Design, synthesis, and biological evaluation of new urolithin amides as multitarget agents against Alzheimer's disease.

A series of urolithin amide (i.e., URO-4-URO-10 and THU-4-THU-10) derivatives was designed and synthesized, and their chemical structures were confirmed with spectroscopic techniques and elemental analysis. The title compounds and synthesis intermediates (THU-1-THU-10 and URO-1-URO-10) were evaluated for their potential to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidase B (MAO-B). Compounds THU-4 and THU-8 were found to be the most potent inhibitors for the cholinesterases and MAO-B, respectively. The docking studies were also employed to evaluate the binding modes of the most active compounds with AChE, BuChE, and MAO-B. Furthermore, the moderate-to-strong activities of the compounds were also displayed in amyloid-beta inhibition and antioxidant assay systems. The results pointed out that the urolithin scaffold can be employed in drug design studies for the development of multitarget ligands acting on various cascades shown to be important within the pathophysiology of Alzheimer's disease.

Studies on the Metabolism of Nitrogen Compounds by Prof J. W. Gorrod.

The scientific research papers by Professor John William Gorrod who died in December 2015 are reviewed. He was one of the most important scientists in the area and investigated mainly the biological oxidation of nitrogen containing drugs and xenobiotics. In this review, more than 200 papers belong to him are evaluated, most of which involved the results from in vitro microsomal oxidative metabolism of nitrogen containing xenobiotics. These studies include the carcinogenicity of tobacco smoke constituents, aromatic amines, aminophenols, rubber and aminobiphenyls, the assay for ferriheamoglobinemia forming compounds, metabolism of aralkyl azo compounds, aromatic amines, aromatic azaheterocycles, synthesis of N-oxidative metabolites i.e. N-oxides, nitrones and hydroxylamines, mutagenicity of amines, metabolism of adenine derivatives, alicyclic amines and aromatic heterocyclic amines, in vivo and in vitro metabolism of nicotine and related tobacco alkaloids, effects of various substrates on MAO enzyme and reviews related to nicotine and N-oxidation of other nitrogen containing compounds. In the major part of these studies, the spectroscopic and chromatographic methods were developed to evaluate and determine the investigated compounds.

In vitro and in vivo metabolism of ethyl 4-[(2-hydroxy-1-naphthyl)azo]benzoate.

Azo compounds are extensively used for colouring food, drink, pharmaceuticals, cosmetics, textiles and printing inks. Publications in the literature have shown that azo dyes can pose threats to public health by metabolic and chemical oxidation and reduction reactions. In the present study, the in vivo and in vitro biotransformation of ethyl 4-[(2-hydroxy-1-naphthyl)azo]benzoate, an azo compound which is structurally similar to 1-phenylazo-2-naphthol was studied to investigate its in vivo and in vitro metabolic products. For the in vitro biotransformation study, rat liver microsomal preparations fortified with NADPH as a co-factor were used. Three unidentified metabolic products were observed. For the in vivo biotransformation study, a concentrated solution of this substrate was given orally to female rats. After the administration of substrate, blood samples of rats are taken at certain intervals. The blood plasma were obtained by centrifuging blood samples. The cold acetonitrile was added to plasma to precipitate plasma proteins and plasma was centrifuged. The supernatant was evaporated at room temperature. The residue was reconstituted with acetonitrile and examined by the HPLC. The unchanged substrate together with the corresponding reduction and acetylation products were detected in plasma. However, no initial hydrolysis occurred in the ester moiety.

The stability studies and in vitro hepatic microsomal metabolism of some alpha-phenyl-N-substituted nitrones in rats.

Nitrones are a very important class of synthetic chemicals as synthetic intermediates, antioxidant agents, and metabolic oxidation products of secondary amines and imines used drug, food, cosmetic and printing industry. In the present study, the stability experiments and in vitro metabolism studies using rat microsomal preparations fortified with NADPH were carried out using three different alpha-phenyl-N-substituted nitrones ie alpha-phenyl-N-tert-butylnitrone (PTBN), alpha-(2,6-dichlorophenyl)-N-phenylnitrone (DCPPN) and alpha-phenyl-N-adamantanylnitrone (PADN). The separation of these compounds from the potential degradation, isomerization and metabolic products were performed using a reverse phase HPLC system with a diodearray uv detection. Following stability experiments at 37 degrees C using methanolic nitrone solutions, it was observed that PTBN produced trace amounts of benzaldehyde and the corresponding amide. DCPPN also produced trace amounts of amide. After 12 hours, the amount of the amide significantly increased. PADN produced trace amount of benzaldehyde but not any amide. The proposed compounds were incubated with rat microsomal preparations fortified with NADPH, extracted into dichloromethane (DCM) and finally evaporated under nitrogen in the dark conditions. PTBN was metabolized into corresponding amide whereas DCPPN and PADN did not. With all of the substrates, the corresponding aldehydes are observed with both test and control tubes using denaturated microsomes and without co-factors.

Condensed 1,4-dihydropyridines with various esters and their calcium channel antagonist activities.

New alkyl 2,6,6-(2,7,7)-trimethyl-4-(2-fluoro-3-chloro-5-trifluoromethylphenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates and 9-(3-chloro-2-fluoro-5-trifluoromethylphenyl)-6,6(7,7)-dimethyl-6,7-dihydrofuro[3,4-b]quinoline-1,8-diones have been synthesised and their calcium antagonistic activities on isolated rabbit sigmoid colon have been investigated and compared with Nifedipine. The investigation examined the influence of ester groups in the 3-position of the HHQ ring and the 2-methoxyethyl analogs were found to be the most active derivatives.

Synthesis, evaluation of the calcium antagonistic activity and biotransformation of hexahydroquinoline and furoquinoline derivatives.

The objective of this study was to synthesise new condensed 1,4-dihydropyridine derivatives and investigate their calcium channel blocking activity. In addition, the in vitro hepatic microsomal bio-transformation of one hexahydroquinoline derivative was studied, 2,6,6-Trimethyl-3-carbmethoxy (carbethoxy)-4-aryl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives were synthesised bymodified Hantzsch synthesis. 1,3,4,5,6,7,8,9-octahydro-7,7-dimethyl-9-arylfuro [3,4-b]quinoline-1,8-dione derivatives were synthesised the reaction of hexahydroquinoline derivatives with pyridinium bromide perbromide. The calcium antagonistic activities of the compounds were determined by tests performed on isolated rat ileum and lamb carotid artery. In vitro hepatic biotransformation of one compound was studied in rat microsomes. Although compounds 3, 18 and 28 showed promising relaxant activity, they were less active than nicardipine (CAS 55985-32-5) in isolated rat ileum. In all studied concentrations, compounds 5 and 20 were more active than nicardipine in lamb carotid artery. These compounds showed high tissue selectivity compared with nicardipine. In addition, in vitro hepatic microsomal biotransformation of compound 2 produced its lactone derivative (compound 34). This metabolite was verified by HPLC. In the hexahydroquinoline series, the compounds having ortho substituted phenyl substituent were more active than the meta isomers. Lactone derivatives were found less active than hexahydroquinoline derivatives in respect to calcium antagonistic activity.