Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT4R) agonist activities as potential agents against Alzheimer's disease: the design of donecopride.

In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease.

Synthesis and evaluation of cytotoxic activities of new guanidines derived from carbazoles.

Several new alkylguanidines derived from carbazole have been synthesized in a simple one-pot reaction starting from 3-aminocarbazole derivatives. The aminocarbazoles were reacted with ethoxycarbonylisothiocyanate, to give thiourea intermediates, followed by the addition of an alkylamine and HgCl2 to give ethoxycarbonylguanidine intermediates. The reaction mixture was then heated at 160 °C to give the N-(1,4-dimethyl-9H-carbazol-3-yl)-N'-alkylguanidines. The cytotoxic activity of all the synthesized guanidines was evaluated against different cell lines.

Virtual screening discovery of new acetylcholinesterase inhibitors issued from CERMN chemical library.

In our quest to find new inhibitors able to inhibit acetylcholinesterase (AChE) and, at the same time, to protect neurons from beta amyloid toxicity, i.e., inhibitors interacting with the catalytic anionic subsite as well as with the peripherical anionic site of AChE, a virtual screening of the Centre d'Etudes et de Recherche sur le Medicament de Normandie (CERMN) chemical library was carried out. Two complementary approaches were applied, i.e., a ligand- and a structure-based screening. Each screening led to the selection of different compounds, but only two were present in both screening results. In vitro tests on AChE showed that one of those compounds presented a very good inhibition activity, of the same order as Donepezil. This result shows the real complementary of both methods for the discovery of new ligands.

Synthesis, reactivity and biological evaluation of novel halogenated tripentones.

We describe herein the synthesis and the biological evaluation of a novel series of a potent anticancer agents: the tripentones. For the first time, a halogen atom was introduced in high yields on the pyrrole ring of the tricycle. This synthesis and the reactivity of the novel halogenated tripentones in metallo-catalysed cross-coupling reactions will be described in that article. Finally their influence on biological activity will be discussed.

Synthesis and preliminary in vivo evaluation of new 2-Aryl-6-methyl-1,2-dihydro-1H-pyridin-4-ones and 2-Aryl-6-methylpiperidin-4-ols, as potential anti-amnesiant agents.

A revisited synthesis of 2-aryl-6-methyl-1,2-dihydro-1H-pyridin-4-ones and their saturated analogues 2-aryl-6-methylpiperidin-4-ols is described. A five steps procedure, using the sulfinimine chemistry, to prepare a key intermediate beta-(6-chloronicotinic)-beta-amino ester is also reported. In vivo spontaneous working memory activity of these compounds has been investigated in the mouse. Results obtained with 2-(3-chlorophenyl)-6-methyl-1,2-dihydro-1H-pyridin-4-one 9b, the most effective derivative in this model, have been reported.

Synthesis and preliminary in vitro evaluation of antimycobacterial activity of new pyrrolo[1,2-a] quinoxaline-carboxylic acid hydrazide derivatives.

New pyrrolo[1,2-a]quinoxaline-2- or -4-carboxylic acid hydrazide derivatives were synthesized from nitroaniline or 1,2-phenylenediamine, and evaluated in vitro for their antimycobacterial activity as part of a TAACF TB screening program. Two compounds 7c and 13 showed an interesting activity at 6.25 microg/mL against Mycobacterium tuberculosis H37Rv, with a 94 and 100 percentage inhibition, respectively.

Synthesis and biological evaluation of thienopyrrolizines, a new family of CDK/GSK-3 inhibitors.

Fifteen new thieno[2,3-b ]- and thieno[3,4-b]pyrrolizines were synthesized and tested against two protein kinases, CDK1/cyclin B and GSK-3. Among these compounds, 3-(3-hydroxy-4-methoxyphenyl)-8H-thieno[2,3-b]pyrrolizin-8-one 4g was identified as a moderate inhibitor of these kinases. Its molecular modeling study brought to the fore the pivotal role of the 2-methoxyphenol grouping and the interest in replacing it by bioisosteric moieties in future pharmacomodulations.

Synthesis and biological evaluation of cyclopenta[c]thiophene related compounds as new antitumor agents.

A series of 22 cyclopenta[c]thiophene related compounds was obtained by the pharmacomodulation of 6-amino-5,6-dihydro-4H-cyclopenta[c]thiophen-4-ones 1a-g. All compounds were evaluated for potential anticancer activity in the NCI's in vitro human disease-oriented tumor cell line screening panel that consisted of 60 human tumor cell lines arranged in nine subpanels, representing diverse histologies. Among these tested compounds, seven were found to be cytotoxic, especially against leukemia cell lines, allowing us to point out some structure-activity relationships. These derivatives were further evaluated for potential in vivo anticancer activity in the hollow fiber assay developed at the NCI, which selected two compounds, 1f and 3a for standard xenograft testing.