Studies on the 1,1-diphenyl-2-picrylhydrazyl radical scavenging mechanism for a 2-pyrone compound

The radical scavenging mechanisms for the 2-pyrone compound, 4-hydroxy-3,6-dimethyl-2H-pyrane-2-one (1), and the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical (4) in several solvent systems were evaluated by the quantitative change in compounds detected at 270 nm and subsequent HPLC analyses. The HPLC profile for each condition suggested that the reaction proceeded by a different mechanism in each solvent system. In organic solvents (CHCl3, iso-propanol, and EtOH), 1-[4-(3,4-dihydro-3,6-dimethyl-2,4-dioxo-2H-pyran-3-yl) phenyl]-1-phenyl-2-picrylhydrazine (2) was produced as an adduct of the DPPH radical and 1. On the other hand, the reaction in a buffer solution (an acetate buffer at pH 5.5) gave several degradation products with 1[4-(2,3-dihydro-2,5-dimethyl-3-oxo-fur-2-yl) phenyl]-1-phenyl-2-picrylhydrazine (5), this being structurally elucidated by spectroscopic analyses. The decrease of the DPPH radical in each reaction system suggests that compound 1 could scavenge about 1.5-1.8 equivalents of the radical in organic solvents and about 3.5-3.9 in the buffer solution.     

Isolation of a 2-Pyrone Compound as an Antioxidant from a Fungus and Its New Reaction Product with 1,1-Diphenyl-2-picrylhydrazyl Radical

The indophenol-reducing compound, 4-hydroxy-3,6-dimethyl-2H-pyrane-2-one (I), was isolated from the culture filtrate of an unidentified fungus. I also reacted with the DPPH radical to form a reaction product IV which was determined to be 1-[4-(3,4-dihydro-3,6-dimethyl-2,4-dioxo- 2H-pyran-3-yl)phenyl]-1-phenyl-2-picrylhydrazine. This is the first report describing the formation of an adduct of the DPPH radical and its scavenger.     

Novel DPPH Radical Scavengers,Demethylbisorbibutenolide and Trichopyrone,from a Fungus

In our screening program for antioxidants with 1,1-diphenyl-2-picrylhydrazyl (DPPH)-radical scavenging activity, two novel compounds, demethylbisorbibutenolide (1) and trichopyrone (2), were isolated from the fermentation broth of the fungus of USF-4860 strain isolated from a soil sample. The structures of these compounds were determined from spectroscopic evidence. The biosynthetic origin of the carbon atoms of 2 was unambiguously determined by feeding experiments using ¹³C-labeled precursors and elucidation of the ¹³C-NMR spectrum of ¹³C-labeled 2. These studies showed that 2 was derived from five acetates and a methyl group of methionine. In the DPPH-radical scavenging assay, 1 and 2 gave ED₅₀ values of 149 and 167 μM after standing for 2.0 hr. Compound 2 reacted with the DPPH radical to form reaction product 3 which was determined to be 1-[4-(3,4-dihydro-3-methyl-6-{1,3-pentadienyl}-2,4-dioxo-2H-pyran-3-yl)-phenyl]-1-phenyl-2-picrylhydrazine from spectroscopic evidence.     

New Phenylpropanoid Glycosides from Illicium majus and Their Radical Scavenging Activities

Chemical investigation of the ethanol extract of the branch and leaves of Illicium majus resulted in the isolation of four new phenylpropanoid glycosides ( 1 – 4 ) and one new phenolic glycoside ( 9 ), along with 13 known ones. Spectroscopic techniques were used to elucidate the structures of the new isolates such as 3-[(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-yl]propyl β-D-glucopyranoside ( 1 ), [(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-2,3-dihydro-1-benzofuran-3-yl]methyl 2-O-α-L-rhamnopyranosyl-β-D-glucopyranoside ( 2 ), [(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-2,3-dihydro-1-benzofuran-3-yl]methyl 2-O-α-L-rhamnopyranosyl-β-D-xylopyranoside ( 3 ), 3-[(2R,3S)-3-({[2-O-(4-O-acetyl-α-L-rhamnopyranosyl)-β-D-xylopyranosyl]oxy}methyl)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-2,3-dihydro-1-benzofuran-5-yl]propyl acetate ( 4 ), and 4-(2-hydroxyethyl)phenyl 3-O-β-D-glucopyranosyl-β-D-glucopyranoside ( 9 ). Free radical scavenging activities of the isolates were elucidated through the DPPH assay method. The most active compounds, 1-O-caffeoyl-β-D-glucopyranose ( 17 ) and soulieana acid 1 ( 18 ), exhibited moderate radical scavenging activities (IC₅₀=37.7±4.4 μM and IC₅₀=97.2±3.4 μM, respectively). The antibacterial activities of the isolates against Staphylococcus aureus and Escherichia coli were also assessed, and no activity was shown at the measured concentration (<32 μg/mL).     

Novel DPPH radical scavengers, demethylbisorbibutenolide and trichopyrone, from a fungus

In our screening program for antioxidants with 1,1-diphenyl-2-picrylhydrazyl (DPPH)-radical scavenging activity, two novel compounds, demethylbisorbibutenolide (1) and trichopyrone (2), were isolated from the fermentation broth of the fungus of USF-4860 strain isolated from a soil sample. The structures of these compounds were determined from spectroscopic evidence. The biosynthetic origin of the carbon atoms of 2 was unambiguously determined by feeding experiments using (13)C-labeled precursors and elucidation of the (13)C-NMR spectrum of (13)C-labeled 2. These studies showed that 2 was derived from five acetates and a methyl group of methionine. In the DPPH-radical scavenging assay, 1 and 2 gave ED(50) values of 149 and 167 muM after standing for 2.0 hr. Compound 2 reacted with the DPPH radical to form reaction product 3 which was determined to be 1-[4-(3,4-dihydro-3-methyl-6-{1,3-pentadienyl}-2,4-dioxo-2H-pyran-3-yl)-phenyl]-1-phenyl-2-picrylhydrazine from spectroscopic evidence.     

Synthesis and Biological Evaluation of 1,3,5-Trisubstituted 2-Pyrazolines as Novel Cyclooxygenase-2 Inhibitors with Antiproliferative Activity

A new series of 1,3,5-trisubstituted 2-pyrazolines for the inhibition of cyclooxygenase-2 (COX-2) were synthesized. The designed structures include a COX-2 pharmacophore SO₂CH₃ at the para-position of the phenyl ring located at C-5 of a pyrazoline scaffold. The synthesized compounds were tested for in vitro COX-1/COX-2 inhibition and cell toxicity against human colorectal adenocarcinoma cell lines HT-29. The lead compound (4-chlorophenyl){5-[4-(methanesulfonyl)phenyl]-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl}methanone ( 16 ) showed significant COX-2 inhibition (IC₅₀=0.05±0.01 μM), and antiproliferative activity (IC₅₀=5.46±4.71 μM). Molecular docking studies showed that new pyrazoline-based compounds interact via multiple hydrophobic and hydrogen-bond interactions with key binding site residues of the COX-2 enzyme.     

Synthesis and antibacterial activity of a new series of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one derivatives

A series of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one (4a–k) were synthesized by reaction of 3-[2,3-dibromo-3-(substituted phenyl)propanoyl]-2H-chromen-2-one (3 a-k) with phenyl hydrazine in presence of triethylamine in absolute ethanol, characterized by spectral data and screened for their in vitro antibacterial activity against gram-positive and gram-negative bacteria. Among the series, compounds 4d, 4h and 4i displayed an encouraging antibacterial activity profile as compared to reference standard drug ciprofloxacin against tested bacterial strains.     

A systematic study of ligand intermolecular interactions in crystals of copper(II) complexes of bidentate guanidino derivatives

The synthesis and X-ray structures of copper(II) complexes of the bidentate ligands, N-(4-oxo-5,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-N′-phenylguanidino, 2-uanidinobenzimidazolo and N-(4-oxo-3-phenyl-1,3-diazaspiro[4.4]non-1-en-2-yl)guanidino, are reported. These complexes, which possess potential doublet (DA) or triplet (DAD) hydrogen bonding motifs, can form supramolecular structures based on synthons involving hydrogen bonding or phenyl embraces. The changes in supramolecular structure resulting from small changes in ligand structure, as well as from the use of different solvents for their crystallisation, are examined. The structures adopted are compared with others reported previously for complexes of related ligands.     

Discovery of novel antitubercular 1,5-dimethyl-2-phenyl-4-([5-(arylamino)-1,3,4-oxadiazol-2-yl]methylamino)-1,2-dihydro-3H-pyrazol-3-one analogues

In search of potential therapeutics for tuberculosis, we describe herewith the synthesis, characterization and antimycobacterial activity of 1,5-dimethyl-2-phenyl-4-([5-(arylamino)-1,3,4-oxadiazol-2-yl]methylamino)-1,2-dihydro-3H-pyrazol-3-one analogues. Among the synthesized compounds, 4-[(5-[(4-fluorophenylamino]-1,3,4-oxadiazol-2-yl)methylamino]-1,2-dihydro-1,5-dimethyl-2-phenylpyrazol-3-one (4a) was found to be the most promising compound active against Mycobacterium tuberculosis H(37)Rv and isoniazid resistant M. tuberculosis with minimum inhibitory concentrations, 0.78 and 3.12μg/mL, respectively, free from any cytotoxicity (>62.5μg/mL).     

Synthesis,Antimicrobial and Antioxidant Activity of Pyrazole Based Sulfonamide Derivatives

A series of new sulfonamides have been synthesized from Ampyrone with different benzene sulfonyl chlorides to yield the N-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) benzenesulfonamides (4a–e). All synthesized compounds were characterized on the basis of FTIR, ¹H NMR, and ¹³C NMR, and also by the aid of mass spectral data. Further, all synthesized compounds have studied for their in vitro antimicrobial activities against selected bacterial as well as fungal strains by the agar well diffusion method. Free radical scavenging activity has been investigated by using DPPH method. Among all the synthesized compounds, 4b, 4d, and 4e exhibited significant antimicrobial and antioxidant activities.     

Specific Deprotonation Reactions of the Pyrimidine Radical Cation Resulting from the Menadione Mediated Photosensitization of 2′-Deoxycytidine

Menadione(2-methyl-1, 4-naphthoquinone) was shown to sensitize 2′-deoxycytidine to near ultraviolet light according to two main mechanisms. Reaction of a water molecule with the initially photo-induced pyrimidine radical cation and subsequent addition of molecular oxygen leads to the preponderant formation of the four cis and trans diastereoisomers of 5,6-dihydroxy-5,6-dihydro-2′-deoxyuridine. Pyrimidine ring opening and rearrangement products are also generated through the intermediate 6-hydroxy-5,6-dihydro-2′-deoxyurid-5-yl radical. The competitive deprotonation reaction of the radical cation is likely to involve two sites. Loss of an amino group proton is the likely initial event to explain the formation of 2′-deoxyuridine which is resistant to further photooxidation. The second deprotonation reaction involves the osidic carbon C(1′). The resulting radical will further react with oxygen leading to the release of free cytosine with concomitant formation of 2-deoxy-D-ribono-1,4-lactone. This reaction which is not prevented by hydroxyl radical scavengers constitutes to our knowledge the first example of a pyrimidine radical which is able to initiate selective intramolecular reaction at position 1 within the sugar moiety.     

Synthesis and antihyperglycemic evaluation of new 2-hydrazolyl-4-thiazolidinone-5-carboxylic acids having pyrazolyl pharmacophores

In the search of new antihyperglycemic agents and following rational approach of drug designing here new 2-hydrazolyl-4-thiazolidinone-5-carboxylic acids (4a–g) with pyrazolyl pharmacophore have been synthesized via thia Michael addition reaction of 1-((3-(4-substituted phenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thiosemicarbazides (3a–g) with maleic anhydride. The required precursors, (3a–g) were obtained by condensing known 3-(4-substituted phenyl)-1-phenyl-1H-pyrazole-4-carbaldehydes (1a–g) with thiosemicarbazide in ethanol. The newly synthesized compounds (4a–g) have been evaluated for the antihyperglycemic activity in sucrose loaded rat model and among these compounds 4d, 4f and 4g have displayed significant antihyperglycemic activity.     

Use of a carrier for quantitation of a new dihydropyridine calcium antagonist (OPC-13340) in human plasma by highly sensitive gas chromatography with negative-ion chemical ionization mass spectrometry

A sensitive gas chromatographic—mass spectrometric method for the quantitation of (±)-methyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (OPC-13340, I), a new dihydropyridine calcium antagonist with a potent and long-acting antihypertensive and antianginal effect, was developed in order to elucidate its pharmacokinetics. Dihydropyridine calcium antagonists have been usually quantified by this technique in the negative-ion chemical ionization mode. However, direct application of this method to quantify trace amounts of I in biological fluids completely failed, owing to its adsorption on the column and oxidation of its dihydropyridine ring. Human plasma containing I and (±)-[²H₅]methyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (II), the internal standard, was extracted with n-hexane—diethyl ether under weakly basic conditions (pH 8). In order to prevent adsorption of the compounds on the column, (±)-[²H₃]ethyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (III), an analogue of I, was added to the extracts as a carrier. In addition, this carrier was also effective in preventing the oxidation of I. The quantitation limit of I in human plasma by this method was found to be less than 30 pg/ml. Thus, the method is sufficiently sensitive to study the pharmacokinetics of I in humans.     

Enantiomers of 2-methyl- and 2,4-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid: Preparation by resolution,determination of absolute configuration,and Curtius rearrangement

Both enantiomers of 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid 2 and 2,4-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid 3 were prepared via resolution of the corresponding racemic carboxylic acids with (R)- and (S)-1-phenylethylamine, respectively. Absolute configuration of (−)-(R)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid was determined by X-ray crystallography. Curtius rearrangement of acyl azides prepared from enantiomers of these heterocyclic carboxylic acids carried out in benzyl alcohol afforded enantiomers of the corresponding benzyl carbamates, which upon hydrogenolysis gave racemic 2-amino-2-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-one 4 and 2-amino-2,4-dimethyl-3,4-dihydro-2H-1,4h-benzoxazin-3-one 5. Chirality 10:791–799, 1998. © 1998 Wiley-Liss, Inc.     

Synthesis of novel 2-pyrazoline analogues with potent anti-inflammatory effect mediated by inhibition of phospholipase A2: Crystallographic,in silico docking and QSAR analysis

Oxidative-stress induces inflammatory diseases. Further, infections caused by drug-resistant microbial strains are on the rise. This necessitates the discovery of novel small-molecules for intervention therapy. A series of 3-(2,3-dichlorophenyl)-1-(aryl)prop-2-en-1-ones are synthesized as intermediates via Claisen-Schmidt reaction approach. Subsequently, these intermediates were transformed into 2-pyrazolines by their reaction with phenylhydrazine hydrochlorides in methanol and few drops of acetic acid under reflux conditions. Synthesized compounds were characterized by spectroscopic, crystallographic and elemental analyses studies and then, were evaluated for their in vitro antimicrobial and anti-inflammatory activities. Amongst the series, 3-(4-chlorophenyl)-5-(2,3-dichlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5e), 5-(2,3-dichlorophenyl)-3-(4-fluorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5c) and 5-(2,3-dichlorophenyl)-3-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5h) showed significant inhibition of phospholipase A2 with IC₅₀ values of 10.2, 11.1 and 11.9 µM, respectively. Protein structure modelling and docking studies indicated that the compounds showed binding to a highly conserved calcium-binding pocket on the enzyme. Further, compounds (5e), 1-(3-chlorophenyl)-5-(2,3-dichlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole (5b), and 1-(3-chlorophenyl)-3-(4-chlorophenyl)-5-(2,3-dichlorophenyl)-4,5-dihydro-1H-pyrazole (5f) showed excellent antimicrobial activities against various bacterial and fungal strains. In conclusion, this study is a successful attempt at the synthesis and characterization of chalcone derivatives that can target phospholipase A2, an enzyme that is a prominent player in the physiological inflammatory cascade. Thus, these compounds show promise for development as next-generation nonsteroidal anti-inflammatory drugs.     

Synthesis,Biological Evaluation and in Silico Studies of 3-Hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide Derivatives

In the present study, a series of 3-hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide derivatives were synthesized, characterized and evaluated for theirin vitroactivity, i. e., antimicrobial, antioxidant and anti-inflammatory. The target compounds were synthesized by condensation reaction of 3-hydroxy-2-naphthoic acid hydrazide with substituted benzaldehydes which were subjected to cyclization reaction with thioglycolic acid and ZnCl₂ to get target compounds. The synthesized 3-hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide derivatives were examined for their antimicrobial activity and 3-hydroxy-N-(4-oxo-2-(3,4,5-trimethoxyphenyl)thiazolidin-3-yl)-2-naphthamide ( S20 ) exhibited the highest antimicrobial potential. The N′-(2,3-dichlorobenzylidene)-3-hydroxy-2-naphthohydrazide ( S5 ) displayed good antifungal potential against Rhizopus oryzae, whereas N′-(2,3-dichlorobenzylidene)-3-hydroxy-2-naphthohydrazide ( S20 ) showed the highest antioxidant potential and N-(2-(2,6-dichlorophenyl)-4-oxothiazolidin-3-yl)-3-hydroxy-2-naphthamide ( S16 ) displayed the highest anti-inflammatory activity. The results of molecular docking studies revealed that existence of hydrogen bonding and hydrophobic interactions with their respective proteins. In silico ADMET studies were carried out by Molinspiration, Pre-ADMET and OSIRIS property explorer to predict the pharmacokinetic behaviour of synthesized 3-hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide derivatives.     

Synthesis of some imidazolyl-thioacetyl-pyrazolinone derivatives and their antinociceptive and anticancer activities

In this study, some 4-(1,5-diarylimidazol-2-yl)thioacetyl-1-phenyl-2,3-dimethyl-3-pyrazoline-5-one derivatives were prepared by reacting 4-(2-chloroacetyl)-1-phenyl-2,3-dimethyl-3-pyrazoline-5-one and 2-mercapto-1, 5-diarylimidazole derivatives. The antinociceptive and anticancer activities of the compounds obtained were investigated. It was observed that some of the compounds, 2a, 2d, 2g, and 2j, showed remarkable antinociceptive activity, and one of the compounds, 2i, showed weak anticancer activity.     

2-O-α-D-Glucopyranosyl-L-ascorbic Acid Scavenges 1,1-Diphenyl-2-picrylhydrazyl Radicals via a Covalent Adduct Formation

The 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging mechanism of 2-O-α-D-glucopyranosyl-L-ascorbic acid (AA-2G) was studied. We found two undefined products, named X and Y, in the reaction mixture of AA-2G and the DPPH radical under acidic conditions by HPLC analysis. The reaction mixture was further subjected to LC–MS analysis. X was found to be a covalent adduct of AA-2G and the DPPH radical. On the other hand, Y could not be identified, probably because it was a mixture. A time-course study of the radical-scavenging reaction revealed that one molecule of AA-2G scavenged one molecule of DPPH radical to generate an AA-2G radical, which readily reacted with another molecule of the DPPH radical to form a covalent adduct (X). Subsequently, this adduct slowly quenched a third molecule of the DPPH radical, resulting in reaction products (Y). Therefore, one molecule of AA-2G has only one oxidizable –OH group, but can scavenge three molecules of the DPPH radical. The radical-scavenging mechanism of AA-2G elucidated in this study should be useful in understanding the biological roles of AA-2G per se in the food and cosmetic fields.     

Two Compounds Inhibitory to Penicillinase-Producing Cells of Staphylococcus aureus

2-[4-(4,6-Diamino-1, 2-dihydro-2, 2-dimethyl-S-triazin-1-yl)phenyl]-4'-(fluorosulfonyl) acetanilide ethane sulfonate salt and 4-(p-tert-butylbenzoyl)-3-methyl-1-phenyl-2-pyrazolin-5-one cause a shift in growing populations of plasmid-bearing Staphylococcus aureus cells to a population of cells lacking the plasmid.     

Synthesis and evaluation of in vitro antiviral activity of 2-[3-(substituted phenyl)-4,5-dihydro-1H-5-pyrazolyl]benzofuran-3-yl chloride derivatives

3-Chlorobenzofuran-2-carbaldehyde was condensed with substituted acetophenone by using the Claisen-Schmidt condensation to obtain 3-(3-chlorobenzofuran-2-yl)-1-(substituted phenyl)-2-propen-1-one (2a-m) which upon further treatment with hydrazine hydrate gave 2-[3-(substituted phenyl)-4,5-dihydro-1H-5- pyrazolyl)benzofuran-3-yl chloride derivatives (3a-m). All the newly synthesized derivatives were evaluated in vitro for cytotoxicity and antiviral activity in Crandell-Rees Feline Kidney cell, human embryonic lung (HEL) cell, HeLa cell and Vero cell cultures against different viruses. Several compounds, i.e. 2f, 2g, 2i, 2m, 3b, 3d, 3g, 3h and 3m proved quite cytotoxic to the host cells (minimum cytotoxic concentration: 1-10 μg/mL). No specific antiviral activity [50% antivirally effective concentration (EC₅₀) ≥ 5-fold lower than the minimum cytototoxic concentration] was observed for any of the compounds.