Barbara Di Rienzo

Synthesis and antifungal activity of a new series of 2-(1H-imidazol-1-yl)- 1-phenylethanol derivatives

A new series of aromatic ester and carbamate derivatives of 2-(1H-imidazol-1-yl)-1-phenylethanol were synthesized and evaluated for their antifungal activity towards Candida albicans and non-albicans Candida species strains. The aromatic biphenyl ester derivatives 6a-c were more active than the reference compound fluconazole. 6c possesses a MIC mean values of 1.7 ± 1.4 μg mL(-1)vs C. albicans and 1.9 ± 2.0 μg mL(-1)vs non-albicans Candida species strains. The racemic mixtures of 6a, b were purified to afford the pure enantiomers. The (-) isomers were up to 500 times more active than (+) isomers. (-)-6a and (-)-6b were thirty and ninety times more active than fluconazole towards C. krusei strain respectively. The racemates of 6a-c showed low cytotoxicity against human monocytic cell line (U937) with 6a demonstrating a CC(50) greater than 128 μg mL(-1).

On the regio- and stereoselectivity of pyridinyl radical dimerization

The present work was carried out in order to elucidate the combined effects of the electron spin density on the ring carbons and the steric hindrance of the ring substituents upon the regio- and stereoselectivity of the dimerization of 3-carbamoyl- and 3-cyanopyridinyl radicals. To this purpose the composition of mixtures of diastereoisomeric dimers arising from the one-electron electrochemical reduction of several 3-carbamoyl and 3-cyano substituted pyridinium salts has been studied by 1H NMR spectroscopy. In some cases, single diastereoisomers have been isolated from mixtures by preparative HPLC.The results show that: (a) hindering steric effect of substituents at coupling sites prevails over electron spin density on coupling carbons in governing regioselectivity of 3-carbamoylpyridinyl radical dimerization; (b) large bulky N-ring substituents produce a significant shielding effect on the adjacent dimerization site; (c) the relative amounts of diastereoisomers in the mixtures of 4,4′- and 6,6′-linked dimers indicate that the dimerization process is largely stereoselective; (d) otherwise, nearly equal amounts of 4,4′- and 4,6′-linked dimers, and relative diastereoisomers as well, arise from the reduction of 3-cyano substituted pyridinium salts. This finding indicates that the presence of the carbamoyl substituent at the 3 position is a primary factor in inducing the regio- and stereoselectivity of pyridinyl radical dimerization.

Carprofen Analogues as Sirtuin Inhibitors: Enzyme and Cellular Studies

The best of both: SIRT1/2 inhibitors were developed by combining chemical features of selisistat (SIRT1-selective inhibitor; blue) and carprofen (anti-inflammatory drug; red). The most potent compound (shown) increased acetyl-p53 and acetyl-α-tubulin levels, and induced slight apoptosis at 50 μM in U937 cells, differently from selisistat and carprofen.

Electroencephalographic effects induced by choline pivaloyl esters in scopolamine-treated or nucleus basalis magnocellularis lesioned rats

The electroencephalographic (EEG) effects of two choline pivaloyl esters, [2-(2,2-dimethylpropionyloxy)ethyl]trimethylammonium iodide (1) and [2-(2,2-dimethylpropionyloxy)ethyl]trimethylammonium 2,2-dimethylpropionate (2), were evaluated in scopolamine-treated or nucleus basalis magnocellularis (NBM) lesioned rats. In scopolamine-treated animals, Compounds 1 and 2 prevented or reduced EEG effects, such as increased amplitude of total spectra and high-voltage spindle (HVS) activity as well. Furthermore, choline esters showed a noticeable effectiveness in reversing the EEG changes produced in rats by AMPA-induced lesion of NBM. Indeed, Compounds 1 and 2 were able to induce EEG desynchronisation, a significant decrease in the total EEG power (0.25-16 Hz) and in the lower frequency delta and theta bands (0.25-3 and 3-6 Hz, respectively). The EEG effects produced by Compounds 1 and 2 were well comparable with that evoked by Tacrine, used as a reference compound. The results of the present work allow us to put forward the hypothesis that the EEG effects observed are most likely mediated through the stimulation of the cholinergic neurotransmission ensuing from enhanced cerebral levels of acetylcholine (ACh) consequent upon acetylcholinesterase (AChE) inhibition by choline pivaloyl esters.

Structure of the dimers arising from one-electron electrochemical reduction of pyridinium salts 3,5-disubstituted with electron-withdrawing groups

One-electron electrochemical reduction of the salts 1-benzyl-3,5-bis(methylcarbamoyl)pyridinium bromide 3a and 1-benzyl-3,5-dicarbamoylpyridinium bromide 3b yields mixtures of four isomeric dimers, as shown by HPLC analysis and mass spectrometry. 1H and 13C NMR spectrometry allows us to determine the structures of the mixture components. In both mixtures, the two most abundant products are identified as 4,4′- and 2,4′-tetrahydrobipyridines (5a, 5b and 6a, 6b, respectively), while minor amounts of a pair of diastereomeric 2,2′-linked dimers are also detected in (7a, 8a and 7b, 8b respectively). Therefore, the NMR studies lead to the conclusion that the structure assignment of conformers of 5a, made previously for 6a and 7a, is not correct. All the 2,2′- and 2,4′-linked dimers undergo photochemical dissociation into two pyridinyl radicals which recombine to yield 4,4′-linked dimers.

Electrochemical studies on haloamides. Part 4. Reactivity of haloacetamides and haloacetohydroxamates toward electrogenerated diethyl malonate anion

The reactivity of haloacetamides and acetohydroxamates 1 and 2 toward electrogenerated diethyl malonate anion has been investigated. The course of the reaction primarily depends on the acidity of the amide NH group, which is mainly determined by the nature of the substituent, R, at the nitrogen atom. If this substituent is the same, the nature of the halogen atom also plays an important role. If the malonate anion can act as a base, products arising from foilow-up reactions of the conjugated base of the substrate are formed and their structure is dependent on R. In particular, β-lactams arising from a formal insertion of a malonate residue into the amide skeleton are obtained from haloacetanilides. When the substrate cannot be deprotonnated, the diethyl malonate anion behaves as a nucleophile provided that the leaving group is bromide. Chloro derivatives are rather stable toward malonate anion.

Electrochemical studies on haloamides. Part 3. Haloacetamides and halo-acetohydroxamates

The electrochemical reduction of haloacetamides and acetohydroxamates 1 and 2 at a cathode in DMF–0.1 mol dm–3 TEAP (tetraethylammonium perchlorate)solution has been investigated.The reduction leads to the corresponding dehalogenated products together with cyclic dimers, arising from follow-up reactions of the conjugated base of the starting compound. The same type of products, but in quite different yield, are formed when ethyl isobutyrate anion is electrogenerated in the presence of chloro derivatives 1. The reactivity of the substrates, and in particular the structure of the dimers, primarily depends on the nature of the substituent at the amide nitrogen. Possible reaction pathways leading to the products are suggested.

Electrochemical behaviour of halogenoamides. The role of additional functional groups on the reduction pattern and the nature of the products

The electrochemical reduction of halogenoamides (II)–(V) in dimethylformamide solutions containing Et4NClO4 as supporting electrolyte, was investigated both at mercury and at vitreous carbon electrodes. Bromoamides (II) and (III) undergo one-electron reduction yielding the debrominated amides CH3CONHC6H11(I) and CH3CONHCHCCl2(VI) respectively, together with polymeric material. The nature and yield of these products account for a reduction pathway involving both electrochemically generated (e.g.c.; H2CONHR) and derived (d.c.; HBrCONHR) carbanions. The presence of other functional groups causes a marked alteration of the reaction pathway as shown in the reduction of the amides (IV) and (V), where only products derived from e.g.c. are formed. The formation of amide (VII) together with (VI) from the macroscale electrolysis of bromoacetoxyamide (V) is regarded as an example of electrode-assisted nucleophilic substitution.