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1.
J Med Chem ; 64(4): 1989-2009, 2021 02 25.
Article in English | MEDLINE | ID: mdl-33533632

ABSTRACT

Thirty compounds having 1-[2-(5-substituted-2-benzoxazolinone-3-yl) acetyl]-3,5-disubstitutedphenyl-2-pyrazoline structure and nine compounds having N'-(1,3-disubstitutedphenylallylidene)-2-(5-substituted-2-benzoxazolinone-3-yl)acetohydrazide skeleton were synthesized and evaluated as monoamine oxidase (MAO) inhibitors. All of the compounds exhibited selective MAO-A inhibitor activity in the nanomolar or low micromolar range. The results of the molecular docking for hydrazone derivatives supported the in vitro results. Five compounds, 6 (0.008 µM, Selectivity Index (SI): 9.70 × 10-4), 7 (0.009 µM, SI: 4.55 × 10-5), 14 (0.001 µM, SI: 8.00 × 10-4), 21 (0.009 µM, SI: 1.37 × 10-5), and 42 (0.010 µM, SI: 5.40 × 10-6), exhibiting the highest inhibition and selectivity toward hMAO-A and nontoxic to hepatocytes were assessed for antidepressant activity as acute and subchronic in mice. All of these five compounds showed significant antidepressant activity with subchronic administration consistent with the increase in the brain serotonin levels and the compounds crossed the blood-brain barrier according to parallel artificial membrane permeation assay. Compounds 14, 21, and 42 exhibited an ex vivo MAO-A profile, which is highly consistent with the in vitro data.


Subject(s)
Antidepressive Agents/therapeutic use , Depression/drug therapy , Hydrazones/therapeutic use , Monoamine Oxidase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/metabolism , Antidepressive Agents/pharmacokinetics , Hep G2 Cells , Humans , Hydrazones/chemical synthesis , Hydrazones/metabolism , Hydrazones/pharmacokinetics , Mice , Molecular Docking Simulation , Molecular Structure , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/metabolism , Monoamine Oxidase Inhibitors/pharmacokinetics , Protein Binding , Pyrazoles/chemical synthesis , Pyrazoles/metabolism , Pyrazoles/pharmacokinetics , Structure-Activity Relationship
2.
Bioorg Chem ; 100: 103892, 2020 07.
Article in English | MEDLINE | ID: mdl-32388433

ABSTRACT

A new series of 1,2,4-triazole-5-thione Mannich derivatives containing a naproxen moiety (1a-o) was designed and synthesized to create naproxen analogs, with the aim of developing novel anti-inflammatory/analgesic agents with improved safety profiles. Target compounds were synthesized using classical Mannich reaction (i.e. one-pot three component condensation reaction), by reacting triazole molecule (1), formaldehyde, and diverse secondary amines in ethanol. The synthesized compounds were investigated using FT-IR, 1H NMR, 13C NMR and mass spectroscopies, as well as elemental analysis. Compounds were then evaluated for their potential antinociceptive and anti-inflammatory activities using some validated invivo methods. Data obtained from acetic acid induced-writhing and carrageenan-induced paw edema tests revealed that all compounds induced peripherally-mediated antinociceptive activities, as well as notable anti-inflammatory effects. The results of hot-plate and tail-clip tests indicated that compounds 1a, 1b, 1c, 1d, 1g, and 1j have also centrally-mediated antinociceptive activities in addition to their peripherally-mediated effects. Molecular docking studies were performed to investigate the putative binding modes of the interactions between all compounds and COX-1/COX-2 enzymes using AutoDock Vina software. Docking of the compounds into the COX-2 active site produced binding interactions that are essential for COX-2 inhibitory activity. None of the compounds in the serial, except for 1m and 1j, induced significant gastrointestinal irritation. Overall, the results indicated that triazol Mannich bases bearing a naproxen moiety potentially represent a novel class of antinociceptive and anti-inflammatory agent with an improved gastric safety profile.


Subject(s)
Analgesics/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Edema/drug therapy , Naproxen/therapeutic use , Pain/drug therapy , Triazoles/therapeutic use , Analgesics/chemical synthesis , Analgesics/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Cyclooxygenase 2/metabolism , Drug Design , Edema/metabolism , Humans , Male , Mannich Bases , Mice, Inbred BALB C , Molecular Docking Simulation , Naproxen/analogs & derivatives , Naproxen/chemical synthesis , Pain/metabolism , Triazoles/chemical synthesis , Triazoles/chemistry
3.
Chirality ; 31(1): 21-33, 2019 01.
Article in English | MEDLINE | ID: mdl-30468523

ABSTRACT

A new racemic pyrazoline derivative was synthesized and resolved to its enantiomers using analytic and semipreparative high-pressure liquid chromatography. The absolute configuration of both fractions was established using vibrational circular dichroism. The in vitro monoamine oxidase (MAO) inhibitory profiles were evaluated for the racemate and both enantiomers separately for the two isoforms of the enzyme. The racemic compound and both enantiomers were found to inhibit hMAO-A selectively and competitively. In particular, the R enantiomer was detected as an exceptionally potent and a selective MAO-A inhibitor (Ki  = 0.85 × 10-3  ± 0.05 × 10-3  µM and SI: 2.35 × 10-5 ), whereas S was determined as poorer compound than R in terms of Ki and SI (0.184 ± 0.007 and 0.001). The selectivity of the enantiomers was explained by molecular modeling docking studies based on the PDB enzymatic models of MAO isoforms.


Subject(s)
Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Circular Dichroism , Hep G2 Cells , Humans , Kinetics , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Monoamine Oxidase/genetics , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Stereoisomerism , Structure-Activity Relationship
4.
Bioorg Chem ; 77: 608-618, 2018 04.
Article in English | MEDLINE | ID: mdl-29501028

ABSTRACT

Single enantiomers of the new 5-methyl-3-aryloxazolidine-2,4-diones have been obtained either by an asymmetric synthesis using the chiral pool strategy or by a semipreparative resolution of the racemic compound by HPLC on an optically active stationary phase. The single enantiomers were assayed for their in vitro monoamine oxidase (hMAO) inhibitory activity and selectivity. The most potent inhibitor among the studied compounds has been found as (5R)-3-phenyl-5-methyl-2,4-oxazolidinedione (compound 1-R) which appeared to be a good antidepressant drug candidate since it inhibited hMAO-A selectively, competitively and reversibly with Ki values in the micromolar range (0.16 ±â€¯0.01 µM). To better understand the enzyme-inhibitor interaction and to explain the efficiency and selectivity of the compounds toward hMAOs, molecular modeling studies were carried out on new, high resolution hMAO-A and hMAO-B crystallographic structures. According to binding energies and inhibition constants obtained from molecular docking calculations, compound 1-R has been found as the most selective MAO-A inhibitor and its weak binding affinities to MAO-B (large Ki values) led to the enhancement in MAO-A selectivity. It bounded in close proximity to FAD in the active site of MAO-A and situated near the aromatic cage by means of π-alkyl interactions with Tyr407 and Phe352 whereas its position in MAO-B was 10 Šfar from FAD and it was situated outside the Ile199 gate of the active site. None of the studied compounds showed any cytototoxicity on HepG2 cells at 1 and 5 µM concentrations.


Subject(s)
Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Oxazoles/pharmacology , Cell Survival/drug effects , Dose-Response Relationship, Drug , Hep G2 Cells , Humans , Kinetics , Models, Molecular , Molecular Structure , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , Oxazoles/chemical synthesis , Oxazoles/chemistry , Stereoisomerism , Structure-Activity Relationship
5.
J Neural Transm (Vienna) ; 120(6): 863-73, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23361656

ABSTRACT

A series of 1-[2-((5-methyl/chloro)-2-benzoxazolinone-3-yl)acetyl]-3,5-diaryl-4,5-dihydro-1H-pyrazole derivatives were prepared by reacting 2-((5-methyl/chloro)-2-benzoxazolinone-3-yl)acetylhydrazine with appropriate chalcones. The chemical structures of all compounds were confirmed by elemental analyses, IR, (1)H NMR and ESI-MS. All the compounds were investigated for their ability to selectively inhibit monoamine oxidase (MAO) by in vitro tests. MAO activities of the compounds were compared with moclobemide and selegiline and all the compounds were found to inhibit human MAO-A selectively. The inhibition profile was found to be competitive and reversible for all compounds by in vitro tests. Among the compounds examined, compounds 5ae, 5af and 5ag were more selective than moclobemide, with respect to the K i values experimentally found. In addition, the compound 5bg showed MAO-A inhibitor activity as well as moclobemide. A series of experimentally tested compounds (5ae-5ch) were docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The AUTODOCK 4.01 program was employed to perform automated molecular docking.


Subject(s)
Models, Molecular , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/chemistry , Benzoxazoles/pharmacology , Chalcone/chemistry , Humans , Stereoisomerism , Structure-Activity Relationship , Substrate Specificity/drug effects , Tritium
6.
J Neural Transm (Vienna) ; 120(6): 883-91, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23328949

ABSTRACT

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.


Subject(s)
Hydrazones/chemistry , Models, Molecular , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/drug effects , Monoamine Oxidase/metabolism , Drug Evaluation, Preclinical , Humans , In Vitro Techniques , Molecular Dynamics Simulation , Monoamine Oxidase/chemistry , Protein Binding/drug effects , Stereoisomerism , Structure-Activity Relationship
8.
Bioorg Med Chem ; 17(18): 6761-72, 2009 Sep 15.
Article in English | MEDLINE | ID: mdl-19682910

ABSTRACT

A novel series of 2-thiocarbamoyl-2,3,4,5,6,7-hexahydro-1H-indazole and 2-substituted thiocarbamoyl-3,3a,4,5,6,7-hexahydro-2H-indazoles derivatives were synthesized and investigated for the ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). The target molecules were identified on the basis of satisfactory analytical and spectra data (IR, (1)H NMR, (13)C NMR, (2)D NMR, DEPT, EI-MASS techniques and elemental analysis). Synthesized compounds showed high activity against both the MAO-A (compounds 1d, 1e, 2c, 2d, 2e) and the MAO-B (compounds 1a, 1b, 1c, 2a, 2b) isoforms. In the discussion of the results, the influence of the structure on the biological activity of the prepared compounds was delineated. It was suggested that non-substituted and N-methyl/ethyl bearing compounds (except 2c) increased the inhibitory effect and selectivity toward MAO-B. The rest of the compounds, carrying N-allyl and N-phenyl, appeared to select the MAO-A isoform. The inhibition profile was found to be competitive and reversible for all compounds. A series of experimentally tested (1a-2e) compounds was docked computationally to the active site of the MAO-A and MAO-B isoenzyme. The autodock 4.01 program was employed to perform automated molecular docking. In order to see the detailed interactions of the docked poses of the model inhibitors compounds 1a, 1d, 1e and 2e were chosen because of their ability to reversibly inhibit the MAO-B and MAO-A and the availability of experimental inhibition data. 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. 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. Excellent to good correlations between the calculated and experimental K(i) values were obtained. In the docking of the MAO-A complex, the trans configuration of compound 1e made various very close interactions with the residues lining the active site cavity these interactions were much better than those of the other compounds tested in this study. This tight binding observation may be responsible for the nanomolar inhibition of form of MAOA. However, it binds slightly weaker (experimental K(i)=1.23 microM) to MAO-B than to MAO-A (experimental K(i)=4.22 nM).


Subject(s)
Indazoles/chemistry , Indazoles/pharmacology , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Animals , Catalytic Domain , Computer Simulation , Crystallography, X-Ray , Indazoles/chemical synthesis , Mitochondria, Liver/enzymology , Models, Molecular , Monoamine Oxidase/chemistry , Monoamine Oxidase Inhibitors/chemical synthesis , Protein Binding , Rats , Structure-Activity Relationship
9.
J Enzyme Inhib Med Chem ; 24(1): 29-37, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19127481

ABSTRACT

The synthesis, characterization and pharmacological activities of a new series of (6-difluorobenzoyl)-5-methyl-3-benzoylmethyl-2(3H)-benzoxazolone and 5-methyl-3-(2-hydroxyl-2-phenylethyl)-2(3H)-benzoxazolone are described. Antiinflammatory activity was investigated by the carrageenin-induced paw oedema test and analgesic activity by acetic acid writhing and hot plate tests in mice. Among the synthesized compounds, compound 3e 6-(2,5-difluorobenzoyl)-3-(4-bromobenzoylmethyl-2(3H)-benzoxazolone was found to be the most promising compound for analgesic activity. Reduced compounds (4a-4d) displayed considerable anti-inflammatory activity compared to the other derivatives.


Subject(s)
Analgesics/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Benzoxazoles/chemical synthesis , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Benzoxazoles/pharmacology , Drug Evaluation, Preclinical , Edema/prevention & control , Mice , Pain/prevention & control , Structure-Activity Relationship
10.
Bioorg Med Chem ; 17(2): 675-89, 2009 Jan 15.
Article in English | MEDLINE | ID: mdl-19091581

ABSTRACT

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.


Subject(s)
Monoamine Oxidase Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Quinazolinones/chemical synthesis , Binding Sites , Flavin-Adenine Dinucleotide , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Monoamine Oxidase , Monoamine Oxidase Inhibitors/pharmacology , Pyrazoles/pharmacology , Quinazolinones/pharmacology
11.
Bioorg Med Chem ; 15(17): 5775-86, 2007 Sep 01.
Article in English | MEDLINE | ID: mdl-17611112

ABSTRACT

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.


Subject(s)
Alzheimer Disease , Analgesics/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Monoamine Oxidase Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Alzheimer Disease/drug therapy , Alzheimer Disease/enzymology , Analgesics/chemistry , Analgesics/therapeutic use , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Edema/drug therapy , Edema/pathology , Hindlimb/drug effects , Hydrogen Bonding , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Mice , Models, Molecular , Molecular Structure , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/therapeutic use , Pyrazoles/chemistry , Pyrazoles/therapeutic use , Structure-Activity Relationship
12.
Bioorg Med Chem ; 15(17): 5738-51, 2007 Sep 01.
Article in English | MEDLINE | ID: mdl-17587585

ABSTRACT

Acetic acid hydrazide containing 5-methyl-2-benzoxazolinone (4) was synthesized by the condensation of 2-(5-methyl-2-benzoxazolinone-3-yl)acetate with hydrazine hydrate. Thiosemicarbazide derivatives (5a-5d) were afforded by the reaction of corresponding compound 4 with substituted isothiocyanates. The cyclization of compounds 5a-5d in the presence of triethylamine resulted in the formation of compounds 6a-6d containing 1,2,4-triazole ring. On the other hand, the treatment of compounds 5a-5d with orthophosphoric acid caused the conversion of side chain of compounds 5a-5d into 1,3,4-thiadiazole ring: thus, compounds 7a-7c were obtained. The treatment of compound 4 with aromatic aldehydes resulted in the formation of arylidene hydrazides as cis-trans conformers (8a-8e). The structures of the compounds were elucidated by spectral and elemental analysis. While most compounds were exhibiting high activity in the analgesic-anti-inflammatory field, most of them were found to be inactive against bacteria and fungi.


Subject(s)
Anti-Bacterial Agents/chemistry , Benzoxazoles/chemistry , Hydrazones/chemical synthesis , Hydrazones/pharmacology , Semicarbazides/chemical synthesis , Thiadiazoles/chemical synthesis , Triazoles/chemical synthesis , Analgesics/chemical synthesis , Analgesics/chemistry , Analgesics/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Crystallography, X-Ray , Edema/drug therapy , Edema/pathology , Hindlimb/drug effects , Hydrazones/chemistry , Hydrazones/therapeutic use , Methylation , Mice , Microbial Viability/drug effects , Models, Molecular , Molecular Structure , Semicarbazides/chemistry , Semicarbazides/pharmacology , Semicarbazides/therapeutic use , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/pharmacology , Thiadiazoles/therapeutic use , Triazoles/chemistry , Triazoles/pharmacology , Triazoles/therapeutic use
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