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.

A new therapeutic approach in Alzheimer disease: some novel pyrazole derivatives as dual MAO-B inhibitors and antiinflammatory analgesics.

The increasing life expectancy in our population makes Alzheimer's disease (AD) a growing public health problem. There is a great need to find a way to prevent and delay the disease. It was shown that monoamine oxidase-B (MAO-B) inhibitors and antiinflammatory agents might be effective in treating AD. Therefore, a novel series of 1-thiocarbamoyl-3-substituted phenyl-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole derivatives as promising MAO-B inhibitors was synthesized and investigated for the ability to inhibit selectively the activity of the A and B isoforms of monoamine oxidase (MAO). Most of the synthesized compounds showed high activity against both the MAO-A (compounds 3e-3h) and the MAO-B (compounds 3i-3l) isoforms. All the synthesized compounds were also tested for their in vivo antiinflammatory activity by two different bioassays namely, carrageenan-induced oedema and acetic acid-induced increase in capillary permeability in mice. In addition, analgesic and ulcerogenic activities were determined. The combined antiinflammatory data from in vivo animal models showed that compound 3k exhibited anti-inflammatory activity comparable to that of indomethacin with no ulcerogenic effects. Since compound 3k exhibits both antiinflammatory-analgesic activity and MAO-B inhibition, it needs further detailed studies.

Antitrypanosomal cycloartane glycosides from Astragalus baibutensis.

Baibutoside (5), a new cycloartane-type triterpene glycoside, has been isolated from the roots of Astragalus baibutensis along with four known glycosides, acetylastragaloside I (1), and astragalosides I, II, and IV (2-4, resp.). The structure elucidation of the compounds were achieved by a combination of one- and two-dimensional NMR techniques (DQF-COSY, HSQC, HMBC, and ROESY), and mass spectrometry (ESI-MS), where all the compounds were shown to have cycloastragenol (=(20R,24S)-3beta,6alpha,16beta,25-tetrahydroxy-20,24-epoxy-9,19-cyclolanostane) as aglycone. All compounds were tested for in vitro antiprotozoal activity. Compounds 1-4 displayed notable activity vs. Trypanosoma brucei rhodesiense, with acetylastragaloside I (1) being the most potent (IC50 9.5 microg/ml). Acetylastragaloside I (1) was also lethal to T. cruzi (IC50 5.0 microg/ml), and it is the first cycloartane-type triterpene with remarkable trypanocidal activity against both T. brucei rhodesiense and T. cruzi. However, it exhibits some cytotoxicity on mammalian cells.

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 Alzheimer's and Parkinson's diseases.

In vivo metabolism of 2-[1'-phenyl-3'-(3-chlorophenyl)-2'-propenylyden]hydrazino-3-methyl-4(3H)-quinazolinone in rats.

The aim of this study was to investigate by HPLC the in vivo metabolism of 2-[1'-phenyl-3'-(3-chlorophenyl)-2'-propenylyden]hydrazino-3-methyl-4(3H)-quinazolinone as a substrate, and as a model compound in rats. The substrate was dissolved in DMSO/water (1:4) and administered intraperitoneally at a dose of 100 mg/kg in a volume of approximately 0.1 mL. Blood samples were taken before and 30 min, 1.5, 3, 6, 9, 11, 30 and 48 h after i.p. drug administration. The chromatographic separation of the substrate and its metabolites was performed using a stainless steel Novopak C18 column (150 x 4.6 mm i.d., 5-microm particle size). The optimal composition of the mobile phase was reached by introducing different mixtures of pure acetonitrile and water in a linear gradient system. Following the biotransformation of this compound, 2-hydrazino-3-methyl-4(3H)-quinazolinone (M1) and 3-(3-chlorophenyl)-1-phenylprop-2-en-1-one (M2) derivatives were identified together with substrate by comparing them to reference standards using HPLC-UV/DAD. In addition, the composition of these metabolites and substrate was confirmed by LC-MS in plasma.

Synthesis, anti-inflammatory and analgesic activity of some new 4(3H)-quinazolinone derivatives.

4(3H)-quinazolinone and pyrazole derivatives have been shown to have analgesic and anti-inflammatory properties. In this study, 14 new 3-methyl-4(3H)quinazolinone derivatives bearing 2-[1'-phenyl-3'-(substituted-phenyl)-2'-propenylidene]hydrazino or 2[5'-(substituted phenyl)-3'-phenyl-2'-pyrazolin-1'-yl] groups have been synthesized with the aim of obtaining new analgesic and anti-inflammatory leads. The structures were elucidated by means of UV, IR, 1H-NMR, 13C-NMR, mass spectroscopy, and elemental analysis data. The anti-inflammatory activities of the synthesized compounds were determined by carrageenan-induced hind paw edema test in mice. All the compounds showed statistically significant effects. For analgesic activity assessment, p-benzoquinone-induced writhing test was applied in mice. The results obtained were in accordance with the anti-inflammatory activity tests.

Crystal and molecular structures of 1-[3-(3,4-dimethoxyphenyl)-2-propenoyl]pyrrolidine.

The crystal structure of 1-[3-(3,4-dimethoxyphenyl)-2-propenoyl]pyrrolidine (C15H19NO3) (I) has been determined by X-ray analysis. It crystallizes orthorhombic space group Pbca with a = 24.295(3), b = 15.086(3), c = 7.552(3)A, V = 2768(1)A3, Z = 8, Dcalc = 1.254 g/cm3, mu = (Mo K(alpha)) = 0.87 cm(-1). The title compound has analgesic activity of cycloaliphatic amine part. The molecule is deviated from planar configuration.

1-N-substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines: synthesis and evaluation as MAO inhibitors.

Twelve new 1-N-substituted thiocarbomoyl-3-phenyl-5-thienyl-2-pyrazoline derivatives were synthesized and evaluated their for antidepressant, anxiogenic and mammalian monoamine oxidase (MAO)-A and Binhibitory activities by in vivo and in vitro tests. MAO was isolated and purified from the mitochondrial pellet of bovine liver homogenates and human platelets. All of the new compounds inhibited the total MAO activity of liver homogenates and the inhibition was found to be time-dependent. Four compounds (3 i-3 l) inhibited MAO-B selectively and irreversibly in a classical non-competitive manner with IC(50) values in the range of 22.00-91.50 microM. The rest of the compounds appeared to be non-selective reversible inhibitors. It was suggested that the p-methoxy group on the phenyl ring in the compounds increased the inhibitory effect and selectivity toward MAO-B. The reversible and unselective inhibition of MAO by the remaining compounds was suggested to be related to their properties of acting ability to act as both as substrate and inhibitor at the same time. However, none of the novel compounds showed antidepressant activity as expected suggesting formation of inactive metabolites. We conclude that the compounds appeared as which functioned as selective MAO-B inhibitors might have promising features as therapeutic properties in the treatment of Parkinson disease. In vivo studies are needed to verify this hypothesis.