- ANTIBIOTIC RESISTANCE BREAKERS
-
The invention relates to antibiotic compounds of formula (A1) and pharmaceutically acceptable salts, solvates, tautomers and combinations thereof, wherein X and L are optional linkers and one of RA or R1 comprises Ar1, wherein Ar1 is an antibiotic resistance breaker moiety which comprises an optionally substituted C6-10 aryl, C7-13 aralkyl, C5-10 heteroaryl, C6-13 heteroaralkyl, C5-10 heterocyclyl, C6-13 heterocyclalkyl, C3-10 carbocyclyl, C4-13 carbocyclalkyl, -C(=NR')-NR'R'' or –CH2- CH=CH2 group; wherein after administration of the compound to a bacterial infection this moiety reduces or prevents efflux. The invention also discloses pharmaceutical compositions comprising compounds of formula (A1) and the use of such compounds as medicaments, in particular, to treat bacterial infections, such as drug-resistant bacterial infections.
- -
-
Page/Page column 126
(2019/01/05)
-
- Selective targeting of dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (Dc-Sign) with mannose-based glycomimetics: Synthesis and interaction studies of bis(benzylamide) derivatives of a pseudomannobioside
-
Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and Langerin are C-type lectins of dendritic cells (DCs) that share a specificity for mannose and are involved in pathogen recognition. HIV is known to use DC-SIGN on DCs to facilitate transinfection of T-cells. Langerin, on the contrary, contributes to virus elimination; therefore, the inhibition of this latter receptor is undesired. Glycomimetic molecules targeting DC-SIGN have been reported as promising agents for the inhibition of viral infections and for the modulation of immune responses mediated by DC-SIGN. We show here for the first time that glycomimetics based on a mannose anchor can be tuned to selectively inhibit DC-SIGN over Langerin. Based on structural and binding studies of a mannobioside mimic previously described by us (2), a focused library of derivatives was designed. The optimized synthesis gave fast and efficient access to a group of bis(amides), decorated with an azide-terminated tether allowing further conjugation. SPR inhibition tests showed improvements over the parent pseudomannobioside by a factor of 3-4. A dimeric, macrocyclic structure (11) was also serendipitously obtained, which afforded a 30-fold gain over the starting compound (2). The same ligands were tested against Langerin and found to exhibit high selectivity towards DC-SIGN. Structural studies using saturation transfer difference NMR spectroscopy (STD-NMR) were performed to analyze the binding mode of one representative library member with DC-SIGN. Despite the overlap of some signals, it was established that the new ligand interacts with the protein in the same fashion as the parent pseudodisaccharide. The two aromatic amide moieties showed relatively high saturation in the STD spectrum, which suggests that the improved potency of the bis(amides) over the parent dimethyl ester can be attributed to lipophilic interactions between the aromatic groups of the ligand and the binding site of DC-SIGN. Receptor targeting: For the first time glycomimetics based on a mannose anchor have been tuned to selectively inhibit DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin) over Langerin. Based on structural and binding studies of a mannobioside mimic previously described, a focused library of derivatives was designed (see figure). Copyright
- Varga, Norbert,Sutkeviciute, Ieva,Guzzi, Cinzia,McGeagh, John,Petit-Haertlein, Isabelle,Gugliotta, Serena,Weiser, J?rg,Angulo, Jesús,Fieschi, Franck,Bernardi, Anna
-
supporting information
p. 4786 - 4797
(2013/05/21)
-
- Oxidation of benzylic alcohols and ethers to carbonyl derivatives by nitric acid in dichloromethane
-
Nitric acid in dichloromethane may be successfully employed for the oxidation of benzylic alcohols and ethers to the corresponding carbonyl compounds. The proposed method proved to be of general applicability, affording very good yields of aldehydes and ketones and showing interesting chemoselectivity in many instances, allowing competitive aromatic nitration to be avoided, as well as - in the case of aldehydes - any further oxidation to carboxylic acids. The reaction probably proceeds by a radical mechanism, the active species in the oxidation process being NO2. Competitive formation of nitro esters was observed in some cases, whereas poor results were obtained with allylic and non-benzylic substrates. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Strazzolini, Paolo,Runcio, Antonio
-
p. 526 - 536
(2007/10/03)
-