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Related Concept Videos

Nomenclature of Carboxylic Acid Derivatives: Amides and Nitriles01:11

Nomenclature of Carboxylic Acid Derivatives: Amides and Nitriles

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Naming Amides
The IUPAC and common names of amides are derived from the parent carboxylic acid, by replacing the suffix “oic acid” and “ic acid,” respectively, with “amide.” In the following example, the IUPAC name ethanamide is derived from ethanoic acid, and the common name, acetamide, is obtained from acetic acid.
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Structures of Carboxylic Acid Derivatives01:28

Structures of Carboxylic Acid Derivatives

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Structure of Carboxylic Acid Derivatives
Carboxylic acid derivatives contain an acyl group attached to a heteroatom such as chlorine, oxygen, or nitrogen. The carbonyl carbon and oxygen are both sp2-hybridized with an unhybridized p orbital.
The three sp2 orbitals of the carbonyl carbon form three σ bonds, one each with the carbonyl oxygen, the α carbon, and the heteroatom, whereas the other two sp2 orbitals of the carbonyl oxygen are occupied by the lone pairs. Further, the unhybridized p...
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Preparation of Amides01:29

Preparation of Amides

3.9K
Amides are synthesized by treating carboxylic acids with amines in the presence of dehydrating agents like dicyclohexylcarbodiimide (DCC).
The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
Subsequently, the amine acts as a nucleophile that attacks the acylating agent to form a tetrahedral intermediate. In the...
3.9K
Amines to Amides: Acylation of Amines01:19

Amines to Amides: Acylation of Amines

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Various carboxylic acid derivatives (such as acid chlorides, esters, and anhydrides) can be used for the acylation of amines to yield amides. The reaction requires two equivalents of amines. The first amine molecule functions as a nucleophile and attacks the carbonyl carbon to produce a tetrahedral intermediate. This is followed by the loss of the leaving group and restoration of the C=O bond.
Next, the second equivalent of amine serves as a Brønsted base and deprotonates the quaternary...
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Amides to Carboxylic Acids: Hydrolysis01:28

Amides to Carboxylic Acids: Hydrolysis

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Amides can undergo either acid-catalyzed hydrolysis or base-promoted hydrolysis through a typical nucleophilic acyl substitution. Each hydrolysis requires severe conditions.
Acid-catalyzed hydrolysis:
Hydrolysis of amides under acidic conditions yields carboxylic acids. Since the reaction occurs slowly, hydrolysis requires the conditions of heat.
The mechanism begins with the protonation of the carbonyl oxygen by the acid catalyst. The protonation makes the amide carbonyl carbon more...
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Acid Halides to Amides: Aminolysis01:07

Acid Halides to Amides: Aminolysis

4.1K
Aminolysis is a nucleophilic acyl substitution reaction, where ammonia or amines act as nucleophiles to give the substitution product. Acid halides react with ammonia, primary amines, and secondary amines to yield primary, secondary, and tertiary amides, respectively.
In the first step of the aminolysis mechanism, the amine attacks the carbonyl carbon of the acyl chloride to form a tetrahedral intermediate. In the second step, the carbonyl group is re-formed with the elimination of a chloride...
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Acid Versus Amide-Facts and Fallacies: A Case Study in Glycomimetic Ligand Design.

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Summary

Replacing charged groups with neutral ones in drug design can alter binding affinity. This study shows amide bioisosteres can maintain or improve E-selectin ligand binding by optimizing geometry and conformation, not just electrostatics.

Keywords:
E-selectin antagonistsamides as carboxylate isosteresbioisosteresglycomimeticspre-organizationquantum mechanics methods

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Area of Science:

  • Medicinal Chemistry
  • Structural Biology
  • Computational Chemistry

Background:

  • Replacing charged groups with neutral bioisosteres is common in drug discovery.
  • The effect of these replacements on binding affinity is highly dependent on the specific molecular context.
  • E-selectin ligands are important targets for inflammatory diseases.

Purpose of the Study:

  • To investigate the impact of substituting a carboxylate group with amide and isosteric analogs in a glycomimetic E-selectin ligand.
  • To understand the structural and energetic factors governing the binding affinity of these amide derivatives.
  • To explore the role of geometric and conformational properties in protein-ligand recognition.

Main Methods:

  • Synthesis and characterization of amide derivatives of a glycomimetic E-selectin ligand.
  • Co-crystal structure determination of protein-ligand complexes.
  • High-level quantum chemical calculations to assess electronic properties.
  • Molecular dynamics (MD) simulations to analyze conformational dynamics and pre-organization.
  • Molecular mechanics/Generalized Born surface area (MM-GB/SA) calculations for binding free energy decomposition.

Main Results:

  • Several amide derivatives retained or improved binding affinity compared to the lead carboxylate compound, despite losing a key salt-bridge interaction.
  • Co-crystal structures showed conserved binding poses, with amide carbonyls interacting with Tyr48 and Arg97.
  • Quantum chemical calculations indicated no direct correlation between carbonyl partial charges and affinity.
  • Amide nitrogen pyramidality showed a moderate correlation with binding, suggesting steric fit.
  • MD simulations revealed enhanced pre-organization in solution for high-affinity ligands, reducing entropic penalties.
  • MM-GB/SA decomposition indicated minor lipophilic contributions from amide substituents.

Conclusions:

  • Geometric and conformational factors, such as amide nitrogen pyramidality and solution-phase pre-organization, are crucial for driving affinity in glycomimetic ligand design.
  • Amides can serve as effective carboxylate isosteres, offering nuanced control over protein-ligand interactions beyond simple electrostatics.
  • This study provides valuable insights into optimizing ligand design for E-selectin antagonism and other glycomimetic targets.