Fine molecular tuning at position 4 of 2H-chromen-2-one derivatives in the search of potent and selective monoamine oxidase B inhibitors.
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.
Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona 4, I-70125 Bari, Italy.
Leonardo
L
Pisani
Marco
M
Catto
Orazio
O
Nicolotti
Giancarlo
G
Grossi
Mario
M
Di Braccio
Ramon
R
Soto-Otero
Estefania
E
Mendez-Alvarez
Angela
A
Stefanachi
Domenico
D
Gadaleta
Angelo
A
Carotti
D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002867:Chromones; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase
4-Substituted-7-benzyloxy-2H-chromene-2-ones; Alzheimer's disease; Molecular docking; Monoamine oxidase inhibitors; Neurodegenerative diseases; Parkinson's disease; Selective MAO-B inhibitors