Özen Özgen

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

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 pi-pi 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.

Structure Determination of C23H19N4OBr from Synchrotron Data

A significant part of medicine is based on the discovery and development of drugs. It is very important to know the crystal structure of pharmaceutical compounds for fundamental understanding of structure, physical and chemical properties. Many of these materials are available only as powders. So any structural information must be obtained from powder diffraction. I am going to present following the stages while solving the structure of C23H19N4OBr, 2-[3-phenyl-4(m-bromophenyl)-2-pyrazolin-1-yl]-3-methyl-4(3H)quinazolinone, from 2-pyrazolines derivatives. The compounds are known to display various biological properties such as fungicidal insecticidal, anti bacterial, anti viral activities, pharmacological properties such as antiinflammatory agents and have industral properties(1). The powder diffraction data was collected with Debye Scherrer camera at the BL01C2 beamline at room temperature in National Synchrotron Radiation Research Center(NSRRC), Taiwan. X-ray of wavelength was 1.0333Å. This compound crystallizes in orthorhombic system space group P bca, Z=8, unit cell parameters of a=25.83(1)Å, b=15.55(5)Å, c=10.63(3)Å, and V=4266.0(10)Å3. Reliability factors were reached Rwp=0.075, Rp=0.053, RB=0.086 ve S=1.31 after Rietveld refinement.

5-Benzoyl-1-n-butyl-4-phenyl­pyrimidin-2(1H)-one

The title compound, C21H20N2O2, crystallizes in the monoclinic space group P21/c. The pyrimidine ring is essentially planar. The structure is stabilized by intermolecular C—H⋯O interactions.