ABSTRACT
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.
Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Acetylcholinesterase/chemistry , Alzheimer Disease/drug therapy , Amino Acid Sequence , Animals , Electrophorus/metabolism , Humans , Ligands , Models, Molecular , Molecular Sequence Data , Sequence Alignment , Small Molecule Libraries , Structure-Activity Relationship , Torpedo/metabolismABSTRACT
Virtual screening studies have identified a series of phenylpyrroles as novel 5-HT7 receptor ligands. The synthesis and the affinity for the 5-HT7 receptor of these phenylpyrroles are described. Some of these compounds exhibited high affinity for the 5-HT7 receptors.
Subject(s)
Pyrroles/classification , Pyrroles/pharmacology , Receptors, Serotonin/drug effects , Animals , Binding, Competitive/drug effects , Drug Evaluation, Preclinical , Humans , Ligands , Molecular Structure , Pyrroles/chemical synthesis , Rats , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
CDC2 Protein Kinase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glycogen Synthase Kinase 3/antagonists & inhibitors , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Binding Sites/drug effects , Cell Cycle/drug effects , Crystallography, X-Ray , Cyclin B/antagonists & inhibitors , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Protein Conformation , Protein Structure, Tertiary , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
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.