The outer membrane (OM) of Gram-negative bacteria provides an efficient barrier against external noxious compounds such as antimicrobial agents. Associated with drug target modification it contributes to the overall failure of chemotherapy. In the complex OM architecture, Lipid A plays an essential role by anchoring the lipopolysaccharide in the membrane and ensuring the spatial organization between lipids, proteins, and sugars.Currently, the targets of almost all antibiotics are intracellularly located and required for translocation across membranes. We report herein an integrated view of Lipid A synthesis, membrane assembly, a structure comparison at the molecular structure level of numerous Gram-negative bacterial species as well as its recent use as a target for original antibacterial molecules. This review paves the way for a new vision of a key membrane component that acts during bacterial adaptation to environmental stresses and for the development of new weapons against microbial resistance to usual antibiotics.
Several monocyclic β-lactams have been synthesized via a [2 + 2] ketene-imine cycloaddition reaction (Staudinger reaction) and evaluated for their biological activities. The structure of synthesized products was confirmed by spectral data and elemental analyses. β-Lactams 4 b and 4 h exhibited 31 and 27 anti-inflammatory ratios, respectively, which are as well as the well-known dexamethasone corticosteroid with a 32 antiinflammatory ratio. The two most active compounds 4 b and 4 h showed IC 50 values more than 200 μM against the HepG2 cell line, in comparison with doxorubicin (IC 50 < 1 μM), indicated biocompatibility and nontoxic behavior. 4 d, 4 j, 4 k, and 4 l, were active against S. aureus and E. coli and had broad spectrum property. The tested compounds were subjected to in silico prediction of pharmacokinetics properties (ADMET) to assess the potential in vivo effectiveness. The molecular docking study confirmed that the active inhibitors 4 b and 4 h are well fitted in the iNOS active site. This data suggests that 4 b and 4 h could potentially serve as effective iNOS inhibitors, a represent promising lead compounds for treating inflammatory disorders.
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