Crystal structure of (S)-2-[(3S,8S,9S,10R,13S,14S,-17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta-[a]phenanthren-17-yl]-N-methoxy-N-methylpropanamide (Fernholz Weinreb amide)

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Antimicrobial Activity and Cytotoxicity of Ag(I) and Au(I) Pillarplexes

The biological activity of four pillarplex compounds featuring different metals and anions was investigated. The toxicity of the compounds against four bacterial strains [Bacillus subtilis (ATCC6633), Staphylococcus aureus (ATCC6538), Escherichia coli (UVI isolate), Pseudomonas aeruginosa], one fungus (Candida albicans), and a human cell line (HepG2) was determined. Additionally, a UV-Vis titration study of the pillarplexes was carried out to check for stability depending on pH- and chloride concentration changes and evaluate the applicability in physiological media. All compounds are bioactive: the silver compounds showed higher activity against bacteria and fungi, and the corresponding gold pillarplexes were less toxic against human cells

Degradative behavior and toxicity of alkylated imidazoles

The thermal and oxidative degradation behavior and the corrosiveness of imidazole (Im), 2-methylimidazole (2MIm), 2-ethyl-4-methylimidazole (2E4MIm), 2,4,5-trimethylimidazole (2,4,5MIm), and 1,2,4,5-tetramethylimidazole (1,2,4,5MIm) were investigated in a CO2 rich environment. The imidazoles demonstrated high thermal stability in all solutions; however, Im and 2MIm were corrosive. Polyalkylated imidazoles were less stable toward oxidation compared to Im. Rat cell (PC-12) toxicology screening of Im and 45 alkylated imidazoles showed reduced toxicity for polyalkylated imidazoles compared to Im. Cell viability correlated negatively with cLogP predictions when cLogP > 3. The high rate of oxidative degradation and formation of potentially carcinogenic degradation products will prevent the use of polyalkylated imidazoles in industrial processes directed toward CO2

Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases

Inhibition of bacterial virulence is believed to be a new treatment option for bacterial infections. In the present study, we tested dipicolylamine (DPA), tripicolylamine (TPA), tris pyridine ethylene diamine (TPED), pyridine and thiophene derivatives as putative inhibitors of the bacterial virulence factors thermolysin (TLN), pseudolysin (PLN) and aureolysin (ALN) and the human zinc metalloproteases, matrix metalloprotease-9 (MMP-9) and matrix metalloprotease-14 (MMP-14). These compounds have nitrogen or sulfur as putative donor atoms for zinc chelation. In general, the compounds showed stronger inhibition of MMP-14 and PLN than of the other enzymes, with Ki values in the lower µM range. Except for DPA, none of the compounds showed significantly stronger inhibition of the virulence factors than of the human zinc metalloproteases. TPA and Zn230 were the only compounds that inhibited all five zinc metalloproteinases with a Ki value in the lower µM range. The thiophene compounds gave weak or no inhibition. Docking indicated that some of the compounds coordinated zinc by one oxygen atom from a hydroxyl or carbonyl group, or by oxygen atoms both from a hydroxyl group and a carbonyl group, and not by pyridine nitrogen as in DPA and TPA

Synthesis and biological evaluation of new dipicolylamine zinc chelators as metallo-β-lactamase inhibitors

Antibiotics are key drugs in modern healthcare, especially in hospitals, where multiresistant bacteria resides and is a potential threat to human health. In the present work, a new series of adjuvants working synergistically with the carbapenem meropenem, in which a selective zinc-chelating agent was covalently linked to the small bacterial peptide D-Ala-D-Ala, was synthesized and tested against VIM-2 and NDM-1 metallo-β-lactamases (MBLs). The nature of the linker was modified in a structure-activity relationship study. Compound 1i, having an ethyl piperidine linker, lowered the MIC of meropenem from 32 to 64 mg/L to 2 and 1–2 mg/L against VIM-2- and NDM-1-producing clinical isolates, respectively. The IC50 value of 1i against VIM-2 was 9.8 and 2.2 μM after 5 and 20 min, respectively. Compound 1i also showed intrinsic toxicity against three eukaryotic human tumoral cell lines between 50 and 120 μM

Synthesis, in vitro and in vivo biological evaluation of new oxysterols as modulators of the liver X receptors

Liver X Receptor (LXR) modulators have shown potential as drugs since they target genes affecting metabolism and fatty acid synthesis. LXR antagonists are of particular interest since they are able to reduce the synthesis of complex fatty acids and glucose uptake. Based on molecular modeling, five new cholesterol mimics were synthesized, where four contained a hydroxyl group in the 22-S-position. The new compounds were screened in vitro against several genes affecting lipid metabolism. The compound that performed best in vitro was a dimethylamide derivative of 22(S)-hydroxycholesterol and it was chosen for in vivo testing. However, the blood plasma analysis from the in vivo tests revealed a concentration lower than needed to give any response, indicating either rapid metabolism or low bioavailability

Synthesis and biological evaluation of zinc chelating compounds as metallo-β-lactamase inhibitors

International audienceThe syntheses of metallo-β-lactamase inhibitors comprising chelating moieties, with varying zinc affinities,and peptides partly inspired from bacterial peptide sequences, have been undertaken. The zinc chelatorstrength was varied using the following chelators, arranged in order of ascending binding affinity:dipicolylamine (DPA, tridentate), dipicolyl-1,2,3-triazolylmethylamine (DPTA, tetradentate) dipicolyl ethylenediamine(DPED, tetradentate) and trispicolyl ethylenediamine (TPED, pentadentate). The chosen peptideswere mainly based on the known sequence of the C-terminus of the bacterial peptidoglycan precursors.Biological evaluation on clinical bacterial isolates, harbouring either the NDM-1 or VIM-2 metallo-β-lactamase, showed a clear relationship between the zinc chelator strength and restoration of meropenemactivity. However, evaluation of toxicity on different cancer cell lines demonstrated a similar trend, and thusinclusion of the bacterial peptides did possess rather high toxicity towards eukaryotic cells

Synthesis and preclinical evaluation of TPA-based zinc chelators as metallo-β-lactamase inhibitors

International audienc

ZN148 Is a Modular Synthetic Metallo-beta-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound