Akgül Yeşilada

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.

1-N-Substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines : A novel cholinesterase and selective monoamine oxidase B inhibitors for the treatment of Parkinson's and Alzheimer's diseases

Twelve 1-N-substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazoline derivatives were synthesized and their biological interactions with human plasma and erythrocyte acetylcholinesterase (AChE) and butrylcholinesterase (BuChE) enzymes were assessed. Compounds 3i-3l of newly synthesized N-substituted pyrazolines, which were presented as selective and irreversible MAO-B inhibitors in our previous report, were found to inhibit human erythrocyte and plasma AChE activities selectively and non-competitively suggesting that these compounds may interact with a region close to the peripheral site of the enzyme molecule which could shift the proper positioning of the catalytic center. Compounds 3e-3h inhibited both AChE and BuChE activities of human erythrocytes, but the inhibitory potencies of these compounds towards BuChE were found to be higher than that of towards AChE. Inhibition was found to be non-competitive and reversible. These data suggested that newly synthesized N-substituted pyrazoline derivatives can be evaluated as both MAO-B and cholinesterase inhibitors which may have promising features in the treatment of Alzheimers and Parkinsons diseases.

Second Derivative Spectrophotometric Determination of p-Aminophenol in the Presence of Paracetamol

Abstract A second derivative spectroscopic method for the determination of p-aminophenol in paracetamol powder is described. Second derivative absorbance (d2A/dλ2) values were measured at 223.8 nm (Δ = 4.2 nm) where p-aminophenol showed derivative responses obeying Beers Law but paracetamol had negligible derivative absorption. The concentrations of p-aminophenol solutions prepared in 0.1 N HCl (0.12–7.61 mcg/ml), containing constant amounts of paracetamol (20 mcg/ml) related linearly with the d2A/dλ2 values and gave a straight line (r = −0.9999). The method allowed determination of 0.5% to 38% of p-aminophenol in paracetamol without prior separation, it is rapid, precise and accurate.

Interaction of rat lung SSAO with the novel 1-N-substituted thiocarbamoyl-3-substituted phenyl-5-(2-pyrolyl)-2-pyrazoline derivatives

SummaryInteractions of twelve new synthesized 1-N-substituted thiocarbamoyl-3-substituted phenyl-5-pyrolyl-2-pyrazoline derivatives with rat lung semicarbazide-sensitive amine oxidase (SSAO) were assessed. Pyrazoline derivatives were synthesized according to previous methods and SSAO was purified from the crude microsomal fractions of rat lung.Three compounds (3e, 3f, 3k) with a p-methoxy group at the phenyl ring inhibited rat lung SSAO non-competitively and irreversibly, and showed higher affinity towards SSAO when expressed in terms of IC50 for SSAO/Monoamine oxidase B (MAO-B). Since these novel pyrazoline derivatives have been found to act as suicide inhibitors of SSAO, the semicarbazide group in these molecules may be responsible for the SSAO inhibitory action. It is suggested that these compounds cannot enter the first small active site cavity of SSAO and may interact tightly with another binding site or with some other reactive groups present in the molecule. Compound 3e showed the highest inhibitory activity on rat lung SSAO. The novel pyrazoline derivatives may be used to discriminate between Cu- and FAD-containing amine oxidases and may have promising features as anti-Parkinson agents if the SSAO-inhibitory effects can be supported by in vivo studies.

Development and Validation of a Capillary Electrophoretic Method for the Determination of Degradation Product in Naphazoline HCl Bulk Drug Substance

Abstract In this study a capillary electrophoretic method is described for the identification and quantitation of the main degradation product napthylacetyletylenediamine (NAED) in naphazoline HCl bulk drug. The effect of temperature, operating voltage, and electrolyte concentration on the resolution was determined by using a multivariate experimental design. The separation was achieved at 15 kV, on a 70 cm (62 cm effective) × 75 μm I.D. capillary at 20°C using 0.1 M, pH 3 phosphate buffer as background electrolyte. The method was validated and satisfactory specificity, linearity, precision, and accuracy results were obtained.

Second Derivative Spectrophotometric Determination of Amoxycillin in Oral Suspensions

Abstract Second derivative UV spectroscopy was applied to the determination of amoxycillin in oral suspensions. The method does not require prior separation. The second derivative response values were linear (r=0.9995) in the concentration range 3.32–55.36 μg/ml at 280.7 nm. The method was applied to commercial products. It is precise, accurate and rapid.

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.

Monoamine oxidase inhibitory activities of novel 3,4-dihydroquinolin-(1H)-2-one derivatives.

SummaryThree 3,4-dihydroquinoline-(1H)-2-one derivatives were synthesized and their monoamine oxidase (MAO) inhibitory activities were evaluated. The calculated IC50 values revealed that compound Q (N-amino-3,4-dihydroquinoline-(1H)-2-one), which carries a free amine group in the molecule, inhibited rat liver MAO-B competitively and reversibly suggesting that this relatively small compound may interact with the active site channel of the enzyme while the compounds QB (1-(benzlyden-amino)-3,4-dihydroquinoline-(1H)-2-one), PCN (2-(3-cyano-2-oxo-4-phenyl-2H-quinolin-1-yl-N-cyclohexyl-2-(4-chlorophenyl) acetamide) and MG (tert-butyl-N-[cyclohexylcarbamoyl-(3-hydroxyphenyl)methyl]-N-(2-benzoylphenyl)-carbamate) inhibited rat liver MAO-B non-competitively and irreversibly, suggesting that these compounds may interact with another hydrophobic binding region outside of the active site of the enzyme.