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Chemistry (Weinheim An Der Bergstrasse,... Sep 2022The ubiquity of amide bonds, present in natural products and common pharmaceuticals renders this functional group one of the most prevalent in organic chemistry. Despite...
The ubiquity of amide bonds, present in natural products and common pharmaceuticals renders this functional group one of the most prevalent in organic chemistry. Despite its importance and a wide variety of existing methods for its formation, the latter still can be a challenge for classical activating reagents such as chloridating agents or carbodiimides. As the spent reagents often cannot be recycled, the development of more sustainable methods is highly desirable. Herein, we report an operationally simple and mild indirect electrochemical protocol to effect the condensation of carboxylic acids with amines, forming a wide variety of carboxamides.
Topics: Amides; Amines; Biological Products; Carbodiimides; Carboxylic Acids; Indicators and Reagents; Iodides; Pharmaceutical Preparations
PubMed: 35835720
DOI: 10.1002/chem.202201768 -
European Journal of Medicinal Chemistry Jul 2024The prevention or control of bacterial infections requires continuous search for novel approaches among which bacterial quorum sensing inhibition is considered as a... (Review)
Review
The prevention or control of bacterial infections requires continuous search for novel approaches among which bacterial quorum sensing inhibition is considered as a complementary antibacterial strategy. Quorum sensing, used by many different bacteria, functions through a cell-to-cell communication mechanism relying on chemical signals, referred to as autoinducers, such as N-acyl homoserine lactones (AHLs) which are the most common chemical signals in this system. Designing analogs of these autoinducers is one of the possible ways to interfere with quorum sensing. Since bioisosteres are powerful tools in medicinal chemistry, targeting analogs of AHLs or other signal molecules and mimics of known QS modulators built on amide bond bioisosteres is a relevant strategy in molecular design and synthetic routes. This review highlights the application of amide bond bioisosteric replacement in the design and synthesis of novel quorum sensing inhibitors.
Topics: Quorum Sensing; Drug Design; Amides; Anti-Bacterial Agents; Acyl-Butyrolactones; Molecular Structure; Bacteria
PubMed: 38801798
DOI: 10.1016/j.ejmech.2024.116525 -
European Journal of Medicinal Chemistry Jan 2022A series of novel biaryl amide derivatives were synthesized and evaluated for anti-HCV virus activity. Some significant SARs were uncovered. The intensive structural...
A series of novel biaryl amide derivatives were synthesized and evaluated for anti-HCV virus activity. Some significant SARs were uncovered. The intensive structural modifications led to fifteen novel compounds with more potent inhibitory activity compared to the hit compounds IMB 26 and IMB1f. Among them, compound 80 was the most active, with EC values almost equivalent to the clinical drug telaprevir (EC = 15 nM). Furthermore, it also had a good safety and in vitro and oral pharmacokinetic (oral bioavailability in rats: 34%) profile, suggesting a highly drug-like nature. Compound 80represents a more promising scaffold for anti-HCV virus activity for further study.
Topics: Amides; Antiviral Agents; Cells, Cultured; Dose-Response Relationship, Drug; Hepacivirus; Humans; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship
PubMed: 34883293
DOI: 10.1016/j.ejmech.2021.114033 -
The Journal of Physical Chemistry. B Aug 2022The ability to exploit carbonyl groups to measure electric fields in enzymes and other complex reactive environments by using the vibrational Stark effect has inspired...
The ability to exploit carbonyl groups to measure electric fields in enzymes and other complex reactive environments by using the vibrational Stark effect has inspired growing interest in how these fields can be measured, tuned, and ultimately designed. Previous studies have concentrated on the role of the solvent in tuning the fields exerted on the solute. Here, we explore instead the role of the solute electronic structure in modifying the local solvent organization and electric field exerted on the solute. By measuring the infrared absorption spectra of amide-containing molecules, as prototypical peptides, and contrasting them with non-amide carbonyls in a wide range of solvents, we show that these solutes experience notable differences in their frequency shifts in polar solvents. Using vibrational Stark spectroscopy and molecular dynamics simulations, we demonstrate that while some of these differences can be rationalized by using the distinct intrinsic Stark tuning rates of the solutes, the larger frequency shifts for amides and dimethylurea primarily result from the larger solvent electric fields experienced by their carbonyl groups. These larger fields arise due to their stronger -π conjugation, which results in larger C═O bond dipole moments that further induce substantial solvent organization. Using electronic structure calculations, we decompose the electric fields into contributions from solvent molecules that are in the first solvation shell and those from the bulk and show that both of these contributions are significant and become larger with enhanced conjugation in solutes. These results show that structural modifications of a solute can be used to tune both the solvent organization and electrostatic environment, indicating the importance of a solute-centric paradigm in modulating and designing the electrostatic environment in condensed-phase chemical processes.
Topics: Amides; Electronics; Solutions; Solvents; Static Electricity
PubMed: 35901512
DOI: 10.1021/acs.jpcb.2c03095 -
Molecules (Basel, Switzerland) Jun 2021The almiramide -methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure-activity relationship study has been performed to...
The almiramide -methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure-activity relationship study has been performed to examine the influences of -methylation and conformation on activity against various strains of leishmaniasis protozoan and on cytotoxicity. The synthesis and biological analysis of twenty-five analogs demonstrated that derivatives with a single methyl group on either the first or fifth residue amide nitrogen exhibited greater activity than the permethylated peptides and relatively high potency against resistant strains. Replacement of amino amide residues in the peptide, by turn inducing α amino γ lactam (Agl) and -aminoimidazalone (Nai) counterparts, reduced typically anti-parasitic activity; however, peptide amides possessing Agl residues at the second residue retained significant potency in the unmethylated and permethylated series. Systematic study of the effects of methylation and turn geometry on anti-parasitic activity indicated the relevance of an extended conformer about the central residues, and conformational mobility by tertiary amide isomerization and turn geometry at the extremities of the active peptides.
Topics: Amides; Isomerism; Leishmania; Lipopeptides; Methylation; Protein Conformation; Structure-Activity Relationship
PubMed: 34204673
DOI: 10.3390/molecules26123606 -
Organic & Biomolecular Chemistry May 2022A solvent-free procedure for the formation of amides without exclusion of air and moisture is described. Using tetramethoxysilane 1, hexamethoxydisilane 2 and...
A solvent-free procedure for the formation of amides without exclusion of air and moisture is described. Using tetramethoxysilane 1, hexamethoxydisilane 2 and dodecamethoxy-neopentasilane 3 as coupling agent carboxylic acids and amines are reacted to form amides in good to excellent yields. The formation of these amides was confirmed by NMR spectroscopy and mass spectrometry. Remarkably, neopentasilane 3 exceeds the performance of the currently used monosilanes as coupling agent in terms of group tolerance and yield.
Topics: Amides; Amines; Carboxylic Acids; Solvents
PubMed: 35441639
DOI: 10.1039/d2ob00589a -
Molecules (Basel, Switzerland) Nov 2018Not all amide bonds are created equally. The purpose of the present paper is the reinterpretation of the amide group by means of two concepts: amidicity and...
Not all amide bonds are created equally. The purpose of the present paper is the reinterpretation of the amide group by means of two concepts: amidicity and carbonylicity. These concepts are meant to provide a new viewpoint in defining the stability and reactivity of amides. With the help of simple quantum-chemical calculations, practicing chemists can easily predict the outcome of a desired process. The main benefit of the concepts is their simplicity. They provide intuitive, but quasi-thermodynamic data, making them a practical rule of thumb for routine use. In the current paper we demonstrate the performance of our methods to describe the chemical character of an amide bond strength and the way of its activation methods. Examples include transamidation, acyl transfer and amide reductions. Also, the method is highly capable for simple interpretation of mechanisms for biological processes, such as protein splicing and drug mechanisms. Finally, we demonstrate how these methods can provide information about photo-activation of amides, through the examples of two caged neurotransmitter derivatives.
Topics: Algorithms; Amides; Chemistry Techniques, Synthetic; Models, Chemical; Thermodynamics
PubMed: 30400217
DOI: 10.3390/molecules23112859 -
Viruses Nov 2020Herpes simplex viruses (HSVs) are neurotropic viruses with broad host range whose infections cause considerable health problems in both animals and humans. In fact, 67%... (Review)
Review
Herpes simplex viruses (HSVs) are neurotropic viruses with broad host range whose infections cause considerable health problems in both animals and humans. In fact, 67% of the global population under the age of 50 are infected with HSV-1 and 13% have clinically recurrent HSV-2 infections. The most prescribed antiherpetics are nucleoside analogues such as acyclovir, but the emergence of mutants resistant to these drugs and the lack of available vaccines against human HSVs has led to an imminent need for new antivirals. Valproic acid (VPA) is a branched short-chain fatty acid clinically used as a broad-spectrum antiepileptic drug in the treatment of neurological disorders, which has shown promising antiviral activity against some herpesviruses. Moreover, its amidic derivatives valpromide and valnoctamide also share this antiherpetic activity. This review summarizes the current research on the use of VPA and its amidic derivatives as alternatives to traditional antiherpetics in the fight against HSV infections.
Topics: Alphaherpesvirinae; Amides; Animals; Antiviral Agents; Dose-Response Relationship, Drug; Humans; Microbial Sensitivity Tests; Molecular Structure; Valproic Acid
PubMed: 33256172
DOI: 10.3390/v12121356 -
Proceedings of the National Academy of... Nov 2020Folding and other protein self-assembly processes are driven by favorable interactions between O, N, and C unified atoms of the polypeptide backbone and side chains....
Folding and other protein self-assembly processes are driven by favorable interactions between O, N, and C unified atoms of the polypeptide backbone and side chains. These processes are perturbed by solutes that interact with these atoms differently than water does. Amide NH···O=C hydrogen bonding and various π-system interactions have been better characterized structurally or by simulations than experimentally in water, and unfavorable interactions are relatively uncharacterized. To address this situation, we previously quantified interactions of alkyl ureas with amide and aromatic compounds, relative to interactions with water. Analysis yielded strengths of interaction of each alkylurea with unit areas of different hybridization states of unified O, N, and C atoms of amide and aromatic compounds. Here, by osmometry, we quantify interactions of 10 pairs of amides selected to complete this dataset. An analysis yields intrinsic strengths of six favorable and four unfavorable atom-atom interactions, expressed per unit area of each atom and relative to interactions with water. The most favorable interactions are spO-spC (lone pair-π, presumably -π*), spC-spC (π-π and/or hydrophobic), spO-spN (hydrogen bonding) and spC-spC (CH-π and/or hydrophobic). Interactions of spC with itself (hydrophobic) and with spN are modestly favorable, while spN interactions with spN and with amide/aromatic spC are modestly unfavorable. Amide spO-spO interactions and spO-spC interactions are more unfavorable, indicating the preference of amide spO to interact with water. These intrinsic interaction strengths are used to predict interactions of amides with proteins and chemical effects of amides (including urea, -ethylpyrrolidone [NEP], and polyvinylpyrrolidone [PVP]) on protein stability.
Topics: Amides; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Models, Theoretical; Nitrogen; Oxygen; Protein Stability; Proteins; Thermodynamics; Water
PubMed: 33087561
DOI: 10.1073/pnas.2012481117 -
Brazilian Journal of Medical and... May 2000This article reports on the design and characteristics of substrate mimetics in protease-catalyzed reactions. Firstly, the basis of protease-catalyzed peptide synthesis... (Review)
Review
This article reports on the design and characteristics of substrate mimetics in protease-catalyzed reactions. Firstly, the basis of protease-catalyzed peptide synthesis and the general advantages of substrate mimetics over common acyl donor components are described. The binding behavior of these artificial substrates and the mechanism of catalysis are further discussed on the basis of hydrolysis, acyl transfer, protein-ligand docking, and molecular dynamics studies on the trypsin model. The general validity of the substrate mimetic concept is illustrated by the expansion of this strategy to trypsin-like, glutamic acid-specific, and hydrophobic amino acid-specific proteases. Finally, opportunities for the combination of the substrate mimetic strategy with the chemical solid-phase peptide synthesis and the use of substrate mimetics for non-peptide organic amide synthesis are presented.
Topics: Acyltransferases; Amides; Catalysis; Cysteine Endopeptidases; Endopeptidases; Glutamic Acid; Hydrolysis; Molecular Mimicry; Peptide Biosynthesis; Substrate Specificity; Thrombin; Trypsin
PubMed: 10775878
DOI: 10.1590/s0100-879x2000000500001