Synthesis, Characterization, Molecular Docking, and Biological Activities of Some Natural and Synthetic Urolithin Analogs.

Urolithins (that is, hydroxy substituted benzo[c]chromen-6-one derivatives) are formed within the gastrointestinal tract following to the exposure to various ellagitannin rich diet, particularly involving pomegranate, nuts, and berries. Regarding the bioavailability deficiency of ellagitannins, the biological activities obtained through the extracts of these dietaries are attributed to the urolithin compounds, since they are bioavailable. Particularly, there are studies indicating the importance of ellagitannin-rich food for protective and alternative treatment of Alzheimer's Disease (AD). From this perspective, within this study, the major urolithins (that is, urolithins A and B), their methyl ether metabolites, as well as some synthetic urolithin analogs have been synthesized and screened for their biological activities in various enzyme inhibition (acetylcholinesterase, butyrylcholinesterase, monoamine oxidase B, cyclooxygenase 1, and cyclooxygenase 2) and antioxidant (DPPH radical scavenging) assay systems. The results pointed out the potential of urolithins to act as inhibitors on these receptors. Docking studies were also performed to investigate the possible interactions.

Benzimidazole-derived Compounds Designed for Different Targets of Alzheimer's Disease.

Benzimidazole scaffold has been efficiently used for the design of various pharmacologically active molecules. Indeed, there are various benzimidazole drugs, available today, employed for the treatment of different diseases. Although there is no benzimidazole moiety containing a drug used in clinic today for the treatment of Alzheimer's Disease (AD), there have been many benzimidazole derivative compounds designed and synthesized to act on some of the validated and non-validated targets of AD. This paper aims to review the literature to describe these benzimidazole containing molecules designed to target some of the biochemical cascades shown to be involved in the development of AD.

Traditional Techniques Applied in Olive Oil Production Results in Lower Quality Products in Northern Cyprus.

OBJECTIVES: Olive oil production and its consumption is one of the traditional characteristics of Northern Cyprus. To date, no research has been conducted to analyze the quality of traditionally produced olive oil. Therefore, within this study, we aimed to analyze the olive oil produced within the island concomitant to the determination and comparison of its quality indices. MATERIALS AND METHODS: The standard olive oil analysis techniques acknowledged by the IOOC and ISO were employed. Accordingly, the fatty acid content, peroxide level, total phenol content, the levels of carotenoids and chlorophyll, as well as status of oxidation were all tested concomitant to statistical analysis. RESULTS: In contrast to the regional belief and consideration, the results indicated that the olive oil produced locally is highly exposed to oxidation and therefore, it is of lower quality according to the ISO guidelines. CONCLUSION: The traditional techniques employed for the production, distribution, and storage of olive oil within Northern Cyprus must be re-evaluated and controlled to satisfy the current standards required and employed globally.

Synthesis of Novel Benzothiazole-Piperazine Derivatives and Their Biological Evaluation as Acetylcholinesterase Inhibitors and Cytotoxic Agents.

OBJECTIVE AND METHOD: A new series of benzothiazole-piperazine derivatives was synthesized and a complete chemical characterization of the novel compounds was provided. In vitro cytotoxic activities were screened against colorectal (HCT-116), breast (MCF-7) and hepatocellular (Huh7) cancer cell lines by Sulforhodamine B assay. RESULT AND DISCUSSION: All compounds showed cytotoxic activity against hepatocellular (Huh7) and breast (MCF-7) cancer cell lines. Dihalo substituted benzylpiperazine derivatives (2a, 2e) had the highest cytotoxic activities in all the tested cell lines. In addition, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of synthesized compounds were investigated by in vitro Ellman's method. Compound 2j led to moderate and selective inhibition against AChE. Docking study was utilized to understand the binding mode of compound 2j in comparision with donepezil on AChE. The other tested compounds showed weak or no inhibition against AChE as promising anticancer agents.

Design, synthesis and biological evaluation of novel 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives as potential cholinesterase inhibitors.

Hydroxylated 6H-benzo[c]chromen-6-one derivatives (i.e., urolithins) are the main bioavailable metabolites, and biomarkers of ellagitannins present in various nutrition. Although these dietaries, the sources of urolithins, are employed in folk medicine as cognitive enhancer in the treatment of Alzheimer's Disease, urolithins have negligible potential to inhibit acetylcholinesterase and butyrylcholinesterase enzymes, the validated targets of Alzheimer's Disease. Therefore, within this research, a series of 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives has been designed, synthesized, and their biological activities were evaluated as potential acetylcholinesterase and butyrylcholinesterase inhibitors. The compounds synthesized exerted comparable activity in comparison to rivastigmine, galantamine, and donepezil both in in vitro and in vivo studies.

Synthesis and antimicrobial, acetylcholinesterase and butyrylcholinesterase inhibitory activities of novel ester and hydrazide derivatives of 3(2H)-pyridazinone.

In the current study, some novel ethyl 6- [(substituted-phenylpiperazine]-3(2H)-pyridazinone-2-yl propionate III and 6-[(substituted-phenylpiperazine]-3(2H)-pyridazinone-2-yl propionohydrazide IV derivatives were synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The structures of these new pyridazinone derivatives were confirmed by their IR, 1H-NMR spectra and elementary analysis. 6-Substituted-3(2H)-pyridazinone-2-yl propionate IIIa-e derivatives showed significant inhibitory activity against AChE and BChE. 6-[4-(3-Trifluoromethylphenyl)piperazine]-3(2H)-pyridazinone-2-yl propionate IIIe has been found to be the most active compound in terms of inhibition of either AChE or BChE. Compound IIIe exhibited inhibitory activity close to that of galantamine (CAS 357-70-0) and did not show any selectivity between the two enzymes. Also the antimicrobial activities of III and IV derivatives have been evaluated. All III and IV derivatives exhibited poor antibacterial activities but moderate antifungal activities.

Synthesis and analgesic and anti-inflammatory activity of 6-phenyl/(4-methylphenyl)-3(2H)-pyridazinon-2-propionamide derivatives.

For reducing gastrointestinal toxicity associated with non-steroidal anti-inflammatory drugs (NSAIDs) a variety of 6-phenyl/(4-methylphenyl)-3(2H)-pyridazinon-2-propionamide were synthesized. The structures of these new pyridazinone derivatives were confirmed by their IR, 1H-NMR spectra and elementary analysis. All the new compounds were tested in vivo for their analgesic and anti-inflammatory activities. The analgesic activity of the test compounds was determined by phenylbenzoquinone-induced writhing assay and the anti-inflammatory activity was evaluated by the carrageenan-induced rat paw edema model. 6-Phenyl-3(2H)-pyridazinon-2-yl-[4-(4-fluorophenyl)piperazinyl] propanamide IVa-3 was the most active one among the synthesized compounds. Also this compound exhibited most potent anti-inflammatory activity. Acetylsalicylic acid and indometacin were used as reference drugs. Adverse effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with the reference NSAIDs.

Synthesis, characterization and preliminary screening of regioisomeric 1-(3-pyridazinyl)-3-arylpyrazole and 1-(3-pyridazinyl)-5-arylpyrazole derivatives towards cyclooxygenase inhibition.

In a search for novel compounds with analgesic and anti-inflammatory activity, a series of regioisomeric 1-(3-pyridazinyl)-3-arylpyrazole (5a-f, 6a-f) and 1-(3-pyridazinyl)-5-arylpyrazole (7a-f, 8a-f) derivatives were synthesized. The structure of these regioisomers was confirmed by spectral techniques. The compounds were preliminarily screened at 8 microM concentration for their inhibitory activity against cyclooxygenase enzymes, COX-1 and COX-2, using a human whole blood test. The tested derivatives showed inhibitory activity for both enzymes and are worthy of further investigation for developing better leads.

Synthesis and analgesic and anti-inflammatory activity of ethyl (6-substituted-3 (2H)-pyridazinone-2-yl)acetate derivatives.

A number of 6-substituted-3(2H)-pyridazinones and the corresponding methyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate derivatives carrying the arylpiperazinyl structure present in potent antinociceptive agents reported in the literature were synthesized. As part of a programme a series of diverse arylpiperazine derivatives of ethyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate were prepared and tested for their in vivo analgesic and anti-inflammatory activity by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference non-steroidal anti-inflammatory drugs (NSAIDs). On the basis of available data, the structure-activity relationship in the series of ethyl (6-substituted-3(2H)-pyridazinone-2-yl)acetate derivatives was also discussed. When compared to parent 6-substituted-3(2H)-pyridazinones, the new ester derivatives, for example ethyl (6-4-[(2-fluoro)phenyl]piperazine-3(2H)-pyridazinone-2-yl)acetate exhibited better analgesic and anti-inflammatory activity and a lower ulcerogenic effect.

Synthesis and analgesic activity of some 4,6-disubstituted-3(2H)-pyridazinone derivatives.

A series of 6-morpholino-4-aryl-3(2H)-pyridazinone alkanoic acids, their ester and amide derivatives were prepared and tested for their in vivo analgesic activity by using the p-benzoquinone-induced writhing test. The analgesic activity of the compounds 6-morpholino-4-aryl-3(2H)-pyridazinone (6a-b) were comparable but little lower than that of acetyl-salicylic acid (CAS 50-78-2) as an analgesic agent. The 6-morpholino-4-aryl-3(2H)-pyridazinones having a propanoic acid (10a-b), ester (7a) and amides (12a-b, 12d and 12g) as side chains at the position 2 of the pyridazinone ring showed higher activity than the reference compound without gastric ulceration forming potential. All other compounds generally showed higher activity but caused gastric ulceration in the animals.

Synthesis of new Mannich bases of arylpyridazinones as analgesic and anti-inflammatory agents.

A series of 2-[[4-(substituted-phenyl/ benzyl)-1-piperazinyllmethyl]-6-(4-methoxyphenyl)-3(2H)pyridazinone derivatives was prepared and examined for analgesic and anti-inflammatory activities. The structures of these new pyridazinone derivatives were confirmed by their IR and 1H-NMR spectra and elementary analysis. Among the compounds prepared, 2-[[4-(4-fluorophenyl)-1-piperazinyl]methyl]-6-(4-methoxyphenyl)-3(2H)pyridazinone IVe was found to be a most promising analgesic and anti-inflammatory agent. Compound IVe showed more potent analgesic activity than acetylsalicyclic acid in the phenylbenzoquinone-induced writhing test. Also IVe showed anti-inflammatory activity comparable to that of the standard compound indometacin against the carrageenan-induced paw edema. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed a gastric ulcerogenic effect compared with reference nonsteroidal anti-inflammatory drugs. On the basis of the available data, the structure-activity relationship of the series of 2-[[4-(substituted-phenyl/benzyl)-1-piperazinyl]methyl]-6-(4-methoxyphenyl)-3(2H) pyridazinones is also discussed.

Synthesis and evaluation of the analgesic and anti-inflammatory activity of new 3(2H)-pyridazinone derivatives.

A series of 6-substituted-3(2H)-pyridazinone derivatives were synthesized and evaluated for analgesic and anti-inflammatory activities. The structures of these new pyridazinone derivatives were confirmed by their IR, 1H-NMR spectra and elementary analysis. Analgesic and anti-inflammatory activities of the title compounds have been evaluated. Four of the ten tested compounds possessed significant analgesic effects in the phenylbenzoquinone-induced writhing test (PBQ test). The most active derivatives 8a, 8b, 8d, 8e were void of gastric ulcerogenic effect or acute toxicity at the maximal dose (200 mg/kg p.o.). In the carrageenan-induced paw edema model, compound 8d (6- [4- (2-fluorophenyl) piperazin-1-yl]-3(2H)-pyridazinone) showed anti-inflammatory activity similar to that of the standard drug indometacin (CAS 53-86-1). A significant dependence of the anti-inflammatory effect on the substituents was observed; The pharmacological study of these compounds confirms that modification of the chemical group at position 6 of the 3(2H)-pyridazinone ring influences analgesic and anti-inflammatory activities.

4-(5-chloro-2(3H)-benzoxazolon-3-yl) butanoic acid derivatives: synthesis, antinociceptive and anti-inflammatory properties.

In this study, 4-(5-chloro-2(3H)-benzoxazolone-3-yl)butanoic acid and its ethyl ester as well as its ten new amide derivatives have been synthesized. Their structures have been elucidated by IR, (1)H-NMR spectra and elemental analysis. The compounds were screened for antinociceptive and anti-inflammatory activities. The highest antinociceptive and anti-inflammatory activities were exhibited by Compound 11 which has carboxylic acid structure. A various decrease in antinociceptive and anti-inflammatory activity was observed by amidation of the carboxylic acid moiety of this compound.