Tags

Type your tag names separated by a space and hit enter

Fine molecular tuning at position 4 of 2H-chromen-2-one derivatives in the search of potent and selective monoamine oxidase B inhibitors.
Eur J Med Chem. 2013; 70:723-39.EJ

Abstract

The effects on the inhibition potencies of monoamine oxidase isoforms A (MAO-A) and B (MAO-B) depending upon changes in the physicochemical properties (size, shape, H-bonding, lipophilicity, etc.) of substituents at the C4 position of 2H-chromen-2-one derivatives were extensively investigated, and the results significantly added to our knowledge on this class of MAO inhibitors. All the 67 examined compounds showed high MAO-B selectivity, some of them achieving potency in the low nanomolar range. In particular, the 7-metachlorobenzyloxy-4-oxyacetamido-2H-chromen-2-one (entry 62) showed single digit nanomolar MAO-B potency (IC₅₀ = 3.1 nM) and high selectivity over the MAO-A isoform (selectivity ratio = 7244). The great variety of the investigated substituents at C4 of the 2H-chromen-2-one nucleus, combined with binding models generated from docking studies carried out on selected compounds, allowed us to shed light on the main molecular requirements for potent and selective MAO-B inhibition, highlighting the dominant role of the steric effects. Interestingly, many of the designed substituents could be metabolically related to each other (e.g., CH₃/CH₂OH/CHO/COOH; NH₂/NHCH₃, NHAc), and therefore the results obtained may help in predicting the in vivo activity of some putative metabolites of lead MAO-B inhibitors.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Pisani L
Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona 4, I-70125 Bari, Italy.
Catto M
No affiliation info available
Nicolotti O
No affiliation info available
Grossi G
No affiliation info available
Di Braccio M
No affiliation info available
Soto-Otero R
No affiliation info available
Mendez-Alvarez E
No affiliation info available
Stefanachi A
No affiliation info available
Gadaleta D
No affiliation info available
Carotti A
No affiliation info available

MeSH

ChromonesDose-Response Relationship, DrugHumansModels, MolecularMolecular StructureMonoamine OxidaseMonoamine Oxidase InhibitorsStructure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24231308

Citation

Pisani, Leonardo, et al. "Fine Molecular Tuning at Position 4 of 2H-chromen-2-one Derivatives in the Search of Potent and Selective Monoamine Oxidase B Inhibitors." European Journal of Medicinal Chemistry, vol. 70, 2013, pp. 723-39.
Pisani L, Catto M, Nicolotti O, et al. Fine molecular tuning at position 4 of 2H-chromen-2-one derivatives in the search of potent and selective monoamine oxidase B inhibitors. Eur J Med Chem. 2013;70:723-39.
Pisani, L., Catto, M., Nicolotti, O., Grossi, G., Di Braccio, M., Soto-Otero, R., Mendez-Alvarez, E., Stefanachi, A., Gadaleta, D., & Carotti, A. (2013). Fine molecular tuning at position 4 of 2H-chromen-2-one derivatives in the search of potent and selective monoamine oxidase B inhibitors. European Journal of Medicinal Chemistry, 70, 723-39. https://doi.org/10.1016/j.ejmech.2013.09.034
Pisani L, et al. Fine Molecular Tuning at Position 4 of 2H-chromen-2-one Derivatives in the Search of Potent and Selective Monoamine Oxidase B Inhibitors. Eur J Med Chem. 2013;70:723-39. PubMed PMID: 24231308.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fine molecular tuning at position 4 of 2H-chromen-2-one derivatives in the search of potent and selective monoamine oxidase B inhibitors. AU - Pisani,Leonardo, AU - Catto,Marco, AU - Nicolotti,Orazio, AU - Grossi,Giancarlo, AU - Di Braccio,Mario, AU - Soto-Otero,Ramon, AU - Mendez-Alvarez,Estefania, AU - Stefanachi,Angela, AU - Gadaleta,Domenico, AU - Carotti,Angelo, Y1 - 2013/10/17/ PY - 2013/06/26/received PY - 2013/09/11/revised PY - 2013/09/14/accepted PY - 2013/11/16/entrez PY - 2013/11/16/pubmed PY - 2014/9/23/medline KW - 4-Substituted-7-benzyloxy-2H-chromene-2-ones KW - Alzheimer's disease KW - Molecular docking KW - Monoamine oxidase inhibitors KW - Neurodegenerative diseases KW - Parkinson's disease KW - Selective MAO-B inhibitors SP - 723 EP - 39 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 70 N2 - The effects on the inhibition potencies of monoamine oxidase isoforms A (MAO-A) and B (MAO-B) depending upon changes in the physicochemical properties (size, shape, H-bonding, lipophilicity, etc.) of substituents at the C4 position of 2H-chromen-2-one derivatives were extensively investigated, and the results significantly added to our knowledge on this class of MAO inhibitors. All the 67 examined compounds showed high MAO-B selectivity, some of them achieving potency in the low nanomolar range. In particular, the 7-metachlorobenzyloxy-4-oxyacetamido-2H-chromen-2-one (entry 62) showed single digit nanomolar MAO-B potency (IC₅₀ = 3.1 nM) and high selectivity over the MAO-A isoform (selectivity ratio = 7244). The great variety of the investigated substituents at C4 of the 2H-chromen-2-one nucleus, combined with binding models generated from docking studies carried out on selected compounds, allowed us to shed light on the main molecular requirements for potent and selective MAO-B inhibition, highlighting the dominant role of the steric effects. Interestingly, many of the designed substituents could be metabolically related to each other (e.g., CH₃/CH₂OH/CHO/COOH; NH₂/NHCH₃, NHAc), and therefore the results obtained may help in predicting the in vivo activity of some putative metabolites of lead MAO-B inhibitors. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/24231308/Fine_molecular_tuning_at_position_4_of_2H_chromen_2_one_derivatives_in_the_search_of_potent_and_selective_monoamine_oxidase_B_inhibitors_ DB - PRIME DP - Unbound Medicine ER -