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International audience; Brain amyloid deposits have been identified as the main neuropathological hallmarks of Alzheimer's diseases (AD) and intensive efforts have been devoted to develop aggregation inhibitors preventing the formation of toxic oligomeric Aβ for therapeutic. In addition, evidence indicates that the formation and accumulation of β−amyloid plaques probably precede clinical symptoms by around 20 years and imaging of such plaques would be beneficial for early-stage AD detection. In this study, we investigated phenothiazine-based compounds as novel promising theranostic agents for AD. These multifunctional agents exhibited BBB permeability, low neurotoxicity, good bio-stability as well as strong turn-on fluorescence with a Stokes shift upon binding to Aβ aggregates. They had metal-chelating property which could delay Aβ aggregation and displayed high binding affinity for β−amyloid aggregates. Moreover, they have been simultaneously applied to perform in vivo near-infrared fluorescence imaging of β-amyloid plaques in double transgenic AD mouse model, to prevent self-aggregation of Aβ monomer from forming toxic oligomers and to protect human neuroblastoma SH-SY5Y cells against Aβ-induced toxicity and oxidative stress.

Novel topoisomerase II (Topo II) inhibitors have gained considerable interest for the development of anticancer agents. In this study, a series of carbazole derivatives containing chalcone analogs (CDCAs) were synthesized and investigated for their Topo II inhibition and cytotoxic activities. The results from Topo II mediated DNA relaxation assay showed that CDCAs could significantly inhibit the activity of Topo II, and the structure-activity relationship indicated the halogen substituent in phenyl ring play an important role in the activity. Further mechanism studies revealed that CDCAs function as non-intercalative Topo II catalytic inhibitors. Moreover, some CDCAs showed micromolar cytotoxic activities. The most potent compound 3h exhibited notable growth inhibition against four human cancer cell lines. Flow cytometric analysis revealed that compounds 3d and 3h arrested the HL-60 cells in sub G1 phase by induction of apoptosis. It was further confirmed by Annexin-V-FITC binding assay. Western blot analysis revealed that compound 3h induces apoptosis likely through the activation of caspase proteins.

Starting from 4-tetradecyloxybenzamidine ( PMS815 ), a non-specific inhibitor of GI and GII PLA 2 s, we report in this work the discovery of the specificity through design, synthesis and structure–activity relationships studies of different kinds of PMS815 derivatives. The leading compound, 4,5-dihydro-3-(4-tetradecyloxybenzyl)-1,2,4-4 H -oxadiazol-5-one ( 9b , PMS1062 ) exhibits a micromolar IC 50 towards three group II PLA 2 s, while inactive towards four group I and one group III enzymes in two in vitro enzymatic assay conditions. It is also able to block the PLA 2 -II activities induced by LPS and IL-6 in HepG 2 cell line and no cytotoxicity is observed when PMS1062 is tested up to a concentration of 100 μM in two different cell lines (A549 and LLC-PK 1 ).

Two series of rupestonic acid derivatives, (1-substituted-1H-1,2,3-triazol-4-yl)methyl 2-((5R,8S,8aS)-3,8-dimethyl-2-oxo-1,2,4,5,6,7,8,8a-octahydroazulen-5-yl)acrylate and N-(1-substituted-1H-1,2,3-triazol-4-yl)methyl 2-((5R,8S,8aS)-3,8-dimethyl-2-oxo-1,2,4,5,6,7,8,8a-octahydroazulen-5-yl)acrylamide were easily and efficiently synthesized via click chemistry. These compounds were tested for their in vitro activities against various strains of influenza A virus (H1N1, oseltamivir resistant H1N1, H3N2) and influenza B virus. The results showed that nine compounds were active against the H1N1 strain of influenza A virus and among them the best one 14a, was as active as the reference drugs, Oseltamivir and Ribavirin. Some of them were also active on the Oseltamivir resistant H1N1 strain. In regards to influenza B virus, twenty-one compounds over thirty were active and seven of them 7b, 8b, 9b, 10a, 11b, 12b, 13b showed better activity than Ribavirin. The structure-activity relationship of these compounds is discussed on the basis of each type of the viruses studied. Furthermore, four best representative compounds 7b, 10a, 12b and 14a were evaluated in a plaque assay experiment using MDCK cells and RBV as control compound and the results showed that 7b, 10a and 12b were better than RBV in inhibiting plaque formation, in good accordance with their anti-influenza B activities.

Starting from 4-tetradecyloxybenzamidine (PMS815), a non-specific inhibitor of GI and GII PLA2s, we report in this work the discovery of the specificity through design, synthesis and structure-activity relationships studies of different kinds of PMS815 derivatives. The leading compound, 4,5-dihydro-3-(4-tetradecyloxybenzyl)-1,2,4-4H-oxadiazol-5-one (9b, PMS1062) exhibits a micromolar IC50 towards three group II PLA2s, while inactive towards four group I and one group III enzymes in two in vitro enzymatic assay conditions. It is also able to block the PLA2-II activities induced by LPS and IL-6 in HepG2 cell line and no cytotoxicity is observed when PMS1062 is tested up to a concentration of 100 microM in two different cell lines (A549 and LLC-PK1).

1-Benzoyl-2-alkyl piperazines are strong inhibitors of Group I and II secreted PLA2s. An improvement of their activity was obtained by replacing the amide function by a sulfamide and by introduction of electrodonor substituents on the para position of the benzenesulfonyl moiety. Neither the position on one of the carbon of the piperazine ring nor the absolute configuration of this carbon have an effect on the affinity for one or the other group of PLA2, but the lipophilicity remains for these series an essential parameter. In addition structure–activity relationships allow new hypothesis on interaction of these piperazine derivatives with the catalytic site of PLA2s.