Imidazolylacetophenone oxime-based multifunctional neuroprotective agents: Discovery and structure-activity relationships.

Alzheimer's disease (AD) possesses a complex pathogenetic mechanism. Nowadays, multitarget agents are considered to have potential in effectively treating AD via triggering molecules in functionally complementary pathways at the same time. Here, based on the screening (∼1400 compounds) against neuroinflammation, an imidazolylacetophenone oxime ether (IOE) was discovered as a novel hit. In order to obtain SARs, a series of imidazolylacetophenone oxime derivatives were constructed, and their C=N bonds were confirmed as the Z configuration by single crystals. These derivatives exhibited potential multifunctional neuroprotective effects including anti-neuroinflammatory, antioxidative damage, metal-chelating, inhibition of acetylcholinesterase (AChE) properties. Among these derivatives, compound 12i displayed the most potent inhibitory activity against nitric oxide (NO) production with EC50 value of 0.57 µM 12i can dose-dependently suppress the expression of iNOS and COX-2 but not change the expression of HO-1 protein. Moreover, 12i exhibited evidently neuroprotective effects on H2O2-induced PC12 cells damage and ferroptosis without cytotoxicity at 10 µM, as well as selectively metal chelating properties via chelating Cu2+. In addition, 12i showed a mixed-type inhibitory effect on AChE in vitro. The structure-activity relationships (SARs) analysis indicated that dioxolane groups on benzene ring and rigid oxime ester can improve the activity. Parallel artificial membrane permeation assay (PAMPA) also verified that 12i can overcome the blood-brain barrier (BBB). Overall, this is the first report on imidazolylacetophenone oxime-based multifunctional neuroprotective effects, suggesting that this type of compounds might be novel multifunctional agents against AD.

Paeonol Derivatives and Pharmacological Activities: A Review of Recent Progress.

Paeonol, 2-hydroxy-4-methoxy acetophenone, is one of the main active ingredients of traditional Chinese medicine such as Cynanchum paniculatum, Paeonia suffruticosa Andr and Paeonia lactiflora Pall. Modern medical research has shown that paeonol has a wide range of pharmacological activities. In recent years, a large number of studies have been carried out on the structure modification of paeonol and the mechanism of action of paeonol derivatives has been studied. Some paeonol derivatives exhibit good pharmacological activities in terms of antibacterial, anti-inflammatory, antipyretic analgesic, antioxidant and other pharmacological effects. Herein, the research progress on paeonol derivatives and their pharmacological activities were systematically reviewed.

Prenylated Acetophloroglucinol Dimers from Acronychia trifoliolata: Structure Elucidation and Total Synthesis.

The isolation of 12 secondary metabolites, including seven new acetophenone monomers, from the 50% CH3OH/CH2Cl2 extract (N089419-L/6) of Acronychia trifoliolata was reported previously. In the present work, three new prenylated acetophenone dimers (1-3) and five known dimers (4-8) were isolated, and their structures were elucidated by using various NMR spectroscopic techniques and HRMS. Among the new dimers, an unprecedented 4-isobutyl-3-isopropyltetrahydro-2H-pyran ring was observed in the structure of 1. This study is the first to report the formation of a 2H-pyran ring between two prenylated acetophloroglucinols. Only four related dimers have been reported before, and they were formylated phloroglucinol dimers from the family Eucalypteae. Compounds 2 and 3 are acrovestone-like dimers, and the structure of 3 was confirmed by total synthesis. The evaluation of the antiproliferative activity of isolated and synthesized acrovestone-like dimers indicated that a double bond in the prenyl-like moiety as found in the more active compounds might be important for mediating activity, while the pendant isobutyl group seems to be less important.

Synthesis and anti-inflammatory activity of paeonol analogues in the murine model of complete Freund's adjuvant induced arthritis.

A new series of paeonol alkyl ether analogues were synthesized and confirmed with IR, 1H NMR, 13C NMR and HRMS spectra. They have shown anti-inflammatory activities by scavenging mediator of free radicals and inhibiting lipid mediator of inflammation on complete Freund's adjuvant (CFA) induced arthritis in mice. The in vitro and in vivo scavenging ability of free radicals was determined by using chemical analysis and commercial assay kits, respectively. The in vivo inhibiting lipid mediator of inflammation was examined by ELISA. Our results indicated that the substitution of the hydrogen in hydroxyl group at C2 position of paeonol 1 by short carbon chain, in the presence or absence of bromo atom at C5 position, decreased its scavenging ability on radicals (3a or 4a vs 1), while the long alkyl substitution (Cn>14) increased the activity. Compared with 3a or 4a, scavenging abilities of 3a-h or 4a-h gradually increased following the length elongation of alkyl carbon chain. Compounds 3h and 4h showed great scavenging ability on OH, O2-, DPPH, ATBS+ and MDA, and good promotion on T-AOC and SOD. The results of the in vivo inhibiting lipid mediator of inflammation also demonstrated that 3h, 4h exhibited substantial inhibition on enzyme activity of COX-2, PGE2. Therefore, 3h and 4h have great potential to be the novel anti-inflammatory drug candidates for the therapy of arthritis.

Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor.

The natural product molecule 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) isolated from the medicinal plant Melicope ptelefolia was shown to exhibit potent lipoxygenase (LOX) inhibitory activity. It is known that LOX plays an important role in inflammatory response as it catalyzes the oxidation of unsaturated fatty acids, such as linoleic acid to form hydroperoxides. The search for selective LOX inhibitors may provide new therapeutic approach for inflammatory diseases. Herein, we report the synthesis of tHGA analogs using simple Friedel-Craft acylation and alkylation reactions with the aim of obtaining a better insight into the structure-activity relationships of the compounds. All the synthesized analogs showed potent soybean 15-LOX inhibitory activity in a dose-dependent manner (IC50 = 10.31-27.61 µM) where compound 3e was two-fold more active than tHGA. Molecular docking was then applied to reveal the important binding interactions of compound 3e in soybean 15-LOX binding site. The findings suggest that the presence of longer acyl bearing aliphatic chain (5Cs) and aromatic groups could significantly affect the enzymatic activity.

Synthesis and antimicrobial activity of geranyloxy- and farnesyloxy-acetophenone derivatives against oral pathogens.

The compounds 2',6'-dihydroxy-4'-geranyloxyacetophenone (1) and 2',6'-dihydroxy-4'-farnesyloxy-acetophenone (2) are oxyprenylated secondary metabolites extracted from plants belonging to the Rutaceae family. In this study, 1 and 2 were synthesized and tested for their antimicrobial activity toward major oral pathogens. Compounds 1 and 2 were synthesized by selective prenylation of 2,4,6-trihydroxyacetophenone at the 4' position with geranyl and farnesyl bromide, respectively. Compound 1 showed stronger antimicrobial activity than 2 against major oral pathogens, including Gram positive bacteria (Streptococcus mutans, Streptococcus sobrinus), Gram negative bacteria (Prevotella intermedia, Porphyromonas gingivalis) and Candida albicans. Evidences were obtained that the mode of action of 1 and 2 may be related to their iron-chelating property. This study suggests that 1 and 2 may represent potential natural molecules for the prevention/treatment of common oral infections, including dental caries, periodontal disease, and candidiasis.

Induction of apoptosis and cell cycle arrest in L-1210 murine lymphoblastic leukaemia cells by (2E)-3-(2-naphthyl)-1-(3'-methoxy-4'-hydroxy-phenyl)-2-propen-1-one.

OBJECTIVES: New compounds with biological targets and less cytotoxicity to normal cells are necessary for cancer therapy. In this work ten synthetic chalcones derived from 2-naphtaldehyde were evaluated for their cytotoxic effect in murine acute lymphoblastic leukemia cells L-1210. METHODS: A series of ten chalcones derived from 2-naphtaldehyde and corresponding acetophenones were prepared by aldolic condensation, using methanol as solvent under basic conditions, at room temperature for 24 h. The cell viability was determined by MTT colorimeter method. The cell cycle phase analysis was carried out by flow cytometry after propidium iodide staining. The apoptosis induction was assessed by exposure to phosphatidylserine (ANNEXIN V-FITC). Cytometric analysis was performed to evaluate the expression of p53, Bcl-2 and Bax protein. The caspase-3 expression was studied by immunoblotting analysis. KEY FINDINGS: A preliminary screening of a series of ten chalcones derived from 2-naphtaldehyde showed that chalcone 8, (2E)-3-(2-naphtyl)-1-(3'-methoxy-4'-hydroxy-phenyl)-2-propen-1-one, had the highest cytotoxic effect (IC50 of 54 microM), but not in normal human lymphocytes. To better understand the cytotoxic mechanism of chalcone 8, its effect on cell cycle and apoptosis was assessed. Our results showed that chalcone 8 caused cell cycle arrest in the G2/M phase and a significant increase in the proportion of cells in the subG0/G1 phase. Our results also demonstrated that chalcone 8 promoted a modification in Bax:Bcl-2 ratio and increased p53 expression and caspase-3 activation. CONCLUSIONS: The studied chalcone 8 has cytotoxic effect against L-1210 lymphoblastic leukaemic cells, and this effect is associated with increase of p-53 and Bax expression.

Amelioration of adjuvant induced arthritis by apocynin.

The premise of the study was to investigate the antiarthritic potential of apocynin (APO) in Balb/c mice (in vivo). The experiment showed a dose-dependent decrease in oedema and showed a suppression of proinflammatory cytokines such as TNF-alpha and IL-1beta and mediators such as prostaglandin E(2) (PGE(2)) and LTB(4). At oral doses of 0.5, 1.0, 2.0 and 4.0 mg/kg once daily during the course of the experiment, APO induced an inhibition of T cell mediated immune response causing suppression of CD4+ and CD8+ T cells and of intracellular interferon-gamma (IFN-gamma) by flow cytometry in arthritic mice. In parallel there was a dose-dependent inhibition in vascular permeability causing an inhibition in the migration of leucocytes and exudate volume at the site of the inflammatory reaction. These observations validate the immunoregulatory potential of apocynin.

Bioavailability of apocynin through its conversion to glycoconjugate but not to diapocynin.

Apocynin (4-hydroxy-3-methoxyacetophenone) is a major active ingredient from the rhizomes of Picrorhiza kurroa, a botanical plant used as an herbal medicine for treatment of a number of inflammatory diseases. Recently, apocynin is regarded as a specific inhibitor for NADPH oxidase in cell and animal models. In vitro studies indicated conversion of apocynin to diapocynin in the presence of peroxidases, e.g., myloperoxidase, posing the possibility that diapocynin also contributes to the anti-oxidative action of apocynin. The objectives of this study are to examine the bioavailability of apocynin to plasma, liver and brain tissue after intraperitoneal (i.p.) injection, and to examine whether apocynin is converted to diapocynin in vivo. Diapocynin was chemically synthetized and characterized by NMR and IR. Apocynin (5mg/kg body wt) was injected i.p. to adult male Sprague-Dawley rats and plasma, liver and brain were collected at different times (30min, 1 and 2h) after injection. Samples were treated with beta-glucuronidase to hydrolyze the glycosyl linkage and analyzed by HPLC/MS. At 30min and 1h after injection, approximately 50% of apocynin was converted to its glycosyl derivative and was distributed in plasma, liver and brain. No diapocynin was detected in any samples. These results indicate rapid glycosylation of apocynin and its transport to blood and other organs but no apparent conversion to diapocynin in vivo.

Dose formulation and analysis of diapocynin.

Procedures based on high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection and liquid chromatography-mass spectrometry (LC-MS) are described for analyzing diapocynin. Diapocynin was synthesized by oxidative coupling of two apocynin monomers, through the in situ generation of sulfate radicals. It was purified by washing 3 times each with boiling water, followed by boiling methanol. HPLC was used to determine the concentration of unreacted apocynin and other impurities and the purity of the diapocynin that had been synthesized. Negative-ion, atmospheric pressure chemical ionization (APCI) LC-MS was used to determine the molecular weights of impurities. The method using HPLC with UV detection provided a calibration curve that was linear from 0.16 to 24 microg/mL. The LC-MS method was linear from 0.005 to 2 microg/mL. It was found that diapocynin has low solubility in deionized water and corn oil but is soluble in dimethylsulfoxide (DMSO) and alkaline aqueous solutions. Also, diapocynin is 13 times more lipophilic than apocynin, even though both compounds have the same p K a of 7.4. The log of the octanol/water partition coefficient (log P) was 1.01 for apocynin and 1.82 for diapocynin. A solution of 5.5 mg/mL (16.7 mM) diapocynin in DMSO was found to be stable for at least 30 days when stored at room temperature.

Hypoglycemic prodrugs of 4-(2,2-dimethyl-1-oxopropyl)benzoic acid.

SAH 51-641 (1) is a potent hypoglycemic agent, which acts by inhibiting hepatic gluconeogenesis. It is a prodrug of 4-(2, 2-dimethyl-1-oxopropyl)benzoic acid (2) and 4-(2, 2-dimethyl-1-hydroxypropyl)benzoic acid (3), which sequester coenzyme A (CoA) in the mitochondria, and inhibits medium-chain acyltransferase. 1-3 and 4-tert-butylbenzoic acid all cause testicular degeneration in rats at pharmacologically active doses. 14b (FOX 988) is a prodrug of 3, which is metabolized in the liver at a rate sufficient enough to have hypoglycemic potency (an ED50 of 65 micromol/kg, 28 mg/kg/day, for glucose lowering), yet by avoiding significant escape of the metabolite 3 to the systemic circulation, it avoids the testicular toxicity at doses up to 1500 micromol/kg/day. 14b was selected for clinical studies.

[Pyridazinilides (XIV). The action of p-phenyl-phenacyl bromide on 3-phenyl-pyridazine]. / Piridaziniu-ilide (XIV). Actiunea bromurii de p-fenil-fenacil asupra 3-fenil-piridazinei.

This time the synthesis of some new derivatives obtained by the quaternary substitution of one of the heterocyclic nitrogen atoms and by reactions of dipolar cycloaddition is presented. The results of the tests on their antimicrobial and antiinflammatory actions are discussed.

[Selenazoles. XII. (1) Reaction of 4-(p-tolyl)-selenosemi-carbazides of acetic, benzoic, isonicotinic, nicotinic and picolinic acid with omega-acetophenone]. / Selenazole. XII. (1) Reakcje 4-(p-tolilo)-selenosemikarbazydow kwasu octowego, benzoesowego, izonikotynowego, nikotynowego i pikolinowego z omega-bromoacetofenonem.

The cyclization of 4-(p-tolyl)-selenosemicarbazides of acetic, benzoic, isonicotinic, nicotinic and picolinic acids (Ia-e) with omega-bromoacetophenone was investigated in the medium of methanol (Method A) or in methanol in the presence of anhydrous sodium acetate (Method B). Acid hydrolysis of compounds IIf-i and IVa-c, e was studied. Results of UV and IR spectrometric measurements and of the in vitro microbiological studies are presented. In contradistinction to corresponding thiosemicarbazides, the change in N4 nitrogen atom basicity of the parent selenosemicarbazide I (pKa of p-toluidine = 5.1), in comparison to that of 4-phenyl-selenosemicarbazide (pKa of aniline = 4.63), proved to influence the equilibrium of the reaction with omega-bromoacetophenone only in the methanol medium without addition of anhydrous sodium acetate (Method A).