ABSTRACT
This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) <5 nM) and cellular activity against P. aeruginosa (best minimal inhibitory concentration (MIC) of 4 µg/mL). Lack of activity against E. coli was maintained (IC50 > 20 µM and MIC > 128 µg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.
Subject(s)
Acyltransferases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Pseudomonas aeruginosa/drug effects , Anti-Bacterial Agents/chemistry , Crystallography, X-Ray , Drug Resistance, Bacterial/drug effects , Enzyme Inhibitors/chemistry , Escherichia coli/enzymology , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
The aim of this study was to verify the effect of several cyclic onium based ionic liquids (ILs), including mono- and dicationic derivatives of 1,4-diazabicyclo[2.2.2]octane (DABCO), a dialkyl morpholinium salt and a Brønsted acidic IL, as enhancers of the in vitro transdermal permeation and skin retention of diltiazem through and into hairless rat skin. The drug was used as both the hydrochloride salt (DZHCl) and the free base (DZB) to highlight the relationship between the enhancement effect and the physico-chemical characteristics of the active agent. Permeation tests were carried out using Gummer-type diffusion cells and excised rat skin with a 0.005M aqueous solution of diltiazem hydrochloride or diltiazem free base with and without the addition of 1% w/w ionic liquids. At the end of the permeation experiments with diltiazem hydrochloride, a suitable extraction procedure allowed for the determination of the drug content retained in the skin. Depending on the ionic liquid structure, a significant enhancement in diltiazem hydrochloride levels in the receiving phase was observed, and the transdermal permeation of the diltiazem free base was markedly increased by treatment with all of the ionic liquids. N-dodecyldabco bromide was the best enhancer for both salified and free base drug forms, even though it showed a certain toxicity. On the other hand, N-methyl-N-decylmorpholinium bromide showed a good balance between enhancer activity and cytotoxicity.
Subject(s)
Calcium Channel Blockers/administration & dosage , Diltiazem/administration & dosage , Drug Delivery Systems , Ionic Liquids/chemistry , Administration, Cutaneous , Animals , Calcium Channel Blockers/pharmacokinetics , Chemistry, Pharmaceutical/methods , Diltiazem/pharmacokinetics , Excipients/chemistry , Male , Permeability , Rats , Rats, Hairless , Skin/metabolism , Skin AbsorptionABSTRACT
Ionic liquids (ILs) composed of two different pyrazolium cations with dicyanamide and bis(trifluoromethanesulfonyl)imide anions have been synthesized and characterized by NMR, Kamlet-Taft solvatochromic parameters, conductivity and rheological measurements, as well as ab initio calculations. Density functional calculations for the two pyrazolium cations, 1-butyl-2-methylpyrazolium [bmpz] and 1-butyl-2,3,5-trimethylpyrazolium [bm(3)pz], provide a full picture of their conformational states. Homo- and heteronuclear NOE show aggregation motives sensitive to steric hindrance and the anions' nature. Self-diffusion coefficients D for the anion and the cation have been measured by pulsed field gradient spin-echo NMR (PGSE-NMR). The ionic diffusivity is influenced by their chemical structure and steric hindrance, giving the order D(cation) > D(anion) for all of the examined compounds. The measured ion diffusion coefficients, viscosities, and ionic conductivity follow the Vogel-Fulcher-Tammann (VFT) equation for the temperature dependencies, and the best-fit parameters have been determined. Solvatochromic parameters indicate an increased ion association upon going from bis(trifluoromethanesulfonyl)imide to dicyanamide-based pyrazolium salts, as well as specific hydrogen bond donor capability of H atoms on the pyrazolium ring. All of these physical properties are compared to those of an analogous series of imidazolium-based ILs.
Subject(s)
Imidazoles/chemistry , Ionic Liquids/chemistry , Pyrazoles/chemistry , Anions/chemistry , Cations/chemistry , Electric Conductivity , Hydrogen Bonding , Magnetic Resonance Spectroscopy , ViscosityABSTRACT
The regioselectivity of copper(I)-catalyzed synthesis of 1,2,3-triazoles in dabco-based ionic liquids has been investigated at the DFT level using a supermolecular approach. The analysis of the theoretical results shows that the coordination ability of the ionic liquid (IL) anion to copper(I) catalyst and to all the other species containing the copper (intermediates and transition states) can significantly affect product distribution. Possible catalyst sequestering effects and the ability to stabilize selectively new intermediate species have been envisaged, as probable mechanisms throughout IL anions can affect copper catalyzed reactions inside performed.
