New pyrazoline bearing 4(3 H)-quinazolinone inhibitors of monoamine oxidase: Synthesis, biological evaluation, and structural determinants of MAO-A and MAO-B selectivity

• Published in: Bioorganic & medicinal chemistry 2009-01, Vol.17 (2), p.675-689
• Main Authors: Gökhan-Kelekçi, Nesrin, Koyunoğlu, Semra, Yabanoğlu, Samiye, Yelekçi, Kemal, Özgen, Özen, Uçar, Gülberk, Erol, Kevser, Kendi, Engin, Yeşilada, Akgül
• Format: Article
• Language: English
• Subjects: 2-Pyrazoline; Antidepressant-anxiogenic activities; Binding Sites; Biological and medical sciences; Crystallographic model; Docking; Flavin-Adenine Dinucleotide; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; MAO-A/MAO-B inhibition; Medical sciences; Monoamine Oxidase; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - pharmacology; Neuropharmacology; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyrazoles - chemical synthesis; Pyrazoles - pharmacology; Quinazolinones - chemical synthesis; Quinazolinones - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.11.068

A new series of pyrazoline derivatives were prepared starting from quinazolinone ring and evaluated for antidepressant, anxiogenic and MAO-A and -B inhibitory activities by in vivo and in vitro tests, respectively. Enzyme–inhibitor molecular interaction was obtained by docking experiments with the monoamine oxidase-A and monoamine oxidase-B isoforms. A new series of pyrazoline derivatives were prepared starting from a quinazolinone ring and evaluated for antidepressant, anxiogenic and MAO-A and -B inhibitory activities by in vivo and in vitro tests, respectively. Most of the synthesized compounds showed high activity against both the MAO-A (compounds 4a– 4h, 4j– 4n, and 5g– 5l) and the MAO-B (compounds 4i and 5a– 5f) isoforms. However, none of the novel compounds showed antidepressant activity except for 4b. The reason for such biological properties was investigated by computational methods using recently published crystallographic models of MAO-A and MAO-B. The differences in the intermolecular hydrophobic and H-bonding of ligands to the active site of each MAO isoform were correlated to their biological data. Compounds 4i, 4k, 5e, 5i, and 5l were chosen for their ability to reversibly inhibit MAO-B and MAO-A and the availability of experimental inhibition data. Observation of the docked positions of these ligands revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. Among the pyrazoline derivatives, it appears that the binding interactions for this class of compounds are mostly hydrophobic. All have potential edge-to-face hydrophobic interactions with F343, as well as π–π stacking with Y398 and other hydrophobic interactions with L171. Strong hydrophobic and H-bonding interactions in the MAO recognition of 4i could be the reason why this compound shows selectivity toward the MAO-B isoform. The very high MAO-B selectivity for 4i can be also explained in terms of the distance between the FAD and the compound, which was greater in the complex of MAO-A- 4i as compared to the corresponding MAO-B complex.