Regioselective multicomponent sequential synthesis of hydantoins.

The development of new practical and green methods for the synthesis of small heterocycles is an attractive area of research due to the well-known potential of heterocyclic small molecule scaffolds in the drug discovery process. Herein we report a one-pot, three-component sequential procedure for the synthesis of diversely 1,3,5- and 1,3,5,5-substituted hydantoins, in high yields and very mild conditions, using readily accessible starting materials such as azides, iso(thio)cyanates and substituted α-halo-acetic carboxylic acids. This methodology is especially convenient for the synthesis of spiro-hydantoins, which are particularly interesting bioactive compounds in medicinal chemistry.

Domino synthesis of 1,3,5-trisubstituted hydantoins: a DFT study.

The mechanism of the reaction between carbodiimides and activated α,ß-unsaturated carboxylic acids yielding fully substituted hydantoins and variable amounts of N-acyl urea by-products was studied using density functional theory calculations. Two alternative pathways featuring N-acyl ureas and imino-oxazolidinones as intermediates for the formation of the hydantoin product were taken into account. The results obtained using two different computational models indicate that the overall barriers are similar for the two pathways considered. In all cases, inclusion of a second molecule of carboxylic acid was required to mediate tautomerizations and rearrangement steps. The calculations successfully reproduce the experimentally observed regioselectivity with respect to both N-acyl urea and hydantoin products.

Synthesis and enzymatic evaluation of novel partially fluorinated thiol dual ACE/NEP inhibitors.

A novel family of peptidomimetics incorporating fluoroalkyl groups, mainly a trifluoromethyl, in alpha-position to a zinc(II)-binding thiol function, was synthesized in solution as well as in solid-phase. These compounds showed inhibitory potency in the nanomolar range against both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), whereas no inhibition of endothelin-converting enzyme-1 (ECE-1) was observed. The trifluoromethyl-derivatives were more potent than the parent unfluorinated analogues in the case of ACE, and less potent in the case of NEP.

NESS002ie: a new fluorinated thiol endopeptidase inhibitor with antinociceptive activity in an animal model of persistent pain.

For the past few decades membrane zinc metallopeptidases have been identified as important therapeutic targets in the control of pain. In particular, neutral endopeptidase (NEP) has been shown to play critical roles in the metabolism of the endogenous peptides Met- and Leu-enkephalins. In this study, we have evaluated the activity of a new fluorinated peptidase inhibitor NESS002ie in both in vitro and in vivo assays. NESS002ie has been compared to the peptidomimetic compound thiorphan and the previously reported NEP selective thiol inhibitor C20. The metallopeptidases inhibitory activity of NESS002ie was tested in vitro using a highly, sensitive, continuous, fluorometric, enzyme assay. Also, the analgesic propriety of NESS002ie, thiorphan and C20 have been evaluated in vivo, by intraplantar, intravenous and intrathecal administration, through nociception assays based on formalin test in mice. Metallopeptidases assays have shown an inhibitory potency of NESS002ie in the nanomolar range for NEP and angiotensin-converting enzyme (ACE). The new fluorinated inhibitor showed higher analgesic activity and bioavailability compared to thiorphan and C20 when administered by both intravenous and intrathecal injections. More significantly, intrathecal injection of NESS002ie reduced both the first and the second phases of the formalin biphasic pain response. In addition, naltrindole and naloxone reversed the analgesic effect of NESS002ie with a diverse profile. This study shows an improvement in relief of inflammation and pain, in vivo, using NESS002ie compared to reference compounds thiorphan and C20. This significant effect could be due to the replacement of isobutyl chain of the thiol C20 with the trifluoromethyl group.

Novel pyrazole derivatives as neutral CB1 antagonists with significant activity towards food intake.

In spite of rimonabant's withdrawal from the European market due to its adverse effects, interest in the development of drugs based on CB1 antagonists is revamping on the basis of the peculiar properties of this class of compounds. In particular, new strategies have been proposed for the treatment of obesity and/or related risk factors through CB1 antagonists, i.e. by the development of selectively peripherally acting agents or by the identification of neutral CB1 antagonists. New compounds based on the lead CB1 antagonist/inverse agonist rimonabant have been synthesized with focus on obtaining neutral CB1 antagonists. Amongst the new derivatives described in this paper, the mixture of the two enantiomers (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(2-cyclohexyl-1-hydroxyethyl)-4-methyl-1H-pyrazole ((±)-5), and compound 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-[(Z)-2-cyclohexyl-1-fluorovinyl]-4-methyl-1H-pyrazole ((Z)-6), showed interesting pharmacological profiles. According to the preliminary pharmacological evaluation, these novel pyrazole derivatives showed in fact both neutral CB1 antagonism behaviour and significant in vivo activity towards food intake.

Chitosan-graft-branched polyethylenimine copolymers: influence of degree of grafting on transfection behavior.

BACKGROUND: Successful non-viral gene delivery currently requires compromises to achieve useful transfection levels while minimizing toxicity. Despite high molecular weight (MW) branched polyethylenimine (bPEI) is considered the gold standard polymeric transfectant, it suffers from high cytotoxicity. Inversely, its low MW counterpart is less toxic and effective in transfection. Moreover, chitosan is a highly biocompatible and biodegradable polymer but characterized by very low transfection efficiency. In this scenario, a straightforward approach widely exploited to develop effective transfectants relies on the synthesis of chitosan-graft-low MW bPEIs (Chi-g-bPEI(x)) but, despite the vast amount of work that has been done in developing promising polymeric assemblies, the possible influence of the degree of grafting on the overall behavior of copolymers for gene delivery has been largely overlooked. METHODOLOGY/PRINCIPAL FINDINGS: With the aim of providing a comprehensive evaluation of the pivotal role of the degree of grafting in modulating the overall transfection effectiveness of copolymeric vectors, we have synthesized seven Chi-g-bPEI(x) derivatives with a variable amount of bPEI grafts (minimum: 0.6%; maximum: 8.8%). Along the Chi-g-bPEI(x) series, the higher the degree of grafting, the greater the ζ-potential and the cytotoxicity of the resulting polyplexes. Most important, in all cell lines tested the intermediate degree of grafting of 2.7% conferred low cytotoxicity and higher transfection efficiency compared to other Chi-g-bPEI(x) copolymers. We emphasize that, in transfection experiments carried out in primary articular chondrocytes, Chi-g-bPEI(2.7%) was as effective as and less cytotoxic than the gold standard 25 kDa bPEI. CONCLUSIONS/SIGNIFICANCE: This work underlines for the first time the pivotal role of the degree of grafting in modulating the overall transfection effectiveness of Chi-g-bPEI(x) copolymers. Crucially, we have demonstrated that, along the copolymer series, the fine tuning of the degree of grafting directly affected the overall charge of polyplexes and, altogether, had a direct effect on cytotoxicity.