Synthesis of aminopyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives as serotoninergic 5-HT7 ligands

A series of piperazinopyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives were prepared and evaluated to determine their affinity for the 5-HT7 receptor. Various substitutions on piperazine were explored as well as replacement of the piperazine by other amines

MR22388, a novel anti-cancer agent with a strong FLT-3 ITD kinase affinity.

International audienceThis work describes the study of the mechanism of action and spectrum of activity of MR22388, a novel anti-cancer agent belonging to the tripentone series. MR22388 is highly cytotoxic (within the nanomolar range) against numerous cancer cell lines and studies of its cytotoxicity mechanisms show that it is a weak inhibitor of the polymerization of tubulin and that it induces apoptosis via the MAP kinase pathways. Further MR22388 is a very strong inhibitor of several kinases including the tyrosine kinase FLT3-ITD. FLT3-ITD is a mutated form of the tyrosine kinase receptor (RTK) FLT3, resulting in the constitutive activation of the kinase, occurring in about 25% of normal karyotypes' Acute Myeloid Leukemia (AML) and is linked to a bad prognosis. Consecutively, MR22388 appears as a novel promising anticancer lead agent especially for AML therapy

MR22388, a novel anti-cancer agent with a strong FLT-3 ITD kinase affinity

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3D Pharmacophore, hierarchical methods, and 5-HT4 receptor binding data.

International audience5-Hydroxytryptamine subtype-4 (5-HT(4)) receptors have stimulated considerable interest amongst scientists and clinicians owing to their importance in neurophysiology and potential as therapeutic targets. A comparative analysis of hierarchical methods applied to data from one thousand 5-HT(4) receptor-ligand binding interactions was carried out. The chemical structures were described as chemical and pharmacophore fingerprints. The definitions of indices, related to the quality of the hierarchies in being able to distinguish between active and inactive compounds, revealed two interesting hierarchies with the Unity (1 active cluster) and pharmacophore fingerprints (4 active clusters). The results of this study also showed the importance of correct choice of metrics as well as the effectiveness of a new alternative of the Ward clustering algorithm named Energy (Minimum E-Distance method). In parallel, the relationship between these classifications and a previously defined 3D 5-HT(4) antagonist pharmacophore was established

Boronic species as promising inhibitors of the Staphylococcus aureus NorA efflux pump: Study of 6-substituted pyridine-3-boronic acid derivatives

International audienceIn response to the extensive use of antibiotics, bacteria have evolved numerous mechanisms of defense against antimicrobial agents. Among them, extrusion of the antimicrobial agents outside the bacterial cell through efflux pumps is a major cause of concern. At first limited to one or few structurally-related antibiotics, bacterial resistance have then progressed towards cross-resistance between different classes of antibiotics, leading to multidrug-resistant microorganisms. Emergence of these pathogens requires development of novel therapeutic strategies and inhibition of efflux pumps appears to be a promising strategy that could restore the potency of existing antibiotics. NorA is the most studied chromosomal efflux pump of Staphylococcus aureus; it is known to be implied in resistance of Methicillin-resistant S. aureus (MRSA) strains against a wide range of unrelated substrates, including hydrophilic fluoroquinolones. Starting from 6-benzyloxypyridine-3-boronic acid I that we previously identified as a potential inhibitor of the NorA efflux pump against the NorA-overexpressing S. aureus 1199B strain (SA1199B), we describe here the synthesis and biological evaluation of a series of 6-(aryl)alkoxypyridine-3-boronic acids. 6-(3-Phenylpropoxy)pyridine-3-boronic acid 3i and 6-(4-phenylbutoxy)pyridine-3-boronic acid 3j were found to potentiate ciprofloxacin activity by a 4-fold increase compared to the parent compound I. In addition, it has been shown that both compounds promote Ethidium Bromide (EtBr) accumulation in SA1199B, thus corroborating their potential mode of action as NorA inhibitors

First Identification of Boronic Species as Novel Potential Inhibitors of the Staphylococcus aureus NorA Efflux Pump.

International audienceOverexpression of efflux pumps is an important mechanism of bacterial resistance that results in the extrusion of antimicrobial agents outside the bacterial cell. Inhibition of such pumps appears to be a promising strategy that could restore the potency of existing antibiotics. The NorA efflux pump of Staphylococcus aureus confers resistance to a wide range of unrelated substrates, such as hydrophilic fluoroquinolones, leading to a multidrug-resistance phenotype. In this work, approximately 150 heterocyclic boronic species were evaluated for their activity against susceptible and resistant strains of S. aureus. Twenty-four hit compounds, although inactive when tested alone, were found to potentiate ciprofloxacin activity by a 4-fold increase at concentrations ranging from 0.5 to 8 μg/mL against S. aureus 1199B, which overexpresses NorA. Boron-free analogues showed no biological activity, thus revealing that the boron atom is crucial for biological activity. This work describes the first reported efflux pump inhibitory activity of boronic acid derivatives

Definition of New Pharmacophores for Nonpeptide Antagonists of Human Urotensin-II. Comparison with the 3D-structure of Human Urotensin-II and URP

International audienceStarting from nonpeptide agonists and antagonists of human urotensin-II (hU-II), several pharmacophores were designed and compared to the structure of hU-II. NMR and dynamic studies were realized on hU-II and urotensin-II-related peptide to check the conformation flexibilities of these peptides and the relationships between their potential 3D structures and the pharmacophores. In parallel, a virtual screening was carried out, leading to the discovery of six new derivatives with micromolar affinities. This last result shows the interest of these pharmacophores for the discovery of new ligands

Small molecules interfere with the tip-polarized growth of Arabidopsis and tomato pollen

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Dual Histamine H3R/Serotonin 5-HT4R Ligands with Antiamnesic Properties: Pharmacophore-Based Virtual Screening and Polypharmacology.

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Four Partners, Three-Step, One-Pot Reaction for a Library of New 2-Alkyl(dialkyl)aminoquinazolin-4(3 H )-ones

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