, p 6004 (2021) |
| ISSN: | 1420-3049 |
| Popis: | A small series of nitro group-bearing enamides was designed, synthesized (NEA1–NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC50 value = 0.0092 and 0.016 µM, respectively) than the standards (IC50 value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of > 1652.2 and > 2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with Ki values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC50 values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood–brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders. |
| Databáze: | OpenAIRE |
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