ChemInform Abstract: Synthetic Reactions and Structural Studies of Heterocyclic Containing Nitrogen. Part 14. Dehydration of 2-(2-Arylethyl)-2-hydroxy-4- oxopentanoic Acids and Their Hydrazones to Form Heterocycles (original) (raw)
Related papers
Chemical and …, 2008
A series of new pyridazinylacetic acid derivatives were synthesized and have been investigated for their ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). All compounds were found to be more selective to the MAO-A isoform with compound 5d having the highest SI values. Computational study performed with a docking technique indicated the potential of these compounds in pyridazine-based MAO-A inhibitor drug development.
Nitrogen heterocycles as potential monoamine oxidase inhibitors: Synthetic aspects
Arabian Journal of Chemistry, 2014
The present review highlights the synthetic methods of monoamine oxidase inhibitors (MAO) belonging to a group of nitrogen heterocycles such as pyrazoline, indole, xanthine, oxadiazole, benzimidazole, pyrrole, quinoxaline, thiazole and other related compounds (1990-2012). Moreover, it emphasizes salient findings related to chemical structures and the bioactivities of these heterocycles as MAO inhibitors. The aim of this review is to find out different methods for the synthesis of nitrogen containing heterocycles and their bioactivity related aspects as MAO inhibitors.
Journal of Neural Transmission, 2013
Thirteen 2-[2-(5-methyl-2-benzoxazolinone-3-yl) acetyl]-3/4/5-substituted benzylidenehydrazine derivatives were synthesized by reacting 2-(5-methyl-2-benzoxazolinone-3-yl)acetylhydrazine and substituted benzaldehydes in neutral and acid/base catalyzed conditions, and a comparison was made in terms of their yields and reaction times. The structures of all compounds were confirmed by IR, 1 H NMR, 13 C NMR, mass spectral data, and elemental analyses. All the compounds were investigated for their ability to selectively inhibit MAO isoforms by in vitro tests and were found to inhibit recombinant human MAO-B selectively and reversibly in a competitive manner. Among the compounds examined, compound 16 was found to be more selective than selegiline, a known MAO-B inhibitor, in respect to the K i values experimentally found. Additionally, compounds 9 and 15 showed moderate MAO-B inhibitor activity. The interaction of compounds with MAO isoforms was investigated by molecular docking studies using recently published crystallographic models of MAO-A and MAO-B. The results obtained from the docking studies were found to be in good agreement with the experimental values.
Royal Society Open Science
A new series of N'-substituted benzylidene-2-(4-oxo-2-phenyl-1,4-dihydroquinazolin-3(2H)-yl)acetohydrazide ( 5a–5h ) has been synthesized, characterized by FT-IR, NMR spectroscopy and mass spectrometry and tested against human monoamine oxidase (MAO) A and B. Only (4-hydroxy-3-methoxybenzylidene) substituted compounds gave submicromolar inhibition of MAO-A and MAO-B. Changing the phenyl substituent to methyl on the unsaturated quinazoline ring ( 12a–12d ) decreased inhibition, but a less flexible linker ( 14a–14d ) resulted in selective micromolar inhibition of hMAO-B providing insight for ongoing design.
Bioorganic & Medicinal Chemistry, 2015
A series of quinazolinone amino acid ester and quinazolinone amino acid hydrazides were prepared under microwave irradiation as well as conventional condition. The microwave irradiation afforded the product in less reaction time, higher yield and purity. The structures of the synthesized compounds were confirmed by IR, NMR, and elemental analysis. The new synthesized compounds were studied for their monoamine oxidase inhibitory activity. They showed more selective inhibitory activity toward MAO-A than MAO-B. Compounds 7, 10, and 15 showed MAO-A inhibition activity (IC 50 = 3.6 Â 10 À9 , 2.8 Â 10 À9 , 2.1 Â 10 À9 M, respectively) comparable to that of the standard clorgyline (IC 50 = 2.9 Â 10 À9 M).
Current Medicinal Chemistry, 2006
The present report provides a extended study of the chemistry, the inhibitory activity against monoamino oxidases (MAO), and molecular modeling including the 3D-QSAR hypothesis of 1,3,5trisubstituted-4,5-dihydro-(1H)-pyrazole derivatives. Four series of about eighty novel pyrazoline derivatives were prepared and investigated for their ability to inhibit the activity of the A and B isoforms of MAO selectively. Most of the new synthesized compounds proved more reversible, potent, and selective inhibitors of MAO-A than of MAO-B, and could be taken into account to develop the search further in this field, knowing that reversible and selective MAO-A inhibitors are used as antidepressant and antianxiety drug. The 30 most active compounds show inhibitory activity on MAO-A in the 8.6 x 10-8-9.0 x 10-9 M range. Moreover, it should be pointed out that for most of them a high IC 50 ≥ 10-9 M value is associated with a high A-selectivity (Selectivity Index MAO-B/MAO-A in the 10,000-16,250 range). Furthermore, due to the presence of a chiral centre at the C5 position of the pyrazole moiety, we performed the semi-preparative chromatographic enantioseparation of the most potent, selective, and chiral compounds. The separated enantiomers were then submitted to in vitro biological evaluation, and from the results of these experiments it has been possible to point out a difference in inhibiting the two isoforms selectively between the racemic mixture and the single enantiomers. The molecular modeling work was carried out combining the Glide docking approach with CoMFA with the aim to rationalize the structure-activity relationships of each pyrazoline inhibitor toward MAO-A and MAO-B isoforms and to derive a suitable selectivity model.
2013
We herein report the monoamine oxidases A and B inhibitors of some synthesized substituted pyrimidines, thiazolopyrimidines and pyrazoles derivatives. Seventeen pyrimidine, thiazolo-pyrimidine, pyrazole, and pyridine derivatives 1-17 containing a carboxamide, ester, amide and ketone groups attached to a heterocyclic moiety synthesized and screened for their monoamine oxidases A and B inhibitors activities. The newly synthesized derivatives containing pyrimidine, thiazolopyrimidine, pyrazole, and pyridine moieties linked with different function groups considered as a lead for potent monoamine oxidases A and B inhibitors agents. The detailed synthetic pathways of obtained compounds and monoamine oxidases A and B inhibitors were reported.
Discovery and Optimization of Pyrazoline Derivatives As Promising Monoamine Oxidase Inhibitors
Current Topics in Medicinal Chemistry, 2012
Among different heterocyclic chemotypes incorporating two nitrogen atoms, pyrazolines could be considered a valid pharmacophore for the synthesis of selective monoamine oxidase (MAO) inhibitors because they were developed by the cyclization of the early hydrazine derivatives such as isocarboxazid. Substituted pyrazolines, decorated with different functional groups, are important lead compounds endowed with a large amount of biological activities. As a matter of this, most of them were also evaluated as dual inhibitors with a synergistic action towards different classes of enzymes (ciclooxygenase, acetylcholinesterase, butyrylcholinesterase). Moreover due to the direct correlation with the recognized MAO inhibition, this scaffold displayed antidepressant and anticonvulsant properties in animal models.
Journal of Medicinal Chemistry, 2008
A series of 2-methylcyclohexylidene-(4-arylthiazol-2-yl)hydrazones have been investigated for their ability to inhibit selectively the activity of the human A and B isoforms of monoamine oxidase (MAO). The target compounds, which present a stereogenic center on the cyclohexane ring, were obtained as pure (R) and (S) enantiomers by enantioselective HPLC. The absolute configuration of homochiral forms isolated on a semipreparative scale was obtained by a combined strategy based on chemical correlation and single-crystal X-ray diffraction. All compounds showed higher activity against the human MAO-B isoform with IC 50 values ranging between 26.81 ( 2.74 µM and 14.20 ( 0.26 nM, and the assays carried out on the pure enantiomers showed higher activity for the (R) form. A computational study was performed by molecular mechanics, DFT-based quantomechanics, and docking techniques on the most active and human MAO-B selective inhibitor 8.