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A Fine-Tuned Lipophilicity/Hydrophilicity Ratio Governs Antibacterial Potency and Selectivity of Bifurcated Halogen Bond-Forming NBTIs.

ABSTRACT: Herein, we report the design of a focused library of novel bacterial topoisomerase inhibitors (NBTIs) based on innovative mainly monocyclic right-hand side fragments active against DNA gyrase and Topo IV. They exhibit a very potent and wide range of antibacterial activity, even against some of the most concerning hard-to-treat pathogens for which new antibacterials are urgently needed, as reported by the WHO and CDC. NBTIs enzyme activity and whole cell potency seems to depend on the fine-tuned lipophilicity/hydrophilicity ratio that governs the permeability of those compounds through the bacterial membranes. Lipophilicity of NBTIs is apparently optimal for passing through the membrane of Gram-positive bacteria, but the higher, although not excessive lipophilicity and suitable hydrophilicity seems to determine the passage through Gram-negative bacterial membranes. However, due to the considerable hERG inhibition, which is still at least two orders of magnitude away from MICs, continued optimization is required to realize their full potential.

SUBMITTER: Kolaric A

PROVIDER: S-EPMC8300687 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Preparation and Hydrophilicity/Lipophilicity of Solubility-Switchable Ionic Liquids.

Project description:Various solubility-switchable ionic liquids were prepared. Their syntheses were readily achieved in a few steps from glyceraldehyde dimethylacetal or its derivatives. Pyridinium, imidazolium, and phosphonium derivatives also exhibited solubility-switchable properties; acetal-type ionic liquids were soluble in organic solvents, while diol-type ones exhibited a preference for being dissolved in the aqueous phase. The solubility of the ionic liquids prepared in this study also depended on the number of carbon atoms in the cationic parts of the ionic liquids. Interconversion between the diol-type and the acetal-type ionic liquids was readily achieved under the standard conditions for diol acetalization and acetal hydrolysis. One of the prepared ionic liquids was also examined as a solvent for an organic reaction.

| S-EPMC9798742 | biostudies-literature

Conformational Fine-Tuning of Pore-Forming Peptide Potency and Selectivity.

Project description:To better understand the sequence-structure-function relationships that control the activity and selectivity of membrane-permeabilizing peptides, we screened a peptide library, based on the archetypal pore-former melittin, for loss-of-function variants. This was accomplished by assaying library members for failure to cause leakage of entrapped contents from synthetic lipid vesicles at a peptide-to-lipid ratio of 1:20, 10-fold higher than the concentration at which melittin efficiently permeabilizes the same vesicles. Surprisingly, about one-third of the library members are inactive under these conditions. In the negative peptides, two changes of hydrophobic residues to glycine were especially abundant. We show that loss-of-function activity can be completely recapitulated by a single-residue change of the leucine at position 16 to glycine. Unlike the potently cytolytic melittin, the loss-of-function peptides, including the single-site variant, are essentially inactive against phosphatidylcholine vesicles and multiple types of eukaryotic cells. Loss of function is shown to result from a shift in the binding-folding equilibrium away from the active, bound, α-helical state toward the inactive, unbound, random-coil state. Accordingly, the addition of anionic lipids to synthetic lipid vesicles restored binding, α-helical secondary structure, and potent activity of the "negative" peptides. While nontoxic to mammalian cells, the single-site variant has potent bactericidal activity, consistent with the anionic nature of bacterial membranes. The results show that conformational fine-tuning of helical pore-forming peptides is a powerful way to modulate their activity and selectivity.

| S-EPMC4697923 | biostudies-other

The Important Role of Halogen Bond in Substrate Selectivity of Enzymatic Catalysis.

Project description:The use of halogen bond is widespread in drug discovery, design, and clinical trials, but is overlooked in drug biosynthesis. Here, the role of halogen bond in the nitrilase-catalyzed synthesis of ortho-, meta-, and para-chlorophenylacetic acid was investigated. Different distributions of halogen bond induced changes of substrate binding conformation and affected substrate selectivity. By engineering the halogen interaction, the substrate selectivity of the enzyme changed, with the implication that halogen bond plays an important role in biosynthesis and should be used as an efficient and reliable tool in enzymatic drug synthesis.

| S-EPMC5052520 | biostudies-literature

Halogen Bonding Increases the Potency and Isozyme Selectivity of Protein Arginine Deiminase 1 Inhibitors.

Project description:Protein arginine deiminases (PADs) hydrolyze the side chain of arginine to form citrulline. Aberrant PAD activity is associated with rheumatoid arthritis, multiple sclerosis, lupus, and certain cancers. These pathologies established the PADs as therapeutic targets and multiple PAD inhibitors are known. Herein, we describe the first highly potent PAD1-selective inhibitors (1 and 19). Detailed structure-activity relationships indicate that their potency and selectivity is due to the formation of a halogen bond with PAD1. Importantly, these inhibitors inhibit histone H3 citrullination in HEK293TPAD1 cells and mouse zygotes with excellent potency. Based on this scaffold, we also developed a PAD1-selective activity-based probe that shows remarkable cellular efficacy and proteome selectivity. Based on their potency and selectivity we expect that 1 and 19 will be widely used chemical tools to understand PAD1 biology.

| S-EPMC6713606 | biostudies-literature

The Halogen Bond.

Project description:The halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity. In this fairly extensive review, after a brief history of the interaction, we will provide the reader with a snapshot of where the research on the halogen bond is now, and, perhaps, where it is going. The specific advantages brought up by a design based on the use of the halogen bond will be demonstrated in quite different fields spanning from material sciences to biomolecular recognition and drug design.

| S-EPMC4768247 | biostudies-other

Crystal Structure Survey and Theoretical Analysis of Bifurcated Halogen Bonds.

Project description:The possibility that two Lewis bases can share a single halogen atom within the context of a bifurcated halogen bond (XB) is explored first by a detailed examination of the CSD. Of the more than 22,000 geometries that fit the definition of an XB (with X = Cl, Br, I), less than 2% are bifurcated. There is a heavy weighting of I in such bifurcated arrangements as opposed to Br, which prefers monofurcated bonds. The conversion from mono to bifurcated is associated with a smaller number of short contact distances, as well as a trend toward lesser linearity. The two XBs within a bifurcated system are somewhat symmetrical: the two lengths generally differ by less than 0.05 Å, and the two XB angles are within several degrees of one another. Quantum calculations of model systems reflect the patterns observed in crystals and reinforce the idea that the negative cooperativity within a bifurcated XB weakens and lengthens each individual bond.

| S-EPMC9634799 | biostudies-literature

Activation of a Metal-Halogen Bond by Halogen Bonding.

Project description:In recent years, the non-covalent interaction of halogen bonding (XB) has found increasing application in organocatalysis. However, reports of the activation of metal-ligand bonds by XB have so far been limited to a few reactions with elemental iodine or bromine. Herein, we present the activation of metal-halogen bonds by two classes of inert halogen bond donors and the use of the resulting activated complexes in homogenous gold catalysis. The only recently explored class of iodolium derivatives were shown to be effective activators in two test reactions and their activity could be modulated by blocking of the Lewis acidic sites. Bis(benzimidazolium)-based halogen bonding activators provided even more rapid conversion, while the non-iodinated reference compound showed little activity. The role of halogen bonding in the activation of metal-halogen bonds was further investigated by NMR experiments and DFT calculations, which support the mode of activation occurring via halogen bonding.

| S-EPMC7540446 | biostudies-literature

Nature of the Hydrogen Bond Enhanced Halogen Bond.

Project description:The factors responsible for the enhancement of the halogen bond by an adjacent hydrogen bond have been quantitatively explored by means of state-of-the-art computational methods. It is found that the strength of a halogen bond is enhanced by ca. 3 kcal/mol when the halogen donor simultaneously operates as a halogen bond donor and a hydrogen bond acceptor. This enhancement is the result of both stronger electrostatic and orbital interactions between the XB donor and the XB acceptor, which indicates a significant degree of covalency in these halogen bonds. In addition, the halogen bond strength can be easily tuned by modifying the electron density of the aryl group of the XB donor as well as the acidity of the hydrogen atoms responsible for the hydrogen bond.

| S-EPMC8036253 | biostudies-literature

Halogen Bond Asymmetry in Solution.

Project description:Halogen bonding is the noncovalent interaction of halogen atoms in which they act as electron acceptors. Whereas three-center hydrogen bond complexes, [D···H···D]+ where D is an electron donor, exist in solution as rapidly equilibrating asymmetric species, the analogous halogen bonds, [D···X···D]+, have been observed so far only to adopt static and symmetric geometries. Herein, we investigate whether halogen bond asymmetry, i.e., a [D-X···D]+ bond geometry, in which one of the D-X bonds is shorter and stronger, could be induced by modulation of electronic or steric factors. We have also attempted to convert a static three-center halogen bond complex into a mixture of rapidly exchanging asymmetric isomers, [D···X-D]+ ⇄ [D-X···D]+, corresponding to the preferred form of the analogous hydrogen bonded complexes. Using 15N NMR, IPE NMR, and DFT, we prove that a static, asymmetric geometry, [D-X···D]+, is obtained upon desymmetrization of the electron density of a complex. We demonstrate computationally that conversion into a dynamic mixture of asymmetric geometries, [D···X-D]+ ⇄ [D-X···D]+, is achievable upon increasing the donor-donor distance. However, due to the high energetic gain upon formation of the three-center-four-electron halogen bond, the assessed complex strongly prefers to form a dimer with two static and symmetric three-center halogen bonds over a dynamic and asymmetric halogen bonded form. Our observations indicate a vastly different preference in the secondary bonding of H+ and X+. Understanding the consequences of electronic and steric influences on the strength and geometry of the three-center halogen bond provides useful knowledge on chemical bonding and for the development of improved halonium transfer agents.

| S-EPMC6209183 | biostudies-literature

π covalency in the halogen bond.

Project description:Halogen bonds are a highly directional class of intermolecular interactions widely employed in chemistry and chemical biology. This linear interaction is commonly viewed to be analogous to the hydrogen bond because hydrogen bonding models also intuitively describe the σ-symmetric component of halogen bonding. The possibility of π-covalency in a halogen bond is not contemplated in any known models. Here we present evidence of π-covalency being operative in halogen bonds formed between chloride and halogenated triphenylamine-based radical cations. We reach this conclusion through computational analysis of chlorine K-edge X-ray absorption spectra recorded on these halogen bonded pairs. In light of this result, we contend that halogen bonding is better described by analogy to metal coordination bonds rather than hydrogen bonds. Our revised description of the halogen bond suggests that these interactions could be employed to influence the electronic properties of conjugated molecules in unique ways.

| S-EPMC7335087 | biostudies-literature

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