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Journal of Medicinal Chemistry Nov 2020The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the... (Review)
Review
The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, p, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.
Topics: Amides; Carbamates; Click Chemistry; Drug Design; Pyridines; Structure-Activity Relationship; Triazoles; Urea
PubMed: 32686940
DOI: 10.1021/acs.jmedchem.0c00530 -
Molecules (Basel, Switzerland) Sep 2018Amides are undeniably some of the most important compounds in Nature and the chemical industry, being present in biomolecules, materials, pharmaceuticals and many other... (Review)
Review
Amides are undeniably some of the most important compounds in Nature and the chemical industry, being present in biomolecules, materials, pharmaceuticals and many other substances. Unfortunately, the traditional synthesis of amides suffers from some important drawbacks, principally the use of stoichiometric activators or the need to use highly reactive carboxylic acid derivatives. In recent years, the transamidation reaction has emerged as a valuable alternative to prepare amides. The reactivity of amides makes their direct reaction with nitrogen nucleophiles difficult; thus, the direct transamidation reaction needs a catalyst in order to activate the amide moiety and to promote the completion of the reaction because equilibrium is established. In this review, we present research on direct transamidation reactions ranging from studies of the mechanism to the recent developments of more applicable and versatile methodologies, emphasizing those reactions involving activation with metal catalysts.
Topics: Amides; Catalysis; Metals
PubMed: 30231486
DOI: 10.3390/molecules23092382 -
Molecules (Basel, Switzerland) Jan 2019Over the past few decades, transition metal catalysis has witnessed a rapid and extensive development. The discovery and development of cross-coupling reactions is... (Review)
Review
Over the past few decades, transition metal catalysis has witnessed a rapid and extensive development. The discovery and development of cross-coupling reactions is considered to be one of the most important advancements in the field of organic synthesis. The design and synthesis of well-defined and bench-stable transition metal pre-catalysts provide a significant improvement over the current catalytic systems in cross-coupling reactions, avoiding excess use of expensive ligands and harsh conditions for the synthesis of pharmaceuticals, agrochemicals and materials. Among various well-defined pre-catalysts, the use of Pd(II)-NHC, particularly, provided new avenues to expand the scope of cross-coupling reactions incorporating unreactive electrophiles, such as amides and esters. The strong σ-donation and tunable steric bulk of NHC ligands in Pd-NHC complexes facilitate oxidative addition and reductive elimination steps enabling the cross-coupling of broad range of amides and esters using facile conditions contrary to the arduous conditions employed under traditional catalytic conditions. Owing to the favorable catalytic activity of Pd-NHC catalysts, a tremendous progress was made in their utilization for cross-coupling reactions via selective acyl C⁻X (X=N, O) bond cleavage. This review highlights the recent advances made in the utilization of well-defined pre-catalysts for C⁻C and C⁻N bond forming reactions via selective amide and ester bond cleavage.
Topics: Amides; Catalysis; Chemistry Techniques, Synthetic; Esters; Ligands; Molecular Structure; Oxidation-Reduction; Palladium
PubMed: 30634382
DOI: 10.3390/molecules24020215 -
Journal of Natural Products Apr 2021Phenylalkenoic acid amides, often referred to as phenol amides or hydroxycinnamic acid amides, are bioactive phytochemicals, whose bioactivity can be enhanced by...
Phenylalkenoic acid amides, often referred to as phenol amides or hydroxycinnamic acid amides, are bioactive phytochemicals, whose bioactivity can be enhanced by coupling to form dimers or oligomers. Phenylalkenoic acid amides consist of a (hydroxy)cinnamic acid derivative (i.e., the phenylalkenoic acid subunit) linked to an amine-containing compound (i.e., the amine subunit) via an amide bond. The phenylalkenoic acid moiety can undergo oxidative coupling, either catalyzed by oxidative enzymes or due to autoxidation, which leads to the formation of (neo)lignanamides. Dimers described in the literature are often named after the species in which the compound was first discovered; however, the naming of these compounds lacks a systematic approach. We propose a new nomenclature, inspired by the existing system used for hydroxycinnamic acid dimers and lignin. In the proposed systematic nomenclature for (neo)lignanamides, compound names will be composed of three-letter codes and prefixes denoting the subunits, and numbers that indicate the carbon atoms involved in the linkage between the monomeric precursors. The proposed nomenclature is consistent, future-proof, and systematic.
Topics: Amides; Coumaric Acids; Molecular Structure; Phenols; Terminology as Topic
PubMed: 33787264
DOI: 10.1021/acs.jnatprod.0c00792 -
The Journal of Physical Chemistry... Jul 2022The origin of the peculiar amide spectral features of proteins in aqueous solution is investigated, by exploiting a combined theoretical and experimental approach to...
The origin of the peculiar amide spectral features of proteins in aqueous solution is investigated, by exploiting a combined theoretical and experimental approach to study UV Resonance Raman (RR) spectra of peptide molecular models, namely -acetylglycine--methylamide (NAGMA) and -acetylalanine--methylamide (NALMA). UVRR spectra are recorded by tuning Synchrotron Radiation at several excitation wavelengths and modeled by using a recently developed multiscale protocol based on a polarizable QM/MM approach. Thanks to the unparalleled agreement between theory and experiment, we demonstrate that specific hydrogen bond interactions, which dominate hydration dynamics around these solutes, play a crucial role in the selective enhancement of amide signals. These results further argue the capability of vibrational spectroscopy methods as valuable tools for refined structural analysis of peptides and proteins in aqueous solution.
Topics: Amides; Hydrogen Bonding; Peptides; Proteins; Spectrum Analysis, Raman; Water
PubMed: 35770492
DOI: 10.1021/acs.jpclett.2c01277 -
Angewandte Chemie (International Ed. in... Aug 2016Achieving selective C-H activation at a single and strategic site in the presence of multiple C-H bonds can provide a powerful and generally useful retrosynthetic... (Review)
Review
Achieving selective C-H activation at a single and strategic site in the presence of multiple C-H bonds can provide a powerful and generally useful retrosynthetic disconnection. In this context, a directing group serves as a compass to guide the transition metal to C-H bonds by using distance and geometry as powerful recognition parameters to distinguish between proximal and distal C-H bonds. However, the installation and removal of directing groups is a practical drawback. To improve the utility of this approach, one can seek solutions in three directions: 1) Simplifying the directing group, 2) using common functional groups or protecting groups as directing groups, and 3) attaching the directing group to substrates via a transient covalent bond to render the directing group catalytic. This Review describes the rational development of an extremely simple and yet broadly applicable directing group for Pd(II) , Rh(III) , and Ru(II) catalysts, namely the N-methoxy amide (CONHOMe) moiety. Through collective efforts in the community, a wide range of C-H activation transformations using this type of simple directing group have been developed.
Topics: Amides; Carbon; Catalysis; Chemistry Techniques, Synthetic; Hydrocarbons; Hydrogen; Palladium; Rhodium; Ruthenium
PubMed: 27479708
DOI: 10.1002/anie.201600791 -
Nature Communications Jun 2023General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating...
General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating inhibitory ion channels and inhibiting excitatory ion channels, with the net effect of dampening nervous system excitability. Neuromuscular blockers act by antagonizing nicotinic acetylcholine receptors at the motor endplate; these excitatory ligand-gated ion channels are also inhibited by general anesthetics. The mechanisms by which anesthetics and neuromuscular blockers inhibit nicotinic receptors are poorly understood but underlie safe and effective surgeries. Here we took a direct structural approach to define how a commonly used anesthetic and two neuromuscular blockers act on a muscle-type nicotinic receptor. We discover that the intravenous anesthetic etomidate binds at an intrasubunit site in the transmembrane domain and stabilizes a non-conducting, desensitized-like state of the channel. The depolarizing neuromuscular blocker succinylcholine also stabilizes a desensitized channel but does so through binding to the classical neurotransmitter site. Rocuronium binds in this same neurotransmitter site but locks the receptor in a resting, non-conducting state. Together, this study reveals a structural mechanism for how general anesthetics work on excitatory nicotinic receptors and further rationalizes clinical observations in how general anesthetics and neuromuscular blockers interact.
Topics: Humans; Receptors, Nicotinic; Anesthetics; Anesthetics, Intravenous; Anesthetics, General; Etomidate; Muscles
PubMed: 37264005
DOI: 10.1038/s41467-023-38827-5 -
Journal of the American Chemical Society Jul 2017Quantitative information about amide interactions in water is needed to understand their contributions to protein folding and amide effects on aqueous processes and to...
Quantitative information about amide interactions in water is needed to understand their contributions to protein folding and amide effects on aqueous processes and to compare with computer simulations. Here we quantify interactions of urea, alkylated ureas, and other amides by osmometry and amide-aromatic hydrocarbon interactions by solubility. Analysis of these data yields strengths of interaction of ureas and naphthalene with amide spO, amide spN, aliphatic spC, and amide and aromatic spC unified atoms in water. Interactions of amide spO with urea and naphthalene are favorable, while amide spO-alkylurea interactions are unfavorable, becoming more unfavorable with increasing alkylation. Hence, amide spO-amide spN interactions (proposed n-σ* hydrogen bond) and amide spO-aromatic spC (proposed n-π*) interactions are favorable in water, while amide spO-spC interactions are unfavorable. Interactions of all ureas with spC and amide spN are favorable and increase in strength with increasing alkylation, indicating favorable spC-amide spN and spC-spC interactions. Naphthalene results show that aromatic spC-amide spN interactions in water are unfavorable while spC-spC interactions are favorable. These results allow interactions of amide and hydrocarbon moieties and effects of urea and alkylureas on aqueous processes to be predicted or interpreted in terms of structural information. We predict strengths of favorable urea-benzene and N-methylacetamide interactions from experimental information to compare with simulations and indicate how amounts of hydrocarbon and amide surfaces buried in protein folding and other biopolymer processes and transition states can be determined from analysis of urea and diethylurea effects on equilibrium and rate constants.
Topics: Amides; Hydrocarbons, Aromatic; Molecular Structure; Naphthalenes; Solubility; Urea; Water
PubMed: 28678492
DOI: 10.1021/jacs.7b03261 -
ChemSusChem Mar 2022Formation of amide bonds is of immanent importance in organic and synthetic medicinal chemistry. Its presence in "traditional" small-molecule active pharmaceutical... (Review)
Review
Formation of amide bonds is of immanent importance in organic and synthetic medicinal chemistry. Its presence in "traditional" small-molecule active pharmaceutical ingredients, in linear or cyclic oligo- and polypeptidic actives, including pseudopeptides, has led to the development of dedicated synthetic approaches for the formation of amide bonds starting from, if necessary, suitably protected amino acids. While the use of solid supported reagents is common in traditional peptide synthesis, similar approaches targeting amide bond formation in continuous-flow mode took off more significantly, after a first publication in 2006, only a couple of years ago. Most efforts rely upon the transition of traditional approaches in flow mode, or the combination of solid-phase peptide synthesis principles with flow chemistry, and advantages are mainly seen in improving space-time yields. This Review summarizes and compares the various approaches in terms of basic amide formation, peptide synthesis, and pseudopeptide generation, describing the technological approaches and the advantages that were generated by the specific flow approaches. A final discussion highlights potential future needs and perspectives in terms of greener and more sustainable syntheses.
Topics: Amides; Amino Acids; Chemistry Techniques, Synthetic; Peptides; Solid-Phase Synthesis Techniques
PubMed: 35015338
DOI: 10.1002/cssc.202102708 -
British Journal of Pharmacology Jul 2022Peptides play a key role in controlling many physiological and neurobiological pathways. Many bioactive peptides require a C-terminal α-amide for full activity. The... (Review)
Review
Peptides play a key role in controlling many physiological and neurobiological pathways. Many bioactive peptides require a C-terminal α-amide for full activity. The bifunctional enzyme catalysing α-amidation, peptidylglycine α-amidating monooxygenase (PAM), is the sole enzyme responsible for amidated peptide biosynthesis, from Chlamydomonas reinhardtii to Homo sapiens. Many neuronal and endocrine functions are dependent upon amidated peptides; additional amidated peptides are growth promoters in tumours. The amidation reaction occurs in two steps, glycine α-hydroxylation followed by dealkylation to generate the α-amide product. Currently, most potentially useful inhibitors target the first reaction, which is rate-limiting. PAM is a membrane-bound enzyme that visits the cell surface during peptide secretion. PAM is then used again in the biosynthetic pathway, meaning that cell-impermeable inhibitors or inactivators could have therapeutic value for the treatment of cancer or psychiatric abnormalities. To date, inhibitor design has not fully exploited the structures and mechanistic details of PAM.
Topics: Amides; Animals; Biomarkers; Humans; Mixed Function Oxygenases; Molecular Targeted Therapy; Multienzyme Complexes; Peptides
PubMed: 35124797
DOI: 10.1111/bph.15815