Propionic Acid Derivatives Research Articles

80 : Novel multi-functional drugs for the treatment of neurodegenerative diseases

Oxidative stress (OS), glial activation and formation of plaques and tangles are believed to contribute to progressive neurodegeneration in Alzheimer’s disease (AD). None of the acetylcholinesterase (AChE) inhibitors currently in clinical use are able to reduce OS and inflammatory processes at doses used to treat AD. Therefore, there is a need for a drug which inhibits AChE and butyrylcholinesterase (BuChE), has anti-oxidant and anti-inflammatory activities. Indole propionic acid (IPA) prevents oxidative stress and death of primary neurons and neuroblastoma cells exposed to H2O2 or amyloid beta. Derivatives of indoline propionic acid (InPA) were found to be more potent anti-oxidants than those of IPA in cell culture. Therefore, a series of novel carbamates was synthesized based on the structure of InPA and their AChE, BuChE, anti-oxidant and anti-inflammatory activities were evaluated. Three compounds: Indoline-4-ylethyl methyl carbamate (AN-854), 3-(2-(methoxycarbonyl) ethyl) indolin-4-ylethyl methyl carbamate (AN-827) and 3-(2-(methoxycarbonyl) ethyl)-1-indoline-6-ylethyl methyl carbamate (AN-680) prevented cytotoxicity induced by OS and the release of cytokines from activated microglial cells at concentrations at, or lower than those inhibiting AChE. They inhibited AChE in rat brain and reduced lipid peroxidation and formation of nitrites in mouse brain after injection of lipopolysaccharide (LPS). When injected together with LPS they lowered the levels of COX-2 and pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) in the brain and spleen. The mechanism of anti-inflammatory activity was evaluated in BV2 cells activated with LPS and shown to occur through reduction in phosphorylation of p38 and activation of the transcription factor AP-1. Conclusion: Indoline derivatives which display anti-oxidant and anti-inflammatory and cholinesterase inhibitory activities in vitro and in vivo, may have potential use for the treatment of AD and other neurodegenerative diseases.

Electrochemical degradation of a chlorophenoxy propionic acid derivative used as an herbicide at boron-doped diamond

The electrochemical degradation of diclofop-methyl (DM), an herbicide deriving from aryloxy propionic acid, was carried out by galvanostatic electrolysis at boron-doped diamond electrode. The oxidation process leads in an early step to the cleavage of the aryloxy propionic ester bond and the formation of 4-(2,4-dichlorophenoxy) phenol (P1). The subsequent oxidation of P1 resulted in a quantitative mineralization of DM. Measuring the reduction in chemical oxygen demand and total organic carbon during the electrolysis shows that the mineralization efficiency increases with decreasing current densities. As a result, two mechanistic pathways were proposed for DM electrochemical degradation. The first one is a direct electro-oxidation of the starting molecule leading to the breakdown of aromatic ether bonds. A second evidenced competitive pathway uses electrogenerated hydroxyl radicals as mediators in the mineralization process of DM.

Fatal hypersensitivity reaction to an oral spray of flurbiprofen: a case report

Safety of the anti-inflammatory drug flurbiprofen is comparable with that of other non-steroidal anti-inflammatory drugs of the propionic acid class, which are commonly associated with gastrointestinal and renal side effects. Here we report a case of a fatal hypersensitivity reaction to an oral spray of flurbiprofen taken for sore throat. A 29-year-old man came to the emergency care unit reporting sore throat with an intense burning sensation associated with fever. Pharyngotonsillitis was diagnosed, and local treatment with oral flurbiprofen spray was prescribed. Immediately after using the spray, the patient experienced a severe reaction characterized by serious dyspnoea, followed by death. The cause of death was heart failure with acute asphyxia from oedema of the glottis. The cause of death was concluded to be hypersensitivity to flurbiprofen spray. Oral propionic acid derivatives have been associated with a relatively high frequency of allergic reactions. However, allergy to flurbiprofenhas rarely been documented. Scientific literature reports two relevant cases of hypersensitivity reaction to flurbiprofen: in one case, a patient presented with a maculopapular rash 48h after having taken oral flurbiprofen followed by angio-oedema and hypotension. In another case, a single oral dose of flurbiprofen caused itching and swelling around the eyes, redness and increased lacrimation. We describe, for the first time, a fatal case of hypersensitivity reaction to flurbiprofen oral spray. Hypersensitivity reactions to flurbiprofen are infrequent; however, health professionals should be aware of potential adverse reactions, even during topical administration as oral spray.

Non‐steroidal anti‐inflammatory drugs and venous thromboembolism in women

Non-steroidal anti-inflammatory drugs (NSAIDs) might increase the risk of venous thromboembolism (VTE), and risks might differ by type of NSAID. Compared with men, women have a higher incidence of VTE at younger age, and they more often use NSAIDs. To assess risks of VTE in young and middle-aged women in association with use of NSAIDs. In a nationwide case–control study (Thrombo Embolism Hormone Study) performed in Sweden 2003–2009, we included as cases 1433 women, 18 to 64 years of age with a first time VTE. Controls were 1402 randomly selected women, frequency matched by age. Information was obtained by telephone interviews and DNA analyses of blood samples. We calculated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) adjusting for degree of immobilization, chronic disease, smoking, body mass index, use of hormonal contraception, hormone therapy or other NSAIDs. Use of NSAIDs was not associated with increased risks of VTE (OR = 0.98, 95% CI 0.80–1.19). The OR was 0.88 for propionic acid derivatives (95% CI 0.72–1.10), 1.18 for acetic acid derivatives (95% CI 0.82–1.70) and 1.76 for coxibs (95% CI 0.73–4.27). For users of acetic acid derivatives and coxibs, the ORs increased by cumulative dose. Carriership of the prothrombin gene mutation or factor V Leiden had only minor effects on the results. We found no increased risks of VTE in association with use of NSAIDs. Users of high cumulative doses of acetic acid derivatives and coxibs had the highest risks, suggesting a relationship with cyclooxygenase selectivity and dose.

Exposure to phototoxic NSAIDs and quinolones is associated with an increased risk of melanoma

Ultraviolet radiation exposure is the most important exogenous risk factor for cutaneous malignancies. It is possible that phototoxic drugs promote the development of cutaneous melanoma (CM) by intensifying the effect of ultraviolet light on the skin. We investigated the association between the use of common systemic phototoxic drugs and development of CM. This study was a case-control study in a Dutch population-based cohort. The drug dispensing data was obtained from PHARMO, a Dutch drug dispensing and hospital admissions registry, and linked to PALGA, the nationwide pathology network of the Netherlands. The cases were patients diagnosed with pathologically confirmed primary CM between 1991 and 2004. Controls were sampled from the PHARMO population. Exposure to systemic phototoxic drugs was measured and included antimicrobial agents, diuretics, antipsychotic drugs, antidiabetic drugs, cardiac drugs, antimalarials and nonsteroidal anti-inflammatory drugs (NSAIDs). A multivariate conditional logistic regression analysis was performed to study the association between exposure to phototoxic drugs and CM. The study population included 1,318 cases and 6,786 controls. Any phototoxic drug during the study period was dispensed for 46 % of the cases and 43 % of the controls (p = 0.012). The use of quinolones [odds ratio (OR) 1.33, 95 % confidence interval (CI) 1.01-1.76] and propionic acid derivative NSAIDs (OR 1.33, 95 % CI 1.14-1.54) had a positive association with CM. Our study shows that the use of phototoxic drugs is associated with an increased risk of developing CM. Even a short-term use of phototoxic quinolones and propionic acid derivative NSAIDs may increase the risk for CM. Patient education to promote sun-protective behaviour is essential to avoid immediate adverse effects and possible long-term effects of phototoxic drugs.

Apparent Solubility of Ibuprofen in Dimethyl Dodecyl Ammonium-Propane Sulfonate, DDAPS, Micelles, DDAPS/Butanol Mixtures and in Oil-in-Water Microemulsions Stabilized by DDAPS

Solubility of drugs in aqueous media is a real issue for scientists and a lot of work is going on to resolve the issue. The same is the case for ibuprofen, which is a derivative of propionic acid, belongs to the NSAIDs family and has low solubility in pure water. Therefore, its solubility has been investigated in dimethyl dodecyl ammonium-propane sulfonate, DDAPS, micellar solution, DDAPS/butanol mixtures and in various (hexane, decane and tetradecane) oil-in-water microemulsions to find out a suitable vehicle. The aggregation number, size and flow ability of micelles and microemulsions were estimated using refractive index, viscosity and light scattering measurements. It has been observed that these microemulsions have a higher ability to solubilize ibuprofen than DDAPS/butanol mixtures or DDAPS micelles.

GRP-083 Hospital Pharmacists Can Improve Pharmacovigilance in the Emergency Room

BackgroundHospital pharmacists can play an important role in reporting adverse drug reaction (ADRs). Several publications underscore the fact that adverse drug events account for a substantial percentage of all hospital...

Determination of Drug-Polymer Binding Constants by Affinity Capillary Electrophoresis for Aryl Propionic Acid Derivatives and Related Compounds

The binding constants (K(b)s) of 17 aryl propionic acid derivatives (APADs) and related compounds with polyvinylpyrrolidone (PVP K30) and vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64) in aqueous media were determined by affinity capillary electrophoreses (ACE). The K(b)s of APAD to polymers increase with octanol-water partition coefficients of the compounds. Kollidon VA64 is a stronger binder than PVP K30 to APAD compounds. The K(b)s are greater at pH 4 than at pH 9. Both hydrophobic interaction and hydrogen bonding may be involved. However, hydrophobic interaction appears to be dominant. The ACE method is simple and fast, which could be used to study drug-polymer interaction in aqueous media.

Polyoxalate 및 PLGA 미립구의 혼합 비율별에 따른 Zaltoprofen의 방출거동

잘토프로펜은 프로피온산 유도체인 비스테로이드성 소염진통제로서 카라기난, 나이스타틴에서 유발된 급성염증에 큰 억제 효과를 가지고 있을 뿐만 아니라 급성 및 만성 염증에도 효과를 가지고 있다. 초기 방출 및 지속적인 방출을 위해서 잘토프로펜이 함유된 폴리옥살레이트(POX)와 PLGA 미립구를 각각 O/W 용매증발법으로 제조 후 각각의 미립구의 혼합비율을 달리하였다. 주사현미경, X선 회절 분석법, 시차 주사 열량계, 그리고 적외선 분광 분석기를 이용하여 잘토프로펜이 함유된 미립구의 물리화학적 성질 및 표면형태를 조사하였다. POX 미립구의 혼합비율이 증가할수록 초기 약물방출이 증가하며, PLGA 미립구의 혼합비율이 증가할수록 느린 약물방출을 보인다. 본 연구에서 초기 약물방출량이 높은 POX 미립구를 PLGA 미립구와 혼합비율을 조절함으로써 약물이 함유된 미립구의 초기방출 계수를 제어할 수 있을 것으로 사료된다. Zaltoprofen, a propionic acid derivative non-steroidal anti-inflammatory drug, was known to have powerful inhibitory effects on acute, subacute and chronic inflammation. For initial release and sustained release, the microspheres were prepared using an emulsion-solvent evaporation method like an O/W emulsion method with varying the ratio of zaltoprofen-loaded polyoxalate (POX)/PLGA micropheres. The morphology of the microspheres was confirmed by scanning electron microscopy. The crystallinity of microspheres was analyzed by X-ray diffraction and differential scanning calorimeter. Fourier transform infrared spectroscopy was used to analyze the chemical structure of microspheres. The increased ratio of POX microspheres affected the initial drug release, and the sustained release of drug was influenced by ratio of PLGA microspheres. In this study, the initial release behavior of zaltoprofen can be controlled by the ratio of POX/PLGA microspheres.

Synthesis, antimicrobial evaluation and QSAR studies of propionic acid derivatives

A series of Schiff bases (1–17) and esters (18–24) of propionic acid was synthesized in appreciable yield and characterized by physicochemical as well as spectral means. The synthesized compounds were evaluated in vitro for their antimicrobial activity against Gram-positive bacteria Staphylococcus aureus, Bacillus subtilis, Gram negative bacterium Escherichia coli and fungal strains Candida albicans and Aspergillus niger by tube dilution method. Results of antimicrobial screening indicated that besides having good antibacterial activity, the synthesized compounds also displayed appreciable antifungal activity and compound 10 emerged as the most active antifungal agent (pMICca and pMICan=1.93). The results of QSAR studies demonstrated that antibacterial, antifungal and overall antimicrobial activities of synthesized propionic acid derivatives were governed by the topological parameters, Kier’s alpha first order shape index (κα1) and valence first order molecular connectivity index (1χv).

ChemInform Abstract: Enantioselective Iridium‐Catalyzed Hydrogenation of α‐Arylcinnamic Acids and Synthesis of (S)‐Equol.

AbstractThe use of indium catalyst (I) mostly allows the hydrogenation of α‐arylcinnamic acids under ambient pressure and low loading to afford propionic acid derivatives with excellent enantioselectivities.

Naproxen: An Update on Physicochemical, Analytical and Pharmacological Aspects

Naproxen is a propionic acid derivative related to the arylacetic acid group. This drug is one of the most popular non-steroidal anti-inflammatory agents. It is a non-selective cyclooxygenase inhibitor and is advocated for use in painful and inflammatory rheumatic and non-rheumatic conditions. In low risk patients, naproxen and ibuprofen may be the first choice agents because they are effective, well tolerated and inexpensive. Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95% and elimination half-life is 12 to 17 h. It has a volume of distribution of 0.16 L/Kg and at therapeutic levels, it is more than 99% albumin-bound. Although introduced long back, several efforts have been done to develop its prodrugs and analytical procedures. The current article describes chemistry, pharmacology, pharmacokinetics, adverse effects, interactions and contraindications of naproxen. A special emphasis is laid on the review of recent literature of various prodrugs synthesized and analytical methods developed for determination of naproxen in pharmaceutical preparations.

Comparison of separation performances of novel β-cyclodextrin-based chiral stationary phases in high-performance liquid chromatographic enantioseparation

Three β-cyclodextrin-based chiral stationary phases were developed applying novel bonding chemistry. The separation performances of β-cyclodextrin, (R,S)-2-hydroxypropyl-β-cyclodextrin, and permethyl-β-cyclodextrin-based CSPs were compared in the resolution of structurally divergent analytes, such as coumarins, dansyl amino acids, and propionic acid derivatives. Separations were carried out in reversed phase mode applying 0.1% triethylammonium phosphate (pH 3.5)/MeOH mobile phase systems in different compositions. Of the three novel CSPs the permethyl-β-cyclodextrin bonded phase proved to be the most effective one for the enantioseparation of investigated analytes.

A pharmacovigilance project in ‘San Giovanni di Dio e Ruggi d’Aragona’ – Salerno University Hospital (Italy): hospital pharmacist in department increases pharmacovigilance activity

Background‘MEREAFaPS Project’ is a pharmacovigilance project started in Italy in 2006 with the aim of introduce pharmacists in Emergency Division to collect data on adverse drug reactions (ADR) admissions. In...

Melanoma diagnosed 27 years after a benoxaprofen-induced photosensitivity reaction

The propionic acid derivative Benoxaprofen was introduced for the treatment of rheumatic disorders in 1980. Its product license was then withdrawn 2 years later due to concerns over serious dermatologic, hepatic and renal side effects. Photosensitivity was the most common side effect with reported incidence of up to 50%. We present the first case report of a patient who presented with a melanoma diagnosed 27 years after a benoxaprofen-induced photosensitivity reaction. With an estimated 1.5 million patients previously on benoxaprofen, a large number of patients may potentially face increased risk of developing malignant melanoma. This case report can only suggest an association between solar injury secondary to benoxaprofen-related photosensitivity and subsequent melanoma. However the primary factor that improves survival from melanoma is early diagnosis, and so clinicians treating this group of patients should be aware of this risk. Although benoxaprofen is no longer in clinical use, the long-term sequelae to its photosensitizing effects may still be clinically important. Clinicians treating this group of patients should be vigilant, and consider a low threshold for diagnostic biopsy of suspicious skin lesions.

Direct Synthesis of Aqueous Quantum Dots through 4,4′-Bipyridine-Based Twin Ligand Strategy

We report a new class of derivatized 4,4'-bipyridinium ligands for use in synthesizing highly fluorescent, extremely stable, water-soluble CdSe and CdTe quantum dots (QDs) for bioconjugation. We employed an evaporation-condensation technique, also known as solvated metal atom dispersion (SMAD), followed by a digestive ripening procedure. This method has been used to synthesize both metal nanoparticles and semiconductors in the gram scale with several stabilizing ligands in various solvents. The SMAD technique comprised evaporation condensation and stabilization of CdSe or CdTe in tetrahydrofuran. The as-prepared product was then digestively ripened in both water and dimethyl formamide, leading to narrowing of the particle size distributions. The ligands were synthesized by nucleophilic substitution (S(N)2) reactions using 4,4'-bipyridine as a nucleophile. Confocal microscopy images revealed the orange color of the nanocrystalline QDs with diameters of ~5 nm. The size has been confirmed by using transmission electron microscopy. As a part of our strategy, 85% of the 4,4'-bipyridinium salt was synthesized as propionic acid derivative and used to both stabilize the QDs in water and label basic amino acids and different biomarkers utilizing the carboxylic acid functional group. Fifteen percent of the 4,4'-bipyridinium salt was synthesized as N-propyl maleimide and used as a second ligand to label any protein containing the amino acid cysteine by means of a 1,4-Michael addition.

Synthesis, Antimicrobial, and Anti-inflammatory Activities of Novel 2-[3-(1-Adamantyl)-4-substituted-5-thioxo-1,2,4-triazolin-1-yl]acetic Acids, 2-[3-(1-Adamantyl)-4-substituted-5-thioxo-1,2,4-triazolin-1-yl]propionic Acids and Related Derivatives

The reaction of 3-(1-adamantyl)-4-substituted-1,2,4-triazoline-5-thiones 3a-g with sodium chloroacetate, in ethanolic sodium hydroxide yielded the corresponding N1-acetic acid derivatives 4a-g. The interaction of 3a-g with ethyl 2-bromopropionate in acetone, in the presence of potassium carbonate, yielded the corresponding N1-ethyl propionate derivatives 5a-g, which upon hydrolysis with aqueous sodium hydroxide afforded the corresponding propionic acid derivatives 6a-g. Similarly, the reaction of 3-(1-adamantyl)-4-amino-1,2,4-triazoline-5-thione 7 with sodium chloroacetate in ethanolic sodium hydroxide yielded the corresponding N1-acetic acid derivative 8. On the other hand, the reaction of 2-(1-adamantyl)-1,3,4-oxadiazoline-5-thione 9 with sodium chloroacetate yielded the corresponding S-acetic acid derivative 10. Compounds 4a-g, 5b, 5c, 5g, 6a-g, 8 and 10 were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Several derivatives produced good or moderate activities particularly against Bacillus subtilis. In addition, the in vivo anti-inflammatory activities of these compounds were determined using the carrageenin-induced paw oedema method in rats. Compounds 4a, 4b, 4e, 4f, 6f, 6g and 10 produced good dose-dependent anti-inflammatory activities.

Studies on pyrrolidinones. Synthesis of 4,5-fused-3-hydroxypyridinyl-2-propionic acid derivatives

The synthesis of some condensed indolizinediones derived from pyroglutamic acid is described. Treatment of these ketones in HCl, HBr or MeONa/MeOH furnished aryl propionic acid derivatives. During the ketone transformations, two sequential processes could take place in competitive manner to provide heterocyclic systems bearing carboxylic acid or hydroxycarboxylic acid function. Easy synthesis of amides indicates that potential DNA-intercalating heterocyclic systems fused on γ-carboline and isoquinoline nucleus could be obtained from these series.

Naproxen-induced liver injury

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to induce liver injury. Patterns of the injury usually range from mild elevations of liver enzymes to sometimes severe fulminant hepatic failure. Likewise, naproxen is a propionic acid derivative NSAID that was introduced in 1980 and has been available as an over-the-counter medication since 1994, but has rarely been reported to cause liver injury. We treated a 30-year-old woman with jaundice and intractable pruritus that developed shortly after taking naproxen. We reviewed the medical history and liver histopathology of the patient as well as all previously published case reports of naproxen-associated liver toxicity in the English language literature. The liver biochemical profile of the patient revealed a mixed cholestasis and hepatitis pattern. Consecutive liver biopsies demonstrated focal lobular inflammation, hepatocyte drop-out, and a progressive loss of the small interlobular bile ducts (ductopenia). The biopsy performed two years after onset of the disease showed partial recovery of a small number of bile ducts; however, 10 years passed before the biochemical profile returned to near normal. Naproxen-associated liver toxicity remains a rare entity, but should be considered in any patient presenting with cholestasis shortly after its use. Liver injury is most commonly seen in a mixed pattern characterized by cholestasis and hepatitis. The resulting liver damage may take years to resolve.

Characterizing the effect of UDP-glucuronosyltransferase (UGT) 2B7 and UGT1A9 genetic polymorphisms on enantioselective glucuronidation of flurbiprofen

Flurbiprofen (FPF), available commercially as a racemic mixture, is a propionic acid derivative of non-steroidal anti-inflammatory drugs (NSAIDs) with known stereoselective glucuronidation. The major enzyme catalyzing this conjugation reaction is UDP-glucuronosyltransferase (UGT) 2B7, with minor contributions by UGT1A9. This study examines the role of the genetic variants of UGT2B7 and 1A9 enzymes involved in the formation of acyl glucuronides (FPFGs). Variants caused by three single nucleotide polymorphisms (SNPs) (A71S, 211G>T; H268Y, 802C>T; and D398N, 1192G>A) in UGT2B7 and three SNPs (C3Y, 8G>A; M33T, 98T>C; D256N, 766G>A) in UGT1A9 showed activity changes toward different substrates. However the functional impacts of these SNPs on chiral substrates were not examined. Upon stable expression in Bac-to-Bac system, UGT2B7*71S (A 71S), UGT2B7*2 (H 268Y) and UGT2B7*5 (D 398N) were all associated with a decrease in the formation of FPFGs. Compared with UGT2B7*1 (wild-type), UGT2B7*71S exhibited a >2-fold lower intrinsic clearance mainly by altered capacities ( V max). Furthermore, a >14-fold decreased intrinsic clearance of the *1 protein was produced by UGT2B7*2 and UGT2B7*5. However, no significantly stereoselective difference for the formation of (R)- and (S)-FPFG was found among these UGT2B7 allozymes. UGT1A9*2 (C 3Y) exhibited a higher V max (3.2-fold), K m (2.1-fold) and intrinsic clearance (1.6-fold) toward (S)-FPF than UGT1A9*1 (wild-type). UGT1A9*3 (M 33T) almost lost the catalytic activity to FPF. A significantly stereoselective difference on the glucuronidation of rac-FPF was seen between the two variants compared with the wild type of UGT1A9.