- One drop chemical derivatization - DESI-MS analysis for metabolite structure identification
-
Structural elucidation of metabolites is an important part during the discovery and development process of new pharmaceutical drugs. Liquid Chromatography (LC) in combination with Mass Spectrometry (MS) is usually the technique of choice for structural identification but cannot always provide precise structural identification of the studied metabolite (e.g. site of hydroxylation and site of glucuronidation). In order to identify those metabolites, different approaches are used combined with MS data including nuclear magnetic resonance, hydrogen/deuterium exchange and chemical derivatization followed by LC-MS. Those techniques are often time-consuming and/or require extra sample pre-treatment. In this paper, a fast and easy to set up tool using desorption electrospray ionization-MS for metabolite identification is presented. In the developed method, analytes in solution are simply dried on a glass plate with printed Teflon spots and then a single drop of derivatization mixture is added. Once the spot is dried, the derivatized compound is analyzed. Six classic chemical derivatizations were adjusted to work as a one drop reaction and applied on a list of compounds with relevant functional groups. Subsequently, two successive reactions on a single spot of amoxicillin were tested and the methodology described was successfully applied on an in vitro incubated alprazolam metabolite. All reactions and analyses were performed within an hour and gave useful structural information by derivatizing functional groups, making the method a time-saving and efficient tool for metabolite identification if used in addition or in some cases as an alternative to common methods.
- Lubin, Arnaud,Cabooter, Deirdre,Augustijns, Patrick,Cuyckens, Filip
-
-
Read Online
- Photodegradation and in vitro phototoxicity of aceclofenac
-
Aceclofenac (Airtal) (1) is a photoallergy and phototoxic anti-inflammatory and analgesic agent. This drug is photolabile under aerobic and anaerobic conditions. Irradiation of an ethanol-solution of aceclofenac under oxygen or argon at 290-320 nm affords
- Vargas, Franklin,Rivas,Zoltan,Fuentes,Padron,Diaz,Izzo
-
-
Read Online
- Synthetic Strategies for the Modification of Diclofenac
-
For many heterogeneous sensor applications as well as the synthesis of hapten antigens to produce antibodies, protein conjugates of the target substance are essential. A requirement is that the target substance already offers or is modified to contain a functionality that allows for coupling to a protein, that is, an amino acid residue. Ideally, to avoid shielding of the compound by the carrier protein, a sufficient distance to the protein surface should be provided. With its carboxyl function diclofenac (DCF) allows for direct binding to lysine residues after in situ synthesis of the NHS ester. One problem is that diclofenac as free acid tends to autocondensation, which results in low yields. Here we describe the 'insertion' of a C6 spacer via synthesis of the amide with 6-aminohexanoic acid. To carry out the reaction in solution, first the methyl ester of the amino acid had to be produced. Due to otherwise low yields and large cleaning efforts, solid-phase synthesis on Fmoc Ahx Wang resin is recommended. The crude product is mainly contaminated by cleavage products from the resin which were removed by chromatography. The structure of the highly pure hapten was completely determined by nuclear magnetic resonance (NMR) spectroscopy.
- Schmidt, Stephan,Hanelt, Sven,Canitz, Carsten,Hoffmann, Holger,Garbe, Leif-Alexander,Schneider, Rudolf J.
-
-
Read Online
- Diclofenac n-derivatives as therapeutic agents with anti-inflammatory and anti-cancer effect
-
A series of diclofenac N-derivatives (2, 4, 6, 8c, 9c, 10a-c) were synthesized in order to test their anti-cancer and anti-inflammatory effects. The anticarcinogen activity has been assayed against three cancer cell lines: HT29, human colon cancer cells; Hep-G2, human hepatic cells; and B16-F10, murine melanoma cells. First, we determined the cytotoxicity of the different compounds, finding that the most effective compound was compound 8c against all cell lines and both compounds 4 and 6 in human Hep-G2 and HT29 cell lines. Compounds 4 and 8c were selected for the percentage of apoptosis determination, cell cycle distribution, and mitochondrial membrane potential measure because these products presented the lowest IC50 values in two of the three cancer cell lines assayed (B16-F10 and HepG2), and were two of the three products with lowest IC50 in HT29 cell line. Moreover, the percentages of apoptosis induction were determined for compounds 4 and 8c, showing that the highest values were between 30 to 60%. Next, the effects of these two compounds were observed on the cellular cycle, resulting in an increase in the cell population in G2/M cell cycle phase after treatment with product 8c, whereas compound 4 increased the cells in phase G0/G1, by possible differentiation process induction. Finally, to determine the possible apoptosis mechanism triggered by these compounds, mitochondrial potential was evaluated, indicating the possible activation of extrinsic apoptotic mechanism. On the other hand, we studied the anti-inflammatory effects of these diclofenac (DCF) derivatives on lipopolysaccharide (LPS) activated RAW 264.7 macrophages-monocytes murine cells by inhibition of nitric oxide (NO) production. As a first step, we determined the cytotoxicity of the synthesized compounds, as well as DCF, against these cells. Then, sub-cytotoxic concentrations were used to determine NO release at different incubation times. The greatest anti-inflammatory effect was observed for products 2, 4, 8c, 10a, 10b, and 9c at 20 μg·mL?1 concentration after 48 h of treatment, with inhibition of produced NO between 60 to 75%, and a concentration that reduces to the 50% the production of NO (IC50 NO) between 2.5 to 25 times lower than that of DCF. In this work, we synthesized and determined for the first time the anti-cancer and anti-inflammatory potential of eight diclofenac N-derivatives. In agreement with the recent evidences suggesting that inflammation may contribute to all states of tumorigenesis, the development of these new derivatives capable of inducing apoptosis and anti-inflammatory effects at very low concentrations represent new effective therapeutic strategies against these diseases.
- Galisteo, Alberto,Jannus, Fatin,García-García, Amalia,Aheget, Houssam,Rojas, Sara,Lupia?ez, José A.,Rodríguez-Diéguez, Antonio,Reyes-Zurita, Fernando J.,Quílez Del Moral, José F.
-
-
- Cu(II) complexes of hydrazones–NSAID conjugates: synthesis, characterization and anticancer activity
-
The hydrazones of nonsteroidal anti-inflammatory drugs (NSAIDs) diclofenac and ibuprofen are synthesized with aldehydes of pyridine and imidazole and are characterized by 1H, 13C and mass spectroscopy. Cu(II) complexes of hydrazones constructed from these ligands possess square planar geometry for bidentate diclofenac-hydrazone and tridentate ibuprofen-hydrazone conjugates with [Cu(L)2] and [Cu(L)Cl] compositions, respectively. The observed irreversible Cu(II)/Cu(I) redox couple in the range of +0.20 to +0.61 V is due to the substantial distortion in the square-planar geometry. ESR studies indicate the appreciably covalent character within M–L bonding due to extensive delocalization of electron from d x2–-y2 orbital. The hydrazone–NSAID conjugates exhibit substantial cytotoxicity against A-549, HCT-116 and MDA-MB-231 cancer cell lines with ibuprofen-imidazole-hydrazone ligand possessing the lowest IC50 (2.26 μM) amongst the synthesized NSAID-conjugates. Interestingly, its Cu(II) complex also displays excellent anticancer activity against MDA-MB- 231 with IC50 value of 3.58 μM. Such a feature may be ascribed to the synergistic association of Cu(II)–NSAID–hydrazone linkage. Thus, conjugation of NSAID with hydrazone and its complexation with a bioactive metal ion may be regarded as a potential strategy for designing of non-platinum anticancer agents.
- Bandyopadhyay, Parbati,Basu, Soumya,Chikate, Rajeev,Chikate, Tanmayee,Kaur, Jatinder
-
p. 3186 - 3202
(2020/12/22)
-
- Synthesis of Novel Diclofenac Hydrazones: Molecular Docking, Anti-Inflammatory, Analgesic, and Ulcerogenic Activity
-
This study was aimed to design novel diclofenac hydrazones having anti-inflammatory and analgesic activity with gastric sparing effect. A new series of 2-[2-(2,6-dichloroanilino)phenyl]-N'-[(substituted phenyl) methylidene] acetohydrazide derivatives (1-14) were synthesized and evaluated for their anti-inflammatory, analgesic, and ulcerogenic activity. The compounds were identified and confirmed by elemental analysis and spectral data. During anti-inflammatory activity by carrageenan-induced paw edema method, compounds (2, 3, 7, 8, 11, and 13) were found to be most promising. Compounds 3, 8, and 13 have been found to have significant analgesic activity compared to the reference drug diclofenac in analgesic activity by both the hot plate method and acetic acid-induced writhing method. The compounds which presented highly significant anti-inflammatory and analgesic activity were further tested for their ulcerogenic activity. Compounds 3 and 8 showed maximum ulcerogenic reduction activities. Compound 8 was found to have LD50 of 168 mg/kg. Compound 8 with 3,5-dimethoxy-4-hydroxyphenyl substitution was found to be the most promising anti-inflammatory and analgesic agent with gastric sparing activity. Molecular docking of compounds was performed for COX-1/COX-2 binding site. Lead compound 8 showed better binding affinities of -9.4 kJ/mol with both COX-1 and COX-2 as compared to the standard drug, diclofenac with binding affinities of -6.6 kJ/mol and -8.1 kJ/mol for COX-1 and COX-2, respectively.
- Al-Dhfyan, Abdullah,Al-Omar, Mohamed A.,Al-Tuwajiri, Hanaa M.,Alsaif, Nawaf A.,Bhat, Mashooq A.,Naglah, Ahmed M.
-
-
- Synthetic method of diclofenac sodium
-
The invention relates to a synthetic method of diclofenac sodium, and a synthetic route thereof, in a compound A, X is Cl, Br or I, M is Me, Et or Pro, a catalyst used for the condensation reaction isCuI, CuBr, CuBR2 or CuF2, and a sugar ligand used for the reaction is D-glucosamine hydrochloride, glucose, chitosan, D-galactose and L- arabinose. The method for synthesizing diclofenac sodium according to the invention has a purity of more than 98% and a total yield of two steps of up to 90% or more. According to the synthetic method of the diclofenac sodium, the purity of the product is up tomore than 98%, the total yield of two steps is up to more than 90%, and the yield is high; and D-glucosamine hydrochloride is adopted to replace ligands such as 8-hydroxyquinoline and the like which are high in price and large in environmental pollution, the pollution to the environment is reduced while the production cost is reduced.
- -
-
Paragraph 0017-0026
(2019/04/26)
-
- Diclofenac 1,3,4-oxadiazole derivatives; biology-oriented drug synthesis (BIODS) in search of better non-steroidal, non-acid antiinflammatory agents
-
Background: Inflammation is defined as the response of immune system cells to damaged or injured tissues. The major symptoms of inflammation include increased blood flow, cellular influx, edema, elevated cellular metabolism, reactive oxygen species (ROS) nitric oxide (NO) and vasodilation. This normally protective mechanism against harmful agents when this normal mechanism becomes dysregulated that can cause serious illnesses including ulcerative colitis, Crohn’s disease, rheumatoid arthritis, osteoarthritis, sepsis, and chronic pulmonary inflammation. Method: In this study synthetic transformations on diclofenac were carried out in search of better non-steroidal antiinflammatory drugs (NSAIDs), non-acidic, antiinflammatory agents. For this purpose diclofenac derivatives (2-20) were synthesized from diclofenac (1). All derivatives (2-20) and parent diclofenac (1) were evaluated for their antiinflammatory effect using different parameters including suppression of intracellular reactive oxygen species (ROS), produced by whole blood phagocytes, produced by neutrophils, and inhibition of nitric oxide (NO) production from J774.2 macrophages. The most active compound also evaluated for cytotoxicity activity. Results: Diclofenac (1) inhibited the ROS with an IC of 3.9 ± 2.8, 1.2 ± 0.0 μg/mL respectively 50 and inhibited NO with an IC50 of 30.01 ± 0.01 μg/mL. Among its derivatives 4, 5, 11, 16, and 20, showed better antiinflammatory potential. The compound 5 was found to be the most potent inhibitor of intracellular ROS as well as NO with IC50 values of 1.9 ± 0.9, 1.7 ± 0.4 μg/mL respectively and 7.13 ± 1.0 μg/mL, respectively, and showed good inhibitory activity than parent diclofenac. The most active compounds were tested for their toxic effect on NIH-3T3 cells where all compounds were found to be non-toxic compared to the standard cytotoxic drug cyclohexamide. Conclusion: Five derivatives were found to be active. Compound 5 was found to be the most potent inhibitor of ROS and NO compared to parent diclofenac 1 and standard drugs ibuprofen and L-NMMA, respectively. The most active compounds 1, 4, 5, 11 and 20 were found to be non-toxic on NIH-3T3 cells. Compound 4, 5, and 20 also showed good antiinflammatory potential, compound 11 and 16 showed moderate and low level of inhibition, respectively.
- Shah, Shazia,Arshia,Kazmi, Nida Siraj,Jabeen, Almas,Khan, Khalid Mohammed,Raza, Abeer,Faheem, Aisha,Dastagir, Nida,Ahmed, Tariq,Ahmed, Shakil,Perveen, Shahnaz
-
p. 674 - 687
(2018/11/21)
-
- Diclofenac-Based Hydrazones and Spirothiazolidinones: Synthesis, Characterization, and Antimicrobial Properties
-
We report here the synthesis, structural characterization, and biological evaluation of novel diclofenac-based hydrazone (4a–f) and spirothiazolidinone (5a–f, 6a–f) derivatives designed as potential antimicrobial agents. The compounds were evaluated in vi
- Kocabalkanl?, Ay?e,Cihan-üstünda?, G?k?e,Naesens, Lieve,Matarac?-Kara, Emel,Nassozi, Mebble,?apan, Gültaze
-
-
- Synthesis, pharmacological screening and in silico studies of new class of Diclofenac analogues as a promising anti-inflammatory agents
-
A novel series of 5-[2-(2,6-dichlorophenylamino)benzyl]-3-(substituted)-1, 3,4-oxadiazol-2(3H)-thione (4a-k) derivatives have been synthesized by the Mannich reaction of 5-[2-(2,6-dichlorophenylamino)benzyl]-1,3,4-oxadiazol-2(3H)- thione (3) with an appropriately substituted primary/secondary amines, in the presence of formaldehyde and absolute ethanol. Structures of these novel compounds were characterized on the basis of physicochemical, spectral and elemental analysis. The title compounds (4a-k) were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 10 mg/kg b.w. Compound 4k exhibited the most promising and significant anti-inflammatory profile while compounds 4a, 4d, 4e, 4i, and 4j showed moderate to good inhibitory activity at 2nd and 4th h, respectively. These compounds were also found to have considerable analgesic activity (acetic acid induced writhing model) and antipyretic activity (yeast induced pyrexia model). In addition, the tested compounds were also found to possess less degree of ulcerogenic potential as compared to the standard NSAIDs. Compounds that displayed promising anti-inflammatory profile were further evaluated for their inhibitory activity against cyclooxygenase enzyme (COX-1/COX-2), by colorimetric COX (ovine) inhibitor screening assay method. The results revealed that the compounds 4a, 4e, 4g and 4k exhibited effective inhibition against COX-2. In an attempt to understand the ligand-protein interactions in terms of the binding affinity, docking studies were performed using Molegro Virtual Docker (MVD-2013, 6.0) for those compounds, which showed good anti-inflammatory activity. It was observed that the binding affinities calculated were in agreement with the IC 50 values.
- Palkar, Mahesh B.,Singhai, Anuj S.,Ronad, Pradeepkumar M.,Vishwanathswamy,Boreddy, Thippeswamy S.,Veerapur, Veeresh P.,Shaikh, Mahamadhanif S.,Rane, Rajesh A.,Karpoormath, Rajshekhar
-
p. 2855 - 2866
(2014/05/06)
-
- PHTHALIMIDE DERIVATIVES OF NON-STEROIDAL ANTI-INFLAMMATORY COMPOUNDS AND/OR TNF- MODULATORS, METHOD FOR PRODUCING SAME, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME AND USES THEREOF FOR THE TREATMENT OF INFLAMMATORY DISEASES
-
The present invention relates to phthalimide derivatives of non-steroidal and/or TNF-α modulating anti-inflammatory compounds as well as the process of obtaining the so-called derivatives, pharmaceutical compositions containing such derivatives and their uses, including use in the treatment of inflammatory diseases, especially those related to chronic inflammatory processes, such as rheumatoid arthritis and intestinal inflammatory diseases (for instance, Chron's disease) and the use of the referred to pharmaceutical compositions as antipyretic, analgesic and platelet antiaggregating medications.
- -
-
Page/Page column 34
(2012/03/08)
-
- PHTHALIMIDE DERIVATIVES OF NON-STEROIDAL ANTI-INFLAMMATORY COMPOUNDS AND/OR TNF-ALPHA MODULATORS, METHOD FOR PRODUCING SAME, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME AND USES THEREOF FOR THE TREATMENT OF INFLAMMATORY DISEASES
-
The present invention relates to phthalimide derivatives of non-steroidal and/or TNF-α modulating anti-inflammatory compounds as well as the process of obtaining the so-called derivatives, pharmaceutical compositions containing such derivatives and their uses, including use in the treatment of inflammatory diseases, especially those related to chronic inflammatory processes, such as rheumatoid arthritis and intestinal inflammatory diseases (for instance, Chron's disease) and the use of the referred to pharmaceutical compositions as antipyretic, analgesic and platelet antiaggregating medications.
- -
-
Page/Page column 46
(2012/05/20)
-
- Synthesis and evaluation of anti-inflammatory and analgesic activity of 3-[(5-substituted-1,3,4-oxadiazol-2-yl-thio)acetyl]-2H-chromen-2-ones
-
A novel series of 3-[(5-substituted-1,3,4-oxadiazol- 2-yl-thio)acetyl]-2H- chromen-2-one (7a-i) were synthesized by the condensation between the appropriately substituted 5-substituted-1,3,4-oxadiazolyl-2-thione (4a-i) derived from various existing NSAIDs and 3-(2-bromoacetyl)- 2H-chromen-2-one (6) under reflux in the presence of sodium ethoxide. Structure of the synthesized compounds was established on the basis of physicochemical, elemental analysis, and spectral data. The title compounds were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 200 mg/kg bw. Among the series, four compounds 7c, 7e, 7f, and 7h were found to possess a significant anti-inflammatory and analgesic activity profile. In addition, these compounds were also found to possess a less degree of ulcerogenic potential as compared to standard NSAIDs. Springer Science+Business Media, LLC 2010.
- Ingale, Nista,Maddi, Veeresh,Palkar, Mahesh,Ronad, Pradeepkumar,Mamledesai, Shivalingrao,Vishwanathswamy,Satyanarayana, Darbhamulla
-
experimental part
p. 16 - 36
(2012/06/04)
-
- Synthesis, in vitro and in vivo antimycobacterial activities of diclofenac acid hydrazones and amides
-
Various diclofenac acid hydrazones and amides were synthesized and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis. Preliminary results indicated that most of the compounds demonstrated better in vitro antimycobacterial activity (MIC: 0.0383-7.53 μM) than diclofenac (MIC: 21.10 μM) and ciprofloxacin (MIC: 9.41 μM). Among the synthesized compounds, 1-cyclopropyl-6-fluoro-8-methoxy- 7-[[N4-(2-(2-(2,6-dichlorophenylamino)phenyl)acetyl)-3-methyl]-N 1-piperazinyl]-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (5d) was found to be the most active compound in vitro with MIC of 0.0383 μM and was more potent than first line antitubercular drug isoniazid (MIC: 0.1822 μM). In the in vivo animal model 5d decreased the bacterial load in lung and spleen tissues with 2.42 - and 3.66 - log 10 protections, respectively, at 25 mg/kg body weight.
- Sriram, Dharmarajan,Yogeeswari, Perumal,Devakaram, Ruth Vandana
-
p. 3113 - 3118
(2007/10/03)
-
- A study on the interaction between p60c-Src receptor tyrosine kinase and arylcarboxylic and arylacetic acid derivatives based on docking modes and in vitro activity
-
The fundamental role that receptor tyrosine kinases play in cancer and other proliferative diseases has provided the impetus for an extensive effort on the part of both academic and pharmaceutical laboratories to develop highly specific inhibitors. In thi
- Altuntas, Tunca Gul,Olgen, Sureyya,Nebioglu, Dogu,Akaho, Eiichi
-
-
- Prodrugs and mutual prodrugs: Synthesis of some new pyrazolone and oxadiazole analogues of a few non-steroidal anti-inflammatory drugs
-
Naproxen, probenecid, diclofenac, ibuprofen and indomethacin were converted to hydrazide derivatives via their methyl ester by reacting with hydrazine hydrate, which were further condensed with β-keto esters to get the pyrazolone derivatives. The hydrazide derivatives of probenecid and diclofenac were also reacted with biphenyl acetic acid while naproxen hydrazide was reacted with p-chloro benzoic acid besides biphenyl acetic acid to synthesize their oxadiazole analogues. Some selected members of the compounds prepared were screened for their anti-inflammatory and analgesic activity.
- Sharma, Vibha,Khan
-
-
- Synthesis, structure, and activity of diclofenac analogues as transthyretin amyloid fibril formation inhibitors
-
Twelve analogues of diclofenac (1), a nonsteroidal antiinflammatory drug and known inhibitor of transthyretin (TTR) amyloid formation, were prepared and evaluated as TTR amyloid formation inhibitors. High activity was exhibited by five of the compounds. S
- Oza, Vibha B.,Smith, Craig,Raman, Prakash,Koepf, Edward K.,Lashuel, Hilal A.,Petrassi, H. Mike,Chiang, Kyle P.,Powers, Evan T.,Sachettinni, James,Kelly, Jeffery W.
-
p. 321 - 332
(2007/10/03)
-