Search Results (12)

A nitro-derivative of fenamic acid (4′–nitro–fenamic acid) was synthesized and used as ligand for the synthesis of four Co(II) complexes in the absence or presence of the N,N′-donors 2,2′–bipyridylamine, 1,10–phenanthroline and 2,9–dimethyl–1,10–phenanthroline. The characterization of the resultant complexes was performed with diverse techniques (elemental analysis, molar conductivity measurements, IR and UV-vis spectroscopy, single-crystal X-ray crystallography). The biological evaluation of the compounds encompassed (i) antioxidant activity via hydrogen peroxide (H₂O₂) reduction and free radical scavenging; (ii) antimicrobial screening against two Gram-positive and two Gram-negative bacterial strains; (iii) interactions with calf-thymus (CT) DNA; (iv) cleavage of supercoiled pBR322 plasmid DNA (pDNA), in the dark or under UVA/UVB/visible light irradiation; and (v) binding affinity towards bovine and human serum albumins. The antioxidant activity of the compounds against 2,2′–azinobis–(3–ethylbenzothiazoline–6–sulfonic acid) radicals and H₂O₂ is significant, especially in the case of H₂O₂. The complexes exhibit adequate antimicrobial activity against the strains tested. The complexes interact with CT DNA through intercalation with binding constants reaching a magnitude of 10⁶ M⁻¹. The compounds have a significantly enhanced pDNA-cleavage ability under irradiation, showing promising potential as photodynamic therapeutic agents. All compounds can bind tightly and reversibly to both albumins tested. Full article

The present work analyzes the ¹H NOESY MAS NMR spectra of three fenamates (mefenamic, tolfenamic, and flufenamic acids) localized in the lipid–water interface of phosphatidyloleoylphosphatidylcholine (POPC) membranes. The observed cross-peaks in the two-dimensional NMR spectra characterized intramolecular proximities between the hydrogen atoms of the fenamates as well as intermolecular interactions between the fenamates and POPC molecules. The peak amplitude normalization for an improved cross-relaxation (PANIC) approach, the isolated spin-pair approximation (ISPA) model, and the two-position exchange model were used to calculate the interproton distances indicative of specific conformations of the fenamates. The results showed that the proportions of the A+C and B+D conformer groups of mefenamic and tolfenamic acids in the presence of POPC were comparable within the experimental error and amounted to 47.8%/52.2% and 47.7%/52.3%, respectively. In contrast, these proportions for the flufenamic acid conformers differed and amounted to 56.6%/43.4%. This allowed us to conclude that when they bind to the POPC model lipid membrane, fenamate molecules change their conformational equilibria. Full article

Herein, we discuss the synthesis, structural and spectroscopic characterization, and biological activity of five heteroligand copper(II) complexes with diethylnicotinamide and various fenamates, as follows: flufenamate (fluf), niflumate (nifl), tolfenamate (tolf), clonixinate (clon), mefenamate (mef) and N, N-diethylnicotinamide (dena). The complexes of composition: [Cu(fluf)₂(dena)₂(H₂O)₂] (1), [Cu(nifl)₂(dena)₂] (2), [Cu(tolf)₂(dena)₂(H₂O)₂] (3), [Cu(clon)₂(dena)₂] (4) and [Cu(mef)₂(dena)₂(H₂O)₂] (5), were synthesized, structurally (single-crystal X-ray diffraction) and spectroscopically characterized (IR, EA, UV-Vis and EPR). The studied complexes are monomeric, forming a distorted tetragonal bipyramidal stereochemistry around the central copper ion. The crystal structures of all five complexes were determined and refined with an aspheric model using the Hirshfeld atom refinement method. Hirshfeld surface analysis and fingerprint plots were used to investigate the intermolecular interactions in the crystalline state. The redox properties of the complexes were studied and evaluated via cyclic voltammetry. The complexes exhibited good superoxide scavenging activity as determined by an NBT assay along with a copper-based redox-cycling mechanism, resulting in the formation of ROS, which, in turn, predisposed the studied complexes for their anticancer activity. The ability of complexes 1–4 to interact with calf thymus DNA was investigated using absorption titrations, viscosity measurements and an ethidium-bromide-displacement-fluorescence-based method, suggesting mainly the intercalative binding of the complexes to DNA. The affinity of complexes 1–4 for bovine serum albumin was determined via fluorescence emission spectroscopy and was quantitatively characterized with the corresponding binding constants. The cytotoxic properties of complexes 1–4 were studied using the cancer cell lines A549, MCF-7 and U-118MG, as well as healthy MRC-5 cells. Complex 4 exhibited moderate anticancer activity on the MCF-7 cancer cells with IC₅₀ = 57 μM. Full article

The search for new forms of already known drug compounds is an urgent problem of high relevance as more potent drugs with fewer side effects are needed. The trifluoromethyl group in flufenamic acid renders its chemical structure differently from other fenamates. This modification is responsible for a large number of conformational polymorphs. Therefore, flufenamic acid is a promising structural modification of well-known drug molecules. An effective approach in this field is micronization, employing “green” supercritical fluid technologies. This research raises some key questions to be answered on how to control polymorphic forms during the micronization of drug compounds. The results presented in this work demonstrate the ability of two-dimensional nuclear Overhauser effect spectroscopy to determine conformational preferences of small molecular weight drug compounds in solutions and fluids, which can be used to predict the polymorphic form during the micronization. Quantitative analysis was carried out to identify the conformational preferences of flufenamic acid molecules in dimethyl sulfoxide-d6 medium at 25 °C and 0.1 MPa, and in mixed solvent medium containing supercritical carbon dioxide at 45 °C and 9 MPa. The data presented allows predictions of the flufenamic acid conformational preferences of poorly soluble drug compounds to obtain new micronized forms. Full article

Mefenamic acid has been used as a non-steroidal anti-inflammatory drug for a long time. However, its practical use is quite limited due to a number of side effects on the intestinal organs. Conformational polymorphism provides mefenamic acid with unique properties regarding possible modifications obtained during the micronization process, which can improve pharmacokinetics and minimize side effects. Micronization can be performed by decompression of supercritical fluids; methods such as rapid expansion of the supercritical solution have proven their efficiency. However, this group of methods is poorly applicable for compounds with low solubility, and the modification of the method using a pharmaceutically suitable co-solvent may be useful. In our case, addition of only 2 mol% dimethyl sulfoxide increased the solubility remarkably. Information on the conformational state may be critically important for carrying out micronization. In this work, structural analysis and estimate of conformational preferences of mefenamic acid in dimethyl sulfoxide-d₆ (at 25 °C and 0.1 MPa) and in a mixed solvent supercritical carbon dioxide + dimethyl sulfoxide-d₆ (45 °C, 9 MPa) were performed based on nuclear Overhauser effect spectroscopy. Results show changes in the conformation fractions depending on the medium used. The importance of allowing for hidden conformers in estimating the conformational state was demonstrated in the analysis. Obtained results may be useful for improving micronization parameters. Full article

In order to improve pharmaceutical properties of drugs, complexes are synthesized as combinations with other chemical substances. The complexes of fenamic acid and its derivatives, such as mefenamic-, tolfenamic- and flufenamic acid, with acridine were obtained and the X-ray structures were discussed. Formation of the crystals is determined by the presence of the intermolecular O–H^…N hydrogen bond that occur between fenamic acids and acridine. Intermolecular interactions stabilizing the crystals such as π^…π stacking, C–H^…X (X = O, Cl) intermolecular hydrogen bonds as well as C–H^…π and other dispersive interactions were analyzed by theoretical methods: the quantum theory of atoms in molecules (QTAIM) and noncovalent interaction (NCI) approaches. Full article

Neurodegenerative disorders are desperately lacking treatment options. It is imperative that drug repurposing be considered in the fight against neurodegenerative diseases. Fenamates have been studied for efficacy in treating several neurodegenerative diseases. The purpose of this review is to comprehensively present the past and current research on fenamates in the context of neurodegenerative diseases with a special emphasis on tolfenamic acid and Alzheimer’s disease. Furthermore, this review discusses the major molecular pathways modulated by fenamates. Full article

In epilepsy research, emphasis is put on exploring non-neuronal targets such as astrocytic proteins, since many patients remain pharmacoresistant to current treatments, which almost all target neuronal mechanisms. This paper reviews available data on astrocytic connexin43 (Cx43) signaling in seizures and epilepsy. Cx43 is a widely expressed transmembrane protein and the constituent of gap junctions (GJs) and hemichannels (HCs), allowing intercellular and extracellular communication, respectively. A plethora of research papers show altered Cx43 mRNA levels, protein expression, phosphorylation state, distribution and/or functional coupling in human epileptic tissue and experimental models. Human Cx43 mutations are linked to seizures as well, as 30% of patients with oculodentodigital dysplasia (ODDD), a rare genetic condition caused by mutations in the GJA1 gene coding for Cx43 protein, exhibit neurological symptoms including seizures. Cx30/Cx43 double knock-out mice show increased susceptibility to evoked epileptiform events in brain slices due to impaired GJ-mediated redistribution of K⁺ and glutamate and display a higher frequency of spontaneous generalized chronic seizures in an epilepsy model. Contradictory, Cx30/Cx43 GJs can traffic nutrients to high-energy demanding neurons and initiate astrocytic Ca²⁺ waves and hyper synchronization, thereby supporting proconvulsant effects. The general connexin channel blocker carbenoxolone and blockers from the fenamate family diminish epileptiform activity in vitro and improve seizure outcome in vivo. In addition, interventions with more selective peptide inhibitors of HCs display anticonvulsant actions. To conclude, further studies aiming to disentangle distinct roles of HCs and GJs are necessary and tools specifically targeting Cx43 HCs may facilitate the search for novel epilepsy treatments. Full article

Flufenamic acid (FFA) is a problem drug that has up to eight different polymorphs and shows poor solubility. Variability in bioavailability has been reported in the past resulting in limited use of FFA in the oral solid dosage form. The goal of this article was to investigate the polymorphism and amorphization behavior of FFA in non-heated and heated mixtures with high surface area nanocellulose, i.e., Cladophora cellulose (CLAD). As a benchmark, low surface area microcrystalline cellulose (MCC) was used. The solid-state properties of mixtures were characterized with X-ray diffraction, Fourier-transform infrared spectroscopy, and differential scanning calorimetry. The dissolution behavior of mixtures was studied in three biorelevant media, i.e., fasted state simulated gastric fluid, fasted state simulated intestinal fluid, and fed state simulated intestinal fluid. Additional thermal analysis and dissolution tests were carried out following 4 months of storage at 75% RH and room temperature. Heated mixtures of FFA with CLAD resulted in complete amorphization of the drug, whereas that with MCC produced a mixture of up to four different polymorphs. The amorphous FFA mixture with CLAD exhibited rapid and invariable fasted/fed state dissolution in simulated intestinal fluids, whereas that of MCC mixtures was highly dependent on the biorelevant medium. The storage of the heated FFA-CLAD mixture did not result in recrystallization or changes in dissolution profile, whereas heated FFA-MCC mixture showed polymorphic changes. The straightforward dry powder formulation strategy presented here bears great promise for reformulating a number of problem drugs to enhance their dissolution properties and reduce the fasted/fed state variability. Full article

Recently, flufenamic acid (FFA) was discovered among fenamates as a free radical scavenger and gap junction blocker; however, its effects have only been studied in cancer cells. Normal cells in the surroundings of a tumor also respond to radiation, although they are not hit by it directly. This phenomenon is known as the bystander effect, where response molecules pass from tumor cells to normal ones, through communication channels called gap junctions. The use of the enhanced permeability and retention effect, through which drug-loaded nanoparticles smaller than 200 nm may accumulate around a tumor, can prevent the local side effect upon controlled release of the drug. The present work, aimed at functionalizing MCM-41 (Mobil Composition of Matter No. 41) silica nanoparticles with FFA and determining its biocompatibility with human fibroblasts MRC-5 (Medical Research Council cell strain 5). MCM-41, was synthesized and characterized structurally and chemically, with multiple techniques. The biocompatibility assay was performed by Live/Dead technique, with calcein and propidium–iodide. MRC-5 cells were treated with FFA-grafted MCM-41 for 48 h, and 98% of cells remained viable, without signs of necrosis or morphological changes. The results show the feasibility of MCM-41 functionalization with FFA, and its potential protection of normal cells, in comparison to the role of FFA in cancerous ones. Full article

A facile and efficient method for synthesis of fenamic acid hydrazides from their acids in one-step reaction under microwave irradiation and solvent-free conditions was developed. Compared with the two-step conventional heating method, the process was simple, the reaction time was very short and the yields were almost quantitative. Full article

A series of fenamate pyridyl or quinolinyl analogues of 1,3,4-oxadiazol-2-ones 5a-d and 6a-r, and 1,3,4-oxadiazole-2-thiones 5e-g and 6s-v, respectively, have been synthesized and evaluated for their analgesic (hot-plate) , antiinflammatory (carrageenin induced rat's paw edema) and ulcerogenic effects as well as plasma prostaglandin E2 (PGE2) level. The highest analgesic activity was achieved with compound 5a (0.5 ,0.6 ,0.7 mrnolkg b.wt.) in respect with mefenamic acid (0.4 mmollkg b.wt.). Compounds 6h, 6l and 5g showed 93, 88 and 84% inhibition, respectively on the carrageenan-induced rat's paw edema at dose level of 0.1rnrnol/kg b.wt, compared with 58% inhibition of mefenamic acid (0.2mmoll kg b.wt.). Moreover, the highest inhibitory activity on plasma PGE2 level was displayed also with 6h, 6l and 5g (71, 70,68.5% respectively, 0.lmmolkg b.wt.) compared with indomethacin (60%, 0.01 mmolkg b.wt.) as a reference drug. In addition 6i, 6k, 6p, 6r, 6t and 6v were devoid of any ulcerogenicity. Full article